1

STATE BUDGET EDUCATIONAL ESTABLISHMENT

OF HIGHER PROFESSIONAL EDUCATION
«KURSK STATE MEDICAL UNIVERSITY»
MINISTRY OF PUBLIC HEALTH
AND SOCIAL DEVELOPMENT

CLINICAL IMMUNOLOGY AND ALLERGOLOGY

DEPARTMENT

S.M. Yudina, A.V. Arkhipova,

T.A. Lykina, T.S. Rusanova

GUIDELINES

Immunology
Part II
Clinical Immunology
 2

& Allergology
Kursk - 2018

Yudina S.M., Arkhipova A.V., Lykina T.A., Rusanova T.S. Immunology

(Basic Immunology. Clinical Immunology and Allergology) / Educational manual
on actual questions of immunology (part 2. Clinical Immunology & Allergology). -
Kursk: KSMU, 2018. – 217 p.

Editors: Professor Kalutsky P.V.

Professor Knyazeva L.I.

The modern immunology includes a wide range of questions such as

immunogenetics, immunophysiology, immunochemistry, immunomorphology,
molecular immunology, transplantation immunology, genesial immunology,
immunopathology, allergology, oncoimmunology, immunohematology.
Therefore the manual is designed for students of medical high schools,
interns and post-graduates, and also various profile practicing doctors.
 3

Государственное бюджетное образовательное учреждение

высшего профессионального образования
«Курский государственный медицинский университет»
Министерства здравоохранения и социального развития
Российской Федерации

Кафедра клинической иммунологии и аллергологии

Юдина С.М., Архипова А.В.,

Лыкина Т.А., Русанова Т.С.

Иммунология
часть II
Клиническая иммунология
и Аллергология
 4

Курск – 2018
 5

Печатается по решению
редакционно-издательского
совета ГБОУ ВПО КГМУ
Росздрава

Юдина С.М., Архипова А.В., Лыкина Т.А., Русанова Т.С.

Иммунология (Клиническая иммунология и Аллергология, часть 2)

– Курск: ГОУ ВПО КГМУ Росздрава,

Рецензенты: д.м.н., проф. Калуцкий П.В.

д.м.н., проф. Князева Л.И.

Учебное пособие в 2-х частях рекомендовано для студентов, интернов,

ординаторов, аспирантов, практических врачей

ISBN

 Коллектив авторов, 2018

 ГБОУ ВПО КГМУ Росздрава, 2018
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CONTENTS

Clinical immunology

Immune system diseases…………………………………….. 6

Immune status……………………………………………….. 7
Immunodeficiency…………………………………………… 10
Primary immunodeficiency…………………………………. 11
Secondary immunodeficiency………………………………. 19
Human immunodeficiency virus infection……….…………. 22
Immunotherapy……………………………………………… 41
Immunoprophylaxis ………………………………………… 58
Autoimmune diseases……………………………………….. 68

Allergology
Allergic diseases ……………………………………………. 78
Allergens…………………………………………………….. 79
Pathogenesis of allergic reactions…………………………… 82
Diagnostic methods of allergy………………………………. 92
Treatment of allergic diseases……..………………………… 99
Anaphylactic shock………………………………………….. 111
Serum sickness……………………………………………..... 118
Urticaria and angioedema…....………………………………. 122
Drug allergy………………………………………………….. 129
Acute toxico-allergic reactions………………………………. 144
Food allergy…………………………………………………. 148
Atopic dermatitis…………………………………………….. 157
Contact dermatitis……………………………………………. 176
Latex allergy…………………………………………………. 182
Allergic conjunctivitis……………………………………….. 185
Allergic rhinitis………………………………………………. 193
Bronchial asthma…………………………………………….. 202
Bibliography………………………………………………..... 217
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IMMUNE SYSTEM DISEASES

Immunopathology is the conditions, which are characterized by the

disorders in different parts of the immune system and have the specific
clinical signs.

Development of immunopathology is the following:

Negative factors of environment (chemical, biological, physical,

which are contained in air, water, food, at work place)
↓
Organism predisposed to negative factors
↓
Transitional immunomodulations
↓ ← Antigen
Stable immunomodulations
↓
Immunopathology
↓ ↓ ↓ ↓ ↓
Allergic Autoimmune Secondary Myelolympho- Infections
diseases diseases immunodefici- proliferative of immune
ency diseases system

Injury environment factors causing immunopathology

• Products of full and incomplete organic combustion (toxic radicals
and oxides)
• Chemical substances (formic aldehydes, Phenolums, benzene,
products of synthesis of plastic, petrochemistry, rubber and paint
and varnish industry, substance of household and agricultural
chemistry)
• Metals and salts of lead, mercury, platinum, cobalt, etc.
• Inorganic and organic dust and aerosols
• Medicines
• Biological products (pollen, house dust, other allergens, fungi,
viruses, and etc.)

Classification of the immune system diseases

1. Hypofunction of the immune system:
 primary immunodeficiency (hereditary, congenital)
 8

 secondary immunodeficiency (acquired)

2. Hyperfunction of the immune system:
 autoimmune diseases
 allergic diseases
3. Infections of the immune system:
 Human immunodeficiency virus (T cells’ infection)
 Epstein-Barr virus (B cells’ infection)
4. Lymphoproliferative diseases (lymphoma, leukemia, etc.)
5. Immune complex diseases

IMMUNE STATUS

Immune status is the complex of quantitative and functional

indices, which show the patient’s immune system state at the present
time. Immune system state depends on different factors and is changed
during life periods.
The factors influencing the immune status can be listed as:
 age;
 profession;
 sex;
 ecology status;
 climatic and geographical status;
 life condition;
 work condition;
 acute and chronic diseases.

Types of immune status are:

1. Healthy man immune status
2. Immune status in pathological conditions
a) antigen specific status
i. allergic status (allergen);
ii. autoimmune status (auto antigens);
iii. oncologic status (tumor antigens, onco markers);
iv. transplantation status (isoantigens, HLA antigens, blood
cells’ antigens);
v. reproductive status (fetal antigens);
vi. infectious status (infectious agent);
b) antigen non-specific status
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i. immunodeficiency status (primary and secondary

immunodeficiency);
ii. lymphoproliferative diseases (e.g. lymphogramulomatosis).

Immunonologic monitoring
It is the dynamic supervision of immune status to reveal the
influence of external environment negative factors of man’s immune
system.
Indications to the immune status estimation
1. Preliminary clinical facts of immunopathology
(immunodeficiency, autoimmune diseases, allergic diseases, immune
system infections);
2. Pathology of reproductive system (gestosis, sterility, abortions);
3. Transplantation (pair donor-recipient selection,
posttransplantation reactions monitoring);
4. Oncopathology;
5. Effectiveness of immunotherapy estimation;
6. Risk groups’ screening.

Stages of immune status estimation

1. Anamnesis
2. Objective examination of patient
3. Laboratory tests (immunogram)

Anamnesis consists of the following parts:

1. Complaints
2. History of the disease
3. Life history
a. Climatic and geographical statuses probably changing;
b. Professional injury;
c. Chronic pathology (ulcer, diabetes mellitus, pancreatitis, etc.);
d. Usage of antibiotics, glucocorticosteroids, immunotherapy
treatment of disease;
e. Traumas (stress, operation, narcosis, bum, etc.);
f. Heredity.

Objective examination of patient includes:

1. Examination of skin (rash, hyper- or hypo pigmentation,
cicatrices, abscesses, etc.);
 10

2. Examination of mucosa (candidiasis, herpes, etc.);

3. Examination of the immune system peripheral organs (lymphoid
nodes, tonsils, spleen);
4. Examination of all other organs and systems (according to
propedeutics);

Instrumental and laboratory data include common blood and

urine analysis, biochemical analysis, ultrasonography, gastroscopy, X-
ray, tomography, etc.

IMMUNOGRAM – is the sum of numerical laboratory indices,

which show the parts of immune system condition.
There are two levels of patients’ immune status investigation.

The 1st one named "Test of the 1st level" or "position - finding"
includes:
1. Leucocytes quantity determination (absolutely and per cent);
2. Lymphocytes quantity determination;
3. Proteinogram.
4. T lymphocytes quantity determination;
5. B lymphocytes quantity determination;
6. Ig A, M, G levels determination;
7. Phagocytic index determination;
The result of these tests can give approximate information about
the immune system injury.

The 2nd tests are called "Tests of the 2nd level" or "analytic". The
choice of necessary indicators of tests of the 2 nd level depends on the
prospective type of the immune status. They include:
1. Ig E level determination (using ELISA), Ig E may be common
or allergen-specific;
2. Cytokine level determination;
3. Circulation immune complex level determination;
4. Complement system activity and level of their components or
inhibitors determination;
5. Subclasses of Ig A, G determination;
6. Functional activity of lymphocytes (Reaction of blast
transformation; migration inhibition);
7. Blood antigens and antibodies to them;
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8. Autoantibodies against autoantigens determination;

9. Antiinfectious antibodies and microbial specific antigens;
10. Antitumor antibodies and tumor specific antigens (onco
markers);
11. HLA-typing and antibodies to MHC antigens;
12. Antispermal antibodies.
The results of these tests can give complete information about the
immune system injury and can help in choosing the treatment strategy.

Immunogram interpretation rules are:

1. Complex analysis of all parameters (take into account all data of
immunogram);
2. Dynamic monitoring;
3. Taking into account the clinical picture of the disease;
4. Taking into account the treatment of the disease.

Questions for self-control:

1. Give definition of the immune status.
2. Name types of the immune status.
3. Characterize stages of immune system estimation.
4. Name tests of the 1st and 2nd levels of patients’ immune status
investigation.
5. What tests characterize T-cellular, B-cellular, and macrophage
parts of immunity?
6. Name rules of immunogram interpretation.
7. Name classification of the immune system diseases.

IMMUNODEFICIENCY

Immunodeficiency states are hereditary or acquired hypofunction

of the immune system.
Therefore, the body's ability to fight infections and some other
pathogens is impaired. As a result, the person with immunodeficiency
disorder will have frequent infections that are generally more severe and
last longer than usual. Defects can occur in any component of the
immune system or in more than one component (combined
immunodeficiency). Different immunodeficiency diseases involve
different components of the immune system. The defects can be
inherited and present at birth (congenital) or acquired.
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Congenital immunodeficiency is present at the time of birth, and is

the result of genetic defects. These immunodeficiency disorders are also
called primary immunodeficiencies. Even though more than 70 different
types of congenital immunodeficiency disorders have been identified,
they rarely occur. Congenital immunodeficiencies may occur as a result
of defects in B lymphocytes, T lymphocytes, or both. They also can
occur in the innate immune system.
Acquired immunodeficiency is more common than congenital
immunodeficiency. Acquired immunodeficiency often occurs as a
complication of other conditions and diseases. For example, the most
common causes of acquired immunodeficiency are malnutrition, some
types of cancer, and infections. Sometimes, acquired immunodeficiency
is brought on by drugs used to treat another condition. For example,
patients who have organ transplant are given drugs to suppress the
immune system so the body will not reject the organ. Also, some
chemotherapy drugs, which are given to treat cancer, have the side effect
of killing cells of the immune system. During the period of time that
these drugs are being taken, the risk of infection increases. It usually
returns to normal after the person stops taking the drugs.

PRIMARY IMMUNODEFICIENCY

Primary (hereditary) immunodeficiency (PID) is a breach in the

system of immunity, which occurs because of genetic defects. The onset
is usually in childhood.

Classification of PID according to genetic blocks

 BLOCK 1. The defect of stem cells in bone marrow, which leads
to the absence of all immunocompetent cells in peripheral blood.
The clinical picture is characterized by severe lethal bacterial,
viral or fungal infections.
 BLOCK 2. The absence of T-cells progenitors. In clinical
picture, the viral, fungal infections prevail. The risk of tumor
arising in these patients is 1000 times higher in comparison with
healthy people.
 BLOCK 3. The absence of B-cells progenitors. In clinical
picture, there are mostly severe recurrent bacterial infections.
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 BLOCK 4. The absence or insufficiency of plasma cells

producing Ig A.
 BLOCK 5. The absence or insufficiency of plasma cells
producing Ig G.
 BLOCK 6. The breach of thymocytes maturation mechanism and
the process of their migration to the periphery.

Classification of PID according to

the defected part of the immune system
1. The pathology of the cellular immunity mostly.
2. The pathology of the humoral immunity mostly.
3. The combined pathology (both cellular and humoral parts of the
immune system).
4. The pathology in nonspecific part of the immune system
(defects of phagocytes or complement).

There are several clinical syndromes in PID:

1. Syndrome of septicemia and septicopyemia.
2. Syndrome of respiratory tract infections (rhinitis, sinusitis,
bronchitis).
3. Syndrome of gastro-intestinal tract and urinary tract infections.
4. Syndrome of generalized cutaneous or visceral candidiasis.

PID in humoral part of the immune system

X – Linked Agammaglobulinemia. Formerly called Bruton’s

disease. It is principally a disease of childhood, presenting clinically
within the first 2 years of life with multiple and recurrent sinopulmonary
infections caused primarily by pyogenic bacteria and, to a much lesser
extend, by viruses. Because encapsulated bacteria require antibody
binding for efficient opsonization, these humorally immune-deficient
patients suffer from sinusitis, pneumonia, pharyngitis, bronchitis, and
otitis media secondary to infection with S. pneumonia, other
streptococci, and H. influenza. The patients are
panhypogammaglobulinemic, with decreased levels of Ig G, Ig M, and
Ig A. The basic defect in this disorder appears to be arrested cellular
maturation at the pre-B lymphocyte stage. Lymphoid tissues lack fully
differentiated B lymphocytes (antibody producing plasma cells), and
lymph nodes lack developed germinal centers. The gene that is defective
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in X – linked agammaglobulinemia has been isolated. The defective

gene product, BTK (Bruton’s tyrosine kinase), is a B cell-specific
signaling protein belonging to the cytoplasmic tyrosine kinase family of
intracellular proteins. Gene deletions and point mutations in the catalytic
domain of the BTK gene block normal BTK function, necessary for B
cell maturation.
Common Variable Immunodeficiency. This disorder is often
referred to as acquired or adult-onset hypogammaglobulinemia. It is the
most common serious primary immune deficiency disorder in adults.
Common variable immunodeficiency is a heterogenous disorder in
which the primary immunologic abnormality is a marked reduction in
antibody production. The majority of the patients have some defect in
terminal differentiation of B lymphocytes. Peripheral blood lymphocyte
phenotyping demonstrates normal or reduced numbers of circulating B
lymphocytes, but antibody producing plasma cells are absent in
lymphoid tissues. In approximately 80% of patients, the defect is
intrinsic to the B lymphocyte population. In the rest, a variety of T cell
abnormalities lead to immune defects with subsequent impairment of B
cell differentiation. Affected individuals develop recurrent
sinopulmonary infections, including sinusitis, otitis, bronchitis, and
pneumonia. A number of important noninfectious disorders are
commonly associated with common variable immunodeficiency,
including gastrointestinal malabsorption, autoimmune diseases, and
tumors. Immune disregulation may contribute to the morbidity and the
myriad of autoimmune manifestations associated with common variable
immunodeficiency. Monthly infusions of intravenous immunoglobulins
can reconstitute humoral immunity, decrease infections, and improve the
quality of life.
Selective Ig A Deficiency is characterized by a deficiency of
immunoglobulins in body secretions and the mucous membranes lining
the airways and digestive tract. Ig A normally stands guard at the body
entrances, intercepting bacteria, viruses, toxins, and certain food
components. This is the most common primary immunodeficiency in
adults. Most individuals with this defect have few or no clinical
manifestations, but there is an increased incidence of upper respiratory
tract infections, allergy, asthma, and autoimmune disorders. The cause
of Ig A Deficiency is not known, and it may differ from one person to
another. As in common variable immunodeficiency, the primary
functional defect is an inability of B cells to terminally differentiate to Ig
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A – secreting plasma cells, although the quantity of B-cells is quite

normal. Because of the role of secretory Ig A in mucosal immunity,
patients with this immunodeficiency frequently develop significant
infections involving the mucous membranes of the gut, conjunctiva, and
respiratory tract. There is no specific therapy, but prompt antibiotic
treatment is necessary in patients with recurrent infections.
Hyper – Ig M Immunodeficiency. The principal of this abnormality
is the defective expression of CD 154, a T lymphocyte activation surface
marker (also known as CD40-ligand or gp39). In the course of normal
immune responses, CD154 interacts with CD40 on B cell surfaces
during cellular activation, initiating proliferation and immunoglobulin
isotype switching. Inheritance of this disorder may be autosomal, though
it is most often X – linked. In hyper-Ig M syndrome, defective T cell
expression of CD154 leads to the impairment of B cell isotype switching
and to the subsequent production of Ig M but no production of Ig G or Ig
A. In these patients the serum levels of Ig M and Ig A are very low or
absent but the serum Ig M level is normal or elevated. Clinically, this
syndrome is manifested by recurrent pyogenic infections and an array of
autoimmune disorders.
Ig G Subclass Deficiency is caused by the lack of certain
antibodies. In this case, the person is missing one or two of the four
subclasses of Ig G (Ig G1, Ig G2, Ig G3, and Ig G4). Each Ig G subclass
plays a slightly different role. Ig G1 and Ig G3 antibodies are formed in
response to certain proteins, including toxins produced by some bacteria
and the proteins of some viruses. Ig G2 antibodies target the capsules
that shield certain bacteria. Antibodies of some Ig G subclasses
cooperate with the complement system; others do not. As a result of
such differences, each type of subclass deficiency leaves a person
vulnerable to specific types of infections. Overall Ig G levels may be
nearly normal, so it is necessary to measure each of the Ig G subclasses.
Patients may be immunized with a vaccine against encapsulated bacteria
(such as Streptococcus pneumonia or Haemophilus influenza) to see if
they respond with the appropriate antibodies. Patients with Ig G
Subclass Deficiency have infections that are not severe as those seen
with broader immunoglobulin deficiencies such as X – Linked
Agammaglobuliemia or Common Variable Immunodeficiency. The
usual treatment in Ig G Subclass Deficiency consists of antibiotics to
control and prevent infections. Intravenous injections of
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Immunoglobulin drugs are usually reserved for children who are

seriously ill and who are not responding to antibiotic therapy.

PID in cellular part of the immune system

Congenital Thymic Aplasia (DiGeorge’s Syndrome). The clinical

manifestations of DiGeorge’s syndrome reflect the defective embryonic
development of organs derived from the third and fourth pharyngeal
arches, including the thymus, the parathyroids, and the cardiac outflow
tract. DiGeorge’s syndrome is classified as complete or partial
depending on the presence or absence of immunologic abnormalities. In
this syndrome, the spectrum of immunologic deficiency is wide, ranging
from immune competency to conditions in which there are life-
threatening infections with organisms typically of low virulence.
Patients affected by the complete syndrome have a profound T
lymphocytopenia due to thymic aplasia with impaired T lymphocyte
maturation, severely depressed cell-mediated immunity, and decreased
suppressor T lymphocyte activity. B lymphocytes and immunoglobulin
production are unaffected in most patients. DiGeorge’s syndrome is a
developmental anomaly and can be associated with structural
abnormalities in the cardiovascular system, parathyroid abnormalities,
which can lead to hypocalcaemia, presenting with neonatal tetany. In
addition, it is common for patients to exhibit facial abnormalities such as
micrognatia, hypertelorism, low-set ears.
Cartilage Hair Hypoplasia is an immune system abnormality
linked to dwarfism. The child has abnormally short limbs and thin,
sparse hair. The skin forms extra folds around the neck, hands, and feet,
and the joints are loose. Youngsters with Cartilage Hair Hypoplasia can
get frequent infections of the skin and mouth, the result of too few T-
cells. Their biggest danger is chicken pox which can be deadly. The
prognosis is considerably better than most T-cell immunodeficiencies,
because the susceptibility to infection is less. Some children have been
successfully treated with bone marrow transplantation.

Combined PID

Severe Combined Immunodeficiency Disease (SCID) is a

heterogeneous group of disorders characterized by a failure in the
cellular maturation of lymphoid stem cells, resulting in reduced numbers
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and function of both B- and T-lymphocytes and

hypogammaglobulinemia. The genetic and cellular defects can occur at
many different levels, starting with surface membrane receptors but also
including deficiencies in signal transduction or metabolic biochemical
pathways. In patients with SCID, there is an absence of normal thymic
tissue and the lymph nodes, spleen, and other peripheral lymphoid
tissues are devoid of lymphocytes. In these patients, the complete or
near-complete failure of development of both the cellular and humoral
components of the immune system results in severe infections. The
spectrum of infections is broad, as these patients may also suffer from
overwhelming infection by opportunistic pathogens, disseminated
viruses, and intracellular organisms. Failure to thrive may be the initial
presenting symptom, but mucocutaneous candidiasis, chronic diarrhea,
and pneumonitis are common. Without immune reconstitution by bone
marrow transplantation, SCID is inevitably fatal within 1 – 2 years.
Wiskott-Aldrich Syndrome (WAS) is characterized by a tendency to
bleed easily and the development of an intensely itchy, scaling skin rash
(eczema). This is in addition to the severe recurrent infections seen in
young boys who develop this X-linked syndrome. The infections are
result of abnormal B-cells and certain T-cell function. Because of B-
cells defects, these boys cannot make antibodies against some types of
bacteria. This leaves them susceptible to ear infections, pneumonias,
blood infections, and meningitis. Because of T-cell defects, they are
vulnerable to infections with opportunistic germs, including Candida,
Pneumocystis, and the herpes viruses. Patients with WAS also have
defective blood platelets. Platelets are essential for blood clotting as well
as certain immune responses. The platelets of youngsters with WAS are
too few and too small (the size of the platelets confirms the diagnosis).
The lack of platelets causes bleeding, often for no obvious reason. These
patients develop bruises, bleeding gums, prolonged nose bleedings.
Eczema in WAS can range from mild to severe. It can cause children to
itch and scratch themselves until they bleed. This is aggravated by dry
skin. Thus, it is important to identify food allergies that cause skin to
itch. The leading treatment option for WAS is bone marrow
transplantation. To correct severe bleeding, a life-saving alternative may
be surgery to remove the spleen; it allows platelets to remain in the
bloodstream and prevents dangerous bleeding.
Ataxia-Telangiectasia (AT) is a syndrome that affects several body
systems, and the symptoms grow worse with time. Children with AT
 18

have nervous system problems that cause them to walk unsteadily and
clumsily (ataxia), as well as dilated blood vessels (telangiectasia) in the
eyes and skin. They also develop frequent sinus and respiratory
infections such as bronchitis and pneumonia. The infections in AT can
be traced to defects in both B- cells and T-cells. B-cell responses are
substandard, and levels of Ig A and Ig G may be low. T-cells are few
and weak; the thymus gland is immature. Usually AT is first suspected
when a child is learning to walk, and has trouble with balance and
coordination. A history of infection may or may not be present. The
dilated blood vessels typically don’t develop before the age of 3 or 4.
Treatment is geared to helping the children maintain as normal a
lifestyle as possible. They are encouraged to attend school and
participate in a wide variety of activities. Physical therapy helps the
children to remain mobile and active.
Partial Combined Immunodeficiencies are characterized by both
the antibody and cell-based defenses being impaired, but not totally shut
down. Problems are limited to certain functions of B-cells and certain T-
cells. In these conditions, the immunodeficiency is a part of a complex
clinical picture. Other body systems are involved, too. The result is a
distinctive set of symptoms, or a syndrome.

PID in nonspecific part of the immune system

Chronic Granulomatous Disease is typically X-linked and

characterized by impaired granulocyte function. This disorder of
phagocytic cell function presents with recurrent skin infections,
abscesses, and granulomas at sites of chronic inflammation. Abscesses
can involve skin or viscera and may be accompanied by lymphadenitis.
Catalase-positive organisms predominate; S. aureus is thus the
most common pathogen, though infections with gram-negative bacteria
and Aspergillus species also occur. Chronic granulomatous disease
typically presents in childhood. Defects in the gene coding for
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibit
oxidative metabolism and severely compromise neutrophil killing
activity. In patients with chronic granulomatous disease, other neutrophil
functions such as chemotaxis, phagocytosis, and degranulation remain
intact but microbial killing is deficient. Catalase-negative bacteria are
effectively killed because microbes produce small amounts of peroxide,
concentrated in phagosomes, leading to microbial death. Catalase-
 19

positive organisms scavenge these relatively small amounts of peroxide

and are not killed without neutrophil oxidative metabolism. Genetic
defects have been found affecting any of the four gene products. X-
linked inheritance is most frequently seen, but autosomal recessive
forms and spontaneous mutations can also lead to clinical disease.
Chediak-Higashi Syndrome (CHS) is a rare and potentially severe
disorder caused by a flaw in three distinct types of cells: phagocytes,
platelets, and melanocytes. Because of the flawed phagocytes, the child
has little resistance to frequent and severe infections. The defective
platelets, for their part, result in a mild bleeding disorder. The skin and
hair of patients with CHS lack color (partial albinism), while lack of
pigment in the eyes makes the person overly sensitive to light. The
infections of CHS are treated with antibiotics. Ultimately, however,
CHS will enter an accelerated phase. The patient develops a lymphoma-
like illness, with fever and jaundice; lymphoid organs such as the spleen
fill with T-cells that behave like cancer. Despite treatment with steroids
and anticancer drugs, the condition is usually fatal within months. CHS
can be treated by bone marrow transplantation.
Leukocyte Adhesion Defect (LAD) causes recurrent, life-
threatening infections because phagocytes are unable to migrate to the
scene of an infection. These phagocytes lack a molecule that allows
them to attach to blood walls, a first step in leaving the circulation to
enter tissues. Other white cells also lack adhesion molecules, preventing
them from attaching to target cells and surfaces. LAD typically
manifests itself in infancy. One of the first signs may be a problem with
the baby’s umbilical cord; it fails to drop off, in the normal way, within
a few weeks. The baby has a very high white blood cell count. Children
with LAD are prey to severe infections caused by bacteria and fungi,
especially infections of the soft tissues. They get tissue-eroding
infections of the skin without forming pus, severe infections of the gums
– leading to tooth loss – and infections of the intestinal tract. Wounds
heal poorly and may leave scars. Treatment of LAD begins with early
and aggressive therapy of infections with antibiotics. The effective
treatment is bone marrow transplantation.
Complement deficiencies. For the complement system to function,
all of its components must work closely together. Yet each of the
components can be thrown out of step by a different genetic mutation.
Immunodeficiencies involving the complement system are not common.
Often they don’t cause disease until adulthood. Symptoms vary from
 20

one type to another. Some complement deficiencies foster the same

kinds of bacterial infections seen with antibody deficiencies. Other
complement deficiencies lead to an increase of blood-borne infections
such as meningitis.

Questions for self-control:

1. Give the definition of primary immunodeficiency;
2. Name the pathogenetic classification of PID;
3. Name the clinical signs of primary immunodeficiency;
4. Name the diseases of the T cellular part of the immune system
and characterize them;
5. Name the diseases of the B cellular part of the immune system
and characterize them;
6. Name the syndromes and diseases connected with the
deficiency in phagocytic part of the immune system;
7. Name the clinical signs in complement system components
deficiency;
8. Characterize the peculiarities of PID diagnosing;
9. Name the main principles of PID treatment.

SECONDARY IMMUNODEFICIENCY

Secondary (acquired) immunodeficiency (SID) is the immune

system breach developed in late postnatal period and in adults. Those
conditions are not the result of the genetic defects. It is not a nozology,
but a pathogenetic characteristic of disturbances in immune system.
The secondary immunodeficiency develops on the base of earlier
normal immune system functioning. SID is an acquired clinic-
immunologic syndrome which is characterized by a decreased activity of
the immune system. This condition increases the risk of chronic
inflammatory, autoimmune and allergic diseases and tumors.

Classification according to etiology

1. Inducted immunodeficiency (when the reasons are known:
corticosteroids, cytostatics usage, severe operations, chronic diseases of
the liver, kidney, tumors and etc.);
2. Spontaneous (the reasons are unknown);
3. Acquired (e.g., HIV-infection).
 21

The factors causing SID

I. Stress
1. hard physical training;
2. psychological;
II. Harmfulness of the environment
III. Age
1. childhood;
2. old age;
IV. Pathological conditions
 infections (viral, bacterial, chlamydiasis, fungal)
 protein insufficiency (alimentary, nephritic syndrome,
diarrhea, trauma, bleeding, chronic inflammatory processes)
 drug therapy (corticosteroids, antibiotics, sulpha drugs,
cytostatics).
V. Chemical (toxins, poison, industrial harms, etc.) and physical
(irradiation, etc.) factors.
VI. Metabolic (in serious systemic diseases).

Classification according to pathogenesis

1. T-cellular immune system insufficiency;
2. Humoral immune system insufficiency;
3. Immune system nonspecific factors insufficiency;
4. Combined type.

Classification according to localization

o Systemic
o Local (in different barriers of the organism which have contact
with antigens: skin, mucosa, respiratory tract, urogenital tract,
gastrointestinal tract, organs of hearing and vision);

Physiological immunodeficiency is developed at:

1. age
o children of early age are bound to formation of baby’s immune
system, there is so-called "immune adaptation of child";
o people of senile age are bound to immune organs involution and
immune reactions weakening, especially, concerning infectious
antigens.
2. pregnancy
 22

o in pregnancy develops suppression of adaptive immune reactions

mainly Т cells that is necessary for prevention of immune reactions
against fetus antigens.
Stages of Secondary immunodeficiency diagnostics

1. anamnesis (heredity, professional harms, somatic pathology,

traumas, stresses, immunosuppressive therapy, operations, etc.),
2. objective status (a state of skin and mucous, lymphoid
organs, other organs and systems)
3. laboratory immunologic tests (decrease of lymphocytes in
common blood analysis, T-, B-cells and/or Igs and/or
phagocytosis, and etc. in immunogram).

Clinical signs of the secondary immunodeficiency

1. Chronic inflammatory processes (otitis, sinusitis, bronchitis,
etc.);
2. Recurrent bacterial infections (pyodermia, furuncles,
carbuncules, hydradenitis, phlegmons, pneumonia, meningitis, etc.);
3. Recurrent acute respiratory viral infections;
4. Lymphadenopathy or hypoplasia of the lymph nodes;
5. Recurrent herpes infections (Herpes labialis, Herpes genitalis,
Herpes zoster);
6. Candidiasis of the oral cavity, mucosa, skin, nails, hair);
7. Non motivated subfebrile temperature and fever accompanied
by weakness, appetite loss, general malaise, undue fatigability,
sleepiness;
8. Non motivated diarrhea, disbacteriosis.

Clinical symptoms of secondary immunodeficiencies

(Diseases-masks)
Mainly T cellular immunodeficiency can be suspected at
presence in the patient of:
 frequent viral infection (recurring cytomegalovirus, herpes
infection, etc., chronic persistent viral infection);
 candidiasis (local and generalized forms);
 deep mycoses;
 helminthes’ invasions;
 autoimmune pathology;
 allergic diseases;
 23

 status after transplantation of organs and tissues (marrow, kidney,

heart, etc.)

Mainly B cellular (humoral) immunodeficiency can be suspected

at presence in the patient of:
 chronic, relapsing bacterial infection (staphylococcal,
streptococcal, pneumococcal, etc.), not effective standard
antibacterial therapy;
 persistent hyperplasia of lymph nodes or their hypoplasia.

Defects of phagocytosis can be suspected at presence in the

patient of:
 recurring pyoderma, furunculosis, abscesses of different
localization;
 local bacterial infection.

Principles of the therapy

1. Proper nutrition;
2. Etiotropic treatment – antibiotics, antibacterial, antiviral,
antifungal drugs (depends on infectious complications);
3. Replaceable immunoglobulin therapy;
4. Efferent methods of immunotherapy;
5. Immunocorrection, immunorehabilitation.

Questions for self-control:

1. Give the definition of a secondary immunodeficiency;
2. Name the classification of a SID etiologic factors;
3. Name the different classifications of a secondary
immunodeficiency;
4. Name the clinical signs of a secondary immunodeficiency;
5. Name the main principles of SID treatment.

HIV-INFECTION
Human immunodeficiency virus (HIV) infection: Infection caused
by retroviruses resulting in a wide range of clinical manifestations
varying from asymptomatic carrier states to severely debilitating and
fatal disorders related to defective cell-mediated immunity.
 24

HIV belongs to special class of viruses called retroviruses. Within

this class, HIV is placed in the subgroup of lentiviruses. Other
lentiviruses include SIV (Simian immunodeficiency virus), FIV (Feline
immunodeficiency virus), CAEV (Caprine-ovine arthritis-encephalitis
virus), etc., which cause diseases in monkeys, cats, and goats. Some
retroviruses are oncogenic, and others have pathologic effects that alter
normal cell function or produce cell death. Of the retroviruses known to
infect humans, human T-cell lymphotrophic virus (HTLV) types I and II
are associated with lymphoid neoplasms and neurologic disease and less
commonly with severe immunosuppression, whereas HIV causes
immunosuppression but does not appear to cause neoplasms directly.
Almost all organisms, including most viruses, store their genetic
material on long strands of DNA. Retroviruses are the exception because
their genes are composed of RNA.
The human retrovirus that has had the greatest social and medical
impact is HIV, which was identified in 1984 as the cause of a
widespread epidemic of severe immunosuppression called acquired
immunodeficiency syndrome (AIDS).
AIDS was initially defined by the development of serious
opportunistic infections and/or certain secondary cancers, such as
Kaposi's sarcoma and non-Hodgkin's lymphoma, known to be associated
with defective cell-mediated immunity. Many patients first become
aware of their HIV infection when diagnosed with a life-threatening
opportunistic infection or malignancy without having experienced
preceding chronic symptoms.
Two closely related retroviruses, HIV-1 and HIV-2, have been
identified as causing AIDS in different geographic regions. HIV-1
causes most cases of AIDS in the Western Hemisphere, Europe, Asia,
and Central, South, and East Africa; HIV-2 is the principal agent of
AIDS in West Africa and appears less virulent than HIV-1. In certain
areas of West Africa, both organisms are prevalent.
Also probably, there are rare versions of HIV – HIV-3 and HIV-4
that do not react with HIV-1 and HIV-2 antibodies. They do not play
appreciable role in epidemic.

Structure of HIV
Unlike most bacteria, HIV particles are much too small to be seen
through on ordinary microscope. However, they can be seen clearly with
the electron microscope.
 25

HIV particles surround themselves with a coat of fatty material

known as the viral envelope (or membrane). Projecting from this are
around 72 little spikes (Fig. 1), which are formed from the glycoproteins
gp 160, that are composed of gp120 and gp41 (Table 1). Just below the
viral envelope there is a layer called the matrix, which is made from the
protein p17.

Fig. 1. Scheme of HIV structure.

The viral nucleus (or capsid) is usually bullet-shaped and is made

from the protein p24. Inside the nucleocapsid are three enzymes required
for HIV replication called reverse transcriptase, integrase and protease.
Also held within the nucleus is HIV's genetic material, which consists of
two identical strands of RNA.
HIV has just nine genes. Three of the HIV genes, called gag, pol
and env, contain information needed to make structural proteins for new
virus particles. The other six genes, known as tat, rev, nef, vif, vpr and
vpu, code for proteins that control the ability of HIV to infect the cell,
produce new copies of virus, or cause the disease.

Transmission
HIV transmission requires contact with body fluids containing
infected cells or plasma. HIV may be present in any fluid or exudate that
contains plasma or lymphocytes, specifically blood, semen, vaginal
 26

secretions, breast milk, saliva, or wound exudates. Although

theoretically possible, transmission by saliva or droplet nuclei produced
by coughing or sneezing is extremely rare, if it occurs.

Table 1. Functions of the basic structural proteins of HIV-1.

Name The description Functions

The superficial protein of virion.
It is not covalently connected to
TM gp41. To one gp41molecule
The superficial
gp120 (SU, is bound 3 - 5 molecules of
glycoprotein in
surface) gp120. Plays the important role in
mass 120 kD
the process of virus attachment to
CD4 receptor and penetration into
the cells.
Settles down in enveloping layer
Transmembrane of lipid membrane. Retains gp120
gp41 (TM,
glycoprotein in molecule. Plays the important role
transmembrane)
mass 41 kD in the process of virus penetration
into the cells.
Protein in mass 24 The protein forming shell of
p24 (CA, capsid)
kD nucleoid (capsid) of virus.
About two thousand molecules of
The matrix protein this protein form layer in the
p17 (MA, matrix) in mass 17 kD depth 5 - 7 nanometers, settling
down between surface and
nucleoid.
The nucleokapsid
p7 (NC,
protein in mass 7 Forms complex with viral RNA.
nucleocapsid)
kD

HIV is not transmitted by casual contact or even by the close

nonsexual contact that occurs at work, school, or home.
The most common means of transmission is direct transfer of body
fluids either through sharing contaminated needles or sexual relations.
Risk of HIV transmission from infected medical personnel who observe
good techniques to uninfected patients is very small but is less clear.
Transmission of HIV during medical care is potential problem if
transfused blood is not screened or medical instruments are not
 27

adequately sterilized. Use of enzyme-linked immunosorbent assay

(ELISA) to screen blood donors has vastly reduced the risk of acquiring
HIV by transfusion. However, persons in the early stages of HIV
infection, who have not yet mounted antibody response, may have
transiently negative ELISA and Western blot results while yielding
positive results for HIV p24 antigen in plasma.

Thus, it is described three ways of transfer:

1. Sexual (HIV is transmitted at any kinds of not protected sexual
contacts from the virus carrier. Presence of any gynecologic or
venereal disease, inflammatory processes, and frequent change of
sexual partners rise the danger).
2. Parenteral (at virus hit in blood).
- At transfusion of the infected blood and its preparations
- At sharing of the:
o polluted syringes and needles the persons who are on
drugs intravenously;
o unsterile instrument for drawing of tattoos or piercing,
o manicure or shaving accessories;.
3. Vertical (from mother to the child) From HIV-infected mother to
the child during pregnancy, childbirth and breast feeding. Taken
together these 3 routs may create the risk of 12 to 30 % for the
babies of contaminated mothers.

HIV life cycle

HIV can only replicate inside human CD4+ cells (Fig. 2).
CD4 molecule is the main and necessary receptor for HIV-1, HIV-
2. Gp 120 interacts with CD4. For penetration into cell, HIV uses co-
receptors CCR5, CXCR4 (ligands of chemokines' receptors). CCR5,
CXCR4 – adhesion molecules which are expressed on lymphocytes,
macrophages and some other cells, and possibly, play role in
inflammatory reaction of cells to becoming infected. The role of these
proteins in the immune response up to the end is not clear. Receptor
CXCR4 expresses mainly on naive T lymphocytes, and receptor CCR5 –
on activated T lymphocytes, memory cells.
Gp41 plays key role in fusion of viral cover and cellular
membrane, gp41 is capable to be implanted in target cell membrane.
After coalescence of virus to cell' membrane the viral nucleus is
 28

liberated in cytoplasm. Synthesis of provirus DNA on viral RNA in

cytoplasm of cell under the influence of reverse transcriptase is key
moment in HIV reproduction.

Fig. 2. Stages of HIV penetration in cell.

In non activated T cells proviral DNA formed as a result of return

transcription is not integrate in host cell genome. For viral DNA
integration in host cell DNA activation of cell is needed and moving
viral complex from cytoplasm in nucleus is necessary. HIV finding in
non activated CD4 lymphocytes and other cells-reservoirs is considered
to be principal cause of recovery impossibility.
The replication of retroviruses usually is accompanied by errors
and characterized by high frequency of natural mutations. Mutations can
lead to loss ability of viral replication. Also mutations in which result
the virus gets resistance to anti-virus drugs also can occur and collect.
After activation virus-infected cell begins synthesis regulatory viral
proteins, then structural proteins and enzymes. Congregating of viruses
descends stage by stage: RNA, then nucleocapsid which moves to
cellular membrane. Critical to the final step in the life cycle of HIV is
HIV protease. This enzyme converts immature, noninfectious HIV to its
infectious form by splitting crucial proteins. Then assemblage of mature
viruses comes to the end and they gemmate from cell. At bud
reproduction various proteins of host cell can be presence in virus cover.
Virus-infected cells then enter the blood stream, get attached to
other CD4 cells and continue replicating. As a result, the number of the
virus in the blood rises and that of the CD4 cells declines.

Immune disorders in HIV-infection.

 29

As known, HIV infects major subset of CD4+ T lymphocytes, and

also nonlymphoid cells, such as macrophages, microglial cells, and
various endothelial and epithelial cells. Dendritic cells in the lymph
nodes can bind HIV at the cell surface but are not invaded. As a result of
HIV infection, the number and functions of T cells, B cells, natural killer
cells, and monocytes-macrophages are disturbed. Despite abnormalities
of cells other than CD4+ lymphocytes, much of the immunologic
dysfunction in AIDS appears to be explained by loss of the helper
function of these lymphocytes, which is critical to cell-mediated and
humoral immunity.
Because of this process, immediately after infection, the viral load
of infected individual will be very high and the number of CD4, low.
But, after a while, the body's immune system responds vigorously by
producing more and more CD4 cells to fight the virus. Much of the virus
gets removed from the blood. To fight the fast-replicating virus, as many
as a billion CD4 cells are produced every day, but the virus too increases
on similar scale. The battle between the virus and the CD4 cells
continues even as the infected person remains symptom-free.
The best predictors of onset of the serious opportunistic infections
that define AIDS are the total number of circulating CD4 + lymphocytes
and the level of HIV RNA in plasma (viral load). Normal CD4 count is
about 750 ± 250 cells/µL, but levels are usually reduced by about 40 to
50% early in HIV infection. Vulnerability to opportunistic infections
increases markedly when CD4 lymphocyte levels are < 200/µL. The
viral load (number of HIV-1 RNA copies in 1 mL of plasma) provides a
useful predictor of future clinical course and measure of responses to
antiretroviral therapy. Levels of HIV-1 RNA increase with advancing
immunosuppression, but high levels also predict the future rates of
decline in CD4 counts, even in patients without symptoms or evidence
of severe immunosuppression (> 500 CD4 cells/µL). The risk of
progression to AIDS or death appears to increase about 50% for every
threefold increase in plasma viral RNA.
CD8+ lymphocytes appear to be functionally normal and increased
in number in HIV infection, which may contribute further to
immunosuppression and result in reduction of the CD4:CD8 ratio
(normally 2:1) to < 1. Because other viral infections (CMV, Epstein-
Barr virus, influenza, hepatitis B) may produce transient reductions in
the CD4:CD8 ratio, decreased ratios are not specific.
 30

For infected CD4 cells, the half-life is slower (about 2 days). It

appears that newly infected CD4 cells contribute > 99% of plasma RNA;
after about 2 days of viral replication, these cells die. Thus, even
asymptomatic patients are constantly destroying their CD4 cells at rates
determined by the level of plasma RNA. During effective drug therapy,
plasma HIV RNA levels fall within days and reach lower plateaus or
become undetectable within a few weeks or months.
HIV infected patients show insufficient of IL-2 and IFNγ
production, but synthesis of IL-10 and IL-4 is relatively intact. The
chronic opportunistic infections in AIDS promote TNFα synthesis, and
it activates latent HIV thus aggravating immunodeficiency.
Humoral immunity is also affected. Due to polyclonal activation
by the opportunistic infectious agents, increased IL-6 concentrations,
and HIV general production of immunoglobulins is increased leading to
hyperglobulinemia. But the spectrum of these immunoglobulins mainly
includes IgM of low affinity and autoimmune specificity; total antibody
levels (especially IgG and IgA) may be elevated and titers of antibodies
to specific agents (e.g., cytomegalovirus) unusually high. At the same
time, because of T cell help lack, the induced antibody responses against
new antigens are weak. Moreover, T independent antigens also produce
weakened responses in AIDS patients, as the evidence of some intrinsic
B cell defects in HIV-infection. HIV-infected patients may suffer from
encapsulated bacteria (H. influenza, S. pneumonia).
Unlike T helper cells, monocytes, and macrophages are relatively
refractory to the cytopathic effects of HIV. They play important role in
spreading of HIV: provide a safe vehicle for HIV to be transported to
various parts of the body, particularly the central nervous system.
Additionally, macrophages may be reservoir for HIV in the body. Been
inside of macrophages HIV escapes from antibodies, killer cells,
antiretroviral drugs. Infected macrophages show functional deficit:
production of IL-1, chemotaxis, and capacity to present antigens is low.

Symptoms and Signs

HIV causes broad spectrum of clinical problems, which may
mimic other diseases. Symptoms of HIV-infection and AIDS are
consequence of inducing of immunodeficient state. The majority of
symptoms are caused by opportunistic infections – bacterial, viral,
fungal, parasitic origin or tumors, which do not depend at persons with
high-grade immune system and amaze almost all systems and organs.
 31

Immediately after infection and for some period (from 3 weeks till
3 months, but in small number of persons to 1 year), there is brief
antibody-negative carrier state. During this time, the virus reproduces
rapidly until the immune system begins to react and/or targets are
exhausted. HIV RNA or HIV p24 (capsid) antigen is detectable in
plasma, even when no antibody to HIV is detectable. Within 1 to 4 wk
after infection, some patients develop acute retroviral syndrome or
primary HIV infection with fever, malaise, rash, arthralgia, and
generalized lymphadenopathy, followed within days to 3 months by
seroconversion for antibody to HIV. These early symptoms also are
called the HIV seroconversion illness. Consequently, seroconversion
from HIV antibody negative to HIV antibody positive follows; these are
the antibodies detected with HIV tests. Subsequently, these acute
manifestations disappear (although lymphadenopathy usually persists)
and patients become antibody-positive, asymptomatic HIV carriers.
Some of these patients develop mild, remittent symptoms and signs that
do not meet the definition of AIDS. Leukopenia is common and anemia
and immune-mediated thrombocytopenia may also occur.
The Centers for Disease Control and Prevention's definition
categorizes adolescents and adults as asymptomatic (A), symptomatic
with conditions attributable to HIV (B), and true AIDS (C). HIV patients
are also categorized by CD4+ lymphocyte counts (Table 2).

Table 2. HIV stages in youths and adults (CDC, USA)

Quantity of Clinical symptoms
CD4+ A B C
lymphocytes Acute feverish phase, Symptoms are not AIDS
in blood asymptomatic phase, character for A and C
persisting groups
lymphadenopathy
≥ 500 µl A1 B1 C1
200 – 499 µl A2 B2 C2
< 200 µl A3 B3 C3

Group A – one or several of the following conditions:

 Acute feverish phase;
 Asymptomatic phase of HIV;
 Persisting lymphadenopathy.
 32

Group B – diseases or conditions which are not diagnostic criteria

of AIDS final stage:
 Bacterial angiomatosis;
 Candidiasis of the oral cavity and throat;
 Lingering, recurrent or difficult treated vulvovaginitis;
 Dysplasia of the neck of the uterus or cancer of the neck of the
uterus in situ;
 Common symptoms: fever (38,5°C) and diarrhea, during more
than 1 month;
 Leukoplakia of the mouth;
 Herpes zoster (not less than 2 acute phases or several dermatomes
involving);
 Immune thrombocytopenic purpura;
 Peripheral neuropathy;
 Inflammatory diseases of the genitals in women, especially
complicated by pyosalpinx and ovarian abscess;
 Listeriosis.
Group B patient subsequently can’t be referred to group A even if
treatment resulted in caused by HIV determined diseases’ symptoms
elimination.
Group C – the diagnostic criteria of AIDS. Group C patient
subsequently can’t be referred to group A or B.

WHO clinical staging of established HIV infection i

HIV-associated symptoms WHO clinical stage
Asymptomatic 1
Mild symptoms 2
Advanced symptoms 3
Severe symptoms 4

i WHO (World Health Organization) case definitions of HIV for surveillance and revised clinical
staging and immunological classification of HIV-related disease in adults and children (2006)

WHO clinical staging of HIV/AIDS

for persons with confirmed HIV infection i
stage adults and adolescents children
Asymp- Asymptomatic or Asymptomatic or
tomatic Persistent generalized Persistent generalized
lymphadenopathy lymphadenopathy
 33

Mild Moderate unexplained weight Unexplained persistent

symp- loss (<10% of presumed or hepatosplenomegaly
toms measured body weight) Papular pruritic eruptions
Recurrent respiratory tract Fungal nail infection
infections, sinusitis, tonsillitis,
Angular cheilitis
otitis media and pharyngitis) Lineal gingival erythema
Herpes zoster Extensive wart virus infection
Angular cheilitis Extensive molluscum contagiosum
Recurrent oral ulceration Recurrent oral ulcerations
Papular pruritic eruptions Unexplained persistent parotid
Seborrhoeic dermatitis enlargement
Fungal nail infections Herpes zoster
Recurrent or chronic upper
respiratory tract infections (otitis
media, otorrhoea, sinusitis or
tonsillitis)
ii
Advan- Unexplained severe weight Unexplained moderate malnutrition
ced loss (>10% of presumed or or wasting not adequately
symp- measured body weight) responding to standard therapy
Unexplained chronic diarrhea Unexplained persistent diarrhea (14
toms for longer than one month days or more)
Unexplained persistent fever Unexplained persistent fever
(above 37.6°C intermittent or (above 37.5°C intermittent or
constant, for longer than one constant, for longer than one
month) month)
Persistent oral candidiasis Persistent oral candidiasis (after
Oral hairy leukoplakia first 6–8 weeks of life)
Pulmonary tuberculosis Oral hairy leukoplakia
(current) Acute necrotizing ulcerative
Severe bacterial infections gingivitis or periodontitis
(such as pneumonia, empyema, Lymph node tuberculosis
pyomyositis, bone or joint Pulmonary tuberculosis
infection, meningitis or Severe recurrent bacterial
bacteraemia) pneumonia
Acute necrotizing ulcerative Symptomatic lymphoid interstitial
stomatitis, gingivitis or pneumonitis
periodontitis Chronic HIV-associated lung
Unexplained anaemia (<8 g/dl), disease including brochiectasis
neutropaenia (<0.5 x 109 per Unexplained anaemia (<8 g/dl),
litre) or chronic neutropaenia (<0.5 x 109 per litre)
thrombocytopaenia (<50 x109 and or chronic thrombocytopaenia
per litre) (<50 x 109 per litre)
Severe HIV wasting syndrome Unexplained severe wasting,
symp- Pneumocystis pneumonia stunting or severe malnutrition not

toms iii Recurrent severe bacterial
pneumonia
Chronic herpes simplex
infection (orolabial, genital or
anorectal of more than one
month’s duration or visceral at
any site)
Esophageal candidiasis (or
candidiasis of trachea, bronchi
or lungs)
Extrapulmonary tuberculosis
Kaposi’s sarcoma
Cytomegalovirus infection
(retinitis or infection of other
organs)
Central nervous system
toxoplasmosis
HIV encephalopathy
Extrapulmonary cryptococcosis
including meningitis
Disseminated non-tuberculous
mycobacterial infection
Progressive multifocal
leukoencephalopathy
Chronic cryptosporidiosis (with
diarrhea)
Chronic isosporiasis
Disseminated mycosis
(coccidiomycosis or
histoplasmosis)
Recurrent non-typhoidal
Salmonella bacteraemia
Lymphoma (cerebral or B-cell
non-Hodgkin) or other solid
HIV-associated tumors
Invasive cervical carcinoma
Atypical disseminated
leishmaniasis
Symptomatic HIV-associated
nephropathy or symptomatic
HIV-associated
cardiomyopathy
34
responding to standard therapy
Pneumocystis pneumonia
Recurrent severe bacterial
infections (such as empyema,
pyomyositis, bone or joint infection
or meningitis but excluding
pneumonia)
Chronic herpes simplex infection
(orolabial or cutaneous of more
than one month’s duration or
visceral at any site)
Esophageal candidiasis (or
candidiasis of trachea, bronchi or
lungs)
Extrapulmonary tuberculosis
Kaposi sarcoma
Cytomegalovirus infection: retinitis
or cytomegalovirus infection
affecting another organ, with onset
at age older than one month
Central nervous system
toxoplasmosis (after one month of
life)
Extrapulmonary cryptococcosis
(including meningitis)
HIV encephalopathy
Disseminated endemic mycosis
(coccidiomycosis or
histoplasmosis)
Disseminated non-tuberculous
mycobacterial infection
Chronic cryptosporidiosis (with
diarrhea)
Chronic isosporiasis
Cerebral or B-cell non-Hodgkin
lymphoma
Progressive multifocal
leukoencephalopathy
Symptomatic HIV-associated
nephropathy or HIV-associated
cardiomyopathy
 35

i WHO case definitions of HIV for surveillance and revised clinical staging and immunological
classification of HIV-related disease in adults and children (2006)
ii Unexplained refers to where the condition is not explained by other causes.
iii Some additional specific conditions can also be included in regional classifications (such as
reactivation of American trypanosomiasis [meningoencephalitis and/or myocarditis]) in the
WHO Region of the Americas and disseminated penicilliosis in Asia).
Determination of CD4+ lymphocytes is the critical parameter in
monitoring of HIV-infection (Table 3) and allows:
 To estimate state of immune system and predilection to AIDS
development,
 Along with the clinical information to define the starting of
antiretroviral therapy,
 To define terms for prevention of opportunistic infection,
 To estimate effectiveness of treatment.
Depression of CD4+ cells less than 200 µl is the indication to
starting therapy even in the absence of symptoms and does not depend
on clinical stage of disease.
Table 3. Immunological classification for established HIV infection
(WHO, 2006)
HIV- Age-related CD4 values
associated
immunodefi <11 12–35 36 –59 >5 years
ciency months months months (absolute number
(%CD4+) (%CD4+) (%CD4+) per mm3 or %)
None or not >35 >30 >25 > 500
significant
Mild 30–35 25–30 20–25 350−499
Advanced 25–29 20–24 15−19 200−349
Severe <25 <20 <15 <200 or <15%

Laboratory Diagnosis
The detection of antibodies to HIV is sensitive and specific at most
stages of infection, inexpensive, and widely available. Rapid (10-min)
serum tests, home collection systems, and tests for HIV antibody in oral
secretions and urine are useful in some situations, but they require
confirmation by standard serum testing. Detection of HIV RNA in blood
provides sensitive and specific diagnosis of HIV infection in patients in
the very early stages of infection when antibodies may not yet be
detectable.
 36

Tests for detecting antibody to HIV include ELISA, which can

detect antibodies to HIV proteins. ELISA is both highly sensitive and
specific, but some false-positive ELISA tests occur. When reactive,
ELISA should be repeated on the same sample. If it is positive second
time, test that is more specific should be performed, e.g., the Western
blot, which is immunoelectrophoretic procedure for identifying
antibodies to specific viral proteins separated by their molecular weight.
ELISAs that directly measure viral antigens (p24) rather than
antiviral antibodies are relatively insensitive. Tests of antigen levels
have been supplanted by more sensitive measurements of plasma RNA.
Standard anti-HIV IgG tests (ELISA, Western blot) cannot be used
to reliably indicate child's infection status before 18 months of age.
Several sensitive assays of plasma RNA, such as the reverse-
transcription polymerase chain reaction (RT-PCR), which amplifies viral
nucleic acids, or the branched DNA (bDNA), which amplifies signal, are
sensitive and accurate over a wide range of viral concentrations (up to
1,000,000 copies/mL of plasma). The lower limits of detection are about
400 copies/ml for RT-PCR and 5000 copies/ml for bDNA, and the
sensitivity of these tests is being improved. Other methods for nucleic
acid amplification, such as nucleic acid sequence-based amplification
(NASBA) and transcription-mediated amplification (TMA), are under
development to increase the sensitivity of HIV RNA quantitation.
The augmentation of virus level in plasma more than 100000
copies/ml, also is the indication to initiation of treatment in the absence
of clinical symptoms and does not depend on stage of HIV-infection.

HIV infection is diagnosed based on (WHO, 2006)

Adults and children 18 months or older:

 positive HIV antibody testing (rapid or laboratory-based enzyme
immunoassay). This is confirmed by a second HIV antibody test
(rapid or laboratory-based enzyme immunoassay) relying on
different antigens or of different operating characteristics.
and/or;
 positive virological test for HIV or its components (HIV-RNA or
HIV-DNA or ultrasensitive HIV p24 antigen) confirmed by
second virological test obtained from separate determination.
Children younger than 18 months:
 37

 positive virological test for HIV or its components (HIV-RNA or

HIV-DNA or ultrasensitive HIV p24 antigen) confirmed by second
virological test obtained from separate determination taken more
than four weeks after birth.

Clinical criteria for presumptive diagnosis of severe HIV disease

among infants and children aged under 18 months in situations where
virological testing is not available (WHO, 2006).
A presumptive diagnosis of severe HIV disease should be made if:
 the infant is confirmed as HIV antibody-positive
and
 diagnosis of any AIDS-indicator condition(s)a can be made
or
 the infant is symptomatic with two or more of the following:
- oral thrush b
- severe pneumonia b
- severe sepsis b
Other factors that support the diagnosis of severe HIV disease in
HIV-seropositive infant include:
 recent HIV-related maternal death or advanced HIV disease in the
mother;
 CD4 <20%.
Confirmation of the diagnosis of HIV infection should be sought as
soon as possible.
a. AIDS indicator conditions include some but not all HIV clinical stage 4 conditions
seen in children such as Pneumocystis pneumonia, esophageal candidiasis, cryptococcal
meningitis, cerebral toxoplasmosis, unexplained wasting or malnutrition.
b. Defined in accordance with WHO Integrated Management of Childhood Illness
guidelines:
- Oral thrush: Creamy white soft small plaques on red or normally coloured mucosa which
can often be scraped off (pseudomembranous), or red patches on tongue, palate or lining
of mouth, usually painful or tender.
- Severe pneumonia: Cough or difficult breathing in a child with chest indrawing, stridor
or any of the general danger signs outlined in the WHO Integrated Management of
Childhood Illness guidelines: that is lethargic or unconscious, not able to drink or
breastfeed, vomiting and presence or history of convulsions during current illness,
- Severe sepsis: Fever or low body temperature in a young infant with any severe sign,
such as rapid breathing, chest indrawing, bulging fontanelle, lethargy, reduced
movement, not feeding or sucking breast-milk, convulsions, stiff neck.

Treatment
 38

Several principles of treatment for HIV infection emerged in the

mid-1990s. New methods to quickly measure the effects of drugs on
HIV in the blood, e.g., suppression of plasma HIV RNA levels, and
better understanding of the rapid production of HIV, even in the
clinically inactive stages of infection, have changed the approach (Fig.
3).

Fig. 3. Scheme of HIV drugs’ action.

Plasma HIV RNA levels provide a means of rapidly and directly

measuring effects of antiretroviral drugs. Therapeutic monitoring of
RNA levels assesses the initial (at 4 to 8 wk) and ongoing (every 3 to 4
mo) effect of combination drug regimens. Reduction in plasma RNA has
become the accepted method of measuring the effects of single or
combinations of drugs. Increasing levels may indicate noncompliance
with drugs or the emergence of genetic variants of HIV resistant to the
drugs.
Treatment of patients with measurable plasma RNA levels (> 400
copies/mL) even when they have relatively high CD4 counts (> 500
cells/µL) is now recommended by some experts. Evidence to support
this intensive and expensive approach to therapy in less advanced (CD4
> 500) patients remains circumstantial. The rapid rates of viral
production and clearance demonstrated for most patients at all stages of
HIV infection support this approach.
Current treatment for HIV infection consists of highly active
antiretroviral therapy, or HAART. This has been highly beneficial to
 39

many HIV-infected individuals since its introduction in 1996 when the

protease inhibitor-based HAART initially became available. Current
optimal HAART options consist of combinations (or "cocktails")
composed of at least three drugs belonging to at least two types of
antiretroviral agents. In the absence of HAART, progression from HIV
infection to AIDS occurs between nine to ten years and the median
survival time after developing AIDS is only 9,2 months.

Antiretroviral drugs
The antiretroviral drugs used to treat HIV infection are listed by
their class in by generic and abbreviated names. Three of the four classes
of available drugs act by inhibiting HIV reverse transcriptase; protease
inhibitors interfere with activity of HIV protease (Table 4).

Drugs for HIV-infection treatment can be listed as:

o HIV binds to CD4 cell surface molecules entry into the cell also
requires binding to co-receptors CXCR4 and CCR5. This step can be
inhibited by fusion/entry inhibitors.
o HIV is uncoated inside the cell and reverse transcriptase copies
genomic RNA into DNA, making errors at frequency of about one per
replication cycle. Reverse transcriptase inhibitors were the first class
of HIV inhibitors to be used as drugs.
 Nucleoside analogues (NUKES)
These interfere with the enzyme involved in the replication of viral
genetic material. They provide faulty building blocks that foul up
the process of producing new viral genes.
 Non-Nucleoside analogues (NON-NUKES)
These drugs act directly on the enzyme reverse transcriptase
without providing faulty building blocks. They also block the
production of viral genes.
o The virus uses cellular machinery to synthesize viral proteins.
Several of these are long amino acid chains which must be cleaved by
specific viral protease before new viral particles can become active.
Protease inhibitors block viral maturation at this step.
o Viral DNA can integrate into DNA and become part of the
cellular genome. This step makes the infection irreversible, and may
mean that eliminating the virus from infected individual is not possible.
Integrase inhibitors block the enzyme that brings about this integration.
Drug in this category is Raltegravir (RAL). Other drugs in this class are
still under investigation.
 40

Combination of drugs is now the standard, and use of single drugs

is discouraged. Treatment with two to four drugs can promptly halt viral
reproduction, preserve immune function, and decrease the likelihood of
emergence of drug-resistant viral mutants. The length of response to
various combinations of drugs varies with their success in completely
suppressing viral replication, which usually requires consistent
compliance with combinations of three potent drugs.
Table 4. Antiretroviral drugs.

NUKES NON-NUKES protease fusion/entry

inhibitors inhibitors
Zidovudine (AZT), Eefavirenz (EFV), Darunavir Aplaviroc
Zalcitabine (ddC), Nevirapine (NVP) (DRV), Vincriviroc
Didanosine (ddI), Delavirdine Indinavir (IDV), Maraviroc
Stavudine (d4T), (DLV), Saquinavir
Etravirine (ETR),
Lamivudine (3TC), (SQV)
Emtricitabine (FTC), Combination Lopinavir
Tenofovir disoproxil pills (LPV),
fumarate (TDF), Atripla (EFV with Fosamprenavir
Abacavir (ABC), FTC and TDF). (FPV),
Tenofovir (Nt) Ritonavir
(RTV),
Combination pills Amprenavir
Combivir© (3TC and Nelfinavir
AZT), (NFV),
Epzicom © (3TC and Atazanavir
ABC), (ATV),
Kivexa © Tipranavir
Trizivir © (AZT, 3TC (TPV).
and ABC), Kaletra ©
Truvada © (TDF and
FTC).

Most experts recommend that patients at any stage of HIV

infection with more than 5000 HIV RNA copies/ml of plasma be treated
with combination therapy, including two nucleosides (AZT and 3TC),
or two nucleosides and protease inhibitor (IDV), or two nucleosides and
non-nucleoside reverse transcriptase inhibitor (NVP). Although some
 41

drugs interact with others to influence their removal, in some cases this
is helpful. For example, when two protease inhibitors, SQV and RTV,
are combined, RTV helps to raise the levels of SQV by decreasing its
removal.
Combinations can be harmful if they increase or decrease
elimination of one of the component drugs, leading to drug levels that
are either too high or too low, or if they have combined toxicity.
Information on drug combinations is rapidly accumulating and will
inform future choices.
The adverse effects of antiretroviral drugs, which vary by type of
drug and dose, remain central concern of both patients and physicians.
Many adverse effects (headache from AZT) often become less severe
over time, but others (stomach pain from ddI) may indicate serious
problems (pancreatitis) that require immediate action. Because some
adverse effects (anemia, pancreatitis, hepatitis, glucose intolerance) can
be detected by blood tests before they cause symptoms, regular
monitoring of hematology and serum chemistries as well as symptoms is
crucial. Finally, duration of therapy is uncertain: drugs should be taken
only for as long as the antiretroviral benefits outweigh adverse effects
and costs. Drug resistance is more likely if patients are given
inadequate numbers or doses of drugs or do not take drugs as instructed.
Although drug combinations delay selection of resistant HIV mutants,
they usually do not prevent it unless total suppression of viral replication
is achieved. Close attention to patient compliance and plasma HIV RNA
monitoring help limit the selection of resistant strains.
Some currently untreatable CNS complications of HIV
(progressive multifocal leukoencephalopathy) may respond to
antiretroviral treatment if the primary immune defect is corrected.
Responses to antiretroviral drugs have been documented for HIV-
induced cognitive dysfunction.
End-of-life care even with combined therapy, AIDS remains
terminal disease. At some time, relief of pain and suffering may become
the focus of treatment, and patients may opt for hospice care.

Questions for self-control:

1. Name the main properties of HIV and characterize its structure.
2. Name and characterize the ways of HIV transmission.
3. Characterize the pathogenesis of HIV-infection.
4. What are the peculiarities of immune reactions to HIV?
5. Name the clinical criteria of HIV-infection and AIDS.
 42

6. Name the main laboratory methods of HIV-infection

diagnosing.
7. Name the main principles of HIV-infection treatment and
prophylaxis.
IMMUNOTHERAPY

Immunotherapy is a method of the immune system abilities’

normalization to rehabilitation of the protective and regulatory functions.
Criteria of the immunotherapy effectiveness:
1. The delay of the pathologic process progression;
2. Shortening of the treatment time;
3. The achievement of persistent remission or recovery;
4. Decrease of the relapses quantity.
The physician should be able to compose the plan of
immunotherapy which includes the following points:
 Individuality of the treatment;
 Elimination of the causative factors of the disease;
 Performance under the laboratory control;
 Treatment consists of basic therapy and supporting courses.
There are several types of influence to the immune system:
immunosuppression, immunostimulation, immunomodulation, and
immunocorrection.

Immunosuppression
Immunosuppression is different types of drugs usage to suppress
the immune system activity.
Classification of immunosuppressors
1. "Big" immunosuppressors
- antibiotics – cyclosporine, tacrolimus, sirolimus
- antilymphocyte immunoglobulin (thymoglobulin)
- monoclonal antibodies
- glucocorticosteroids
2. "Small" immunosuppressors
- Gold containing drugs (Crysanolum)
- Penicillaminum
There are several clinical settings where the goal of therapy is to
suppress unwanted immune response. The major current indications for
immunosuppression include organ transplantation, prevention of Rh
 43

hemolytic disease of the newborn, and treatment of autoimmune

disorders.
The following principles underlie the achievement of
immunosuppression clinical effectiveness:
1. Primary (initial) immune responses can be more easily and
more effectively suppressed than secondary immune responses. The
initial steps in the primary immune response (antigen processing, cell
proliferation, lymphokine synthesis, and differentiation) are most
sensitive to immunosuppressive therapy.
2. Immunosuppressive agents do not produce the same effect
on all immune response. The dose required to inhibit immune response
to one antigen may differ from that required to produce the same effect
with the different antigens.
3. Inhibition of the immune response is more likely to occur if
the immunosuppressive therapy is begun before, rather than after,
exposure of the immunogen.

Cyclosporine is polypeptide of 11 amino acids of fungal origin and

is active against helper T cells, preventing the production of IL-2 via
calcineurin inhibition (binds to cyclosporin protein). Cyclosporine has a
very selective effect on T lymphocytes, suppressing the early cellular
response to antigenic and regulatory stimuli. Cyclosporine can be
administered intravenously or orally – soft gelatine capsule
(Sandimmune) or micro emulsion formulation (Sandimmune Neoral).
After absorption in whole blood, 50% to 60% of cyclosporine
accumulates in erythrocytes. Leucocytes also avidly accumulate this
drug, with 10% to 20% of the total amount of drug in the circulation
being associated with the relatively small leukocyte fraction.
Cyclosporine is extensively metabolized in the liver to more than 30
metabolites, although here is considerable interindividual variation in the
drug metabolism. Cyclosporine and its metabolites are excreted mainly
through the bile into the feces; approximately 6% is excreted in the
urine. The major adverse effect of cyclosporine is renal toxicity.
Nephrotoxicity can occur in as many as 75% of patients being treated
with cyclosporine. Other adverse effects include hyperpotassemia,
hypomagnesemia, nausea, vomiting, diarrhea, hypertrichosis, hirsutism,
gingival hyperplasia, hyperlipidemia, glucose intolerance, infection,
malignancy, and hyperuricemi. Hypertrichosis and hirsutism can be
alleviated by switching from cyclosporine to tacrolimus, provided the
 44

patient is carefully monitored. Multiple drug interactions are possible,

primarily with agents affecting the cytochrome P-450 system.
Tacrolimus is a macrolide antibiotic and is active against T helper
cells, preventing the production of IL-2 via calcineurin inhibition (binds
to tacrolimus-binding protein instead of cyclosporine protein). The
clinical uses of tacrolimus appear similar to those of cyclosporine; with
most experience thus far being with organ transplantation (liver, kidney,
heart). Tacrolimus is approximately 100 times more potent than
cyclosporine. Tacrolimus can be administered intravenously (short or
continuous infusion) or orally. Tacrolimus appears to be metabolized
extensively in the liver, with less than 1% of the drug excreted
unchanged. Tacrolimus appears to have a spectrum of toxicities similar
to cyclosporine. As with cyclosporine, nephrotoxicity is anticipated to
be the major problem with clinical use of this drug. In addition,
neurotoxicity (headache, tremor, insomnia, pain, etc.), gastrointestinal
toxicity (diarrhea, nausea, etc.), cardiovascular toxicity (hypertension),
and metabolic toxicity (hyperpotassemia, hypomagnesaemia, and
hyperglycemia) can develop. Long-term immunosuppression produces
the same sequelae as are seen with many of the other
immunosuppressive agents.
Sirolimus is macrolide antibiotic that binds the FK-binding protein,
but its mechanism of action is via the “target of Rapamune”, or TOR. It
inhibits G1- to S-phase cell division and, therefore, cell proliferation.
This agent is used for maintenance immunosuppression and chronic
rejection. Adverse effects include hyperpotassemia, hypomagnesaemia,
hyperlipidemia, hypertiglyceridemia, leucopenia, anemia, impaired
wound healing, and joint pain. Sirolimus can be used concomitantly with
cyclosporine, or mycophenolate mofetil. Multiple drug interactions are
possible, especially because of the extremely long half-life.
Azathioprine is derivate of 6-mercaptopurine. Its functions as an
antimetabolite to decrease DNA and RNA synthesis and is used for
immunosuppression maintenance. Adverse effects include leucopenia,
thrombocytopenia, GI difficulties, cholestasis, and alopecia. Monitor
pancreatic and liver enzyme levels. Decrease the dose if azathioprine is
administered with allopurinol. Myelosuppression can improve with drug
discontinuation. Azathioprine is compatible with cyclosporine and
tacrolimus.
Mycophenolate mofetil inhibits the enzyme inosine monophosphate
dehydrogenase (required for guanosine synthesis) and impairs B- and T-
cell proliferation, sparing other rapidly dividing cells (because of the
 45

presence of guanosine salvage pathways in other cells). This agent is

used for immunosuppression maintenance in chronic rejection. Adverse
effects include nausea, vomiting, diarrhea, leucopenia, anemia, and
thrombocytopenia. Do not administer with azathioprine because of
hematologic toxicity.
Corticosteroids are medicines that are similar to the natural
hormone cortisone and belong to the family of drugs called steroids.
Corticosteroids are used in several forms, to treat different conditions.
Since they reduce itching, swelling, redness, and allergic reactions, they
are often used in treating skin problems, severe allergies, asthma, and
arthritis. These drugs also suppress the body’s immune response, so they
are used in patients who have received organ transplantations, to educe
the chance of rejection. In people whose bodies do not produce enough
natural corticosteroids, the drugs can increase the levels of those
hormones. Corticosteroids are also used to treat certain cancers (with
other drugs), and to reduce inflammation in other medical conditions.
Corticosteroids affect many body processes, including the
breakdown of protein, fat, and carbohydrate; the activity of the nervous
system; the balance of salt and water; and the regulation of blood
pressure. Because of their widespread effects, these drugs are useful in
treating many medical conditions, but they can also have undesirable
side effects.
Mechanisms of immunodepressive and antiinflammatory action of
corticosteroid are bound to repressing of:
 Expressions of proinflammatory cytokines genes
 Activity of receptor to IL-2
 Expressions of MHC 1 and 2 classes
 Activity of receptors to Fc fragment of immunoglobulins and
complement on macrophages
 Expressions of adhesion molecules on endotheliocytes

These medicines come in variety forms, suitable for treating

different conditions. For example, inhalant corticosteroids are used to
prevent asthma attacks, while corticosteroid ointments, cream and gels
are used to treat skin problems. Some examples of corticosteroids are
beclomethasone (Beconase, Vancenase, Vanceril), betamethasone
(Diprolene, Lotrisone), hydrocortisone, mometasone (Elocom),
prednisone (Deltasone, Orasone), and triamcinolone (Azmacort,
Nasacort).
 46

Recommended dosage depends on the patient, the type and

strength of the drug, and the form in which it is used. Also, the physician
can change the dose during the course of treatment.
Corticosteroids may cause serious side effects. Inhalant forms of
these drugs will reduce the frequency and severity of asthma attacks
when taken every day, but will not relieve an asthma attack once it has
started. To relieve asthma symptoms, patients must use bronchodilators.
When using inhalant forms of both bronchodilator and corticosteroid,
the bronchodilator is used first and after several minutes corticosteroid is
used. Gargling and rinsing the mouth with water after using inhalant
corticosteroids helps prevent hoarseness and throat irritation. In older
people, corticosteroids may increase the risk of high blood pressure and
bone disease. Bone problems from corticosteroids are especially likely
in older women. Patients who take corticosteroids regularly should not
stop taking them suddenly, even if their symptoms improve. Gradually
tapering the dose before stopping the drug completely can allow the
body time to adjust. Corticosteroid ointments, creams and gels can be
absorbed through the skin and travel into the blood stream. This is not a
problem unless large amounts are absorbed. Then, unwanted side effects
in other parts of the organism are possible. To reduce the chance of that
happening, do not spread the medicine over too large area and do not
cover it with plastic wrap, adhesive bandage, or any other type of
airtight covering. Patients taking corticosteroids over long periods may
need to follow special diets, reducing the amount of sodium or
increasing the amount of protein they eat, for example. Corticosteroids
can lower person’s resistance to infection and can make infections
harder to treat. Anyone who has a serious infection or injury while
taking corticosteroids should get prompt medical attention and should
make sure the physician in charge knows about the medicine. Avoid
contact with people who have infections, especially chickenpox and
measles. People who are taken or have been taking corticosteroids
should not have immunizations, such as live polio vaccines. They should
also avoid contact with anyone who has taken the oral polio vaccine, as
there is a chance the virus could be passed on to them. Other people
living at home should not take the oral polio vaccine. The injectable
form of the polio vaccine should be used instead because this vaccine is
inactivated.
Side effects are generally rare when corticosteroids are used for a
short time. However, when they are used over time, they may lower the
body’s ability to fight off infections or may make infections harder to
 47

treat. Other common side effects include changes in appetite (increase or

decrease), nervousness, restlessness, sleep problems, and indigestion.
These problems usually go away as the body adjusts to the drug and do
not require medical treatment. Less common side effects may occur with
some forms of corticosteroids. Inhalants may cause dry throat, headache,
nausea, mucosa bruising or thinning, unpleasant taste, and in some cases
– thrush. Nasal spray forms may irritate the nose or throat, and
ointments, gels, or creams may irritate the skin. Again, these side effects
do not need medical attention unless they don’t go away or they interfere
with normal activities. More serious side effects are not common, but
may occur. If breathing problems, wheezing, or tightness in the chest
occur, patient should call the physician immediately. Additional side
effects do not need emergency care, but should have prompt medical
attention. Anyone who is taking corticosteroids and has any of the
symptoms should check with the physician who prescribed the medicine
as soon as possible:
 White, curd-like patches in the mouth or throat;
 Pain when swallowing or eating;
 White patches or sores inside nose or in the anal area;
 Eye pain or vision problems;
 Loss of taste or smell sense;
 Stomach or abdominal pains, nausea, or vomiting;
 Rash, acne, or other skin problems;
 Swelling of face, eyelids, or lips;
 Unusual tiredness or weakness;
 Stuffy, dry, or runny nose;
 Watery eyes;
 Black, tarry stools;
 Irregular heartbeat;
 Menstrual problems;
 Muscle cramps, weakness, or pain;
 Rapid weight;
 Confusion, excitement, restlessness, mood swings, or unusual or
disturbing thoughts or feelings;
 Hallucinations.
Special conditions
Pregnancy. Too much use of corticosteroids during pregnancy may
cause teratogenic effects and problems in the baby after it is born, e.g.,
slower growth, adrenal and poly organic insufficiency, etc. Nasal and
 48

inhalant forms of the drugs are considered safer to use in pregnancy than
corticosteroids taken by mouth or injection. When used properly,
corticosteroids ointments, creams, and gels – used to treat skin
conditions – are not known to cause any problems if used during
pregnancy.
Breastfeeding. The safety of using corticosteroids while
breastfeeding depends on the type of corticosteroid and the form in
which it is being used. When taken by mouth or injection, e.g., the drugs
pass into breast milk and may cause side effects in baby. Creams, gels,
and other forms that are applied to the skin are not known to cause
problems in nursing babies whose mothers use them. However, these
medicines should not be applied to the breast just before. In general,
women who are breastfeeding should ask their physicians before using
any type of corticosteroid.
Diabetes. Corticosteroids may affect blood sugar levels. Any
person with diabetes who notices changes in blood or urine test results
while taking corticosteroids should check with a physician.
Other medical conditions. Before using corticosteroids, people
with any of the following problems should make sure their physicians
are aware of their conditions:
 Osteoporosis or any other bone disease;
 Current or past tuberculosis;
 Glaucoma or cataract;
 Infections of any type (virus, bacteria, fungus, amoeba);
 Sores in the nose or recent nose surgery (if using nasal spray
forms of corticosteroids);
 Underactive or overactive thyroid;
 Liver disease;
 Stomach or intestine problems;
 Diabetes mellitus;
 Heart disease;
 High blood pressure;
 High cholesterol;
 Kidney disease or kidney concrements;
 Myasthenia gravis;
 Systemic lupus erythematosus (SLE);
 Emotional problems;
 Skin conditions that cause the skin to be thinner to bruise more
easily.
 49

Interactions. Corticosteroids may interact with a variety of other

medicines. When this happens, the effects of one or both drugs may
change or the risk of side effects may be greater. Anyone who takes
corticosteroids should let the physician know all other medicines they
are taking. Among the drugs that may interact with corticosteroids are:
 Insulin and diabetes medicines;
 Heart medicine such as digitalis;
 Diuretics (water pills);
 Medicine containing potassium or sodium;
 Immunizations (vaccinations);
 Cyclosporine (Sandimmune);
 Blood thinners, such as warfarin (Coumadin);
 Estrogen drugs, such as conjugated estrogens (Premarin) or oral
contraceptives;
 Antacids (if taken frequently).

The new trend of immunosuppressive therapy is introduction of

specific monoclones.
Monoclonal antibodies (monoclones, MABs) are used to treat the
wide spectrum of different diseases: allergic and autoimmune diseases,
rheumatoid arthritis, vasculitis, multiply sclerosis, leukemia and
lymphoma, tumors, etc.
The system of rules is developed for the name of monoclones. The
terminal part of all names is «mab». To the terminal part of mouse
(murine) monoclones names suffix "o" is added – «omab»
(Tositumomab). To the terminal part of the chimeric antibodies name
suffix «xi» is added – «ximab». Being a chimeric monoclone, used in
treatment of lymphoma, drug Rituxan is defined as «rituximab». Names
of humanized monoclones have received the terminal part «zumab», for
example, popular drug Herceptin which is applied in the treatment of
breast cancer, has got a definition «trastuzumab».
The most demanded drugs for the treatment are human monoclones
(suffix «u», «umab»). Human monoclones were developed by
immunization of transgenic mice (XenoMouse) that are able to produce
light and heavy chains of human immunoglobulin. After immunization
of these animals specific clone of B cells that produced antibody against
antigen were selected and immortalized in Chinese hamster ovary cells.
These cells are used for the full scale manufacture of the 100% human
antibody (Adalimumab).
 50

Monoclonal antibodies have several roles in therapy. Monoclones

have been used in variety of ways in the management of a disease
including diagnosis, monitoring, and treatment of a disease. They are
used in diagnosis, such as the application of flow cytometry in the
identification of different diseases. MABs can be used to monitor the
disease progression, such as the measurement of carcinoembryonic
antigen in colon cancer. Most importantly, we can utilize monoclonal
antibodies directly as a therapy. Monoclones may also be used to
preferentially select normal stem cells from bone marrow or blood in
preparation for hematopoietic stem cell transplantation in patients with
cancer.
Monoclonal antibodies achieve their therapeutic effect through
various mechanisms.
 They can have direct effects in producing apoptosis.
 They can block growth factor receptors, effectively arresting
proliferation of tumor cells.
 Monoclonal antibodies fixing on cells can induce anti-idiotype
antibody formation.
 Monoclones can also block the synthesized substances at various
pathological processes (blocking antibodies to Ig Е in allergy and
the TNF-alpha in various diseases, etc.).
Xolar (Omalizumab) represents humanized IgG1 monoclone which
selectively contacts with IgЕ of a person. The most appreciable clinical
experience (Rheumatoid arthritis) is saved up concerning a drug
Infliximab (Remicade) – chimeric monoclones to TNF-α. Another
representative of TNF-α inhibitor is Adalimumab (Humira) – the first
and while the unique drug representing completely human monoclones
to TNF-α.
Indirect effects include recruiting cells that have cytotoxicity, such
as monocytes and macrophages. This type of antibody-mediated cell
killing is called antibody-dependent cell mediated cytotoxicity (ADCC).
Monoclonal antibodies also bind complement, leading to direct cell
toxicity, known as complement dependent cytotoxicity (CDC).
Additionally to treatment, monoclonal antibodies can react against
specific antigens on cancer cells and may enhance the patient's immune
response. MABs can be programmed to act against cell growth factors,
thus blocking cancer cell growth.
MABs can be conjugated or linked with anticancer drugs,
radioisotopes, other biologic response modifiers, or other toxins. When
 51

the antibodies bind with antigen-bearing cells, they deliver their load of
toxin directly to the tumor (Table 5).
An example of conjugated monoclonal antibody is Ibritumomab
Tiuxetan. This drug carries cancer-killing radioactive particle directly to
the cancerous blood cells of non-Hodgkin lymphoma.
 52

Table 5. The list of the monoclones resolved to application

in clinical practice
MAB name Trade name Type Target Used to treat
Ibritumomab
Zevalin® murine CD 20 non-Hodgkin lymphoma
Tiuxetan*
non-Hodgkin
Tositumomab* Bexxar® murine CD 20 lymphoma,
follicular lymphoma
non-Hodgkin
Rituximab Rituxan® chimeric CD 20 lymphoma,
Rheumatoid arthritis
Infliximab Remicade® chimeric TNF-alpha Rheumatoid arthritis
epidermal
colorectal cancer,
Cetuximab Erbitux® chimeric growth factor
head & neck cancers
receptor
ErbB2
Trastuzumab Herceptin® humanized (epidermal breast cancer
growth factor)
Gemtuzumab acute myelogenous
Mylotarg® humanized CD33
Ozogamicin* leukemia (AML)
chronic lymphocytic
с Campath® humanized CD52
leukemia (CLL)
colorectal cancer,
vascular non-small cell lung
Bevacizumab Avastin® humanized epidermal cancer, breast cancer,
growth factor glioblastoma,
kidney cancer
proliferative diabetic
endothelial retinopathy, age-related
Ranibizumab Lucentis humanized
growth factor A macular degeneration,
age-related vision loss.
Rheumatoid arthritis,
Certolizumab Cimzia humanized TNF-alpha
Crohn’s disease
epidermal
Panitumumab Vectibix® human growth factor colorectal cancer
receptor
chronic lymphocytic
Ofatumumab Arzerra® human CD 20 leukemia (CLL),
Rheumatoid arthritis
Rheumatoid arthritis,
Adalimumab Humira® human TNF-alpha Crohn’s disease,
Psoriasis
epidermal
metastatic colorectal
Panitumumab Vectibix® human growth factor
cancer
receptor
*conjugated monoclonal antibodies
Remikade is a chimerical combination on
the base of hybrid mouse and human Ig G1
 53

monoclonal antibodies. Remikade has high affinity to TNF-α, the

cytokine with wide biological activity. The TNF-α is a mediator of
inflammatory response and participates in immune system reactions and
plays a great role in autoimmune and inflammatory diseases
development. Remikade quickly interacts and forms the stable
combination with both TNF-α forms (soluble and transmembrane), the
result is TNF-α functional activity decreasing.

Immunocorrection
Immunocorrection is the influence on the immune system to
normalize its functioning. It includes bone marrow, thymus
transplantation; immunoglobulins usage; hormones and mediators of the
immune system usage (hormones of thymus, myelopeptides, interferons,
interleukins); synthetic drugs; extracorporal methods (plasmapheresis,
haemosorbtion, method of extracorporal immunotherapy with drugs
usage, etc.).
Transplantation of the bone marrow is used for therapy of leucosis.
The indication for the thymus transplantation is certain primary
immunodeficiency.
Immunoglobulin drugs are prepared commercially from pooled
human plasma obtained from donors. It contains all immunoglobulin
classes and typically has demonstrable antibody titers for common
bacterial, fungal, and viral pathogens. The antibodies available in this
fraction are provided “passively” to the immune-deficient recipient.
There are different types of Immunoglobulin drugs according to their
specificity and ways of usage.
Specific immunoglobulins (Ig) are Antistaphylococcal,
Antiinfluenzal, Antitetanic, and etc. They are used for the treatment of
relative infections, as they contain antibodies against microorganisms or
toxins of these diseases. Allergoglobulin is used for the treatment of
allergy.
Nonspecific Ig contains antibodies with different specificity. There
are intravenous (i/v) and intramuscular (i/m) ways of usage. Ig for i/v
injections are: Human normal Immunoglobulin for i/v (Russia),
Gammavenin (Germany), Venoglobulin (France), Polyglobulin (Russia),
etc. For i/m injections: Human normal Immunoglobulin for i/m (Russia),
Sandoglobulin (Germany), Gammaglobulin (Germany).
The complications of i/v injections of Ig: muscles and back pain,
fever, diarrhea. The half-life period is approximately 3 weeks.
 54

The indications for the immunoglobulin therapy are: various

immunodeficiency states, including agammaglobulinemia, combined
variable immunodeficiency, and primary humoral immunodeficiency,
hematologic disorders, such as idiopathic thrombocytopenic purpura and
autoimmune hemolytic anemia, autoimmune disease, as well as
infectious diseases, such as measles and hepatitis. Immunoglobulins are
also used in the prevention of an infection in chronic lymphocytic
leukemia, multiple myeloma, and Kawasaki disease.
Possible toxicities of immunoglobulins include allergic reactions
such as anaphylaxis. In addition, the potentional danger associated with
agents isolated from pooled human plasma is exposure to hepatitis, HIV,
and etc.
According to the points of influence to the immune system drugs
can be divided into several groups:
1. For T – cell deficiency correction (Tactivinum, Thymosinum,
Thymogenum, Vylosenum, Diuciphonum, Romurtid, Isoprinosine)
2. For B – cell deficiency correction (Myelopidum,
Immunoglobulins)
3. For phagocytosis deficiency correction (Natrii nucleinas,
Methiluracilum)
Tactivinum (T – activinum). The mechanism of this drug action is
normalization of T-cell quantity and functions, stimulation of pre-T-
lymphocytes maturation. Indications: secondary cellular and combined
immunodeficiency, congenital forms of immunodeficiency, autoimmune
and allergic diseases, tumors. Tactivin is given subcutaneously in dosage
of 1,0 ml daily during 7 – 10 days.
Thymosinum provides T-cell specificity to uncommitted lymphoid
stem cells, enhances maturation of pre-T cells, enhances IL-2
production, increases IL-2 receptor expression on T lymphocytes. It is
used in treatment of cancer and chronic active hepatitis.
Thymogenum normalizes the T-helpers and T-suppressors quantity,
induces the T-lymphocytes differentiation, and increases the nonspecific
resistance. Indications are the same as for Tactivin. It is used in/m,
subcutaneously, intranasal. The dosage is 1,0 ml daily during 7 – 10
days.
Vylosenum activates T-suppressors, locally suppresses
phagocytosis processes, and suppresses the production of Ig E. It is
administered intranasally during 10 – 12 days.
The indications for this therapy are the deficiency of T-cells
system of the immunity, allergic diseases of eyes and nose, pollinosis,
 55

deficiency of local immunity of respiratory tract. The contraindications

are gestation and asthma.
Diuciphonum is given in tablets 100 mg – 3 – 4 times a day during
3 days, after 3-4 days – repeat, the course takes usually 20 tablets; or i/m
in the dose of 4 ml 5% solution (0,2 g) once a day.
Romurtid is used in treatment of leukopenia, because it stimulates
haemopoiesis. It is given in i/v injections.
Isoprinosine (Inosiplex) is a synthetic agent that has been shown to
increase natural killer cell cytotoxicity as well as to increase the activity
of T-cells and monocytes. It has been suggested by some investigators to
be minimally beneficial to patients with AIDS.
Myelopidum is a complex of peptides from pigs’ bone marrow. It
reduces T- and B-cells indices of immunity, stimulates antibody
production in the immune response, increases the quantity of B-
lymphocytes in peripheral blood, normalizes immunoregulative index
(IRI) – CD4/CD8 cells. It is given in a dosage of 3-6 mg i/v, i/m,
subcutaneously every day with a 2 day interval. The course includes
3-5 injections. Indications: bacterial infections with pyoprocess,
immunodeficiency in humoral part of immunity. Contraindications:
gestation, lactation.
Natrii nucleinas (Natrium nucleinicum) stimulates the regeneration
processes, stimulates bone marrow functioning, increases phagocytic
activity of macrophages, T- and B-cells’ migration and cooperation. It is
indicated for the treatment of immunodeficiency conditions, leukopenia,
and agranulocytosis. It is prescribed in a dosage of 1,0-1,5-2,0 g a day.
The duration of course – from 2 to 3 weeks and even more.
Methyluracilum stimulates the cells’ regeneration processes,
wound healing, stimulates cellular and humoral factors of immunity. It
can be used in tablets 500 mg 4 times a day during 30-40 days or locally
(unguentumes, compresses and etc.)
The cytokines are a group of diverse proteins produced by
leukocytes and related cells. They have a number of discrete roles in the
regulation of the immune system as well as hematopoiesis. Nowadays
interferons, colony stimulating factors, particularly GM-CSF and G-
CSF, and interleukins are widely used in immunotherapy.
Interferons (IFNs). Among 3 types of IFNs IFN-α, IFN-β and IFN-
γ are used widely. They are derived from white blood cells (IFN-α and
IFN-γ) or from fibroblasts (IFN-β) or synthesized in bacteria by
recombinant genetic techniques, which are glycoproteins that have
antitumor and antiviral activity, which may originate partially from
 56

immunologically mediated mechanisms. Depending on the dosage, IFNs

may either enhance or decrease cellular and humoral immune functions
and may affect macrophage and NK cell activity. IFNs also inhibit the
division and certain synthetic processes in a variety of cells. Human
clinical trials have indicated that IFNs have antitumor activity in hairy
leukemia, chronic myelocytic leukemia, and AIDS-associated Kaposi’s
sarcoma. Some responsiveness has been seen to a lesser degree in non-
Hodgkin’s lymphoma, multiple myeloma, and ovarian carcinoma.
However, IFNs are quite toxic; patients may develop fever, malaise,
leucopenia, alopecia, and myalgia.
Reaferonum (IFN-α2a) is a human recombinant α-2a interferon. It
shows the antiviral, immunomodulative, and antitumor activity.
Indications: viral infections and tumors. Contraindications: allergic
diseases, gestation.
Vyferonum – human recombinant α2b interferon. Also it contains
antioxidants: vitamin E and vitamin C in therapeutically effective doses.
Indications: in complex therapy of infectious inflammatory diseases of
newborn, babies, and adults including pregnant women:
 In newborn treatment: acute respiratory viral infections,
pneumonia, meningitis, sepsis, chlamydiosis, herpes, cytomegaly,
ureaplasmosis, visceral candidosis, mycoplasmosis;
 In pregnancy: acute respiratory viral infections, pyelonephritis,
bronchopneumonia, chronic nonspecific lung diseases, urogenital
infections, viral hepatitis B and C;
 Treatment of chronic viral hepatitis B, C, D in children and
adults.
Vyferonum is used in suppositories and cream. The doses and
schemes depend on certain diseases. Contraindications: increased
sensitivity to cocoa oil and other components.
Betaferon is interferon β1b, has antitumor and antiviral effects.
Due to the specific interaction with receptors on T lymphocytes and
macrophages betaferon suppresses the production by these cells
proinflammatory cytokines: IFNs and TNF, at the same time betaferon
stimulates the production of anti-inflammatory cytokines. Betaferon is
given subcutaneously. Contraindications: liver diseases in decompensate
stage, gestation, epilepsy, increased sensitivity to IFN and human
albumin.
Interleukin 2 (IL-2, Roncoleukin) is currently available as
recombinant protein. IL-2 binds to IL-2 receptors on the surface of
responsible cells, inducing proliferation and differentiation of T-helper
 57

and T-cytotoxic cells. IL-2 has also been demonstrated to induce B-cell
proliferation, stimulate macrophages activity, and increase the toxicity
of natural killer cells. Also it shows the immunomodulative action:
activates antibacterial, antiviral, antifungal, and antitumor immune
response. It is effective in secondary immunodeficiency. Indications:
sepsis, purulent complications in surgery operations, purulent processes
in non effective previous traditional therapy, lymphopenia,
leukocytosis, systemic inflammatory reaction in absence of localized
infection, melanoma, tumors of kidneys, brain, acute leukosis,
lymphogranulomatosis. It is used i/v, endolymphal, extracorporal,
subcutaneously. It can induce severe hypotension with life-threatening
cardiovascular toxicity. Other toxicities include renal toxicity (the
increased serum creatinine), hematologic toxicity (manifests itself as a
bone marrow suppression), CNS toxicity including somnolence or
delirium, and skin toxicity, with local inflammatory changes being seen
with the subcutaneous use. The optimal dose still remains to be
established. It appears that many of the toxicities can be ameliorated by
slowing the rate of the infusion.
Leikinferon – a combined drug, including interferon, factor of
macrophages migration and other cytokines. It has antiviral and
immunomodulative activity, activates the processes of proliferation,
differentiation of T-cells subpopulations, activates cytolytical and
phagocytic reactions in the organism, protects from the
immunosuppression after cytotoxic, chemical and radiotherapy.
Indications: viral infections (herpes, viral hepatitis, HIV).
Syperlymph is a complex of cytokines (IL-1, IL-6, TNF, GF-β,
MIF). It stimulates phagocytosis, cytokines production (IL-1, TNF),
induces antitumor activity of macrophages, promotes the intracellular
parasites’ death, regulates macrophages’ and lymphocytes’ migration.
Because of macrophage-monocytes cells’ stimulation cellular and
humoral immune response mechanisms are stimulated. Also,
Syperlymph has direct antibacterial and antiviral action, suppresses
inflammatory reaction development, and stimulates regeneration.
Indications:
 In surgery: purulent wounds, flegmons, abscesses, trophic ulcers,
traumas, burns, in patients with immunodeficiency after operations;
 In gynecology: papilloma virus infection, cytomegalovirus
infection, herpes infection of uterus, as prophylaxis and treatment of
inflammatory processes after operations;
 In urology: herpes infections and prostatitis;
 58

 In ENT: acute and chronic rhinosinusitis, pharyngitis, tonsillitis,

otitis;
 In stomatology: parodontitis, gingivitis;
 In ophthalmology: eye traumas and burns, viral keratitis, as
prophylaxis of hyper scars formation after operations.
Syperlymph is used in a solution to wash mucosa, in suppositories.
The schemes and dosage depend on severity of the process, and its
localization. Contraindications: gestation.
Betaleukin is recombinant human IL-1b. It has the main biological
effects: haemostimulation; immunostimulation, antitumor immunity
increasing, antiinfectious activity increasing – antiviral (hepatitis,
herpes, and CMV infections), antibacterial (sepsis, tuberculosis,
chlamydiosis) activity. Betaleukin stimulates leucopoiesis, increases the
functional activity of different leukocytes’ types. The drug stimulates the
nonspecific immunity by increasing the granulocytes’ functional activity
(phagocytosis and oxygen radicals’ production), and leads to the cellular
immunity activation by the increased IL-2 production, expression of
receptors for IL-2, proliferation of lymphocytes, quantity of NK cells
and IFN level increasing. Indications:
 In oncology: a combined therapy of cancer during chemo- and X-
ray therapy.
 In internal medicine: treatment of infectious diseases, including
tuberculosis, chronic viral hepatitis B and C, secondary
immunodeficiency;
 In surgery: treatment of traumas, burns, trophic ulcers, abscesses,
flegmons;
 In ENT: treatment of chronic purulent rhinosinusitis and otitis;
 In urology and gynecology: treatment of chlamydial and herpes
infections.

Inductors of interferons are drugs capable to raise endogenous

production of interferons. They have immunomodulative, antibacterial,
antiviral, antitumor, radio protective activities. Advantage of interferon
inductors is a lack of allergenicity and the side effects inherent to
interferons, the long-term circulation and possibility of combination to
other drugs.
Cycloferon is a low-molecular inductor of IFNs. It stimulates
interferons’ production by immunocompetent cells, promotes immune
function correction, induces early IFNα synthesis.
 59

Indications: HIV-infection, complex therapy of neuroinfections,

treatment of persistent viral infections; acute and chronic bacterial and
fungal infections; burns; chlamydial infections; joint diseases.
Contraindications: gestation, lactation.
Amixin is a low-molecular inductor of IFNs. It stimulates
interferons’ production by neutrophiles, T-lymphocytes, hepatocytes,
cells of intestinal epithelium. The antiviral action depends on the
suppression of viral replication in infected cells.
Indications: treatment and prophylaxis of flu, treatment of
persistent viral infections (hepatitis A, B, C, herpes, cytomegalovirus),
complex therapy of neuroinfections, TB, and chlamydiasis.
Contraindications: gestation, lactation, children under 7 years.

The extracorporal immunotherapy.

The method of plasmapheresis consists of blood taken from the
patient in the volume of 600-800 ml, its centrifugation as the next step,
which separates erythrocytes and their return to the patient. The
indications are autoimmune, immunocomplex and allergic diseases.
More over it can be used for the treatment of severe intoxications.
The method of haemosorbtion is used for the treatment of allergic
diseases, such as urticaria, angioedema, etc. The method includes
purification of blood by specific sorbents.
The method of extracorporal immunotherapy consists of blood
taken in volume of 400-600 ml from the patient, centrifugation, and
extraction of plasma. The next step is the isolation of lymphocytes,
which are incubated with drugs and returning them to the patient. In
using the immunosuppressors (glucocorticoids) the depression of the
immune response is reached. Using the immune stimulators (cytokines)
results in the activation of immune system. This method is used in cases
of severe immunodeficiency diseases, such as sepsis, burns, pyo-
inflammatory processes, severe allergic reactions, autoimmune disease
and others.

Questions for self-control:

1. Give the definition of the immunotherapy.
2. Name the main types of the immunotherapy.
3. Name the indications for each of the immunotherapy types.
4. Name the groups of drugs used for immunostimulation.
5. Name the groups of drugs used for immunosuppression.
6. Name the indications for the immunosuppressive therapy.
 60

7. Characterize monoclones.
8. Name the drugs for correction of the defects mainly in
cellular, humoral, and phagocytic parts of the immune system.
9. Name the drugs of cytokines which are more often used in
clinical practice, characterize them.
10. Characterize inductors of interferons.

IMMUNOPROPHYLAXIS

Immunoprophylaxis is a part of the preventive immunology to

make effective immune defense against the infection contaminations.
In a human body, all mechanisms of protection take place. Innate
immunity is a first line of antiinfectious defense. Inflammatory cell
products, cytokines, complement activation, phagocytosis, and cell-
mediated cytotoxicity are the principal means of innate host defense.
Adaptive immune mechanisms of anti-infectious protection can
be classified as natural and artificial. Both are divided into active and
passive.
Natural active immunity develops after infectious contamination at
the expense of memory cells, passive – depends on passing specific
antibodies from the mother’s blood through placenta into the fetal blood
or i/v blood transfusion. Artificial passive immunity is formed in
introduction (injection) into organism of the prepared antiinfectious or
antitoxic antibodies (serotherapy), active – is produced after vaccination,
and results in the immunological memory formation.
Vaccination is the administration of antigenic material (a vaccine)
to produce immunity to disease. Vaccines can prevent or ameliorate the
effects of infection by many pathogens. In the generic sense, the process
of artificial induction of immunity, in effort to protect against infectious
disease, works by 'priming' the immune system with 'immunogen'.
Stimulating immune response, via the use of infectious agent, is known
as immunization. Vaccinations involve the administration of one or
more immunogens, which can be administered in several forms.
There is a strong evidence for the efficacy of the influenza vaccine,
the HPV vaccine and the chicken pox vaccine among others.
Vaccination is generally considered to be the most effective and cost-
effective method of preventing infectious diseases. Many vaccines
require multiple doses for maximum effectiveness, either to produce
sufficient initial immune response or to boost response that fades over
 61

time. For example, tetanus vaccine boosters are often recommended

every 10 years.
Smallpox was the first disease people tried to prevent by purposely
inoculating themselves with other types of infections; smallpox
inoculation was started in China or India. In 1718, Lady Mary Wortley
Montagu reported that the Turks had a habit of deliberately inoculating
themselves with fluid taken from mild cases of smallpox, and that she
had inoculated her own children. In 1796 British physician Edward
Jenner tested the possibility of using the cowpox vaccine as an
immunization for smallpox in humans.
The word vaccination was first used by Edward Jenner in 1796.
Louis Pasteur furthered the concept through his pioneering work in
microbiology. Vaccination (Latin: vacca – cow) is so named because the
first vaccine was derived from a virus affecting cows – the relatively
benign cowpox virus – which provides a degree of immunity to
smallpox, a contagious and deadly disease. In common, 'vaccination' and
'immunization' generally have the same colloquial meaning. This
distinguishes it from inoculation which uses unweakened live pathogens,
although in common usage either is used to refer to immunization. The
word "vaccination" was originally used specifically to describe the
injection of smallpox vaccine.
Vaccination efforts have been met with some controversy since
their inception, on scientific, ethical, political, medical safety, religious,
and other grounds. In rare cases, vaccinations can injure people and they
may receive compensation for those injuries. Early success and
compulsion brought widespread acceptance, and mass vaccination
campaigns were undertaken which are credited with greatly reducing the
incidence of many diseases in numerous geographic regions.

Adjuvants and preservatives

Vaccines typically contain one or more adjuvants, used to boost the
immune response. Tetanus toxoid, for instance, is usually adsorbed onto
alum. This presents the antigen in such a way as to produce a greater
action than the simple aqueous tetanus toxoid. People who get an
excessive reaction to adsorbed tetanus toxoid may be given the simple
vaccine when time for a booster occurs.
In the preparation for the 1990 Gulf campaign, Pertussis vaccine
was used as adjuvant for Anthrax vaccine. This produces a more rapid
 62

immune response than giving only the Anthrax, which is of some benefit
if exposure might be imminent.
They may also contain preservatives, which are used to prevent
contamination with bacteria or fungi. Until recent years, the preservative
thiomersal was used in many vaccines that did not contain live virus.
Preservatives may be used at various stages of production of vaccines,
and the most sophisticated methods of measurement might detect traces
of them in the finished product, as they may in the environment and
population as a whole.
Thus, preservatives are a part of the vaccines made all over the
world. Their appointment consists in maintenance of preparations
sterility when there are conditions for bacterial contamination
(occurrence of microcracks at transportation, storage opened primary
multi doses packing). The indicating on necessity of preservatives
presence contains in references the WHO. As to the substances used as
stabilizers and excipients in manufacture of vaccines those from them
which are admitted for introduction in human body are used.

Types of vaccines
All vaccinations work by presenting a foreign antigen to the
immune system in order to evoke immune response, but there are several
ways to do it. The four main types that are currently in clinical use are as
follows:
1. Inactivated vaccine has destroyed viral particles which cannot
replicate, but the viral capsid proteins are intact enough to be
recognized and remembered by the immune system and evoke a
response. Virus strains are grown in culture and then killed using
method such as heat or formaldehyde, radioactivity or antibiotics .
Since the properly produced vaccine does not reproduce, booster
shots are required periodically to reinforce the immune response.
2. Attenuated vaccine has live viral particles with very low virulence.
They reproduce very slowly. As they do reproduce and continue to
present antigen beyond the initial vaccination, boosters are
required rarely. Viruses for vaccine are produced by passaging
virus in cell cultures, in animals, or at suboptimal temperatures,
allowing selection of less virulent strains.
3. Toxoid is prepared from bacterial toxin, not having the expressed
toxic properties, but thus capable to induce development of
 63

antitoxic antibodies to initial toxin. Receive via decontaminating of

toxin by formalin.
4. Genetic-engineering vaccines:
 Subunit vaccine presents antigen to the immune system without
introducing viral particles, whole or otherwise. One method of
production involves isolation of specific protein from virus or
bacteria (such as bacterial toxin) and administering this by itself. A
weakness of this technique is that isolated proteins may have
different three-dimensional structure than the protein in its normal
context, and will induce antibodies that may not recognize the
infectious organism. In addition, subunit vaccines often elicit
weaker antibody responses than the other classes of vaccines.
 Virus-like particle vaccines consist of viral protein(s) derived from
the structural proteins of virus. These proteins can self-assemble
into particles that resemble the virus from which they were derived
but lack viral nucleic acid, meaning that they are not infectious.
Because of their highly repetitive, multivalent structure, virus-like
particles are typically more immunogenic than subunit vaccines.
The human papillomavirus and Hepatitis B virus vaccines are two
virus-like particle-based vaccines currently in clinical use.
 Recombinant viral vectors. Method is short: genes of the virulent
microorganism, responsible synthesis of protective antigens, build
in gene of any microorganism, which at cultivation produces and
accumulates corresponding antigen. As an example, the vaccine
against virus hepatitis B.

A number of other vaccine strategies are under experimental

investigation (DNA vaccination, etc).
Vaccines may be monovalent (univalent) or multivalent
(polyvalent). Monovalent vaccine is designed to immunize against
certain antigen or single microorganism. Polyvalent vaccine is designed
to immunize against two or more microorganisms and/or toxins. In
certain cases, monovalent vaccine may be preferable for rapidly
developing strong immune response.

Vaccine administration practices

Appropriate vaccine administration is key element to ensuring the
optimal safety and efficacy of vaccines. Vaccine administration practices
are based on clinical trials that determine the dose, route and schedule
 64

for each vaccine. Professional standards for medication and vaccine

administration and federal/provincial/territorial policies and procedures,
where these exist, also guide vaccination practices. All providers of
vaccines should receive education and competency-based training on
vaccine administration before providing vaccines to the public.
Programs should be in place to monitor the quality of immunization
services. The following information provides general guidance for
vaccine administration practices.
Pre-vaccination counselling
Prior to vaccination, the vaccine provider should ensure that the
vaccine recipient is capable of consenting to the procedure or that, when
required, appropriate guardian or substitute decision maker is present to
give consent. Information regarding the risks and benefits of both
receiving and not receiving the vaccination should be provided, along
with the opportunity to ask questions. Vaccine reactions that occur
frequently and any adverse effects that are severe should be discussed
with the individual, guardian or substitute decision maker. This person
should be asked about all relevant contraindications and precautions to
receiving the vaccine. Care should be taken to determine whether there
is risk of anaphylaxis, such as previous anaphylaxis or severe allergy to
any of the vaccine components or latex, if contained in the vaccine
products.
Vaccine administration
Vaccines should be administered using the recommended dose,
route, site and schedule to optimize vaccine effectiveness and reduce the
risk of local reactions or other adverse events.
Most vaccines are given by hypodermic injection as they are not
absorbed reliably through the intestines. Live attenuated polio, some
typhoid and some cholera vaccines are given orally in order to produce
immunity based in the bowel.
Vaccine preparation
Vaccine inspection: The vaccine identification label and expiry
date on the vaccine vial or package should be checked by the vaccine
provider before administration. Vaccines should not be used beyond
their expiry date. If only the month and year are provided for the expiry
date, the vaccine can be used to the end of that month. Multi-dose vials
should be labelled with the date of first entry into the vial and, unless
 65

otherwise specified by the manufacturer, should be discarded after 30

days of the date of first entry. Before use, vaccine vials should be
inspected for any irregularities, e.g., particulate matter, damage or
contamination. Vaccines should be mixed with careful swirling motion
until uniform suspension is achieved prior to administration.
Vaccine reconstitution: Vaccines requiring reconstitution, i.e., a
lyophilized product that is mixed with diluent, should be mixed only
with the diluent supplied for the vaccine unless otherwise permitted by
the manufacturer.
Pre-loading vaccines in syringes: Ideally, vaccine should be
withdrawn from the vial by the vaccine provider administering the
vaccine. Pre-loading syringes with vaccine is discouraged because of the
uncertainty of vaccine stability in syringes, risk of contamination,
increased potential for vaccine administration errors and vaccine
wastage. Pre-loading of syringes in the hospital setting where vaccines
are drawn up and labeled in the pharmacy may be considered. In
addition, to facilitate timely and efficient administration of single
vaccine to large number of people in an immunization clinic setting, pre-
loading of syringes may be considered.
Syringe selection: Separate, sterile syringe should be used for each
injection, and different vaccines should not be mixed in the same syringe
unless specified by the manufacturer as part of the reconstitution and
administration procedure. Depending on the dosage, a 3 mL or 1 mL
syringe should be selected.
Needle selection: Needle selection should be based on the route of
administration, individual's age, size of the muscle mass and viscosity of
the vaccine. The needle should be inserted as far as possible into the
muscle.
After the vaccination
Vaccine recipients should be counselled on common side effects
and the reporting and management of these reactions. Vaccine providers
should identify and observe individuals who are particularly anxious
about receiving the vaccine. Individuals with presyncopal symptoms
such as pallor or sweating should sit or lie down until symptoms resolve,
to keep the person in the clinic for 15 minutes after vaccination. This
will also facilitate the management of the rare anaphylactic event. All
vaccination providers should have the necessary training and equipment
to manage anaphylactic events.
 66

Infection prevention and control

Immunization providers should incorporate routine infection
control practices into all immunization procedures:
 The vaccine vial should be uncapped, wiped with a suitable
disinfectant (e.g., isopropyl alcohol) and allowed to dry prior to
withdrawal of vaccine into the syringe.
 Before injection, the skin should be cleansed with a suitable
antiseptic and allowed to dry.
 A separate, sterile needle and syringe should be used for each
injection.
 Hand hygiene should be performed before vaccine preparation,
between vaccine recipients, and whenever the hands are soiled.
Alcohol-based hand sanitizers are an alternative to hand washing
with soap and water. Glove use during immunization is not
routinely recommended, unless the skin on the vaccine provider's
hands is not intact.
The human body can react to vaccination variously. There are two
types of organism reactions: vaccine reactions and side-effects –
complications:
 Vaccine reactions – arise owing to vaccination, are shown local or
sometimes system inflammatory reactions, as a rule, not
demanding treatment and are not contraindications to the
subsequent vaccination.
 Complications (undesirable reactions) are changes of organism
functions, overflowing physiological fluctuations and not
promoting immune defense development.
Probable mechanisms of vaccination’ complications
o Pharmacological action of vaccines (e.g., pertussis ingredient –
fever, cramps, encephalopathy, etc.);
o Postvaccinal infection contamination (after using of live attenuated
vaccine: BCG – lymphadenitis, osteomyelitis, tubercular lupus;
vaccines-associated poliomyelitis, etc.);
o Tumorogenesis (e.g., genetic-engineering vaccines – DNA-
vaccine);
o Allergy induction;
o Formation of non-protective antibodies (e.g., multicomponent
vaccines);
 67

o Immunomodulatuve effect (production of mediators or their

presence at vaccines);
o Induction of autoimmune reactions (e.g., pertussis vaccine);
o Immunodeficiency induction;
o Psychogenic effect.
Possible side-effects from vaccines
Vaccines are continually monitored for safety, and like any
medication, vaccines can cause side effects. For the most part these are
minor (for example, a sore arm or low-grade fever) and go away within
a few days. Listed below are vaccines licensed in Centre of Disease
Control's Vaccine Information Statements, which in turn are derived
from the Advisory Committee on Immunization Practices
recommendations for each vaccine.
However, decision not to immunize child also involves risk and
could put the child and others who come into contact with him at risk of
contracting potentially deadly disease.
Mild Problems
 Tenderness
 Redness
 Itch
 Infiltrate
 Muscle aches or temporary limitation of movement
 Headaches
 Fatigue
 Subfebrile fever
Severe Problems
 High fever
 Non-stop baby's crying, for 3 hours or more
 Long-term seizures of convulsions, coma, or lowered
consciousness and other nervous system disorders
 Hives and serious allergic reaction
 Serious injury, or death.
Prophylaxis of complications:
 The cleared vaccines usage;
 Selection of patients (sanitation of the chronic infection, remission
of diseases, drug preparation, interdiction of virus vaccines’
 68

introduction the patient sensitized to chicken proteins and to

aminoglycosides);
 Keeping of vaccination rules (way of introduction, dose,
observation over the patient, presence of antishock set);
 Keeping of rules of transportation and storage of vaccines.

Vaccination schedule
A vaccination schedule is series of vaccinations, including the
timing of all doses, which may be either recommended or compulsory,
depending on the country of residence (Table 6).
Vaccine schedules are developed by governmental agencies or
physicians groups to achieve maximum effectiveness using required and
recommended vaccines for a locality while minimizing the number of
health care system interactions. Over the past two decades, the
recommended vaccination schedule has grown rapidly and become more
complicated as many new vaccines have been developed.

Table 6. National Immunisation schedule in Russia.

4,5 20 14 ≥25
Vaccine Birth 1 month 3 mo. 6 mo. 12 mo. 18 mo. 6 yrs 7 yrs
mo. mo. yrs years
HepB
Hepatitis B (24 HepB HepB
hours)
BCG
BCG (3-7 BCG BCG
days)
Td
Diphtheria,
(every
tetanus, and DTaP DTaP DTaP DTaP Td
10
pertussis
years)
Polio vaccine
IPV IPV IPV PV PV PV
(inactivated)
Measles,
mumps, and MMR MMR
rubella
It is made according to instruction on
Influenza
application of vaccines annually

The vaccination made in all regions of the country within the limits
of vaccination’s calendar is named planned.
Some vaccines are recommended only in certain areas (countries,
subnational areas or at-risk populations) where disease is common.
Vaccination made to the population living in territories with infection
 69

high risk, and also to persons travelling to the endemic areas is

concerned to vaccination under epidemic indications. For instance,
yellow fever vaccination is on the routine vaccine schedule of French
Guiana, is recommended in certain regions of Brazil but in the United
States is only given to travelers heading to countries with a history of the
disease. In developing countries, vaccine recommendations also take
into account the level of health care access, the cost of vaccines and
issues with vaccine availability and storage.
The United Kingdom childhood vaccination schedule is
recommended by the Department of Health and National Health Service,
and uses combination immunizations where available (Table 7).
Acute infectious and noninfectious, exacerbation of chronic
diseases is temporary contraindications for carrying out of vaccination.
Planned vaccination is made through 2 - 4 weeks after recover or in
reconvalescence or remission.
Table 7. United Kingdom Vaccine Schedule: 2010
12–13 13–18
Vaccine 2 mo. 3 mo. 4 mo. 12 mo. 3–4 yrs
yrs yrs
Diphtheria, tetanus, and
DTaP DTaP DTaP DTaP Td
pertussis
Haemophilus influenzae type b Hib Hib Hib Hib
Pneumococcal vaccine PCV PCV PCV
Polio vaccine (inactivated) IPV IPV IPV IPV IPV
Measles, mumps, and rubella MMR MMR
Meningococcus MenC MenC MenC
Human papillomavirus vaccine HPV1
1.
Females only
 BCG vaccine is given at birth "to babies who are more likely to come into contact with
Tuberculosis than the general population."
 Hepatitis B vaccine is given at birth "to babies whose mothers are hepatitis B positive."

The World Health Organization monitors vaccination schedules

across the world, noting what vaccines are included in each country's
program, the coverage rates achieved and various auditing measures.
Additional vaccines are given to individuals that are much more likely to
come into contact with certain diseases due to their occupation or travel
to regions where the disease is present (including members of the
Military), or only after potentially infectious exposure. Examples
include Rabies vaccine, Anthrax vaccine, Cholera vaccine and Smallpox
vaccine.
 70

Questions for self-control:

1. Name mechanisms of immune responses formation to vaccines;
2. Name classification of vaccines;
3. Characterize live, inactivated, DNA, subunit and peptide vaccines;
4. Enumerate compound of vaccines;
5. Classify reactions on bacterial and viral vaccines;
6. List mechanisms of postvaccinal allergic complications
development;
7. What features are there postvaccinal reactions to bacterial
anatoxins?

AUTOIMMUNE DISEASES

Autoimmune disease is immune reaction against self-antigens.

Autoimmunity is the cause of certain diseases in humans. Autoimmunity
implies lost of self-tolerance and immune reactions to host antigens.
Autoimmune diseases may be classified as organ specific or non-
organ specific depending on whether the response is primarily against
antigen localized to particular organs or widespread antigen.
Hashimoto’s thyroiditis
Spectrum of autoimmune diseases
Primary myxoedema
Thyrotoxicosis
Autoimmune diseases form spectrum on one end of which are
Pernicious anemia
conditions in which Autoimmune
auto antibodiesatrophicare directed against single organ or
gastritis
tissue, therefore resulting in localized tissue damage. There are
Addison’s disease
Premature menopause
remarkable overlaps Insulin
at each end of the spectrum. The mechanisms of
dependent diabetes mellitus
immunopathological Goodpasture’s
damage vary depending on where the disease lies
syndrome
in the spectrum. Myasthenia gravis
Male infertility
There are 3 requirements
Pemphigus vulgaris
should be met before disorder is
categorized as truly due to autoimmunity.
Pemphigoid
1. Presence of autoimmune reaction;
Sympathetic ophthalmia
Phacogenic uveitis
2. Clinical or Multiple
experimental
sclerosis
evidence that such reaction is not
secondary to tissue damage buthaemolytic
Autoimmune is of primary
anaemiapathogenesis significance;
3. Absence of another
Idiopathicwell defined cause
thrombocytopenic of the disease.
purpura
Idiopathic leucopenia
Primary biliary cirrhosis
Active chronic hepatitis
Organ specific Cryptogenic cirrhosis
Ulcerative colitis
Sjogren’s syndrome
Rheumatoid arthritis
Dermatomyositis
Scleroderma
Mixed connective tissue disease
Discoid lupus erythematosus
 71

Non-organ specific

The most important step in the development of autoimmune

disease is the activation of self-reactive T and B cells. These self
reactive (Th-1 or Th-2) cells can induce either cell-mediated or antibody
– mediated autoimmune reactions (Table 8).

Etiology and Mechanisms of development

Mechanisms of tolerance and its breakdown: After the

discovery that central tolerance is incomplete, the question how
peripheral tolerance is established and maintained became major focus
of research. In fact, some researchers now believe that organism is only
tolerant to the most common self antigens that are expressed in the
thymus or bone marrow at sufficiently high concentrations to trigger
deletion of T or B cells that recognize these self antigens (clonal
deletion). Out of all self antigens only very few are deleting. Thus it is
no tolerance to most self antigens.

Table 8. Autoimmune diseases listed by the main target organs

Type of Autoimmune Diseases Target of the Immune
 72

Immune
Response
Response
Antibody to Myasthenia gravis Acetylcholine receptor
receptors Insulin resistant diabetes Insulin receptor
Lambert-Eaton myasthenia Calcium channel receptor
Antibody to Systemic lupus DsDNA, histones
cell erythematosus
components Rheumatoid arthritis Fc of IgG
other than Rheumatic fever Heart and joint tissue
receptors Hemolytic anemia RBC membrane
Idiopathic Platelet membranes
thrombocytopenic purpura
Goodpasture’s syndrome Basement membrane of
kidney & lung
Pernicious anemia Intrinsic factor and parietal
cells
Hashimoto’s thyroiditis Thyroglobulin
Insulin dependent diabetes Islet cells
mellitus
Addison’s disease Adrenal cortex
Acute glomerulonephritis Glomerular basement
membrane
Periarteritis nodosa Small and medium sized
arteries
Guillain-Barre’s syndrome Myelin protein
Wegener’s granulomatosis Cytoplasmic enzymes of
neutrophils
Cell mediated Allergic encephalomyelitis Reaction to myelin protein
and multiple sclerosis causes brain
(T cells and demyelinization.
macrophages)

Two complementary explanations have been proposed to account

the absence of autoimmune disease in healthy individuals despite the
open nature of the immune repertoire. One is that it is very hard to evoke
immune responses. Transport of antigens to lymphoid organs and
presentation by professional APCs is necessary which have to be
induced to express co-stimulatory activity. As a consequence, immune
 73

cells do not react against many self antigens, although there are
lymphocytes specific to them (immunological ignorance). The other
explanation postulates that immune responses can not only be induced,
but can also effectively downregulated (suppression). Recently some of
the endogenous factors that suppress T cells have been identified.
Transforming growth factor (TGF-β) is one of them.
TGF-β is produced by several tissues known to be
"immunoprivileged sites". They are defined by the observation that
grafts or antigens placed within them are tolerated indefinitely.
Examples are the brain, the eye, testis, uterus (fetus), thyroid gland, and
etc.
Oral tolerance: The concept of endogenous immunosuppression or
"active tolerance" is further supported by the fact that organism becomes
tolerant to antigens that are ingested orally despite being immunogenic
when introduced subcutaneously. Oral tolerance is active phenomenon
as it can be transferred to non-tolerant animals by T cells from tolerant
animal. Recently T cells have been cloned from gut lymphoid tissue
(Peyer's patches) and found to produce TGF-β. The induction of oral
tolerance is presently being tested for autoantigens that are known to be
the targets of autoimmune diseases (insulin, myelin basic protein and
others).
Despite the rapid progress of immunological theory, precise
mechanistic understanding of the primary cause is not available for any
autoimmune disease. Autoimmune diseases are thought to be of
multifactorial origin, involving genetic, hormonal, infections and other
environmental factors.
Genetic factors It is clear however that in most cases genetic
factors play role, most notably HLA (MHC) genes. This is plausible as
MHC genes play key role in antigen specific T cell activation. Linkage
to certain MHC alleles is usually determined by measuring the
frequency of specific MHC alleles in patients afflicted with autoimmune
disease compared to the general population. Vice versa, statistical
association of disease with MHC alleles is often used as one of the
criteria that point to autoimmune etiology. Ankylosing spondylitis is
associated with B27 allele, Idiopathic insulin-dependent diabetes
mellitus – DR3/DR4, Systemic lupus erythematosus – DR3, Subacute
thyroiditis – B35 (Table 9).
 74

Table 9. HLA association and sex preference of some common

autoimmune diseases.
Disease HLA allele Relative Sex ratio
risk (female / male)
Rheumathoid arthritis DR4 4.2 3
Systemic lupus erythematosus DR3 5.8 10-20
Type I diabetes DR3 / DR4 3.2 ~1
Graves' disease DR3 3.7 4-5
Myasthenia gravis DR3 2.5 ~1
Hashimoto's thyroiditis DR5 3.2 ~1
Pemphigus vulgaris DR4 14.4 ?
Ankylosing spondylitis B27 87.4 0.3
Acute anterior uveitis B27 10.04 <0.5
Goodpasture's syndrome DR2 15.9 ?
Multiple sclerosis DR2 4.8 10

Studies with identical twins have provided important information

about the role of MHC genes in disease susceptibility. Thus, identical
twin of diabetic child has 30% chance of developing diabetes, which is
far higher than the general population. However, 70% of the twin
siblings do not develop disease, suggesting that MHC genes play
important role, but other factors must be important too. The most likely
ones are infections and nutrition. The genes people inherit contribute to
their susceptibility for developing autoimmune disease. Certain diseases
such as psoriasis can occur among several members of the same family.
This suggests that specific gene or set of genes predisposes family
members to psoriasis. In addition, individual family members with
autoimmune diseases may inherit and share set of abnormal genes,
although they may develop different autoimmune diseases. For example,
one first cousin may have lupus, another may have dermatomyositis, and
one of their mothers may have rheumatoid arthritis.
Infections and other environmental factors. Infectious pathogens
have been implied in triggering several autoimmune diseases. It is
 75

thought that the immune response to pathogen component crossreacts to

self antigen, process also known as "molecular mimicry". For example,
rheumatic fever depends on presence of streptococcal antigens.
Microbial superantigens lead to polyclonal activation of
lymphocytes. Some of these clones with auto reactivity can be in
effector immune response regime. Tissues’ destruction by pathogen
results in releasing of internal cellular antigens and induction of immune
auto reactivity.
Any inflammatory reactions are accompanied with
proinflammatory cytokines’ production, which results in increasing of
complex MHC+self antigens expression on the surface of different cells
and initiation of auto reactivity. HBsAg is determined in high frequency
in autoimmune diseases.

Diagnostics of the autoimmune diseases

For diagnostics of autoimmune diseases the clinical criteria
characterizing each disease are accepted. Also the X-ray is if necessary
considered. The preliminary diagnosis is established on set of criteria,
and then necessary laboratory analyses are made.

The indirect data of the autoimmune process are:

 Disorder in the population and subpopulation of the lymphocytes
(CD4+ T-lymphocytes and B-lymphocytes increasing);
 Gammaglobulines’ level increasing in the blood serum;
 Complement system components C3 and C4 decreasing in blood
serum;
 Disorder of cytokine levels;
 The autoantibodies’ titer increasing in blood serum.

The laboratory data which can show the presence of the certain
autoimmune process are:
 The specific autoantibodies in the blood serum;
 The sensibilized T lymphocytes in the blood;
 The increased immune complexes concentration in blood serum
or immune complexes presence in tissues (in histological
investigations);
 Lymphocytic tissue infiltration in histological bioptate
investigations.
 76

Treatment of the autoimmune diseases

Until nowadays the specific pathogenetic therapy of the
autoimmune diseases is not devised. Methods of the therapy include:
1. Inflammatory reaction suppressing in the organs and tissues.
The nonsteroid and steroid drugs, immunodepressants are used;
2. Extracorporal methods (plasmapheresis, haemosorbtion);
3. The drugs on the base of monoclonal antibodies usage
(remikade – the antibody to TNFα).
As the perspective – devise of drugs on the base of monoclonal
antibodies against autoreactive T- and B-lymphocytes, vaccines.

RHEUMATOID ARTHRITIS (RA)

RA is systemic chronic inflammatory disease of not clear etiology
and is characterized by polyarthritis which may be progressive and
permanently deforming and by extra-articular manifestations, such as
rheumatoid nodules, pericarditis, and arteritis. Adult RA is commonly
associated with peculiar group of anti-IgG autoantibodies called
rheumatoid factors (RFs) which mainly belong to IgM (some time IgG
or IgA classes), bind to the Fc portion of IgG molecules, and form
IgG+anti-IgG complexes in the circulation or joint fluid. RFs are
detected in serum in up to 80% of adult patients with RA and often at
high titer and in repeated tests. Nevertheless, RFs are not specific for RA
and occur in other connective tissue diseases (CTDs), such as Sjogren's
syndrome, in chronic infectious diseases, such as infectious endocarditis,
tuberculosis, and hepatitis В and, although usually at low titer, in up to
20% of overtly normal elderly individuals.
Pathologically, RA is characterized by chronic inflammatory and
proliferative changes in the synovial membrane (interior of joint capsule
lined with synoviocytes), accompanied by inflammatory effusion in the
joint space and destructive erosion of joint cartilage and adjacent bone
cortex. Ultimately, the joint space may become obliterated and the bone
ends united by fibrous or bony union (ankylosis).
In advanced RA, the synovial membrane becomes densely
infiltrated with lymphocytes, plasma cells, and macrophages and extends
over the articular surface as membrane, called rheumatoid pannus, which
erodes and replaces the underlying articular cartilage.
RA may also be accompanied by extra-articular lesions of which
the rheumatoid nodule, granuloma occurring in subcutaneous sites or
 77

elsewhere, is characteristic. Rheumatoid nodules occur in subcutaneous

tissue most often but are also seen in tendon, lungs, and heart.
Cell-mediated immune mechanisms and proinflammatory
cytokines are now a focus of interest in the study of the pathogenesis of
RA. Briefly, T-lymphocytes, mainly T-helper/inducer cells and many of
them activated are the most abundant cells in the rheumatoid synovial
membrane. Many activated macrophages, macrophage-like
synoviocytes, and interdigitating reticular cells (strongly expressing
HLA-DR antigen) are intermixed with the recruited T-cells and B-cells.
Among the several inflammatory cytokines released by the activated
macrophages are TNF-alpha and IL-1 which are considered to be major
mediators of joint inflammation in RA. Recent clinical approaches in the
treatment of active RA include the use of new classes of
immunomodulatory drugs that inhibit the action of these inflammatory
cytokines, for example, that neutralize or block TNF-alpha by binding to
it or to its cell surface receptor.

POLYARTERITIS NODOSA (PAN)

PAN, or simply polyarteritis, is classical model of noninfectious
systemic necrotizing vasculitis and involves small and medium-sized
arteries of almost any organ (kidney, heart, intestine, skin) with the
possible exception of lung. Pathologically, polyarteritis is characterized
by segmental fibrinoid necrosis and polymorphonuclear leukocyte
infiltration of all three layers of the vessel wall.
Involvement of the intima results in thrombotic occlusion and
infarction of regions supplied by the affected artery. Destruction of the
elastic lamina results in aneurismal dilatations (nodosa) in some cases.
Destructive action is realized via activation of immune cells, especially
neutrophiles that invade blood vessels, produce many toxic molecules,
and contribute to the damage of the blood vessels. Reactive oxygen
intermediate molecules and other toxic molecules are made by
overproductive macrophages and neutrophils.
Significantly, up to 20-30% of patients with polyarteritis have
hepatitis В virus antigen. HB surface antigen (HBsAg) + anti-HBsAg
antibodies complexes are present in the circulation and deposited along
with complement in the vascular lesions of such patients.

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

 78

SLE is multisystem chronic inflammatory disease of not clear

etiology which has strong predilection for young women in the
reproductive years, affects many organs, and is characterized by the
production of multiple autoantibodies, typically antinuclear and anti-
DNA antibodies (ANAs). In some patients, autoantibodies are also
produced against platelets, lymphocytes, and other cellular antigens.
The clinical expression of SLE is extremely varied, but the most
common findings include: fever, erythematous rash, arthritis, serositis
(pleuritis, pericarditis), and nephritis. Skin photosensitivity, oral ulcers,
hematologic disorders, and neurological abnormalities are also seen.
The presence of multiple auto antibodies and other immunologic
abnormalities (decreased suppressor T-cell function, spontaneous
polyclonal B cell activation, and impaired macrophage function) point to
basic defects in immunoregulatory controls that normally maintain self
tolerance.
Contributory factors may be genetic, hormonal, or environmental
in nature. Genetic influence is suggested by family clusters of SLE,
significant (approx. 25%) concordance of SLE in homozygous twins,
and associations with HLA (DR2, DR3) and with inherited complement
deficiencies. Hormonal influence is suggested by the 9:1 female:male
ratio of SLE, the predilection for females during the reproductive years,
and the frequency of onset in the early postpartum period.
Environmental factors are indicated by drug-induced (iatrogenic) lupus
syndromes caused by procainamide, hydralazine, and other drugs, and
by skin sensitivity to sunlight exposure which may provoke the onset of
SLE. The possible etiologic role of specific infectious agent is
speculative at this time.
ANAs also react specifically with isolated and characterized
nuclear antigens, such as deoxyribonucleoprotein, DNA in double
stranded (ds) and single (ss) stranded configuration, and histones. Some
ANAs also react with non-histone proteinscalled antibobies to
extractionated nuclear antigens, such as Sm antigen, various nuclear
ribonucleoproteins (RNPs), and others. None of these reactivities has
absolute specificity for any disease entity. The most specific for active
SLE are anti-dsDNA antibodies which are rarely found at significant
levels in other diseases.
Anti-DNA antibodies are involved in the pathogenesis of (type III)
IC-initiated tissue injury and inflammation in SLE expressed as
nephritis, vasculitis, and serositis. Autoantibodies are also produced in
 79

some lupus patients against platelets, erythrocytes, and T cells, and these
may cause (type II) antibody-mediated cell injury resulting in
thrombocytopenia, hemolytic anemia, and lymphopenia.
The fluorescent antinuclear antibody (FANA/ANA) test is the most
widely used diagnostic screening test for SLE.
This test is positive, often in high titer, in >95% of patients with
active untreated SLE, but positive reactions also occur in other CTDs, as
previously noted, other conditions, and rarely in overtly healthy subjects,
particularly family members of patients with SLE. While the ANA test
has high sensitivity, it has low specificity for SLE. It is a useful
diagnostic screening test in the evaluation of patients suspected of
having SLE or a strongly ANA-related CTD or in ruling out these
diseases.

Questions for self-control:

1. Give the definition and classification of autoimmune diseases.
2. Name the examples of organ-specific and systemic autoimmune
diseases.
3. Name etiopathogenetic factors of the autoimmune diseases.
4. Characterize the autoimmune processes’ development which
leads to the cells’ and tissues’ lesion, organ or systemic pathology
progressing.
5. Name the laboratory data of the autoimmune process.
6. Name the main principles of the autoimmune diseases
treatment.
 80

ALLERGIC DISEASES

During last years the frequency of allergic diseases increased,

especially in well developed countries and in countries with bad
ecologic situation. Due to prognosis of scientists the XXI century will be
the century of allergic diseases.
There are a lot of reasons which lead to the allergic diseases
quantity increasing:
The first is infections sickness rate structure changing. At present it
is considered that during pregnancy and just after birth function of T-
helpers class 2 prevail. But during immune system development
normally will be correlation changing - functioning increasing of Th1.
To do that bacterial and viral antigens are needed. They activate
macrophages and induce secretion of interleukin-12. IL-12 influences
upon Th0 and induce their differentiation into T-helpers 1. Th1 produce
INFγ, and this interleukin suppresses Th2 function. So, decreased
quantity of bacterial and viral diseases in childhood (including
tuberculosis) leads to the intensification of Th2 functioning and
developing of allergic reactions in future.
The second is hereditary factors. It is determined those genetic
predispositions to allergy have polygenic character and include genetic
control of:
a) IL-4 and IL-5 production by Th2;
b) IgE hyper production;
c) Bronchi hyper reactivity.
There is inherited component, because if one parent is atopic the
child has 25-40% chance of also being atopic; if both parents are
affected the risk rises to 50-75%. This is compared to background
incidence in the developed world of approximately 30% (this percent is
continually rising). There is also association with HLA-A1, B8, Dw3
and HLA-A3, Dw2, although no specific 'allergy gene' has been
identified.
The third is environmental factors. It is shown that exhaust gas,
tobacco-smoke contain NO2, SO2 or NO which induce the hyper
reactivity of Th2 and IgE production. Besides that substances influence
the airway epithelial cells and lead to their activation and
proinflammatory cytokines (IL-8, IL-6) production. This cytokines make
toxic effect to epithelial cells and assist the allergic inflammation
development.
 81

Allergy is hyper sensitization of organism to allergen (antigen)

during repeated contact with it and clinically is characterized by lesion
of those tissues through which allergen penetrates into the organism:
bronchi mucosa, GIT mucosa, nasal cavity mucosa, skin, conjunctiva.
Mechanisms of sensibilization
 active (natural contact with allergen)
 passive (introduction of preparing antibodies to intact recipient)
 latent (more often to drugs)
◦ intrauterine sensibilization of fetus
◦ baby after the birth (in breast-feeding)
◦ cross reaction (hyper sensitization to other allergens which
have common chemical structure of epitopes)

ALLERGENS

Allergens are antigens which induce sensibilization and

anaphylaxis of the predisposed organism.

Classification of allergens
Classification according to the origin:
 pollen;
 insects;
 fungus spores;
 home, library dust;
 house mites;
 animal skin cells (dander) and saliva;
 food;
 chemical substances;
 drugs.
Ways of allergen’s contact with the organism include airways and
mucosa (aeroallergens), GIT (food, some drugs), skin (contact
allergens), parenterally (insect poisons, some drugs).
Possible place of meeting are consumer and professional.
Consumer allergens include different types of dust (home, library).
House dust contains spores of microbes and their toxins, mites.
More often sensitization develops to lipopolysaccharide and toxins of
 82

Enterobacter spp., Esherichia vulneris, Pseudomonas, Streptococcus

pneumonia, Staphylococcus aureus, Mycoplasma pneumonia.
Different types of mites present in house dust. More important
from them are Dermatophagoides pteronissimus, Dermatophagoides
farinae, Dermatophagoides microceras, Euroglyphis mainei.
The places of their life are bedclothes, carpets, furniture. Optimum
conditions are 70-80 % humidity of air, temperature – 22-27о C.
Spores of mould present in house dust. High concentration of
mould contains in bathroom, library room, damp room and basement.
There are Alternaria, Cladosporium, Aspergillus, Penicillium, Mucor.
Pollens can induce seasonal symptoms of allergy. Morbidity
depends on climatic condition and type of vegetation. Allergenic
properties of pollen depend on containing of alkaloids, saponins,
essential oils, proteins. Basically antigenic properties of pollen are
caused by the proteins which have been found out in sporoderm. The
pollen possessing following properties can cause sensibilization:
1. Belonging to wind pollinated plants,
2. Light and flying,
3. Plants should be widely presented in certain region,
4. To be small in size.
Pollen allergy is commonly caused by allergy to seasonal pollens
and outdoor molds (Table 10, 11). There are 3 main season of
pollination:
 trees — birch, alder, hazel, hornbeam, willow, poplar, platanus,
Ashe juniper
 grass — ryegrass, timothy-grass, cereal grasses
 weeds — ragweed, plantago, nettle, artemisia vulgaris, sorrel
Table 10. The schedule of the most widespread plants blooming
in the Central Russia
plants April May June July August September
Tree (Alder, Birch) +++ +++ +++
Dandelion +++ +++
Meadow grass +++ +++
Weed pollens
+++ +++ +++
(Orach, Wormwood)
 83

Epidermal allergens are the allergens of cat, dog, horse, and

hamster. Hair, dandruff, saliva, urine of animal can provoke allergy.
More often cattle-breeder, poultry farmer, circus actor, veterinary have
allergy to animal. There are reactions to introduction of heterological
Serums (antirabies, antitetanic, etc.) at patients with epidermal allergy
probably development.
Table 11. The schedule of the most widespread plants blooming
in Europe
plants February March April May June July August September
Tree (Alder, Birch) ++ +++ +++ +++ ++
Grasses ++ +++ +++ +++ +
Weed pollens +++ +++ +++ ++ ++ +++ +++

Food allergens are proteins of milk, egg, fish, and nuts. Allergy to
bread can show in the patients with hyper sensitization to cereals.
Hyper sensitization to insect allergens develops on sting of bee,
bumble-bee, wasp, mosquito, midge, black beetle and locust. Poison of
insects contains biogenic amines (histamine, serotonin), proteins, and
enzymes. It can induce allergic or toxic reactions.
Chemical allergens are substances, which can be used in consumer
services and industry. They are metals, acid, alkali, synthetic polymers,
organic substances (formic aldehyde, latex, etc.). It can lead to
professional diseases.
Any medical preparation can act as allergen, but is the most
frequent – antibiotics (penicillin), Sulfa drugs, local anesthetics,
nonsteroid anti-inflammatory drugs, vaccines, Serums, etc. Feature of
allergenic properties is presence of the common antigenic determinant at
drug, capable to cross sensibilization. Serious problem also are
development of reactions to the metabolites of medicinal substances.
The main signs of true allergic reaction are:
1. Primary contact of organism’s immune system with allergen
(antigen) is needed;
2. Period of sensitization (in other words it is the presence of
definite time interval for immune response reactivity changing. As the
result is Antibody or sensitized T-lymphocytes production);
3. Presence of repeated contact with the certain (specific) allergen
 84

– antigen;
4. Developing of typical clinical picture, having as basement of
specific immune mechanisms.
In all cases of true allergic disease the individual must have been
previously sensitized to the allergen. However, not all individuals who
produce IgE antibody to environmental allergens suffer with atopic
disease; other factors play part:
 Age. Exposure in the first few years of life is more likely to induce
atopic disease. In addition, childhood atopic disease tends to
improve with age.
 Intercurrent infections. Viral infections may induce atopic disease,
potentially by damaging the respiratory mucosa and allowing
greater allergen penetration and sensitization.
 Non-specific irritants. Pollutants such as diesel emission particles
(DEPs) and cigarette smoke increase bronchial reactivity and may
also damage the mucosa.
 Immunodeficiency. Patients with underlying immunodeficiency
are more susceptible to atopic disease. This may be due to greater
allergen exposure after damage to the respiratory or gut mucosa by
infection or due to decreased T cell regulation of IgE production.

PATHOGENESIS OF ALLERGIC DISEASES

The look and feel of allergic reaction depends on the body part
involved and the severity of the reaction. Some reactions may be
localized and limited, while others could involve multiple body systems.
Reactions to the same allergen vary among individuals.
However allergic reactions of different types that complicates
current of allergic pathology and its therapy can simultaneously or
participate in illness pathogenesis consistently.
Hypersensitive reactions according to the duration of period from
contact of sensitized organism with antigen till the beginning of clinical
signs of allergic reaction are divided into 3 types.
1. Allergic reactions of immediate type (or it is also called
immediate hypersensitivity) develop during 15-20 minutes (or even
quicker);
2. Late allergic reactions – develop during 4-6 hours;
3. Delayed allergic reactions (delayed hypersensitivity) – develop
in 48-72 hours.
 85

However this classification does not characterize the specific

mechanisms participating in allergic reactions’ realization. At present
days Gell and Coombs classification (1964) is widely used. According
to this classification there are 4 types of allergic reactions.
1. immediate (anaphylactic, IgE-mediated) type;
2. cytotoxic type;
3. immune complex type;
4. delayed (T cell mediated) hypersensitivity.
During last years the 5th type was added. The basis of I, II, III and
V types is interaction of immunoglobulins (antibodies) with antigens.
The basis of IV type is functioning of sensitized T lymphocytes which
carry out on their membrane structures for specific recognition of the
antigen.
There are 3 stages of the true allergic reaction.
The 1st is named «immune stage». It lasts from the first contact
between allergen and immune system till the sensitization development.
The 2nd is «pathochemical stage». It begins after the repeated
contact of immune system with the certain specific allergen, leading to
immunopathological mechanisms activation, resulting in secretion of
great quantity of biologic active substances (BAS).
The 3rd stage is called «pathophysiologic» and is characterized by
organisms, tissues and cells breach of function and their lesion by the
influence of BAS secreted during pathochemical stage.

Mechanisms of allergic reactions

The first is anaphylactic type, which is conditioned by IgE
production. IgE have high affinity to must cells and basophiles of
peripheral blood and can fix on these cells.
During first allergen penetration into the organism, the allergen is
engulfed by antigen presenting cells (macrophages, B-cells, dendrite
cells) and undergoes the processing. During processing there goes on
formation of allergen peptides and presentation them on the surface of
APC with complex HLA for recognition by T-helpers class 2. After
recognition Th2 are activated and produce cytokines, such as IL-4, IL-5,
IL-3, etc. IL-4 realizes 2 main functions:
1. B-lymphocyte transforms into plasma cell and begins to produce
Ig E;
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2. By influence of IL-4 and IL-3 the basophiles proliferation is

intensified and quantity of receptors to Fc fragment of Ig E increases on
the membrane of basophiles.
So, during the first stage goes on production of Ig E and their
fixation on the tissue basophiles and basophiles of peripheral blood.
Interleukins 3, 5 intensify the eosinophiles migration activity, their
ability to produce BAS, prolong their life period. On the eosinophiles
migration adhesion molecules are expressed in high quantity.
During repeated penetration of the allergen into the organism,
allergen binds with Ig E and this leads to the basophiles degranulation
and expression of platelet activation factor, histamine, leucotrienes,
prostaglandins and other biologic active substances. BAS secretions
induce several effects.
They are:
1. Activation of platelet and excretion of serotonin;
2. Complement system activation and formation of
anaphylotoxines – C3a, C5a, also haemostasis is activated;
3. Histamine secretion and vessel permeability increasing;
4. Unstriated muscles contraction intensification by the influence
of leucotrienes and prostaglandins.
Mediators, secreted in allergic reaction type I, can be divided into 2
groups: those, which are already contained in granules of basophiles and
those, which are synthesized in the cells by the influence of
phospholipase (the arachidonic acid metabolism).
Summary these group mediators can be listed as
Preformed mediators
 Histamine
 serotonin
 Neutrophil and eosinophil chemotactic factors (NCF and ECF)
 enzymes (tryptase, histaminases, aryl sulphatase, phospholipase)
Newly formed mediators (membrane-derived) – slow-reacting
substance of anaphylaxis (SRS-A)
 Leukotrienes,
 prostaglandins
 thromboxanes
 platelet-activating factor.

Nowadays it’s known that histamine is the main mediator in

allergic reaction.
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Histamine is vasoactive amine producing in histidine’s

decarboxilization, is short-living molecule. Action of histamine realized
via histamine receptors.
There are different types of histamine receptors in the organism.
H1-receptors are located mainly in unstrained muscles and blood
vessels. Activation of these receptors leads to the spasm of trachea and
bronchi muscles (bronchospasm) and vessels permeability increase,
sneeze, itch and epiphora. Using H1-histamine receptors
proinflammatory effects are realized by lysosomal enzyme excretion
from neutrophiles. Antagonists of H1-receptors are classic
antihistaminic drugs (antiallergic).
H2-histamine receptors are present in different tissues. The
interaction between histamine and this type of receptors results in gastric
secretion stimulation and catecholamine synthesis, relaxing of uterus,
increasing of myocardial contractility, relaxing of bronchi unstried
muscles. Antagonists of H2-receptors are widely used in
gastroenterology.
It is determined that histamine may be synthesized in nervous
tissue. Histamine interacts with H3-receptors and this leads to
suppression of further histamine excretion by nervous system.
Arachidonic acid is generated in sensitized cells from membrane
lipids following the binding of specific allergen (Fig. 4). It is
subsequently metabolized to produce prostaglandins (cyclo-oxygenase
pathway), leukotrienes (lipoxygenase pathway) or platelet-activating
factor (acetylation), depending on which cell type is being activated.
Leukotrienes and prostaglandins are together termed eicosanoids. The
arachidonic acid metabolites involved in type 1 hypersensitivity
reactions are platelet-activating factor (PAF), leukotrienes (LT) B 4, C4,
D4 and E4 and prostaglandins (PG) D2, E2 and F2.
The arachidonic acid metabolites have four main actions:
 Inflammatory cell infiltration. This is mediated by LTB4 and PAF,
which attract and activate neutrophils, eosinophils and
monocytes/macrophages. LTB4 is released by activated mast cells
and macrophages, and PAF is released by mast cells, neutrophils
and eosinophils.
 Bronchoconstriction. This is mediated by several metabolites
including PAF, LTC4, LTD4, LTE4, PGD2 and PGF2. LTC4 and
PGD2 are the major arachidonic acid metabolites released by mast
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cells. The remaining eicosanoids are generated by human lung

tissue and/or alveolar macrophages.
 Bronchial mucosal edema is mediated by LTC4, LTD4 and PGE2.
PGE2 is released from alveolar macrophages and human lung
tissue.
 Mucus hypersecretion is mediated by LTC4 and LTD4.
Platelet-activating factor (PAF) is secondary mediator that causes
platelet aggregation, releasing of histamine, bronchospasm, increased
vascular permeability, and vasodilation. In addition, it has important
proinflammatory actions. PAF is chemotactic for neutrophils and
eosinophils. At higher concentrations, it activates the newly elicited
inflammatory cells, causing them to aggregate and degranulate. Because
of its ability to recruit and activate inflammatory cells, it is considered to
be important in the initiation of the late-phase response. Although its
production is also triggered by the activation of phospholipase A2, it is
not product of arachidonic acid metabolism.

Fig. 4. Pathways for biosynthesis and release of membrane-derived

lipid mediators from mast cells.
In the 5-lipoxygenase pathway LTA4 is the intermediate from which the terminal-
pathway enzymes generate the distinct final products, LTC 4 and LTB4, which leave the cell by
separate saturable transport systems. Gamma glutamyl transpeptidase and dipeptidase then
 89

cleave glutamic acid and glycine from LTC 4 to form LTD4 and LTE4, respectively. The major
mast cell product of the cyclooxygenase system is PGD2.

This reaction is termed the early-phase response. The late-phase

reaction comes 4-6 hours later and is characterized by inflammatory cell
infiltrates with neutrophils, eosinophils and lymphocytes.
Eosinophiles play important role in I type of allergic reaction. They
have two main functions:
1. Secretion of mediators, such as: main basic protein of
eosinophiles, cationic proteins, peroxidases, nitrotoxing trombocytes
activating factor, leukotrienes, etc. This leads to the arising of symptoms
in late phase of allergic reaction – cell inflammation, epithelium
destruction, mucus hyper secretion, bronchi constriction.
2. Eosinophiles produce several substances to suppress allergic
reaction. They are:
a. Histaminase (inactivates histamine);
b. Aryl sulphatase (inactivates leucotrienes);
c. Phospholipase D (neutralizes PAF);
d. Prostaglandin E (decrease the histamine secretion).
Major basic and eosinophil cationic proteins are toxic to epithelial
cells. Activated eosinophils and other leukocytes also produce
leukotriene C4 and PAF and directly activate mast cells to release
mediators. Thus, the recruited cells amplify and sustain the
inflammatory response without additional exposure to the triggering
antigen. It is now believed that this late-phase inflammatory response is
major cause of symptoms in type I hypersensitivity disorders, such as
allergic asthma.
During the second part of immediate allergic reaction the aryl
sulphatase, histaminase, phospholipase D, prostaglandin E2 secretion
promotes the suppression of secreted mediators functioning.
Wholly the pathophysiologic stage of immediate reaction is
characterized by:
1) increasing of vessels’ permeability,
2) fluid going out from vessels,
3) developing of edema,
4) severe inflammation,
5) increasing of mucus excretions production.
To this type of allergic reaction the pathogenesis of the following
diseases belong to: allergic bronchial asthma, allergic rhinitis, allergic
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conjunctivitis, urticaria, angioneurotic Quincke`s edema, skin itch,

anaphylaxis (Fig. 5).

Fig. 5. General mechanism underlying type I hypersensitive reaction.

Cytotoxic type of hypersensitivity is realized by antibodies, but in

this case there are IgM and IgG (except IgG4).
Antigens reacting with this antibodies can be natural cell structures
(antigenic determinants), for example after blood cells lesion. Also
antigens can be extra cellular structures, for example antigens of renal
glomerulus’s basal membrane. But any way these antigenic determinants
have to acquire auto antigenic properties. In allergic reactions allergen or
hapten induces superficial cellular conformation changes. The reasons
for this process are:
1) cell antigen conformation changes;
2) membrane lesion and arising of new “occult” antigens;
3) formation of complex “Cell antigen+hapten”.
As the result of immune response IgM, IgG are produced. They
react by Fab-fragments with the cell antigens and form complex
(antibody+cells' antigen).
Due to complexes formation three mechanisms are activated:
1. Complement system activation and complement mediated
cytotoxity is realized;
2. Activation of phagocytosis (opsonization);
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3. Killer cells activation and antibody dependent cell-mediated

cytotoxity (ADCC) realization.
During pathochemical stage activation of complement is
accompanied by opsonisation, activation of inflammatory cells'
migration, increasing of phagocytosis, secretion of histamine because of
C3a, C5a influence, secretion of kinines, cell membrane destruction.
Activation of neutrophiles, monocytes and eosinophiles results in
secretion from this cell lysosomal enzymes, production of super oxide
anionic radical. These substances take part in cell membrane destruction.
The clinical examples of allergic reactions of type II are
autoimmune hemolytic anemia, autoimmune thyroiditis, allergic drug
agranulocytosis, thrombocytopenia.
The next type of hypersensitivity is called immune complex type.
In this reaction IgM, IgG also take part. But the difference from
cytotoxic type is that immunoglobulins react with soluble antigens but
not with the antigens localized on the cell membranes. As the result of
binding of antigen and antibody pathological circulating immune
complex arise. Circulating immune complex (CIC) can be fixed in the
microcirculation bed and induce complement system activation,
lysosomal enzymes secretion, kinin production, super oxide radical
production, histamine and serotonin secretion, endothelium cell lesion
and thrombocyte aggregation. This results in tissue destroying.
Pathological nature of CIC in this type of hypersensitivity is
formed by the following factors:
1. Immune complex is soluble; it’s formed in plenty of antigens.
Immune complex has molecular mass about 900-1000kD;
2. In structure of immune complex Ig G or Ig M have to be, able to
activate complement;
3. Immune complex circulates for long time (this can be during
long penetrating of the antigen in the organism and during the breach of
elimination mechanisms: overwork of monocytes/macrophage system,
blocking of Fc, C3b, C4b receptors);
4. Increased permeability of vessels’ walls (this can be by the
influence of vasoactive amines of basophiles and thrombocytes, and
lysosomal enzymes).
In this type of reaction in the focus of inflammation neutrophiles
predominate at the beginning, then – macrophages and at last
lymphocytes.
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Examples of IIIrd type reactions are: serum sickness, exogenous

allergic alveolitis, glomerulonephritis, drug and food allergy,
autoimmune diseases.
The IVth type is reactions of cell-mediated hypersensitivity.
It is delayed hypersensitivity. The base of this reaction is
interaction of cytotoxic sensibilized T lymphocyte and specific antigen.
This leads to the secretion from T lymphocyte cytokines which mediate
delayed hypersensitivity.
Cell mechanism is “used” by organism when antigen is
heterologous cells or infect (Antigen) is situated intracellularly (some
bacteria, protozoa, fungi, transplanted cells and organs), or in case when
Ag is the cell with changed surface antigens (e.g., inclusion of antigen –
hapten to skin proteins and contact dermatitis development).
So during immunologic stage the formation of cytotoxic
(sensitized) T-lymphocytes goes on in the organism. After that cytotoxic
T lymphocytes and inflammatory cells secrete the following cytokines:
1. Factor suppressing macrophages’ migration. It can induce
increasing of phagocytosis and takes part in granuloma formation;
2. Factor stimulating production of endogenous pyrogenes. It is
IL-1;
3. Mytogenic (growth) factors. They are IL-2, IL-3, IL-6;
4. Chemotaxic factors – IL-8;
5. Granulocyte-monocyte colony stimulating factors (GM-CSF);
6. Lymphotoxines;
7. Tumor necrosis factors;
8. Interferons.
Cytokines secreted from sensitized lymphocytes activate and
attract cells of monocytes/macrophage system to the focus of
inflammation.
During the last stage of allergic reaction the cells and tissues
destroying reactions are the result of:
1. Direct cytotoxic action of T lymphocytes;
2. Cytotoxic action of macrophages and neutrophiles;
3. Action of enzymes and other cytotoxic substances (e.g.,
oxidants) secreted by monocytes and macrophages.
As the example of disease in this type allergic contact dermatitis,
graft rejection, tuberculosis, mycosis can be named.
And at last, the Vth type – stimulating type of hypersensitivity. In
this type there is no destruction of the cells. From one side activation of
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cell function goes on; peculiarity of this reaction is that antibodies do not
have complement activation activity. In this type antibodies directed
against receptors take part in physiological activation of the cell, then
there will be stimulation of this cell types. From other side Igs binding
with receptors induce their block and in this case can activate
complement system or ADDC. The result is inability to receive specific
activation signals.
Non immune (Pseudo-allergic) reactions
The pseudo-allergy is often met reaction to various factors
including synthetic polymers, food (fish, orange, tomatoes, strawberry,
cheese, sausage, beer, wine and sea products), drugs (antibiotics, iodine,
atropine, morphine), physical factors (cold or heat), bee sting, and etc.
This reaction is induced by high dose of irritante, clinical picture
same to true allergic reaction, in pathogenesis does not have immune
stage. It depends on activation of mast cells by non immune
mechanisms and occurs on first contact with provoking substance.
Thus, mediators can be released by the following mechanisms:
1. direct mechanism releasing agents (histamine – liberating
substances). They can be drugs (more than 100). The most common are
morphine, codeine, polymexin, radiocontrasting drugs, iodine-
containing preparations, and others. It also can be food, chemical agents,
cold, sunlight, trauma, pressure, rubbing, and so on.
2. activation of the alternative complement pathway, that results in
releasing of C3a, C4a, C5a fractions possessing the functions of
anaphylotoxine and able to alter the sensitivity of tissues to histamine.
3. disorder of arachidonic acid metabolism, proceeding with
blocking the cyclooxygenase pathway of arachidonic acid metabolism.
This leads to enhanced production of leucotrienes and release of
histamine. The main cyclooxygenase inhibitors are analgetics,
nonsteroid anti-inflammatory agents (aspirin particularly).

Questions for self-control:

1. Name classification of allergens;
2. Name the allergic reactions’ classification of Gell and Coombs;
3. Characterize stages of allergic reactions’ development;
4. Characterize the mechanism of anaphylactic type;
5. Name the mediators of the I type of allergic reactions;
6. Name the diseases which are developed according to the I type
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of allergic reactions;
7. Characterize the II type of allergic reactions;
8. Name the examples of the diseases which are developed
according to the II type of allergic reactions;
9. Characterize the III type of allergic reactions and name diseases
of this type;
10. Characterize the mechanism of the cell-mediated allergic
reaction.

DIAGNOSTIC METHODS IN ALLERGY

Diagnostics of allergic diseases quite often causes difficulties. It is

bound by that implications can be various, and also with possibility of
development of pseudo-allergic or not immune reactions. Exact and
well-timed diagnostics of allergy at early stages; when a disease
proceeds without complications, polysensibilizations, nonspecific
hypersensitivity, allows spending effective treatment and rehabilitation
of patients.
Diagnostics of allergic diseases, as well as any other illnesses, is
based on studying of symptoms of illness, inspection of the patient and
performance of certain diagnostic tests.
Diagnostics of allergic diseases can be divided into 5 stages.
1. allergic anamnesis
2. clinical-laboratory investigation (examination)
3. skin allergic tests
4. provocative tests
5. immunological investigation.

The 1st stage is taking allergic history. Correctly collected allergic

history has very important significance in diagnostics. Taking allergic
history doctor try to reveal:
1. Allergic nature of the disease;
2. Proposed etiologic factor – Allergen;
3. Risk factors which can promote the allergic disease
development. These factors are:
 hereditary predisposition to allergic disease (family
anamnesis);
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 environmental factors;
 climate, weather character, physical factors, connection
with certain season;
4. Concomitant diseases;
5. Other allergic diseases;
6. Influence of every day (social/house) factors; for example: pets,
overcrowding, dampness, soft furniture, carpets, etc.
7. Connection between acute phase of the disease and other
pathology (GIT diseases, pathology of endocrine system, CNS);
8. Professional harms;
9. Connection between clinical symptoms and allergens’
elimination;
10. Effect from antiallergic drugs usage and allergens’ elimination.
Result of allergological anamnesis studying the doctor should
specify clearly there is seasonal or all-the-year-round allergen,
professional allergen or intolerance of nutrition that it was possible to
plan purposeful carrying out of the further diagnostic stages.
The 2nd stage – clinical - laboratory investigation. Objective
examination is carried out. Then the common blood analysis, urine
analyses are prescribed. Also sputum analysis, X-ray of the chest, nasal
sinuses are needed. Presence and degree of airway obstruction can be
determined.
Due to the results of this investigation doctor can reveal:
1. Process localization (nose, eyes, skin, bronchi, GIT, and etc.);
2. Type of the disease (pollinosis, asthma, dermatitis, and etc.);
3. Phase of the disease (acute, remission);
The 3rd stage – skin allergic tests. Dermal testing allows to tap
causally significant allergens and to establish the allergic nature of
diseases.
There are following types of skin tests:
1. Epicutaneous (with drops, application);
2. Scarification;
3. Prick-test;
4. Intradermal tests.
Indications for skin tests are positive allergic anamnesis, when
certain allergen can be considered to be the etiology of the disease. But
there are contraindications for skin tests to be carried out. They are:
1. Acute phase of allergic disease;
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2. Acute infectious diseases;

3. Acute phase of concomitant chronic pathology;
4. Tuberculosis, HIV-infection;
5. Decompensate conditions in diseases of heart, liver, kidney;
6. Blood pathology, tumors;
7. Autoimmune diseases;
8. Period of antihistaminic drugs, membranostabilizators,
hormones, bronchospasmolytics usage;
9. Convulsive syndrome, nervous and psychological diseases;
10. Pregnancy, lactation, period of menstruation;
11. Age before 3 years or older 60 years;
12. Anaphylactic shock, Stevens-Johnson syndrome, Lyell's
syndrome in anamnesis.
Epicutaneous tests
Tests with drops are used in patients with high sensitiveness,
especially to the chemical substances and to the drugs some times.
Technique of probe: drop with allergen is put to the defatted flexion
surface of forearm and as a control – drop with isotopic solution.
Estimate after 20 minutes.
Application probe is used for the diagnostics of professional
allergy, contact dermatitis. Technique of probe: the gauze piece damped
in the allergen solution is put to the flexion surface of forearm skin, and
as a control – gauze damped in indifferent fluid. Estimate the result after
30 minutes.
Scarification skin tests
These tests reveal the Allergen – etiology of the disease in the
patient and the level of sensitization to this Allergen. Technique of this
test is the following. Skin of forearm flexion surface is defatted by ethyl
alcohol and then drops with different Allergens are put in interval of 4-5
centimeters. Using sterile scarificators in every drop two parallel
scratches are made. After 10 minutes drops are blotted and after 10
minutes more the result can be estimated.
Negative result with control fluid and positive result with
histamine is needed.
How to estimate the results (Fig. 6):
1. Negative is when all scarifications like control fluid scratch.
2. Doubtful is when hyperemia without wheal (blister) is present.
 97

3. Poor positive when you see wheal to 2-3 millimeters plus

hyperemia.
4. Positive result – wheal to 5 millimeters plus hyperemia.
5. Strong positive - wheal to 5-10 millimeters plus hyperemia plus
pseudopodia.
Estimating the skin test result it is useful to know that pseudo
positive result takes place.
1. During hypersensitivity of skin to mechanical irritation or in
case of reactions to the control fluid components (for example – phenol);
2. Reaction to Allergen-during not correct technique of the test
(too deep scratches) or individual hypersensitivity to skin mechanical.
Some time there can be pseudo negative result (absence of
hyperemia, blister)
1. To histamine - during individual sensitivity to histamine
decreasing or if the patient uses antihistaminic drugs, hormones;
2. To Allergens – if the spectrum of Allergens is not complete: or
if there is no correct keeping of Allergens; or if there is no correct
technique of the test (superficial scratches) or skin tests carryied out
during acute phase of allergen of a patient taking drugs (antihistaminic,
membranostabilizators, hormones).

Fig. 6. Positive scarification skin test

Prick-test
This test is made by special instrument with the needle. That
allows standardizing the depth of the injection (prick), excluding the
drop crushing during the prick. Allergen and control drop are put on the
skin of the patient’s arm in the same way as in scarification testing. The
result of the probe is registered after 15-20 minutes (the biggest diameter
of wheal is measured). The result is considered to be positive when
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wheal’ diameter is 5 millimeters or more, doubtful (questionable) result

– when diameter of 3 mm, hyperergic – when diameter is 15 mm or
more.
Intradermal tests
This type of tests is made mostly with infection allergens
(bacterial, fungal, etc.) Using noninfectious Allergens this test is made
only if epicutaneous or scarification tests were doubtful or negative but
with certain positive allergic history.
Technique of the test: skin of forearm flexion surface is defatted by
ethyl alcohol. After that using insulin or tuberculin syringe infectious
Allergen in dosage of 0,05-0,1 milliliters is injected intradermally in 10
degrees less than concentration used in scarification test. As control the
control fluid is injected intradermally and scarification test with
histamine is made. The result is estimated after 20 minutes
(noninfectious allergen) and after 24-48 hours (infectious allergen). If
injected allergen is noninfectious the dosage of it is 0,02 milliliters.
Intradermal test estimation:
Negative result. After 20 minutes: looks like control. After 24-48
hours looks like control.
Doubtful: After 20 minutes: blister resorption delay. After 24-48:
weak hyperemia without infiltration.
Poor positive: wheal (blister) is 4-8 millimeters in diameter
surrounded by hyperemia. After 24-48: hyperemia, infiltration of 5-10
mm in diameter.
Positive result is considered to be when there is wheal or blister of
9-15 mm in diameter surrounded by hyperemia. After 24-48h:
hyperemia and infiltration are 11-15 mm in diameter.
Strong positive result. After 20 minutes: wheal or blister is 16-20
mm in diameter with pseudopodia surrounded by hyperemia. After 24-
48h: hyperemia, infiltration of 16-20 mm in diameter.
Very strong positive result. After 20 minutes: wheal or blister is
more than 20 mm with pseudopodia, lymphangiitis, vesicles. After 24-
48h: hyperemia, infiltration are more than 20 mm in diameter,
sometimes vesicles.
The specificity of intradermal test is less than others and this type
of testing may be pseudo positive. That is why the Allergen quantity
during intradermal test does not exceed 4-5.
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The 4th stage of allergen diagnosing is provocative tests which

allow achieving the contact of shock organ and allergen. These tests are
used in case of difference between allergen anamnesis and skin tests
results. According to the ways of allergen penetration into the organism
and the type of allergen there are several provocative tests: nasal,
conjunctival, inhalational, sublingual, oral. Contraindications are the
same as for skin tests.
Nasal test is made with any home allergen, epidermal, bacterial
allergens and pollen for diagnostics of allergic rhinosinusitis, tracheitis,
bronchitis, bronchial asthma.
Conjunctival test is made with the same allergens (like nasal), but
for diagnostics of allergic diseases of eyes.
Inhalation test is usually used to diagnose bronchial asthma. The
main indications for this test are:
1. Etiologic allergens revealing;
2. Drug treatment effectiveness estimation;
3. Revealing of specific factors inducing bronchospasm;
4. Estimation of professional factors of the patient.
This test is carried out with home, epidermal, pollen and bacterial
allergens if the nasal test result was negative or if there is a difference
between the allergic history and skin tests results. This test is made
during remission. At the beginning spirography is made. After that the
patient inhalates (using inhaler) solution of allergen begins from the
lowest dosage to the dosage which will induce clinical reaction.
Spirogram is made with each inhalation.
If data decrease more than 20 % test is considered to be positive.
Sublingual test is used to diagnose food and drug allergy.
Allergen is put on the mucosa of sublingual zone. In food allergy
products are used with solution 1:10, in drug allergy medicine is used
1/8 - 1/4 of single dose. Test is considered to be positive if hyperemia of
sublingual zone, edema, and itch arise. Also in the patient there may be
pulse ratio increasing, rush on the skin, sneezing and cough.
Elimination test This type of provocative test is used for
diagnosing food allergy. In this case food is used. 2-3 days before testing
the certain product is excluded from the patient ration. After this period
the patient is allowed to eat this product. Doctor examines common
condition of the patient and shock-organ condition.
If there are some clinical signs of shock-organ during 1 st hour the
test is supposed to be positive.
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Gemocytes’ decreasing test is used in food allergy, sometimes in

drug allergy. When patient leads elimination diet, twice during 1 hour
the quantity of peripheral blood leucocytes is estimated. Then the
Allergen is given and after 30, 60, 90 minutes the peripheral blood
leucocytes quantity is estimated. If the quantity of these cells decreases
more than 1.109 per a liter the test is positive.
Provocative tests with different allergen (especially inhalation test)
may be used only if there are some difficulties in diagnosing allergic
diseases. It is important to keep in mind that the development of
anaphylactic complications is quite possible, so personnel, doctors
should be ready for these reactions and (it ’s important) the patient should
be informed about these complications.
The 5th stage – immunolaboratory investigation. Nowadays
these methods are widely used because they have some advantages:
1. Possibility to make investigation in child (over 3 years) and in
elderly;
2. Possibility to make investigation during acute phase of the
disease and also in the patients with high level of sensitization;
3. To reveal the polyvalent sensibilization, when there is no
possibility to make testing in vivo;
4. This test can be used if skin tests were pseudo positive or pseudo
negative;
5. Safety for the patient, because this test can’t induce additional
sensitization and complications;
6. Investigation with many allergens simultaneously.

Laboratory tests are:

1. Determining the common IgE concentration;
2. Radioallergosorbent test (to determine specific IgE against
different Allergens);
3. Tissue basophiles degranulation test;
4. Shelly’s test;
5. Leukocytolisis reaction;
6. Neutrophiles lesion test;
7. Leucocytes migration inhibition test;
8. Lymphocytes blast transformation reaction.
Among nonspecific methods the following tests can be named:
1. Determining histamine and histaminase concentration in blood;
 101

2. Determining blood serum histaminopexial activity.

3. The modern investigation method is determining of tryptase level.
It is specific proteolytic enzyme of tissue basophiles which is
excreted from these cells during degranulation.
If there is need to estimate immune status of the patient then
different laboratory tests are used: the determination of T-, B-
lymphocytes quantity and functional activity, immune complexes
concentration, immunoglobulins concentration, neutrophiles, and natural
killers’ functions, and etc.

Questions for self-control:

1. What stages does diagnostic of allergic diseases include?
2. Name the features of allergic anamnesis;
3. Name the types of skin tests;
4. Name the types of provocative tests;
5. Name indications and contraindications for skin and provocative
tests carrying out;
6. Name laboratory specific and nonspecific tests in diagnostics of
allergic diseases.

TREATMENT OF ALLERGIC DISEASES

(ANTI–ALLERGIC DRUGS)

Allergy treatment provides measures to which number, besides

healthy way of life, the immunotherapy, diet, pharmacological
preparations concern. Today the last plays paramount role. Constantly
there is working out and application in practice new medical products.

All treatment procedures can be divided into two types:

1) In acute phase
First of all stopping of contact between organism and allergen.
Second is elimination of allergen.
The beginning treatment is etiological treatment, which includes
revealing the allergen and its elimination. After that there is
pathogenetic treatment. Its aim is to stop the acute clinical symptoms of
the disease.
2) Treatment in the remission period
Its aim is prophylaxis of the relapse.
This type includes:
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 the elimination of allergen (complete and incomplete),

 organism reactivity to the allergen changing (in case when
elimination is impossible) – allergen specific immunotherapy.
Main approaches of the treatment are:
1) Environmental control measures and allergen elimination;
2) Supervision of specific antibodies synthesis or excluding their
(Ag and Ab) interaction:
a) specific;
b) nonspecific;
2) Mediators synthesis and excretion suppression:
a) H1-histamine receptors blockers;
b) Other antimediator drugs;
3) Suppression of mediators action effects:
a) adrenomimetic drugs;
b) sympathomimetic drugs;
c) sympatholytic drugs.

Global environmental control is inappropriate without

identification of specific triggers.
Pollens and outdoor molds. Because of their widespread presence
in the outdoor air, pollens can be difficult to avoid. Reduction of outdoor
exposure during the season in which a particular type of pollen is present
can be somewhat helpful. In general, tree pollens are present in the
spring, grass pollens from the late spring through summer, and weed
pollens from late summer through fall, but there exist exceptions to these
seasonal patterns.
Pollen counts tend to be higher in dry, sunny, windy days. Outdoor
exposure can be limited during this time, but this may not be reliable
because pollen counts can also be influenced by a number of other
factors. Keeping the windows and doors of the house and car closed as
much as possible during the pollen season (with air conditioning, if
necessary, on recirculating mode) can be helpful. Taking a shower after
outdoor exposure can be helpful in removing pollen that is stuck to the
hair and skin.
Despite all of these measures, patients who are allergic to pollens
usually continue to be symptomatic during the pollen season and usually
require some other form of management. As well as with pollens,
avoidance of outdoor/seasonal molds may be difficult.
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Indoor allergens. Depending on the allergen, environmental control

measures for indoor allergens can be quite helpful. For dust mites,
covering the mattresses and pillows with impermeable covers helps
reduce exposure. Bed linens should be washed every 2 weeks in hot (at
least 130°F) water to kill any mites present. Thorough and efficient
vacuum cleaning of carpets and rugs can help, but, ultimately, carpeting
should be removed. The carpet can be treated with one of a number of
chemical agents that kill the mites or denature the protein, but the
efficacy of these agents does not appear to be dramatic. Dust mites
thrive when indoor humidity is above 50%, so dehumidification, air
conditioning, or both is helpful.
Indoor environmental control measures for mold allergy focus on
reduction of excessive humidity and removal of standing water. The
environmental control measures for dust mites can also help reduce
mold spores.
For animal allergy, complete avoidance is the best option. For
patients who cannot, or who do not want to, completely avoid animal or
pet, confinement of the animal to noncarpeted room and keeping it
entirely out of the bedroom can be of some benefit. Cat allergen levels at
home can be reduced with high-efficiency particulate air (HEPA) filters
and by bathing the cat every week (although this may be impractical).
Occupational allergens: As with indoor allergens, avoidance is the
best measure. When this is not possible, a mask or respirator might be
needed.
Nonspecific triggers: Exposure to smoke, strong perfumes and
scents, fumes, rapid changes in temperature, and outdoor pollution can
be nonspecific triggers in patients with allergic rhinitis, asthma, etc.
The methods of allergens’ removing from organism can be listed as:
1) Extra corporal specific sorption:
a) immunosorption (removal of Ag or Ab);
b) haemosorption (removal of different Ab, CIC, Allergens,
mediators);
c) plasmaferresis (Plasma contains allergens, CIC, mediators;
1200-1600 ml of blood effusion, then its centrifugation and plasma
removing, but blood cells are returned to the patient).
2) Enterosorption (to remove Ab, Ag, CIC from GIT) (e.g., active
carbon, Polyphepan, Filtrum, etc);
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During immune stage the following medicines are used to suppress

antibody’s production, cells’ proliferation, and stabilization of cell’s
membranes:
o corticosteroids (block every stage of allergic reaction);
o immunosuppressive drugs (suppress B cell activation and
antibody’s production, T cell proliferation);
o anti Ig E antibody (Xolar) – suppression of specific antibody’s
production (monoclonal antibody to Ig E)
o membranostabilizers (stabilizers of cells' membranes, block
mediators excretion).
The next step of treatment depends on the type of allergic reaction
but still it should follow the way of decreasing mediator production
and/or their inactivation.
I TYPE Drugs, which are used in this type are:
 Antibody’s production suppressors and drugs, which block
mediators excretion;
 H1-histamine receptors blockators;
 antimediator drugs (antiserotonin, and etc).
II and III TYPES
 corticosteroids;
 proteolytic enzyme inhibitors;
 complement system inhibitors;
 antiserotonin drugs;
 antihistamine.
IV TYPE
 corticosteroids;
 antiserum;
 antihistamine;
 lymphokynes.
During pathophysiologycal stage the treatment depends on organs
and tissues involved into the pathologic process. The groups of drugs
which are used in this stage are broncholytics, drugs which stop vessels
spasm, mucolytics, and etc.

Corticosteroids
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In normal condition cortisone and corticosterone are produced in

cortex of adrenal glands. They induce several effects in allergic reaction:
 Suppression of Ig production;
 Stabilization of cells’ membranes;
 Suppression of mediators' action.
Effects of corticosteroids:
1. Suppression of local inflammatory reaction (exudation, edema,
proliferation, decreasing of capillary permeability);
2. Lymphocytes proliferation depression;
3. Decreasing of α-adrenergic and cholinergic receptors
stimulation;
4. Increasing of cyclic adenosine monophosphate, that reflects in
the different effects;
5. Increasing of β-adrenergic receptors activity (no misbalance
among different receptors);
6. Depression of synthesis and excretion of mediators (histamine,
chemotaxic factor, thrombocytes activation factor);
7. Lymphopenia;
8. Lymphocytes redistribution into the bone marrow and tissues.
This results in suppression of lymphocytes’ effector reaction;
9. Acceleration of Ig metabolism.
Classification of corticosteroids according to the ways of use:
1. Topical:
 For external application – ointments (Celestoderm, Advantan,
Ftorocort, etc.)
 Eye drops (Hydrocortizon, Prednisolon, dexamethason),
 Nasal preparations (Nasobec, Nasonex, Flixonase, etc.)
 Inhalation (Beclason, Pulmicort, Flixotide, etc.) and Inhalation
combined (Symbicort, Seretide, etc.)
2. Systemic:
 Oral (Prednisolon, dexamethason, etc.),
 Parenteral (Hidrocortizon, Prednisolon, dexamethason, etc.).

Topical corticosteroids are used for treatment of symptoms in a

target organ.
Advantages of local corticosteroids using:
• high level of safety,
• low level of systemic bioaccess,
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• low frequency of complications,

• high effectiveness (high affinity with receptors),
• high local antiinflammatory action.
Corticosteroids in the form of injections are used in a severe
emergent state of allergic diseases.
Indications for the parenteral corticosteroids usage:
1) Absolute
d) anaphylactic shock
e) asthmatic status
f) severe toxic-allergic reactions
2) Relative
a) severe relapsing allergic diseases and bronchial asthma
b) dermatitis, serum sickness, urticaria and angioedema.
Oral corticosteroids are potent at resolving and preventing most
allergic disease. Unfortunately, the usefulness of chronic systemic
corticosteroid use is limited by the potentially devastating side effects of
these agents, which include weight gain, abnormal fat deposition,
adrenal suppression, cataracts, type 2 diabetes mellitus, and
osteoporosis. Oral corticosteroids are prescribed only for short bursts
and do not require tapering off, because therapy for less than 2 weeks is
not associated with adrenal suppression. Longer courses are reserved for
patients whose condition has been refractory to all other standard
therapies.

Membranostabilizers
They may aid in the phosphorylation of protein that terminates
secretion of mast cell granules; they may increase calcium influx into the
cell preventing membrane changes; and/or they may reduce membrane
fluidity prior to mast cell degranulation. The final result is decreasing of
mast cells degranulation, which prevents release of histamine and other
factors that are present in the preformed and newly formed state. Note
that mast cell stabilizers do not relieve existing symptoms and are to be
used on prophylactic basis to prevent mast cell degranulation with
subsequent exposure to the allergen. Therefore, they need to be used for
a long period of time in conjunction with various other classes of
medications.
These drugs are:
 Sodium cromolyn (disodium cromoglycate, sodium
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cromoglicate)
 Sodium nedocromil (tilade)
 Ketotifenum (zaditen, histaten)
They can be used orally, intranasal, in inhalations, in drops.
Maximum of action – after 2 hours.
Length of effect – 6-8 hours.
Contraindications: pregnancy, liver pathology.
Advantage of membranostabilizers is high profile of safety.
Disadvantages can be listed as:
1. Are less effective in comparison with antihistamine preparations,
2. Considerably concede in efficiency to topical corticosteroids,
3. Possess a slow beginning of action,
4. Have a short-term action (are used 4-6 times a day).

ANTIHISTAMINIC DRUGS

In treatment of allergic diseases antihistamine preparations

blockers Н1 of histaminic receptors are traditionally used, for the first
time they were synthesized in 1937. Antihistaminic drugs do not prevent
basophiles degranulation. They have a structure similar to histamine
structure and so they compete with histamine and block H1-receptors.
Exerted during allergic reactions histamine can’t interact with sufficient
quantity of H1-receptors and as a result the histamine effect is not so
significant or is absent at all.
There are 2 generations of antihistaminic drugs.
Antihistaminic drugs of the first generation
 dimedrolum (diphenylhydramine hydrochloride)
 suprastin (chloropyramine)
 diprazinum (promethazine hydrochloride)
 tavegil (clemastine)
 diazolinum (mebhydrolini napadisylas)
 phencarolum (quifenadine)
 dimethindene (fenistil)
Pharmacological effects of antihistamine of the Ist generation
1) Block of histamine effects;
2) Central cholinolytic effects (sedative and soporific);
3) Anticholinergic effect (suppression of endogenous secretion and
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increase in mucus viscosity);

4) Local anesthetic and spasmolytic effects;
5) Intensification of catecholamine effects and central nervous
system depressants (analgetic drugs);
6) Excretion of histamine from mast cells in pseudoallergic
reaction.
Antihistamines of the Ist generation have several peculiarities:
1) Short duration of their effects;
2) No complete interaction with H1-receptors (30 per cent);
3) These drugs can pass through haemotoencephalitic barrier;
4) Tachyphylaxis (getting used to this drugs within 7-12 days, this
leads to decrease in their effectiveness);
5) Stimulation of appetite;
6) Potention of sedative effect in combination with alcohol and
central nervous system depressant.
These peculiarities of classic antihistamines lead to the different
side-effects of antihistaminic drugs:
1. CNS: 4. Urinary tract:
 sedative action;  dysuria;
 soporic action;  poluria;
 nystagmus; 5. Skin and mucosa:
 toxic neuritis;  xeroderma;
 areflexia;  xeromycteria;
 xerostomia;
2. Cardiovascular system (CVS):  obstruction (because the
 hypoxia; mucus viscosity is increased);
 hypotension; 6. Blood:
 tachycardia;  agranulocytosis;
3. Gastrointestinial tract (GIT):  leucopenia;
 vomiting;  hemolytic anemia;
 nausea;
 constipation;

Antihistaminic drugs of the second generation

 Loratadine (Claritin)
 Cetirizine (Zyrtec)
 Dezloratadine (Erius)
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 Fexophenadine (Telfast).
 Levocetirizine (Xisal)
 Ebastine (Kestine)
 Levocabastine (Gistimet)
 Azelastine (Allergodil)
 Acrivastine (Semprex)
The peculiarities of H1-blockators of the IInd generation are:
1) high affinity to H1-receptors;
2) their effects begin quickly;
3) long period of action (12-24 hours);
4) absence of other receptors blockage;
5) they do not pass through the haematoencephalic barrier, so they
do not have sedative effects;
6) absence of dependent on food taking;
7) absence of tachyphylaxis during long period of usage;
8) possibility to use these drugs alongside with central nervous
system depressant.
The advantages of the IInd generation drugs over the Ist generation
drugs are explained by several peculiarities of their action:
1) absence of sedative effects (it’s possible to use these drugs by
those people who need good attention during working time);
2) absence of influence on cardiovascular system, urinary tract,
gastro-intestinal tract, mucosa, etc.;
3) they are taken once a day, independently on food taking;
4) possibility of usage during a long period, without side effects.
Mainly antihistaminic activity has no H1-blockators of the II nd
generation, but their metabolites. This fact explains the variable
effectiveness of these drugs in different patients which may be
connected with individual metabolism of these drugs. In case of
significant metabolism disorder in a patient's organism there may be
high concentration of drug which results in arising of side-effect: cardio
toxic (heart repolarization inhibition, blocking potassic canals and
increasing of interval QT). This can lead to the heart rhythm disturbance,
tachycardia and sudden death. The use of some antihistamines, such as
terfenadine (bronal), astemizole (hismanal) is stopped.
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Also, H1-blockators of the IInd generation, which are active

metabolites (Dezloratadine, Fexophenadine) can be used in clinical
practice. They have less side effects.
Antileukotriene drugs
Leukotriene antagonists (either receptor antagonists or 5-
lipoxygenase inhibitors) also have anti-inflammatory properties.
Leukotrienes are found at sites of allergic inflammation. Although
corticosteroids affect many other inflammatory pathways, they do not
seem to have clinically significant impact on the generation and release
of leukotrienes. These molecules are capable of inducing further
inflammation by causing the release of additional mediators, as well as
the recruitment of inflammatory cells to sites of allergic disease.
4 classes of antileukotriene preparations have been synthesized
lately:
1. Direct inhibitors of 5-lipoxygenase (zileuton).
2. Inhibitors of the activating protein warning linkage of protein
with arachidonic acid.
3. Antagonists of cysteic (С4, D4, Е4) leukotrienes’ receptors
(Montelukast (Singular), Zafirlukast (Acolate), Pranlukast, etc.).
4. Antagonists of В4 leukotrienes’ receptors.
Therapeutic effects of zileuton, montelukast, zafirlukast are most
studied.
Main indication – bronchial asthma. The use of these drugs in
treatment of chronic urticaria, atopic dermatitis, and allergic rhinitis is
discussed as well.
Antimediator drugs
1) Antiserotonine drugs are:
 Cyproheptadin hydrochlorid (cyproheptadine, peritol)
 Quifenadine (pfencarolum)
 Sequifenadine hydrochloride (bicarphenum)
2) Antibradikinin drugs are:
 Pyridinolcarbat (parmidinum)
 Tribenozide (glyvenol)
3) Anti enzyme drugs are:
 Contrycal (trasylol, tsalol)
 Gordox
 Acidum aminocapronicum (aminocapronic acid)
4) Inhibitors of kallikrein system:
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 Acidum aminocapronicum (aminocapronic acid)

 Heparinum
4) Inhibtors of complement system components:
 Acidum aminocapronicum (aminocapronic acid)
 Androgenic hormones
 Anabolic hormones
 Heparinum
Allergen specific immunotherapy (ASIT)
The method of allergen specific immunotherapy (or allergen
specific hyposensibilization) is treatment based on introducing to the
patient’s organism the sensitizing allergen in the increasing doses.
Mechanism of ASIT is the re-organizing of the immune response
character to the allergen, the main of which is synthesis of class Ig G
“blocking” antibodies. This Ig G doesn’t sensitize the tissues, but has the
allergen-binding activity and thus reduces the interaction between
allergen and Ig E fixed on target cells. After ASIT there is decrease of
must cells quantity, decrease of inflammatory cells (eosinophiles,
neutrophiles) quantity, releasing of mediators from target cells (mast
cells and basophiles) in their stimulation by the allergen is suppressed.
Also, ASIT influences to lymphoid cells – displacement of their profile
from Th2 lymphocytes to Th1 lymphocytes goes on.
So, ASIT has the therapeutic action on all stages of the allergic
process, it results in immune response shifting from Th2 to Th1 type,
suppressing both at the early and late phases of the Ig E – mediated
allergic reaction, suppression of allergic inflammation cells activity and
nonspecific tissue hyper reactivity.
Indications for ASIT are:
 the impossibility to prevent the contact with allergen (e.g., house
dust, pollen);
 the main mechanism of the disease development is allergic hyper
sensitization;
 there are no complications of the disease.
Contraindications for ASIT are:
 severe immunopathologic conditions and immunodeficiency;
 oncological diseases;
 severe psychological disorders;
 treatment by β-blockers;
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 severe form of bronchial asthma;

 cardio-vascular system diseases;
 children under 5 years old;
 a patient has contraindications to introduction of Epinephrin.
Pregnancy is not contraindicated for ASIT but, in general,
treatment is not carried out during the whole period of gestation.
Methods of ASIT are:
- general parenteral method is characterized by subcutaneous
injection of allergen in the increasing doses;
- oral method. Allergen is given in the form of drops, or in
capsules, or in tablets;
- sublingual method. The allergen is given sublingually within 1 –
2 minutes;
- intranasal method. Solution or powder of the allergen is
introduced into the nasal cavity;
- endobronchial method. By means of a special inhalator soluble or
powdered allergen is given into bronchi of a patient.
Complications of ASIT. During ASIT course there is development
of possible local and systemic reactions.
Local reactions arise in the place of the allergen introduction and
are characterized by hyperemia, itching, and local edema. These
reactions usually occur within the first 30 minutes after the injection has
been made but it is possible to observe these reactions later. In case of
local reaction the dose of allergen for the next injection should be
decreased.
Systemic reactions develop in the place of injection during several
minutes after the allergen injection has been made, more rare in 30
minutes. They are: headache, joints pain, discomfort feeling, light signs
of rhinitis and bronchial asthma, urticaria, Quinke’s edema, and
anaphylactic shock. In case of systemic reactions drugs administration
and changes in the ASIT program are needed. In development of serious
systemic reactions (anaphylactic shock), continuation of ASIT is
contraindicative.
Nonspecific hyposensibilization
In impossibility of carrying out ASIT or polyvalent sensitization
(hyper sensitization to many allergens), and also for treatment of pseudo
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allergic diseases bound to increased production of histamine the

nonspecific hyposensitisation can be used.
Histaglobulinum, Allergoglobulin can be injected.
Mechanisms:
– induce the production of antihistaminic antibodies,
– increase the inactivation of free histamine in blood.
Side-effects:
• hyperemia,
• local edema,
• headache.
Contraindications:
 fever,
 corticosteroids usage,
 allergic reactions to serum in anamnesis.

Questions for self-control:

1. Name the main approaches of allergic disease treatment.
2. What does the pathogenetic treatment of allergic diseases
include?
3. Characterize membrane stabilizers.
4. Name the classification of antihistaminic drugs.
5. Characterize mechanism of antihistaminic drug action.
6. What are the advantages of the 2nd generation of antihistaminic
drugs?
7. Name the antileukotrienes drugs.
8. Name the indications and possible complications of allergen
specific therapy.
9. Name the mechanisms of the allergen specific therapy action.
10. Characterize nonspecific hyposensitisation.

ANAPHYLACTIC SHOCK

Anaphylactic shock (AS) is acute generalized allergic reaction in

sensibilizated organism which depends on the production of IgE, and
arise on the repeated exposure of the allergen and is characterized by
decrease of blood pressure, body temperature, the CNS disorder,
increase of the vessel permeability, and the smooth muscles spasm.
Anaphylactic shock one of the most serious implications of allergic
reactions is condition menacing to life.
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AS can develop owing to introduction of drugs into organism,

diagnostic preparations (X-ray contrast agents, allergic tests or ASIT),
after the sting of different insects – hymenoptera sting (bee, wasp,
hornet, fire ant), snake venom and also because of the food allergens
(shellfish, egg albumin, nuts), but seldom. In recent time shock reactions
have been marked due to some chemical substances which can penetrate
into the organism through the skin, respiratory tract or as admixture of
drugs and food.
The list of drugs and substances that can cause anaphylactic shock
is virtually endless. The most important drugs are penicillin and its
derivates, cephalosporins, aminoglycosides, nitrofurantoin, para-amino
salicylic acid, sulfa drugs, salicylates and NSAD, anesthetic, vitamins,
trypsin, heterologous antisera, vaccines and others.
The period of time between exposure to the inciting agent and
onset of symptoms can vary from minutes to hours, although the
majority of reactions occur within 1 hour. This interval depends on the
sensitivity of a patient and the route, quantity, and rate of antigen
administration. Although uncommon, biphasic reaction is experienced
by some patients, when symptoms may recur several hours after the
initial reaction.
AS develops according to immediate type of allergic reaction.
Three stages are distinguished in the development of shock:
immunological, pathochemical, and pathophysiologic.
In period of sensibilization B cells secrete IgE. The period of half-
life of free immunoglobulin E 2-3 days, but its most part contacts with
mast cells where it can be for a long time. Also memory cells are
formed. As a result of repeated penetration allergen interacts with Ig Е
fixed on mast cells which result in activation of cells, degranulation of
their membrane and releasing of mediators.
The main role in the shock development belongs to histamine,
acetylcholine, heparine, slow-reacting substance of anaphylaxis
(eicosanoids – PG, LT), and others. The effect of these mediators
manifests in the form of increase in the vessels’ permeability, spasm of
the smooth muscles, disorder of microcirculation and hemodynamic, and
also increase in mucus secretion.
Shock-organs are skin, bronchi, intestine, uterus, CNS, and
cardiovascular system. Clinical picture of AS is characterized by sudden
onset.
Prevalent symptoms include:
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 skin manifestations: diffuse rapidly spreading hives and itching

on any part of the body; sensation of warmth, and rapidly increasing
swelling of the eyelids, lips, face and tongue;
 respiratory manifestations: tightness in the chest, wheezing,
coughing, or rales;
 cardiac manifestations: deepening hypotension, and dizziness
and/or syncope;
 nausea, vomiting or diarrhea;
 difficulty in breathing or swallowing;
 throat tightness or closure;
 panic or sense of doom;
 fainting or loss of consciousness.
The signs and symptoms of anaphylaxis vary both in the spectrum
of system involvement and severity. Reactions may be limited to the
skin, as in mild wheal reaction, or catastrophically involve multiple
systems, leading to shock and death.
In general, systemic reactions include cutaneous involvement such
as pruritis, flushing, erythema, urticaria, and, in more severe cases,
angioedema. Mucous membrane involvement may be limited to pruritis
and congestion of the eyes, nose, and mouth. Swelling of the lips or
tongue can potentially impair swallowing and breathing.
Immediate life-threatening feature of anaphylaxis is obstruction of
upper airways that results from edema of the larynx, epiglottis, and other
surrounding structures. This may be experienced as subtle discomfort in
the throat or as obvious stridor and respiratory distress. Anaphylaxis also
can cause disease of lower airways secondary to bronchospasm. This
leads to symptoms similar to acute asthma such as sense of chest
tightness, cough, dyspnea, wheezing, and retractions. Another potential
life-threatening feature of anaphylaxis is cardiovascular collapse and
hypotonic shock.
Arrhythmias and electrocardiographic evidence of myocardial
ischemia also may be seen.
The central nervous system involvement can include dizziness,
syncope, seizures, and altered level of consciousness.
The gastro-intestinal symptoms are relatively common and include
nausea, vomiting, diarrhea, and sharp abdominal pain.
There are light, middle and severe forms of shock. Sometimes
there is fulminant form of shock, at which prognosis the least favorable.
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A light form is characterized by prodromic period which lasts from

a few minutes till one hour. There can be different symptoms such as
urticaria, erytematous eruption, papular eruption, skin hyperemia,
pruritus, sense of heat, cough, retrosternal pain, pain in the abdomen,
dyspnea, and etc. Examination of the patient shows pallor of the face
skin, cyanosis of lips, excitation or flaccidity, sopor, and seldom – loss
of consciousness. Also there can be bronchospasm, pain in the abdomen,
vomiting, tachycardia, filiform pulse. Arterial pressure is sharply
decreased to 80/40 or 60/20 mm Hg.
A middle form of AS also can manifest in the same prodromic
symptoms as in the light form, but loss of consciousness develops more
quickly, pressure decreases sharply, or is not determined at all, pulse is
small rather, arrhythmic, tachycardia can be changed by bradycardia.
There are dull cardiac sounds. One can observe pale skin, Hippocratic
facies, acrocyanosis, cold clammy sweat. There may be observed
enuresis, involuntary defecation, metrorrhagia, nasal bleeding.
A severe form of AS is characterized by disorders of CNS,
cardiovascular, respiratory systems, which are developed from a few
seconds till a few minutes. If emergency medical aid is not rendered,
patient can die.
In a fulminant form the prodromal stage lasts less that 1-2 minutes
or is absent, the BP is not defined. The most frequent causes of death are
vascular insufficiency, hypoxia, and asphyxia owing to bronchospasm or
larynx edema.
There are the following clinical forms of AS: classic (typical),
hemodynamic, asphyxial, abdominal, cerebral.
Typical AS is characterized by arterial hypotension, disorder of
consciousness, pulmonary insufficiency, skin syndrome, convulsions.
In hemodynamic variant of AS disorder of cardiovascular system is
mainly observed. During asphyxial type of AS acute respiratory
insufficiency is connected with bronchospasm, edema of lungs. Cerebral
form is characterized by excitation, loss of consciousness, acute brain
swelling, epileptic fits. There are pains in abdomen, vomiting, rectal
tenesmus in abdominal variant of AS. The clinical picture of acute
abdomen is discovered.
AS can give relapses, which are developed in 1 – 2 days, especially
when prolonged drugs are used. Duration of complications depends on
clinical picture of shock and can retain from 2 till 4 weeks. Clinical
picture of complications is various. There is allergic myocarditis, acute
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nephritis, toxicoallergic hepatitis, persistent hypertension, arachnoiditis,

polyneuritis, hemolytic anemia, agranulocytosis, and thrombocytopenia.
Laboratory studies:
Specific, accessible to use in wide practice laboratory methods are
absent. The evidence of mast cells activation is the high concentration of
histamine and tryptase.
Histamine level in blood reaches maximum in 10-15 minutes and
comes back to initial level in 30-60 minutes. As histamine in urine exists
for a very short time, it is not suitable for diagnostics. Determination of
methyl histamine (histamine’s metabolite) which remains in urine within
24 hours can be used.
Tryptase level in blood during the development of allergic reaction
reaches its peak in 1-2 hours after occurrence of the first symptoms. Its
raised concentration can be determined, as a rule, within 12 hours. Thus,
the more severe reactions are characterized by the above tryptase level.
Because tryptase level can raise at any hypereosinophilic syndromes, the
tryptase maintenance in blood can be only distinctive criterion of
anaphylactic shock from the similar conditions accompanied by
hemodynamic disturbances (cardiogenic shock, syncope, etc.).
Therapy of AS includes complex of urgent measures, such as:
1. Liquidation disorders of hemodynamic and breath;
2. Compensation of adrenocortical insufficiency;
3. Neutralization of allergic reaction mediators;
4. Allergen elimination;
5. Therapy of clinical symptoms.
Since laryngeal edema and vascular collapse are the preeminently
most dangerous manifestations, they require the most urgent attention.
Maintenance of the airway and oxygenation. 100% oxygen is
administered. If there is complete airway obstruction, immediate
endotracheal intubation should be attempted. If intubation is
unsuccessful, cricotracheotomy is indicated.
Simultaneously Epinephrine is administered. Epinephrine is the
first-line drug for anaphylaxis. Epinephrine can be given subcutaneously
in the patient with reasonable perfusion (epinephrine 1:1000, 0.01 ml/kg
to a maximum of 0.5 ml). If the patient is hypotensive or hypoperfused
or the initial subcutaneous dose is ineffective, then epinephrine is
administered intravenously or through intraosseus needle as 1:10,000
solution (10 μg/kg over 1 – 2 minutes). This should be followed by a
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continuous infusion of 0.1 μg/min, which can be titrated to effect up to

maximum of 1.0 μg/kg/min.
Bronchospasm should be treated aggressively with supplemental
oxygen, β2-agonists such as albuterol or epinephrine, and
corticosteroids.
Maintenance of the circulation. Hypotensive patients should be
placed in the Trendelenburg position, and rapid bolus of 20 ml/kg of
crystalloid solution should be administered immediately and repeated as
necessary. Since plasma volume may fall precipitously by 20 to 40%,
large amounts of fluid may be necessary. If hypotension persists,
continuous infusion of epinephrine should be started as previously
described.
Corticosteroids do not have effect during the initial resuscitative
phase of anaphylaxis. In significant reactions, however, their early
administration may block or reduce the late-phase reactions over the
next several hours or days. They can be administered as
methylprednisolone (1 – 2 mg/kg I/V) or prednisone (2 – 5 mg/kg I/V; 1
– 2 mg/kg orally).
If appropriate, venous tourniquet above the injection site of the
offending agent and local infiltration of epinephrine 1:1000 (0.005 ml/
kg) may decrease further absorption.
Antihistamines can be used only after stabilization of arterial
pressure and under the BP control. Preparations are not applied to
shock emergent therapy. Diphenhydramine, chloropyramine (1 – 2 ml
I/M or I/V) are indicated.
Disposition. Patients with severe reactions that involve upper
airway obstruction or shock generally should be admitted and observed
for 24 hours. Children with history of asthma appear to be at increased
risk for the delayed and severe reactions and also should be admitted and
observed. Patients with less severe manifestations can be discharged
home with the course of antihistamines and, in specific cases,
corticosteroids. As a rule, therapy initiated in the emergency department
should be continued for a minimum of 48 hours. Follow-up with the
child’s primary care physician is also advised.
Prevention and management procedures:
When a patient who is subjected to extreme allergic reactions is
identified by the parent, the principal will coordinate the development of
procedures to enhance the safety of the patient. The following elements
will be addressed in the plan. A prevention plan to minimize the
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patient’s exposure to the triggering material, appropriate to the maturity

and reliability of the patient and the severity of the problem, should be
developed.
Prevention measures may include:
 self-supervision;
 education programs for patients;
 minimizing the presence of triggering material.

IgE - independent emission (straight line) of mediators

Earlier this variant was classified as anaphylactoid reaction which
develops, unlike anaphylaxis, on non immune mechanisms. Nowadays
the term «anaphylactoid reaction» is not used widely since clinically
anaphylactic and anaphylactoid reaction is indiscernible, and treatment
identical at both forms.
Degranulation of mast cells occurs without participation of IgE.
Preliminary formation of individual sensitivity at the first contact is not
present. And, hence, the shock can already develop at the first
introduction of a medicine or substance.
Non IgE-mediated mast cell and basophil degranulation can occur
from variety of substances. Although the mechanisms are different, the
clinical manifestations can appear the same. Causes can include
radiocontrast dye, opiates, vancomycin (e.g., red man syndrome), and
etc.
Patients can be pretreated with glucocorticosteroids and both H1
and H2 antihistamines prior to exposure to iodinated radiocontrast dye.
This, together with the use of low-osmolar nonionic dye, reduces the
risk of repeat reaction to approximately 1%.
Aspirin and non steroid anti-inflammatory drugs (NSAD) can also
cause reactions by causing release of leukotrienes via the 5-lipoxygenase
pathway of arachidonic acid metabolism. Patients susceptible to this
syndrome can develop acute asthma exacerbation, nasal congestion,
urticaria, or angioedema after ingestion. However, note that in rare
cases, patients can have what are thought to be true IgE-mediated
anaphylactic reactions to specific NSAD. In these cases, no cross-
reactivity occurs with other NSADs.

Questions for self-control:

1. Give the definition of anaphylactic shock.
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2. Name the etiologic factors of the anaphylactic shock.

3. What reactions are anaphylactoid? Name the similarity and
difference between anaphylactic and anaphylactoid shock.
4. Name the clinical forms of anaphylactic shock and their
features.
5. Name the main diagnostic criteria of anaphylactic shock.
6. Name the stages of anaphylactic shock emergent treatment.
7. Name the prevention procedures for anaphylactic shock.

SERUM SICKNESS

Serum sickness occurs after using of foreign proteins (often

heterologous serum) or anatoxins, vaccines and human
immunoglobulins for treatment or prophylaxis.
Pseudoserum reactions (clinically similar to serum sickness)
develop on the different haptens and more often on the introduction of
drugs such as penicillin, sulfa drugs, and others.
Causes of serum sickness may include the following:
 Heterologous serum used in the prophylaxis and/or treatment of
botulism, diphtheria, gas gangrene, organ transplant rejection, and snake
and spider bites
 Allergen extracts
 Blood products
 Hormones
 Hymenoptera venom
 Infectious agents
 Vaccines
Drugs that have been implicated in the development of serum
sickness-like reactions include the following: allopurinol (Zyloprim),
arsenicals and mercurial derivatives, barbiturates, captopril (Capoten),
cephalosporins, furazolidone (Furoxone), gold salts, griseofulvin
(Fulvicin, Grifulvin), halothane, hydralazine (Apresoline), iodides,
methyldopa, para-aminosalicylic acid, penicillamine, penicillins,
phenytoin (Dilantin), piperazine, procainamide (Procan SR, Procanbid,
Pronestyl-SR), quinidine (Quinaglute, Quinalan, Quinidex, Quinora),
streptokinase (Streptase, Kabikinase), sulfonamides, and thiouracils.
Not all the substances that are recognized as foreign ones by the
immune system elicit immune response. The antigen must be of
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characteristic size or have specific antigenic determinants and

physiological properties to be effective stimulator of the immune
system. After appropriate antigen has been introduced, individual's
immune system responds by synthesizing antibodies class Ig M and Ig G
after 4-10 days. It is 3rd (immune complex) type hypersensitivity.
The antibody reacts with the antigen, forming soluble circulating
immune complexes that may diffuse into the vascular walls, where they
may initiate fixation and activation of complement. Complement-
containing immune
complexes generate entering
of polymorphonuclear
leukocytes into the vessel
wall, where proteolytic
enzymes that can mediate
tissue damage are released.
Immune complex deposition
and the subsequent
inflammatory reactions are
responsible for the
widespread vasculitic
lesions seen in serum
sickness (Fig. 7).

Fig. 7. Scheme of
serum sickness
pathogenesis.

Primary serum sickness occurs 6-21 days after the administration

of the inciting antigen. The onset may be more rapid with subsequent
exposures to the same antigen, with symptoms occurring 1-4 days after
exposure.
There are two clinical forms of serum sickness: anaphylactic and
typical (classic). The course of serum sickness may be acute or chronic.
Anaphylactic form of serum sickness develops in the organism
which has previous sensitization, during reintroduction of the serum and
is characterized by hyperergic reaction like anaphylactic shock.
The classic form of serum sickness is characterized by multiform
symptoms. The classic clinical manifestations (prodromal period)
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consist of subfebrile fever, arthralgia, regional lymphadenopathy. Pain,

pruritus, and erythematous swelling at the injection site usually precede
the onset of disease. Patients also may report joint and muscle aches,
chest pain, and difficulty in breathing.
Physical examination in the peak of disease may reveal spread of
skin symptoms; fever; generalized lymphadenopathy; arthritis or
arthralgia; edema; and renal, cardiovascular, neurologic, or pulmonary
manifestations.
 Skin symptoms (95%) may include the following:
o Urticaria
o Scarlet fever-like rash
o Maculopapular or purpuric lesions
o Erythema multiforme
 Fever is invariably present and may precede rash in 10-20% of
cases;
 Lymphadenopathy (10-20%) may be generalized or may involve
tenderness in the nodes that drain the injection site; splenomegaly may
occur;
 Arthritis or arthralgia (10-50%) usually affects multiple large
joints, but occasionally, small joints and joints of spine and
temporomandibular joint may be inflamed. Myalgia or myositis also
may occur;
 Edema may arise, particularly about the face and neck;
 Renal manifestations include proteinuria, microscopic hematuria,
and oliguria;
 Cardiovascular findings may include myocardial and pericardial
inflammation. Generalized vasculitis occurs rarely;
 Neurologic manifestations include peripheral neuropathy,
brachial plexus neuritis, optic neuritis, cranial nerve palsies, Guillain-
Barré syndrome, and encephalomyelitis.
 Pulmonary manifestations, such as pleurisy, are rare. However,
dyspnea and cyanosis are not uncommon.
Laboratory studies:
 Although laboratory studies are not helpful in establishing
diagnosis, certain laboratory findings have been reported;
 Complement levels vary;
 CBC and differential tests may reveal leukocytosis or leukopenia
with or without eosinophilia;
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 The erythrocyte sedimentation rate usually is slightly elevated;

 Serum protein electrophoresis may reveal hyper gamma-
globulinemia with free circulating light chains;
 Urinalysis may reveal proteinuria and/or hematuria.

Treatment. The goal of therapy is to treat the clinical syndrome

resulting from the effects of soluble circulating immune complexes that
form under conditions of antigen excess.
Removing of antibodies, antigens, mediators, and circulating
immune complexes – plasmaferresis, haemosorbtion, immunosorbtion,
entersorbtion are used.
Antipyretics Bed rest and mild analgesic-antipyretic therapy are
often helpful in relieving fever, arthralgia, and myalgia associated with
the syndrome.
Corticosteroids These agents have both anti-inflammatory
(glucocorticoid) and salt-retaining (mineralocorticoid) properties and
cause profound and varied metabolic effects.
Antihistamines These agents are used for symptomatic treatment of
pruritus. Antihistamines may decrease the incidence of serum sickness
by negating the action of vasoactive amines and preventing the increased
vascular permeability that they induce.
Complications of serum sickness:
 Vasculitis
 Neuropathy
 Glomerulonephritis (rare)
 Anaphylaxis
 Shock
 Death
Prognosis: Most cases are mild and resolve within a few days.
However, subjective complaints and objective findings may persist for
several weeks.
Prevention: Avoidance of the offending agent is the best way to
prevent serum sickness. However, in some circumstances, avoidance is
not possible.
Skin tests are indicated before antiserum administration,
particularly in patients with history of allergy to horse dander or in those
who have previously received the material. Skin tests reveal the presence
of immunoglobulin E antibodies and, thus, help to identify individuals at
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risk of anaphylaxis. However, these tests are not reliable in the

identification of individuals with increased risk for serum sickness.
If rapid administration of antiserum is necessary, establish
intravenous access in each arm (one access for the infusion of antiserum
and the other for the treatment of complications) and premedicate the
patient with 50-100 mg of diphenhydramine (Benadryl) or 60-90 mg of
prednisolone. If reaction occurs, temporarily discontinue the infusion,
and administer epinephrine and other necessary medications. Once the
adverse reaction is halted, resume slow infusion.

Questions for self-control:

1. Give the definition of serum sickness.
2. Name the etiologic reasons of the serum sickness development.
3. Characterize the serum sickness pathogenesis.
4. Name the clinical signs of the serum sickness.
5. Name the main diagnostic clinical criteria of serum sickness.
6. Name the main treatment principles of the serum sickness.
7. Name the prevention procedures for serum sickness.

URTICARIA AND ANGIOEDEMA

Urticaria is disease the main characteristics of which are rapidly

appearing and more or less disseminated wheals and edema of the
papillary layer of the skin.
As a rule urticaria is associated with angioedema because it has
similar mechanisms of development. (Obsolete term is Quinke’s edema
nowadays the term angioedema is used). So angioedema is considered to
be one of the urticaria (giant hives), but it involves the deeper layers of
the skin and the subcutaneous tissue. Sometimes the process may occur
at the mucosa of the respiratory and gastrointestinal tract.
Urticaria and angioedema are at the second place among allergic
diseases after asthma. Urticaria and angioedema occur in all groups, but
chronic urticaria and/or angioedema are more common in middle age
(from 20 to 60 years) especially in women. That can be explained by
dyshormonal disorders.

Classification of urticaria and angioedema

is based on the etiology and pathogenic mechanisms
1. Immune form
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 Allergic
 Autoimmune
 Complement-dependent
2. Non-immune form

Immune form
Drug urticaria and angioedema. Almost all drugs are able to cause
allergic reactions. Penicillins, aspirin, cephalosporins, analgesics and
others are known to be the most frequent on this way. Besides, tartrazine
yellow due, which is used as coloring agent in some medicines also may
cause urticaria as well as allergy.
Food urticaria. Many cases of acute urticaria or angioedema are
caused by food allergy. Fish, seafood, eggs, nuts, tomatoes, chocolate,
citruses are among the most frequent offenders.
Inhalants. Urticaria and angioedema can be caused by inhaled
allergens. Thus, the inhalants may be epidermal (animals’ dandruff, e.g.
as cats or dogs, horses).
Pollen (the cases of seasonal urticaria, associated with hay fever).
Insect urticaria is caused by stings of different insects.
Infectious urticaria. Sometimes urticaria is associated with virus,
parasitic, pyogenic infection, cutaneous fungus.
Autoimmune form, it includes secondary urticaria or angioedema,
associated with systemic diseases of connective tissue, neoplasms.
Urticaria, associated with helminth invasion.
Non-immune form which is caused by different factors
(histaminergic, holinergic, as the result of complement activation,
kinines’ cumulating, disorders in arachidonic acid metabolism, C1-
inhibitor insufficiency):
Drugs. Among medicines the most common offenders are iodine-
containing drugs, radio-contrast substances, dextranes and others.
Food. Among food are eggs, frozen fish, strawberry, citruses,
bananas, which contain high concentration of histamine, serotonine and
other biologic active substances.
Physical agents. There can be:
o cold urticaria
o heat urticaria
o solar urticaria
o aquagenic urticaria (after contact with water)
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o cholinergic urticaria, attacks of which are caused by fever, a hot

bath, emotional stress and almost always attributed to disorders of
thermoregulation.
Internal factors:
- enzymopathic disorders
- dyshormonal disorders (climacteric)
- disorders of GIT functioning (liver diseases, gastritis, disorders
of digestion and absorption, etc.)
Urticaria and angioedema are differentiated at acute course that
lasts 3-5 days, subacute course – 3-5 weeks, and the course that lasts
more than 6 weeks is a chronic form.
Pathogenesis.
Allergic reactions ensuring urticaria and angioedema mainly
develop as the first type of hypersensitivity (Ig E – dependent immediate
hypersensitivity or anaphylaxis). The pathophysiological stage of this
allergic reaction is characterized by the formation of mediators such as
histamine, serotonine, kinins, and arachidonic acid metabolites.
Histamine is the primary chemical mediator of urticaria. The mast cell is
central in all forms of urticaria. Histamine may be released directly from
cutaneous mast cells in response to certain allergens or medications.
Specific immunoglobin E (Ig E) antibodies bind to mast cell surfaces
that recognize certain antigens (e.g. penicillin, certain foods, insect
venom), causing the release of histamine after combining with antigen.
In infection, complement fragments (C3a, C5a) may activate mast cells
to release histamine. Eicosanoids may also induce mast cell mediator
release, and other cytokines have been implicated in urticaria. Papular
urticaria represents a delayed hypersensitivity reaction in which basophil
infiltrates can be found around dermal blood vessels. In physical
urticaria, in addition to histamine, neuropeptide and complement
products are also suspected as a cause of skin lesions.
The release of these mediators and their pharmacologic effects
result in the clinical symptoms of immediate type of allergic reaction. In
the case of urticaria and angioedema that is wheal-and-flare reactions,
pruritus, pathology of which is usually characterized by oedema in the
upper dermis or in subcutaneous tissue, vascular dilatation, increased
vascular permeability, perivascular infiltrate (which consists of
lymphocytes, eosinophiles, neutrophils).
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Non-immune (pseudoallergic) form of urticaria and angioedema

summarizes all types of hives caused by the same mediators but without
immunological mechanism.
The clinical picture of hives is characterized by circumscribed,
slightly elevated swellings that usually are multiplied and vary in size
from 1 or 2 mm to some centimetres in diameter (Fig. 8). They are
asymmetric, involve any area of the body, but the most common sites
are extremities, external genitalia, and face particularly the region of
eyes and lips. Rash is also accompanied with itch. Rash appears quickly
(in several minutes and hours) and completely disappears in 24 hours.
Urticarial vasculitis vice versa needs more time for development and
regresses longer and results in hyperpigmentation (Fig. 9).

Fig. 8. Wheal on the arm. Fig. 9. Urticarial vasculitis.

Since angioedema develops in the

subcutaneous tissues where there are fewer
sensory nerve endings these lesions present
clinically as diffuse swellings with a small or no
pruritus. They are usually developed in areas
with loose subcutaneous tissue such as eyelids
and lips (Fig. 10).

Fig. 10. Angioedema.

Complications: Anaphylaxis
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Determining whether urticaria is a part of anaphylactic reaction is

important. If anaphylactic reaction occurs, the patient needs prompt
treatment and careful monitoring.
The diagnosis of urticaria is not difficult because of typical clinical
manifestations, especially in cases of clear causative factors. However,
the secondary genesis of urticaria and angioedema to neoplasms,
helmints, and syphilis must be excluded in cases of recurrent episodes of
urticaria and angioedema during more than two weeks.
Laboratory Studies:
IgE antibody presence in radioallergosorbent test (RAST), ELISA:
Order if the history is suggestive of a rash caused by foods, drugs, insect
venom, or latex. This test may be needed to rule out an atopic
component and label the urticaria as idiopathic.
Thyroid profile; antithyroid microsomal antibodies and
antithyroglobulin antibody: Order if the patient has a strong family
history of thyroid disorder or symptoms of hypothyroidism (more
frequent in females). However, patients are often euthyroid.
C1 esterase inhibitor and C3, C4: Order if the patient has a family
history of angioedema or if the child had concomitant history of
swallowing or breathing problems with urticaria.
Stool for ova and parasites or/and specific antibodies against
parasites’ antigens in blood serum (ELISA, etc.): Order if the patient
reports ingestion of poorly cooked meats or travel in unsanitary areas.
Antinuclear antibody, urinalysis with microscopic examination:
Order if the patient may have arthritis, photosensitivity, or other signs or
symptoms of collagen vascular disease.
Complete blood cell count (CBC), C-reactive protein, erythrocyte
sedimentation rate: Order if the patient's history indicates underlying
vasculitis or inflammatory diseases.
Cold agglutinins and cryoproteins in patients with cold urticaria:
The presence of a cryoglobulin suggests chronic hepatitis or malignancy.
In patients with acute urticaria, laboratory testing is not usually
needed unless particular medical condition is suspected.
Provocative tests.
Physical urticaria can be confirmed with
physical challenge tests. These involve the
application of the suspected stimuli (heat,
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pressure, light, vibration, scratching, cold [ice cube]) to the skin (Fig.
11). Exercise testing can also be performed.

Fig. 11. Positive reaction to the cold test.

Suspected food allergies can be confirmed or disproved with the

use of food diaries. Food or symptom diary for fixed duration (e.g., 2-4
wk) may be helpful. Note all activities in which the patient was involved
for 6-8 hours prior to the onset of urticaria. Documented cases exist in
which food or activity (such as jogging) by itself results in no symptoms
but together (e.g., eating shrimp cocktail and then jogging) may result in
urticaria with or without progression to anaphylaxis.
Angioedema also should be differentiated from hereditary
(angioneurotic, or Quinke’s disease) angioedema.
C1-inhibitor insufficiency is the key for angioedema development.
Also, not only hereditary, but acquired secondary insufficiency of C1
inhibitor indices the pathology (e.g., liver and GIT diseases, malignant
tumors, some cases of autoimmune diseases (SLE).
The provocative factors for C1-inhibitor insufficient angioedema
are mechanical pressure (even sleep in state pose, long term static pose),
high physical trainings, psychological stress, medical procedures
(injections, gastroscopy), tooth extractions, operations, traumas (even
microtraumas). It is important to recognize this entity because of its
potentially serious prognosis.
The major features of hereditary angioedema are:
1. onset usually in childhood;
2. family history often positive;
3. slow progression (12 – 36 hours) and regression (1 – 3 days);
4. not associated with urticaria;
5. attacks of abdominal pain are common;
6. laryngeal oedema is common;
7. low levels of C1 and C4 complement system components;
8. antihistamines’ and corticosteroids’ usage has low effect;
9. responds to attenuated androgen and serotherapy.
Patients with C1-inhibitor insufficiency angioedema before
medical manipulations need the special preliminaries: fresh frozen
plasma infusions, ε-aminocapronic acid infusions or oral administration
(under the blood coagulation control).
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The course of this disease is genetically determined by the

deficiency of α2-glycoprotein that inhibits the activation of the first
component of complement.
Treatment. The preferable form of treatment for urticaria is
avoidance of the causative agents when those can be identified. Allergen
avoidance is an important strategy if the allergen can be identified.
Because drug-induced urticaria accounts for most acute urticaria in
children, drug use should be specifically reviewed in the history.
Removing offending ectoparasites can avoid papular urticaria. If the
allergen cannot be identified or avoided, most cases of urticaria will
respond to medications. If urticaria is caused by ingestion of a particular
food, hypo allergic diet can prevent future reactions.
The main drugs, which are used for treatment of urticaria and
angioedema are: antihistaminic drugs, membrane stabilisators,
enterosorbents. Hormones are administered only in severe cases. In the
cases of absence or minimal effect extracorporal methods are used, such
as hemosorbtion, plasmapheresis.
In emergency corticosteroids and antihistamines are administered
in infusions.
Prevention:
Allergen avoidance is an important strategy if the allergen can be
identified. Patients should avoid offending foods and drugs.
Removing offending ectoparasites can prevent papular urticaria.
Insect repellent may lessen the chance of bites or stings from
offending insects.
Recognition of the precipitating events for physical urticaria can
allow avoidance strategies.
Desensitization strategies are not recommended except for stinging
insect venoms.
Prognosis
Although the cause can be difficult to determine, in most cases,
lesions are expected to resolve in 1 month.
Extensive allergy workup is usually not indicated for children who
have had urticaria for fewer than 6 weeks.
Evaluation of chronic urticaria should be guided by history.
Papular urticaria should resolve after 6-12 months.
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Physical urticaria is more persistent and lasts 2-4 years in most

children. Some may experience it in the adult life.

Questions for self-control:

1. Give the definition of urticaria and Quinke’s oedema.
2. Name the forms of urticaria and its etiologic factors.
3. Characterize urticaria and angioedema pathogenesis.
4. Name the features of the non-immune forms of urticaria
and angioedema pathogenesis.
5. Name the main differential diagnostic clinical criteria of
the allergic and hereditary angioedema.
6. Name the main principles of urticaria and angioedema
treatment.

DRUG ALLERGY

Drug allergy is a significant problem in medical practice and can

happen while using any medicines. The diagnosis is made primarily
from the clinical history as there are few specific, accurate diagnostic
tests. If patient has drug allergy, alternative drugs should be used in the
future. However, if the particular drug is considered essential in
subsequent therapy, various techniques may allow its usage.
Not all adverse reactions to drugs are allergies. In fact, fewer than
10% of adverse drug reactions are allergic. Other causes of adverse
reactions are interactions between two or more drugs, inability to break
the drug down completely in the body (as occurs with liver or kidney
damage), overdose, and irritating side effects such as nausea, vomiting,
or diarrhea.
Adverse drug reactions are majority of iatrogenic illnesses – 1% to
15% of drug courses
 Non-immunologic (90-95%)
 Immunologic (5-10%)
Adverse reactions to drugs can be categorized as follows (Table 12):
1. Drug intolerance – thus extremely difficult to predict except in
persons with a prior history or a family history of intolerance to
that specific drug. Some drug intolerances are known to result
from genetic variants of drug metabolism.
2. Idiosyncratic drug reactions
3. Pseudoallergic drug reactions
 132

4. Immunologic drug reactions (drug allergy).

Non-immunologic reactions (usually are prognosed):
 side effects,
 toxic reactions,
 overdose,
 drug dependence,
 drug interactions,
 secondary or indirect effects (bacterial overgrowth)
Table 12. Adverse reactions to drugs.
Type Example
Drug intolerance Tinnitus after a single ASA tablet
Idiosyncrasy Glucose 6-phosphate deficiency: anemia
after antioxidant drugs
Pseudoallergic reactions opiate reactions, ASA/NSAID reactions
Immunologic reactions Anaphylaxis from beta-lactam antibiotics

Drugs alone are poor stimulators of immune responses due to their

simple structure and low molecular weight. Drugs can fulfill the
requirement for multivalency and elicit an immune response in two
ways: (1) form hapten-carrier complexes and (2) be converted into
reactive intermediates (Fig. 12).
A hapten in this case would be a particular drug, which would be
immunogenic in protein-conjugated but not free form. Example would
be penicillins and other beta-lactams that bind covalently to proteins.
 133

Fig. 12. Scheme of immune reaction to drug.

Conversion into reactive intermediates

– This may occur via drug metabolism in the liver or elsewhere.
– This is the case with sulfonamides, which are acetylated and
oxidated to yield the predominant N4-sulfonamidoyl hapten.
Types of reactions
Type 1: Immediate (IgE-mediated) hypersensitivity occurs within
minutes to 4-6 hours of drug exposure (anaphylaxis, Quincke`s edema,
urticaria) – beta lactam antibiotic, etc.
Type 2: Cytotoxic reaction – antibody-drug interaction on the cell
surface results in destruction of the cell (hemolytic anemia due to
penicillin, quinidine, cephalosporins, quinine)
Type 3: Immune complex – serum sickness (antisera), serum
sickness-like reactions (penicillin commonest cause)
Type 4: Delayed type hypersensitivity – sensitized to drug, the
vehicle, or preservative (e.g., PABA, parabens, thimerosal) – Dermatitis
Sensibilization to drug develops actively after the drug usage. It is
also topical when latent mechanisms of sensibilization take place. It can
happen in intrauterine sensibilization of fetus, baby after the birth (in
breast-feeding), cross reaction (hyper sensitization to other drugs which
have common chemical structure of epitopes).
Generalized reactions
Anaphylaxis. This is the most fearsome response with its potential
for sudden death. Its features include urticaria, angioedema, asthma,
laryngeal edema, hypotension, cardiac arrhythmias and gastrointestinal
disturbance. The entire reaction is abrupt, explosive, but brief.
Anaphylaxis versus Anaphylactoid Reactions. Anaphylaxis refers
to systemic, immediate hypersensitivity reaction due to the IgE-mediated
release of mediators from mast cells and basophiles. Anaphylactoid
reactions refer to clinically similar events as anaphylaxis but are not
mediated by IgE. They cause, via unknown mechanism, the
degranulation of mast cells and/or basophiles.
Serum sickness. This reaction comprises fever, urticaria, joint
involvement and lymphadenopathy. It typically develops 1-3 weeks after
the drug therapy is commenced and may continue for weeks after the
drug is stopped.
 134

Drug induced autoimmunity. Some drugs are capable of inducing

autoantibodies which may not result in disease but can cause lupus
erythematosus, hepatitis, etc.
Single organ involvement. Numerous drugs induce immunological
reactions in particular organs, e.g., penicillin (acute urticaria), neomycin
(contact dermatitis), methyldopa (hemolytic anemia) and penicillamine
(nephrotic syndrome).
Evaluation of patients with suspected drug allergy
History It is key in the diagnosis of allergy and includes the
following points
– suspicion that unexplained clinical event may be caused by a
drug
– complete and accurate documentation of all drugs, including
nonprescription ones, taken over the previous month
– temporal relationships between drug administration and the
onset of symptoms or signs
– correlation of the clinical manifestations with known reactions
induced by a particular drug
– previous tolerance to the drug (sensitization)
– prior history of similar reaction to the same or crossreacting
drug.
A few points should be stressed regarding the temporal
relationships. It is virtually impossible to react allergically on the first
exposure to drug never previously taken unless the patient has had
crossreacting drug or unknown subclinical exposure to the drug or
related compounds such as meat tenderisers (chymopapain) or
quaternary ammonium compounds in cosmetics (muscle relaxants).
Reactions rarely occur within the first 7 days of treatment; rather, within
2-4 weeks. Further, if a drug has been taken continuously for a year or
more, it is unlikely to cause reaction. However, the classic IgE-mediated
drug allergy typically appears after the first dose of a new course.
Patients who report allergic response may have had adverse
reaction to the drug. Adverse reactions to drugs are common and drug
allergy represents only about 10% of them. Certain clinical features help
to distinguish allergy from other reactions:
– only small number of patients react in this way
– minute doses may trigger response
 135

– the signs and symptoms are similar to those of allergic

responses triggered by other substances (foods, animals, insect
stings)
– they develop soon after the drug is started and resolve soon
after it is withdrawn
– they are quite different from the usual pharmacological actions
of the drug
– specific tests may define the allergic response

Factors that increase the risk of drug allergic reactions

• Chronic diseases that require continuous or frequent courses of
therapy with the same or cross-reactive drugs
• Some allergic reactions are more likely to occur with certain
infections, e.g., aminopenicillins with EBV infection, sulfonamides with
AIDS patients
• Atopy, genetically determined state of hypersensitivity, manifested
as asthma, hay fever, and atopic dermatitis
• History of other drug allergy
• Family history of allergic drug reactions
Principles of testing
Testing is primarily restricted to the detection of drug-specific IgE
antibodies.
Skin testing. Finding suitable test reagent is problematic as most
drugs have a low molecular weight and are not immunogenic. Therefore,
they must form macromolecular complex, presumably in combination
with host protein. Furthermore, drug metabolites may cause the reaction.
In short, for most drugs, the antigenic determinants are unknown.
General approach. Immediate type skin tests are the most rapid,
convenient and reproducible method of detecting drug-specific IgE
antibodies. They are most accurate in evaluating reactions induced by
drugs which are proteins (insulin, chymopapain, foreign antisera).
Although skin tests for lower molecular weight compounds such as
sulphonamides are of questionable value, exceptions include the major
antigenic determinant of penicillin (benzylpenicilloyl (BPO) compound)
and some drugs used in general anaesthesia.
Method. Prick testing should be done initially. For testing only
allowed drugs can be used. The drug is appropriately diluted (e.g.,
1:1000) with normal saline, drop placed on the ventral surface of the
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forearm and the skin pricked through the drop. A positive response, read
at 20 minutes, is a wheal 2 mm or greater than that of normal saline
control, and surrounding flare. If negative, intradermal tests are done
with serial dilutions. The forearm is injected intradermally with 0.05 mL
of the lowest concentration (1:10 000 to 1:100 depending on the drug
and the patient's history). Positive response at 20 minutes is wheal and
flare, with the wheal being larger than that raised by the initial injection
and the normal saline control. If negative, the next (higher, usually 10-
fold) concentration is injected.
Precautions
1. Tests are generally risk-free, but sometime anaphylaxis
develops.
2. They should be done by personnel familiar with the theory and
practice of the procedure.
3. The tester must be aware of appropriate starting dilutions as well
as the concentrations likely to induce irritant (non-allergic) responses.
4. False negative results may occur from
– inappropriate test reagent
– too short time interval between the adverse reaction and test – at
least two weeks are needed because severe anaphylactic event
temporarily depletes the circulating IgE antibodies and also the chemical
mediators from the mast cells.
5. The patient may exhibit anxiety or vasovagal response.
6. Appropriate means of reversing a severe reaction must be
readily available.
7. Informed consent and accurate documentation are essential.
In vitro testing. This has the advantage that adverse reactions to
testing can be avoided. The most widely used is the radioallergosorbent
test (RAST) which measures circulating drug-specific IgE antibodies. It
is generally less specific and less sensitive than skin testing, thus
limiting its clinical usefulness. In RAST testing, given allergen is bound
to polydextran bead. Serum is then added and antigen-specific IgE will
bind to the immobilized antigen. Radiolabeled anti IgE is then added.
The amount of bead-bound radioactivity is proportional to the
concentration of antigen-specific IgE in the serum.
SPECIAL CONSIDERATIONS
There are four classes of beta-lactam antibiotics:
• penicillin,
 137

• cephalosporin,
• carbapenem,
• monobactam.
The first three all have bicyclic nuclei in contrast to monobactams
(aztreonam), which lacks second ring adjacent to the beta-lactam
nucleus.
Penicillin
Allergy to penicillin is the best studied drug reaction. Anaphylaxis
most commonly occurs between the ages of 20 and 49 years, but
children and the elderly are not exempt. It is more likely to occur when
the drug is given parenterally rather than orally. With the passage of
time, 85% of patients ‘lose’ their hypersensitivity. Thus, allergy to
penicillin (and presumably to other drugs) is not necessarily life-long.
The reported history of penicillin allergy ranges from 0.7% to 10%.
Penicillin allergic patients have 10 times the risk of other people of
reacting adversely to other antibiotics.
Major and minor determinants. The beta-lactam ring is unstable
and readily acylates lysine residues in proteins. The penicilloyl epitope
(BPO) is produced, which is called the “major determinant” since over
75% of all IgE mediated reactions are directed against this epitope.
Beta-lactams can also haptenize covalently through carboxyl and
thiol groups, which results in a variety of less dominant or “minor”
determinants. Minor determinant IgE responses have been associated
with anaphylaxis, while penicilloyl IgE responses are usually associated
with wheal reactions.
Signs and symptoms Allergic symptoms commonly include:
erythematous, maculopapular and usually pruritic rash, urticaria. Less
common symptoms include angioedema, serum sickness, arthralgia,
bronchospasm, laryngeal edema, and anaphylaxis.
Testing: BPO accounts for 95% of the metabolites of penicillin.
Other metabolites, `minor determinants', are also capable of inducing
anaphylactic responses. A useful additional test reagent is freshly
prepared benzylpenicillin (BP) (6000 U/mL) which may also detect
patients allergic to minor determinants. Testing with BPO alone fails to
detect significant number of patients at risk, but the addition of BP will
improve the detection rate to 80%. This rate can be increased by
additional testing with semisynthetic penicillins and particularly with
preparations of their minor determinants. There is still significantly high
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false negative group, so subsequent treatment with penicillin in test-

negative patients must be carried out with careful monitoring. Today, no
skin test-negative patient is known to have developed severe reaction.
That testing is useful, it has been indicated by studies of patients
undergoing testing and subsequent treatment. In patients with positive
tests, there is a high incidence of subsequent reactivity; those with
negative tests have a very low incidence of reactions.
Ampicillin/amoxycillin
Maculopapular rashes induced by ampicillin and amoxycillin are
seen commonly in patients with infectious mononucleosis,
cytomegalovirus and chronic lymphatic leukemia. They typically
develop 48 hours or more after drug administration and persist for a
week or so. Unless the rash is clearly wheal, it is unlikely to be IgE-
mediated.
Cephalosporins
Cephalosporin and penicillin share the beta-lactam ring in their
basic structure. However, clinical cross-reactivity occurs in
approximately 10% of patients. For patients allergic to penicillin, their
chances of reacting to the cephalosporin appear no greater than those of
reacting to other unrelated antibiotics. The overall incidence of
cephalosporin allergy in the general population is about 4%, so the 8%
incidence of reactions in the PCN-allergic group is only 2-fold increase.
When PCN-allergic patients receive any drug, the incidence of adverse
drug reactions is 3 times higher compared to those with no history of
PCN allergy.
Skin testing with Cephalosporin. Currently there are no reliable
cephalosporin allergens available for skin testing. Allergic reactions to
cephalosporin do not appear to correlate with positive penicillin test
reactions.
Multiple drug allergy
Many patients are being recognized as having allergic reactions to
a number of antigenically unrelated drugs, antibiotics in particular.
Clinical management is difficult, but should follow these basic
principles:
o preference should be given to antibiotics known to be
tolerated
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o patients who have reacted to one type of penicillin will not

necessarily react to other types
o of the new classes of beta-lactams, the carbapenems
(imipenem) cross-react with the minor determinants of
penicillin, whereas the monobactams (astreonam) do not
o third generation of cephalosporins have a lower incidence of
allergic reactions than the first and second generation.
Sulphonamides and other antibiotics
"Sulfa allergy" is term used to describe adverse drug reactions to
sulfonamides, group of drugs that includes those with and without
antibiotic characteristics. Antibiotic sulfonamides were the first
antibiotics used to treat infections, although today they are used much
less frequently given their common side effects.
Common sulfa antibiotics include Septra®, Bactrim® and
Pediazole®. The overall incidence of adverse drug reactions to sulfa
antibiotics is approximately 3%, similar to other antibiotics such as
penicillin. Certain groups appear to be at higher risk for sulfa allergy,
including those that metabolize these medications more slowly and those
with immune problems such as AIDS.
Symptoms.
Skin reactions are the most common adverse reactions to sulfa
medications, ranging from various benign rashes to life-threatening
Stevens-Jonson syndrome and toxic epidermal necrolysis. Hives and
increased sensitivity to sunlight (photosensitivity) are also possible.
There is possibility that if the sulfa medication is continued despite mild
rash occurring, the rash could progress to a more severe form of skin
reaction.
Liver: hepatitis. Kidney injury: kidney failure. Lung reactions:
with pneumonia-like reactions, worsening asthma and vasculitis. Blood
reactions: decreased white blood cells, red blood cells, and platelets,
through immunologic-mediated manner. Other symptoms include:
aching joints and muscles, swollen lymph nodes, nausea and vomiting.
Despite the severity and frequency of allergic reactions, especially
the trimethoprim/sulfamethoxazole combinations, there are no specific
diagnostic reagents which have been developed for commercial use to
identify patients at risk of anaphylaxis. If desired, testing could be done
with individual antibiotics as outlined above. There is small potential for
the Stevens-Johnson syndrome when testing for sulphonamides.
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Treatment. In most cases, if person is experiencing adverse

reaction to sulfa medication, that medication should be stopped. The
symptoms of the reaction may need to be treated, especially in those
experiencing Stevens-Johnson syndrome or toxic epidermal necrolysis.
In some cases, in which sulfa medication is needed to treat certain
infections, person can be desensitized to the medication. This is done by
initially giving very small amounts of the medication, with increasing
amounts given over period of time so that the medication is tolerated.
Symptoms such as rash, hives, and itching can often be controlled with
antihistamines, and occasionally corticosteroids. For coughing and lung
congestion bronchodilator inhalers may be prescribed.
Local anesthetics
These drugs are unlikely to cause IgE-mediated responses. Skin
testing is probably warranted, with concentrations increasing to typical
therapeutic dose.
Radiographic contrast media
Anaphylactoid reactions develop in 2-3% of patients. They may be
more common with the use of ionic media. This group of drug is potent
histamine liberator. Most reactions are mild (e.g., urticaria), but
fatalities have been recorded. The etiology is obscure, but IgE antibodies
have never been demonstrated. Some features are
o they often occur on the first exposure
o specific testing is useless
o patients with seafood allergy are at no greater risk
o pretreatment with antihistamines and steroids will reduce the
risk of serious reactions.
Insulin
Bovine and pork insulin differ from human insulin in three and one
amino acid sequences respectively. Adverse reactions to human
(recombinant DNA) insulin are less likely to develop, but there have
been isolated reports of patients allergic to animal insulin which has
positive cutaneous reactivity to the human insulin.
There are two adverse immune responses: allergy and resistance.
Large local swellings due to allergy are common and usually ease by
means of continued treatment with antihistamines. Systemic reactions
are rare and may require desensitization. RAST and skin tests may be
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done. Insulin resistance is also rare and results from antiinsulin IgG
antibodies which neutralize exogenous insulin.
Chymopapain
Anaphylaxis has occurred in 1% of patients treated by
chemonucleolysis with chymopapain. As it often develops on first
exposure, sensitization may resulte from meat. Skin testing immediately
before treatment is essential. The testing is done in sequence: prick tests
of 1 mg/ml, 10 mg/ml and intradermal test of 0.2 ml (100 mg/ml). If
each of them is negative, the risk of anaphylaxis is minimal.

Streptokinase
Allergic reactions have been reported in up to 17% of patients
treated with streptokinase. Intradermal test with 0.1 ml of 1000 IU/ml, if
positive at 15 minutes, should detect those at risk of anaphylaxis.
Vaccines in egg-sensitive patients
Small amounts of egg protein may be found in vaccines for
influenza, measles, mumps, rubella, and yellow fever. Although allergic
reactions in egg-sensitive patients who are given these vaccines are rare,
when in doubt, preliminary testing, firstly by prick and then
intradermally, can be done.
Aspirin and other nonsteroidal antiinflammatory drugs
(ASA/NSAIDs)
NSAD allergy is estimated to be present in approximately 1% of
the general population. In patients with asthma, approximately 10% may
have their asthma symptoms worsened by NSAIDs. If a person with
asthma also has chronic sinusitis/nasal polyps, the chance of NSAIDs
allergy increases to 40 percent. In patients with chronic hives and/or
swelling, NSAIDs may worsen skin reactions.
Mechanisms of allergic reaction to NSAIDs. NSAIDs inhibit the
enzyme cyclo-oxygenase 1 (COX-1), which produces prostaglandins
such as PGE2 (See chapter "Pathogenesis of allergic reactions").
PGE2 is necessary to protect against excessive leukotriene release in
susceptible individuals. The release of leukotriene from the affected
target organs causes the clinical symptoms.
During inflammatory respiratory disease, leukotrienes, histamine,
and eosinophilic cationic protein are formed and released with
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subsequent increase in vascular permeability, mucus secretion, and

bronchial hyperreactivity.
5-lipoxygenase (5-LO) and COX catalyze the production of
leukotrienes and prostaglandins, respectively. Prostaglandin E2 has
several immunoregulatory effects, including inhibition of 5-
lipoxygenase and preventing the release of mediators from mast cells.
When ASA is given, COX-1 and COX-2 are disabled, PGE2 synthesis
stops and its modulating effects on mast cells and 5-LO are removed,
and mediators are released or synthesized. Leukotrienes are continuously
and aggressively synthesized in patients before any exposure to
NSAIDs/ASA, and during ASA-induced reactions, marked acceleration
of synthesis occurs. It is not known why interruption of PGE2 synthesis
does not induce respiratory reactions in all humans.
Signs and symptoms. Respiratory tract symptoms (acute rhinitis,
bronchospasm), urticaria/angioedema, gastrointestinal symptoms
(nausea, vomiting, diarrhea) can be shown.
Testing. Unlike allergic reactions to pollens, animal dander and
foods, in which there are allergic antibodies (IgE) against the trigger
factors, reactions to aspirin and other NSAIDs generally, do not occur as
a result of IgE. Therefore, allergy testing is not usually of benefit. In
some cases, oral challenge may be performed under the supervision of
allergist to evaluate for sensitivity or tolerance to specific NSAIDs.
Treatment. Avoidance of all of the NSAIDs is the usual treatment
for NSAIDs allergy. It is important to be aware of the huge variety of
medications that contain aspirin or related NSAIDs. In addition to
avoidance, it is also recommended that NSAID-allergic patients wear
a Medic-Alert bracelet to notify emergency personnel of their condition
in the event they are unable to communicate. In some situations, such as
certain medical conditions, NSAID is required therapy. For these people
desensitization procedure is possible treatment, and should only be
performed by allergy physicians skilled in the desensitization of drugs.
Desensitization to NSAIDs may be successful for patients with
respiratory-NSAD allergy or anaphylaxis, but does not work for skin-
NSAD allergy.
NSAIDs cannot be used (are contraindicated) in the following
cases:
– Allergy to aspirin or any NSAIDs
– Aspirin should not be used under the age of 16 years
– During pregnancy
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– During breast feeding

– Suffering from the defect of the blood clotting system
(coagulation)
– Active peptic ulcer
Care is needed if a patient has:
– Asthma
– Kidney impairment
– Heart impairment
– Liver impairment
It is important to remember that some food products contain rather
high levels of ASA. For example, tomatoes, grape, strawberry, beer,
tinned food. Also, NSAIDs/ASA show cross-reactivity with yellow
color food dye (tartrazin). Thus, taking any yellow pills, sweets,
marmalade, cake’s cream lead to allergic reaction development.
Prescription medications to avoid in the patients with the allergic
reactions to NSAIDs.
– Diclofenac (Voltaren®) – Ketorolac (Toradol®)
– Diflunisal (Dolobid®) – Meloxicam (Mobic®)
– Etodolac (Lodine®) – Nabumetone (Relafen®)
– Fenoprofen (Nalfon®) – Naproxen (Aleve®,
– Flurbiprofen (Ansaid®) Naprosyn®, Anaprox®
– Ibuprofen (Motrin® products, products)
Advil® products, many – Oxaprozin (Daypro®)
generic forms) – Piroxicam (Feldene®)
– Indomethacin (Indocin®) – Salsalate (Disalcid®)
– Ketoprofen (Orudis®) – Sulindac (Clinoril®)
– Tolmetin (Tolectin®
products)

Drugs which can be used in the patient with allergic reaction to

NSAIDs. Except in extremely rare cases, Tylenol® (acetaminophen) is
safely tolerated and is considered to be the drug of choice in NSAID-
allergic patients. Newer COX-2 inhibitors, currently available only as
celecoxib (Celebrex®) in the United States, are usually tolerated as well,
although it is recommended a patient to be monitored in physician’s
office for the first full dose of these medications. Most narcotics are
 144

safe, with the exception of some combination products containing

NSAIDs. Any person with known or suspected NSAIDs allergy is
recommended to consult with physician or allergist before using any
product that may be related to NSAIDs.

General management principles

for patients with history of allergy to specific drug are:
– obtain full clinical details of the reaction
– if allergy is suspected, use an alternative, non-cross-reacting drug
(available in most situations) (Table 13).
– if none appropriate, refer to someone competent in the testing for
drug allergy
– testing for suspected penicillin allergy should ideally employ
different kinds of penicillins and cephalosporins as well
Table 13. The groups of medicines having the common chemical
determinants

Common Drug having common determinant (cross-reactive)

determinant
I. β-laktam ring 1. Penicillin (natural and semi synthetic)
Oxacillin, Methicillin, ampicillin, and etc.,
combined – amoxiclav, augmentin, and etc.
2. carbapenem
3. monobactam
4. Cephalosporins (cefazolin, Kefzolum, Ceporexum, etc.)
5. D- penicillamine
II. Aniline (phenyl 1. Novocain, Anesthesin and congenerous substances
amine) 2. Paraaminosalicylic acid
3. Sulfanilamides (Norsulfazolum, Sulfozinum,
Sulfadimezinum, Urosulfanum, and etc.).
Can react and with III group as have the SO2NH2-
group bound to benzene ring
III. 1. Sulfanilamide (Urosulfanum, Sulfapyridazinum, etc.)
Benzolsulfamide 2. Sulphonylurea derivative (Butamidum, Carbutamide,
group Chlorpropamide, Cyclamidum, etc.)
3. Tiazide diuretics (Hypothiazide, Hydrochlorthiazide,
etc.)
4. Furosemide
5. Carbonic anhydrase inhibitors (Diacarb).
Have Sulfamide group not bound to benzene ring,
there can be cross reactions.
 145

IV. Fenotiazine 1. Neuroleptics (aminazine, Propazine, etc.)

group 2. Antihistaminic preparations (Pipolphenum)
3. methylene dark blue (Methylenum coeruleum)
4. Antidepressants (Phtoracizinum)
5. Coronarodilator preparations (Chloracizinum)
6. Antiarrhytmic agents
V. Iodine 1. Iodine and inorganic Iodidums (potassium or Natrii
iodidum, iodine solution, Lughole’s solution)
2. Iodine containing radiopaque agents (Cardiotrastum,
Omnipaque, etc.)
3. Calciiodinum
VI. Ethylene 1. Euphyllinum
diamine 2. Suprastin
3. The creams containing this substance

– if the tests are negative, give test dose first where full resuscitation
facilities are available
– treat minor allergic responses (especially rashes) symptomatically
if continuation of the drug is considered essential; however, to be
aware of Stevens-Johnson syndrome which is potentially fatal
– provide adequate follow-up of patients
– if the drug is required again, objective testing may be repeated
– know how to treat anaphylaxis
– if tests are positive, avoid the drug; however, desensitization
according to accepted protocols may be used as last measure.
Drug Desensitization
 Effective in the treatment of type I allergic reactions and may be
effective for other reactions that are delayed in onset but are not
IgE-mediated
 Antigen-specific mast cell desensitization appears to be
responsible for the tolerant state
 Specific mast cell desensitization is poorly understood
Successful known desensitization
antibiotics other agents
o Penicillins o Chemotherapeutics
o Sulfonamides o Heterologous sera
o Aminoglycosides o Insulin
 146

o Clindamycin o Deferoxamine
o Cephalosporins o LHRH
o Vancomycin o Measles vaccine
o Pentamidine o Heparin
o Anti-tubercular agents o Tetanus toxoid
o D-penicillamine
o Corticotropin
o Carbamazepine

The starting dose for the drug can be determined by performing

intradermal skin tests with the native drug at dose that does not cause
non-specific irritant reaction. For example, if 0,02 ml intradermal
injection of drug in 1 mg/ml concentration does not cause local or
systemic reaction, oral desensitization may be started in the dose
injected (the tolerated dose, 20 µg). Parenteral desensitization should be
used 1/10 or 1/100 of the dose that was administered intradermally.
Desensitization is REVERSIBLE process that is dependent on the
continued presence of the drug.
It is also drug-dose dependent in that substantial dose increase may
result in breakthrough allergic symptoms.

Questions for self-control:

1. Classification of adverse drug reactions.
2. Characteristics of drug allergens.
3. Immune mechanisms to drug allergens.
4. Definition of cross-reacting allergens.
5. Diagnostic methods in drug allergy.
6. Classification of provocative tests with drug allergens.
7. Prophylaxis of drug allergy.

ACUTE TOXICO-ALLERGIC REACTIONS

Acute toxico-allergic reactions (ATAR) are rare, life-threatening

conditions that are usually induced by reaction to drugs. They are
characterized by the detachment of the epidermis from the dermis.
Classification of ATAR:
 Light course
 Medium course (multiform exudative erythema – MEE)
 147

 Serious course (Stevens-Johnson syndrome)

 Extreme serious course (Lyell's syndrome – Toxico-allergic
epidermal necrolysis).
Some authors consider diseases to have various genesis, however,
others believe this very disease to be of various severity level and to
depend on the size of skin and mucosa lesions.
Cytotoxic, cell-mediated or immune complex-mediated
hypersensitivity reactions are thought to occur to the presence of toxic
drug metabolites which are accumulated in the skin. This reaction results
in the destruction of keratinocytes. The mechanism has not still been
understood and is complex.
Drug specific CD8+ cytotoxic lymphocytes can be detected in the
early blister fluid. They have some natural killer cell activity and can
probably kill keratinocytes by direct contact.
Cytokines implicated include perforin/granzyme, Fas-L and TNF-
alpha. There are probably two major pathways involved:
1. Fas-Fas ligand pathway of apoptosis has been considered a
pivotal step in the pathogenesis of ATAR. The Fas ligand (FasL), a form
of tumor necrosis factor, is secreted by blood lymphocytes and can bind
to the Fas ‘death’ receptor expressed by keratinocytes.
2. Granule-mediated exocytosis via perforin and granzyme B
resulting in cytotoxicity (cell death). Perforin and granzyme B can be
detected in early blister fluid and it has been suggested that levels may
be associated with disease severity.
ATAR causing factors:
Certain drugs: usually the reaction begins within 4 to 8 days after
starting a new drug. There are many culpable medications. Those most
commonly used are:
o Sulfonamides.
o Non-steroid anti-inflammatory drugs.
o Ampicillin.
o Anticonvulsants, especially phenobarbital, phenytoin,
carbamazepine, valproate.
o Allopurinol.
o Antiretrovirals (Nevirapine).
o Paroxetine.

Erythema exsudativum multiforme is acutel developing disease,

which are characterized by polymorphic erythema on the skin and
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mucosa. There are two forms of exudative erythema – idiopathic and

toxico-allergic. The idiopathic has cyclic current and predilection to
relapses, mainly in spring and in autumn; toxico-allergic reaction
develops in intolerance to medicines or in some infectious diseases.
Stevens-Johnson's syndrome represents very serious acutely
developing disease which is characterized by polymorphic rashes in the
form of erythematic maculae and bubbles, it is frequent with the
hemorrhagic contents, localized on skin, mucosa of oral cavity
(stomatitis), on conjunctiva (conjunctivitis) and the urinary channel
(urethritis); it is accompanied by the intoxication.
Lyell's syndrome, has been named after Alan Lyell who first
described 4 cases of toxic epidermal necrolysis (TEN) in 1956 as
eruption resembling scalding of skin (Fig. 13).
There is a prodromal phase lasting from 2-3 days to up to 1 week
with fever, symptoms similar to upper respiratory tract infection, rash,
conjunctivitis, pruritus, malaise, arthralgia and myalgia. The skin has
appearance similar to scald. Mucous membrane involvement occurs
early in 90% of cases and commonly accompanied by other symptoms.
The conjunctivae, buccal, nasal, pharyngeal, tracheobronchial, perineal,
vaginal, urethral and anal mucosa may be involved. Ill-defined red
'burning/painful' macular or papular rash then develops, spreading from
the face or the upper trunk. Bulla are formed and then coalesced. They
generally increase in number within 3-4 days (sometimes hours). The
epidermis can then slough in sheets. There may be pernicious fever (39-
41o C). Hypotension and tachycardia can develop as secondary reactions
to dehydration and hypovolemia. The Nikolsky sign (Fig. 14): if areas
of seemingly normal skin between lesions are rubbed, the epidermis
easily separates from its underlying surface. Severe complications are
secondary infections, and development of myocarditis, pneumonia,
meningitis, and septicemia may occur. Mortality is in 40 - 80% of cases.
 149

Fig. 13. Skin lesion in Fig. 14. Positive Nikolsky

Lyell's syndrome symptom.

Infection, malignancy and vaccination have also been suggested as

other possible etiologies. There may be no obvious trigger (idiopathic
(non-allergic) toxic epidermal necrolysis).
The reaction is more rarely triggered by some immunizations and
following bone marrow or organ transplantation. The skin
manifestations of graft-versus-host disease are thought to have similar
etiology to TEN. Infections such as mycoplasma and HIV are also
associated. Systemic lupus erythematosus and malignancy are thought to
increase the risk of TEN.
Investigations
There are no confirmatory tests. Albumin, total protein and
proteinuria must be closely monitored. Screening blood, urine and skin
cultures should be collected. Multiple organ involvement occurs as
ATAR progresses.
Skin biopsy and immunofluorescence staining should be
considered if pemphigus/pemphigoid is suspected. There is full
thickness epidermal necrosis in TEN plus epidermal detachment and
sloughing.
Treatment of Lyell's syndrome
Patients need transfer to unit where they can receive intensive care,
ideally burns unit.
Nutritional and fluid replacement by intravenous and nasogastric
routes – reviewed and adjusted daily.
Temperature maintenance – as body temperature regulation is
impaired. Fluid and electrolytes, infection and nutritional status need
 150

very careful monitoring and treatment should be started as soon as

possible.
Skin and mucosa care:
 topical antiseptics,
 avoid using adhesive tapes
 pain relief (aerosols, solutions).
Studies, in which high doses of corticosteroids (prednisolone 300-
1500 mg/d, I /V) were given for short period at the start of the reaction,
appeared to be beneficial. However concerns have been raised that they
may increase the risk of infection, impair wound healing and other
complications. Anticoagulation treatment reduces the risk of
thromboembolism. In addition, it is necessary to use plasmapheresis,
antihistamines, antibiotics of wide spectrum, Intravenous human
immunoglobulins. Now efficiency of immunosuppressive drugs
(Cyclosporine, Infliximab) using is shown.

Questions for self-control:

1. Classification of Acute toxic allergic reactions.
2. Characteristics of Stevens-Johnson syndrome.
3. Characteristics of Lyell's syndrome.
4. Treatment of Acute toxic allergic reactions.

FOOD ALLERGY

Food sensitivity is abnormal response to particular food. The same

food is safe for the vast majority of consumers to ingest.
The actual prevalence of food allergies is estimated to be
approximately 6% in infants and children and 3.7 % in adults. Several
published prospective investigations have determined the prevalence of
certain common food allergies in children (e.g., cow milk, 2.5%; eggs,
1.3%; peanuts, 0.8%; wheat, 0.4%; soy, 0.4%). Prospective studies from
several different countries indicate that approximately 2.5% of newborn
infants experience hypersensitivity reactions to cow milk in the first year
of life. Hypersensitivity reaction to peanuts occurs in approximately
0.5% of children in the United Kingdom. Surveys from the United
Kingdom indicate that 1.4-1.8% of adults experience adverse food
reactions and 0.01-0.23% of adults are affected by adverse reactions to
food additives. Studies from the Netherlands demonstrate that
approximately 2% of the adult Dutch population is affected.
 151

There is increased risk of food allergies if other cases of allergy,

such as hay fever, asthma, hives or eczema, are common in the family. A
child who has one parent with an allergy has about a 50 percent chance
of allergy development. If both parents suffer from allergies, the child
has about 70 percent chance of allergy development.
Food allergies are most common in children, especially toddlers
and infants. Getting older, digestive system matures and body is less
likely to absorb food or food components that trigger allergies.
Fortunately, children typically outgrow allergies to milk, soy, wheat and
eggs. Severe allergies and allergies to nuts and shellfish are more likely
to be lifelong.
Types of reactions to food
Food sensitivities can be divided into two major categories: food
allergies and food intolerances. In fact, food sensitivities can involve
several types of mechanisms. There are practical reasons for
distinguishing between true food allergies and food intolerances, from
both clinical and regulatory perspective.
Food intolerance and other conditions: Not food allergies.
As with true food allergies, food intolerances affect limited number of
individuals. Food intolerances can be defined as any form of food
sensitivity that does not involve immunologic mechanisms.
Because food intolerance may involve some of the same signs and
symptoms as a food allergy does — such as nausea, vomiting, cramping
and diarrhea — people often confuse the two.
In case of food intolerance, person may be able to eat small
amounts of problem foods without reaction. By contrast, in true food
allergy, even tiny amount of food may trigger allergic reaction.
One of the tricky aspects of diagnosing food intolerance is that
some people are sensitive not to the food itself but to substance or
ingredient used in the preparation of the food. For example, sulfite
preservatives can trigger asthma signs and symptoms in sensitive people.
Common non-allergy related problems include:
Absence of enzyme needed to fully digest food. No adequate
amounts of some enzymes needed to digest certain foods. Insufficient
quantities of the enzyme lactase, for example, make it difficult to digest
lactose, the main sugar in milk products. Lactose intolerance can cause
bloating, cramping, diarrhea and excess gas.
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Irritable bowel syndrome. Certain foods may trigger the signs and
symptoms of irritable bowel syndrome. Certain foods will cause
cramping, constipation or diarrhea. Steer clear of these foods to avoid
the symptoms.
Food poisoning. Sometimes food poisoning can mimic allergic
reaction. Some types of mushrooms and rhubarb, for example, can be
toxic. Bacteria in spoiled tuna and other fish also can make toxin that
triggers adverse reactions. This one-time reaction is caused by
organism or toxin in food that has been contaminated, undercooked or
left at room temperature too long. It doesn’t mean that the same food
will give reaction the next time.
Recurring stress or psychological factors. Sometimes the mere
thought of food may make person sick. The reason is not fully
understood.
Food allergies
Food allergies are abnormal responses of the immune system to
certain food components. The allergens in foods are, typically, naturally
occurring proteins. In wheat, for instance, gluten, gliadin, globulin and
albumin proteins all can cause allergic reactions.
True food allergies can be divided into two further categories:
immediate hypersensitivity reactions and delayed hypersensitivity
reactions. In immediate hypersensitivity reactions, symptoms begin to
develop within minutes to hour or so after ingestion of even minute
amounts of the offending food. Basically, any food that contains protein
has the potential to elicit allergic sensitization in some individuals. The
reactions involved in immediate hypersensitivities can sometimes be
quite severe.
In contrast, the symptoms associated with delayed hypersensitivity
reactions do not begin to appear until 24 hours or more after ingestion of
the offending food. The role of delayed hypersensitivity reactions in
adverse reactions to foods remains rather poorly defined, with the
exception of celiac disease. The symptoms of delayed hypersensitivity
reactions do not reach the level of severity involved in the more severe
cases of immediate hypersensitivity reactions. However, the level of
tolerance to the offending food is also very low for delayed
hypersensitivity reactions.
From practical viewpoint, true food allergies should be
distinguished from other types of food sensitivities because they can
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elicit serious adverse reactions in some individuals and because people

with food allergies can tolerate little of the offending food. For example,
individuals with milk allergy can tolerate little milk, as their allergy may
involve systemic and sometimes serious reactions. In contrast, lactose
intolerance, involves only gastrointestinal symptoms, and affected
individuals can often tolerate appreciable quantities of milk in their
diets.
The great majority of food allergies are triggered by certain
proteins in Eggs, Peanuts, Fish, Shellfish, such as shrimp, lobster and
crab, Tree nuts, such as walnuts and pecans. It is controversial whether
food additives - such as dyes, thickeners, and preservatives - likely cause
true allergic reaction.
In children, food allergies are also commonly triggered by proteins
in these foods: Cow's milk, Wheat, Soybeans. Chocolate, long thought
by some parents to be culprit among children, seldom is a cause of food
allergy.
Mechanisms of IgE-mediated food allergy
Immune responses mediated by specific IgE antibodies are the
most widely recognized mechanism of food hypersensitivity. Patients
with atopy produce IgE antibodies to specific epitopes of the food
allergen. These antibodies bind to high-affinity IgE receptors on
circulating basophils and tissue mast cells present in the skin,
gastrointestinal tract, and respiratory tract. Subsequent allergen exposure
binds two adjacent IgE antibodies, resulting in receptor cross-linking
and intracellular signaling that initiates the release of numerous
mediators, including histamine, prostaglandins, leukotrienes,
chemotactic factors, and cytokines. The effects of these mediators on
surrounding tissues result in vasodilatation, smooth muscle contraction,
and mucus secretion, which, in turn, are responsible for the spectrum of
clinical symptoms observed during allergic reactions to food.
Food allergens are typically water-soluble glycoproteins resistant
to heating and proteolysis with molecular weights of 10-70 kd. These
characteristics facilitate the absorption of these allergens across mucosal
surfaces. Numerous food allergens are purified and well-characterized.
Closely related foods frequently contain allergens that cross-react
immunologically (lead to the generation of specific IgE antibodies
detectable by skin prick or in vitro testing) but less frequently cross-react
clinically. Finally, cross-reactive allergens have been identified among
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certain foods and airborne pollens (Pollen-food allergy syndrome).

Conserved homologous proteins shared by pollens and foods likely
account for this cross-reactivity.
Table 14. Common cross-reactivity between pollens and fruits and vegetables.
pollen Birch pollen Ragweed pollen Grasses Mugwort pollen
Food Apples Melons Melons Carrots
allergy to: Peaches (watermelon, Kiwis Celery
Plums cantaloupe and Tomatoes Spices
Nectarines honeydew)
Cherries Bananas
Carrots Tomatoes
Celery
Hazelnuts
Almonds
Raw potatoes

Pollen-food allergy syndrome (Oral allergy syndrome)

Patients with this syndrome develop itching or tingling of the lips,
tongue, palate, and throat following the ingestion of certain foods. In
addition, edema of the lips, tongue, and uvula and sensation of tightness
in the throat may be observed. In fewer than 3% of cases, symptoms
progress to more systemic reactions, such as laryngeal edema or
hypotension. Specific gastrointestinal symptoms include nausea,
vomiting, abdominal pain, and cramping. Diarrhea is found less
frequently.
This syndrome is caused by cross-reactivity between certain pollen
and food allergens (Table 14). For example, individuals with ragweed
allergy may experience oropharyngeal symptoms following the
ingestion of bananas or melons, and patients with birch pollen allergy
may experience these symptoms following the ingestion of raw carrots,
celery, potato, apple, hazelnut, or kiwi.

Gastrointestinal food allergy

Mixed IgE/non-IgE (eosinophilic gastroenteritis).
Typical symptoms include postprandial nausea, abdominal pain,
and sensation of early satiety. One of the hallmarks in children is weight
loss or failure to thrive. CBC count and differential findings may show
eosinophilia in approximately 50% of patients; however, this is not
diagnostic. Typically, endoscopy and biopsy must be performed in order
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to establish the presence of eosinophils in the intestinal wall. While

dense eosinophil infiltrate may be seen anywhere from the lower
esophagus throughout the large bowel, involvement is patchy and
variable. Ultimately, elemental or oligoantigenic diet is necessary to aid
in the diagnosis. If the patient does not respond to the elemental diet, a
trial of systemic oral corticosteroids can be useful for resolving the
clinical symptoms.
Non–IgE-mediated.
Dietary protein enterocolitis is a syndrome that typically manifests
in the first few months of life in a child who has severe projectile
vomiting, diarrhea, and failure to thrive. Cow milk and soy protein
formulas are usually responsible for these reactions, which occur 2 or
more hours after food ingestion. Infants typically appear lethargic,
wasted, and dehydrated. To establish the diagnosis, oral challenge study
must be performed.

Food-induced pulmonary hemosiderosis (Heiner syndrome)

This is rare disorder characterized by recurrent episodes of
pneumonia associated with pulmonary infiltrates, hemosiderosis,
gastrointestinal blood loss, iron deficiency anemia, and failure to thrive
in infants. While the precise immunologic mechanism is unknown, it is
thought to be secondary to non-IgE hypersensitivity process.
Food-induced anaphylaxis
Severe anaphylactic reactions, including death, can occur
following the ingestion of food. Typical symptoms observed in food-
induced anaphylactic reaction involve the skin, gastrointestinal tract, and
respiratory tract. Frequently observed symptoms include oropharyngeal
pruritus, angioedema (e.g., laryngeal edema), stridor, dysphonia, cough,
dyspnea, wheezing, abdominal pain, nausea, vomiting, diarrhea,
flushing, urticaria. Fatalities result from severe laryngeal edema,
irreversible bronchospasm, refractory hypotension, or combination
thereof.
Peanuts, tree nuts, and shellfish are the foods most often implicated
in severe food-induced anaphylactic reactions, although anaphylactic
reactions have been reported to wide variety of foods.
Risk factors for fatal food-induced anaphylaxis include: the
presence of asthma, especially in patients with poorly controlled disease;
previous episodes of anaphylaxis with the incriminated food; failure to
recognize early symptoms of anaphylaxis; and delay or lack of
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immediate use of emergency medications (e.g., epinephrine,

antihistamines) to treat the allergic reaction.

Diagnostics of food allergy

Necessary elements of thorough medical history
– Develop complete list of all foods suspected to cause
symptoms.
– Discuss the manner of preparation of the food (cooked, raw,
added spices or other ingredients).
– Determine the minimum quantity of food exposure required
to cause the symptoms.
– Determine the reproducibility of symptoms upon exposure to
the food.
– Obtain thorough description of each reaction, including the
following:
• The route of exposure (ingestion, skin contact,
inhalation, injection) and dose
• The timing of the onset of symptoms in relation to food
exposure
• All observed symptoms and each one’s severity
• The duration of the reaction
• The treatment provided and the clinical response to
treatment
• The most recent reaction: inquire about a personal or
family history of other allergic disease.
Clinical sings (skin reactions)
These are the most common clinical manifestations of allergic
reaction to food or food additive. Symptoms range from acute urticaria
(most common) to flushing to angioedema to exacerbations of atopic
dermatitis. Food allergy is rarely the cause of chronic urticaria or
angioedema
Laboratory studies
• Peripheral serum measurements of eosinophils or total IgE
concentrations: Results from these tests support but do not confirm
the diagnosis of food allergy. Likewise, normal values do not
exclude diagnosis.
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• Serum testing for specific IgE or/ and IgG antibodies to foods.
Results from food-specific immunoglobulin G (IgG) or IgG
subclass antibody concentration testing have not been proven to be
helpful with diagnosis
• Basophil histamine-release assays: These tests are mainly limited
to research settings and have not been shown conclusively to
provide reproducible results useful for diagnostic testing in clinical
setting.
 Testing for food antigen-antibody complexes has no proven
diagnostic value.
 Performing leukocyte cytotoxic tests is not supported by
objective scientific evidence.
Diet diary
This consists of keeping chronological record of all foods eaten
and any associated adverse symptoms. It is inexpensive endeavor that
documents the frequency of symptoms and their occurrence in
relationship to food ingestion. In addition, it encourages patients to focus
on their diet.
This record is occasionally helpful for identifying the food
implicated in adverse reaction; however, it is not usually diagnostic,
especially when symptoms are delayed or infrequent.
Occasionally, review of the diet diary reveals that the patient is not
experiencing reaction even when eating, as ingredient in other foods,
significant amount of a food to which they were thought to be allergic.
Elimination diet
This is used in determining the diagnosis as well as in the
treatment and prevention of food allergy. When used as diagnostic tool,
the elimination diet requires complete avoidance of suspected foods or
groups of foods for given time period (usually 7-14 d) while monitoring
for associated decrease in symptoms. Success depends on identifying the
correct food allergen and completely eliminating it in all forms from the
diet. These diets are increasingly difficult to develop and follow as more
foods or foods that commonly occur in the diet are eliminated.
Additional limitations of this method include potential effects of patient
or physician biases, variable patient compliance, and the time-
consuming nature of the endeavor.
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When the elimination diet is used as treatment, identified food

allergens are removed from the diet indefinitely unless evidence exists
that the food allergy has been outgrown.
Skin testing
Prick and puncture tests are the most common screening tests for
food allergy. However, the reliability of the results depends on multiple
factors, including use of the appropriate extracts and testing technique,
accurate interpretation of the results, and avoidance of medications that
might interfere with testing (e.g., antihistamines). When used in
conjunction with standard criterion of interpretation and appropriate
controls (e.g., histamine: positive, saline: negative), these tests provide
useful and reproducible clinical information in a short period (15-20
min) with minimal expense and negligible risk to the patient. This is
reliable method of excluding IgE-mediated food allergies. The negative
predictive accuracy is greater than 95%; however, the positive predictive
accuracy is generally less than 50%, which limits clinical interpretation
of positive skin test results.
Positive skin test results, in addition to the suggestion of clinical
reactivity based on the history, must often be confirmed by an oral food
challenge unless the patient has thoroughly convincing history of
significant food allergy.
Intradermal skin testing
The risk of inducing systemic reaction with this type of testing is
increased in comparison to the prick or puncture method; as a result,
intradermal skin testing should be avoided. In addition, the results
obtained by using this method are less specific compared to those
obtained by using prick or puncture testing.

Treatment
Dietary Avoidance: Avoiding the offending allergen in the diet is
the primary treatment of food allergy. Once food to which the patient is
sensitive has been identified, the food must be removed from the diet.
To do this, patients need to read lengthy, detailed lists of ingredients on
the label for each food they consider to eat. Many allergy-producing
foods such as peanuts, eggs, and milk appear in foods that are not
ordinarily associated with them. For example, peanuts are often used as
protein supplements, eggs are in some salad dressings, and milk is in
bakery products. The FDA requires that the ingredients in food are listed
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on its label. People can avoid most of the foods to which they are
sensitive if they carefully read the labels on foods and, when in
restaurants, avoid ordering foods that might contain ingredients to which
they are allergic.
Treating anaphylactic reaction: Patients with severe food allergies
must be prepared to treat anaphylactic reaction. Even those who know a
lot about their own allergies can either make error or be served food that
does not comply with their instructions. To protect themselves, people
who have had anaphylactic reactions to food should wear medical alert
bracelets or necklaces stating that they have food allergy and that they
are subjected to severe reactions. These individuals should always carry
syringe of adrenaline (epinephrine), obtained by prescription from their
doctors, and be prepared to self-administer it if they think they are
developing allergic reaction. They then should immediately seek
medical help by either calling the rescue squad or having themselves
transported to emergency room.
Treating other symptoms of food allergy: several medications are
available for treating the other symptoms of food allergy. For example,
antihistamines can relieve gastrointestinal symptoms, hives, sneezing,
and runny nose. Bronchodilators can relieve the symptoms of asthma.
These medications are taken after person inadvertently has ingested food
to which he is allergic. They are not effective, however, in preventing
allergic reaction when taken prior in eating the food. In fact, no
medication in any form is available to reliably prevent allergic reaction
to certain food before eating that food.
Lifestyle
 Avoidance offending foods. Careful reading of all package
ingredients (many foods are processed with peanuts, eggs, or milk
products such as whey); calling ahead when eating out; and taking
your own food with you on trips may be helpful.
 Food allergies of any type at any age require careful attention to
what you eat. Learning how to avoid your food allergens is as
important as knowing how to treat allergic reaction with
medications. Learn to recognize the different names for your
allergen. Sometimes ingredient lists are not complete; learn about
product alerts to help avoid allergic reactions.
 Avoidance eating out at specific restaurants or ordering certain
dishes. When the patients order foods, you need to specify exactly
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what ingredients they can’t eat. For example, restaurant chef may
forget that butter is a dairy product and may use that to cook food
despite request for no milk products. People with peanut allergies
need to avoid most Thai food, because peanuts are used frequently
in Thai dishes. Patients will learn to be incredibly specific when
eating out.
• If patients have history of anaphylactic shock, they should keep
preloaded syringe of epinephrine. Doctor will teach patients and
close family member how to use it in case the need arises. Plus,
patients should wear medical bracelet or necklace indicating
particular food allergies.

Questions for self-control:

1. Give classifications of food intolerances, food allergens for
children and adults.
2. Characterize mechanism of food allergies development.
3. Enumerate symptoms of food allergy.
4. Enumerate risk factors for fatal food-induced anaphylaxis.
5. Characterize pollen-food allergy syndrome.
6. Name specific diagnostics of food allergy.
7. Characterize principles of food allergy treatment.

ATOPIC DERMATITIS

Atopic dermatitis (AD) is pruritic disease of not clear origin that

usually starts in early infancy (adult-onset variant is recognized); it is
characterized by pruritus, eczematous lesions, xerosis (dry skin), and
lichenification (thickening of the skin and increase in skin markings).
AD may be associated with other atopic (IgE-mediated) diseases (e.g.,
asthma, allergic rhinitis, acute allergic reactions to foods). AD
has enormous morbidity, and the incidence and prevalence appear to be
increasing.
Males and females are affected with equal incidence and severity.
AD may occur in people of any age, but it often starts in infants aged 2-6
months. 75% of individuals experience marked improvement in the
severity of AD by age 10-14 years, but the remaining 25% continue to
have relapses during their adult life.
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Causes
Genetics: Family history of AD is common. Genome-wide scans
have highlighted several atopic dermatitis related loci on 3q21, 1q21,
16q, 17q25, 20p, and 3p26. Several candidate genes have been identified
(5q31-33); they all encode cytokines involved in the regulation of IgE
synthesis. Concerning HLA the AD can be associated with HLA А24, -
В5, -В9, -В12, and - В27.
Infection: The skin of patients with AD is colonized by S. aureus.
Clinical infection with S. aureus often causes flare-up of AD, and S.
aureus has been proposed as cause of AD by acting as superantigen.
Hygiene: The hygiene hypothesis is touted as cause for the increase
in AD. This attributes the rise in AD to reduced exposure to various
childhood infections and bacterial endotoxins.
Climate: AD flares occur in extremes of climate. Heat is poorly
tolerated, as is extreme cold. Dry atmosphere increases xerosis. Sun
exposure improves lesions, but sweating increases pruritus. These
external factors act as irritants, ultimately setting up inflammatory
cascade.
Food antigens: The role of food antigens in the pathogenesis of
AD is controversial, both in the prevention of AD and by the withdrawal
of foods in persons with established AD. Most reported studies have
methodologic flaws. Because of the controversy regarding the role of
food in AD, most physicians do not withdraw food from the diet.
Nevertheless, acute food reactions (urticaria and anaphylaxis) are
commonly encountered in children with AD.
Probiotics: The role of probiotics in the diet of patients with AD
remains controversial.
Aeroallergens: A role of aeroallergens and house dust mites has
been proposed, but this awaits further corroboration.
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Immune mechanisms.
Good evidence indicates that genetic factors are important in the
development of atopic dermatitis, but the pathophysiology is still poorly
understood. Two main hypotheses have been proposed regarding the
development of the inflammatory lesions. The first suggests immune
dysfunction resulting in IgE sensitization and secondary epithelial-
barrier disturbance. The second proposes defect in epithelial cells
leading to the defective barrier problem, with the immunological aspects
being epiphenomena.
In healthy individuals, balance exists between 2 important
subpopulations of T cells (Th1, Th2). The immune hypothesis invokes
imbalance in the T lymphocytes, with Th2 cells predominating;
this results in cytokine production of interleukins 4, 5, 12, and 13 and
granulocyte-macrophage colony-stimulating factor, causing increase in
IgE and lowered γ-interferon levels. Later, in persons with chronic AD,
the Th1-type cells predominate. Other cell types are also involved in the
process, including eosinophils, Langerhans cells, keratinocytes, and B
cells.
The second hypothesis involves defective barrier function in the
corneous cells’ stratum of AD patients, leading to the entry of antigens
that result in the production of inflammatory cytokines. Some authors
question whether the antigens can also be absorbed from the gut (e.g.,
from food) and the lungs (e.g., from house dust mites). Xerosis is known
to be associated sign in many AD patients. Evidence has shown multiple
loss-of-function mutations in the filaggrin gene (FLG) on band 1q21.3 in
patients with AD in Europe and other filaggrin mutations in Japanese
patients. This gene is mutated in persons with ichthyosis vulgaris; it
is associated with early-onset AD and with airway disease in the setting
of AD. These changes are only found in 30% of European patients,
begging the question of whether other genetic variants may also be
responsible for some of the findings in the pathogenesis of AD.
In AD, transepidermal water loss is increased. Defective lamellar
bodies may be caused by abnormalities of ceramide production. Whether
the inflammation causes primary or secondary epidermal barrier
breakdown is not known, but with the knowledge that filaggrin is
involved in epithelial disruption, it is now thought that this finding leads
to increased transepidermal penetration of environmental allergens,
increasing inflammation and sensitivity.
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Clinical picture
Incessant pruritus is the only symptom of atopic dermatitis;
children often scratch themselves uncontrollably. Although pruritus may
be present in the first few weeks of life, parents become more aware of
the itch as the itch-scratch cycle matures when the patient is aged
approximately 3 months. The disease typically has intermittent course
with flares and remissions occurring, often for unexplained reasons.
Primary findings of AD include xerosis, lichenification, and eczematous
lesions. Excoriations and crusting are common. The eczematous changes
and its morphology are seen in different locations depending on the age
of the patient.
Infancy
 AD is usually noticed soon after birth. Xerosis occurs early
and often involves the whole body; the diaper area is
usually spared.
 The earliest lesions affect the creases (antecubital and popliteal
fossae), with erythema and exudation (Fig. 15). Over the
following few weeks, lesions usually localize to the cheeks,
the forehead and scalp, and the extensors of the legs; however,
they may occur in any location on the body, usually sparing
the diaper area. Lesions are ill-defined, erythematous,
scaly, and crusted (eczematous) patches and plaques.
 Lichenification is seldom seen in infancy.
Childhood
 Xerosis is often generalized. The skin is flaky and rough.
 Lichenification is characteristic of childhood AD (Fig.
16). It signifies repeated rubbing of the skin and is seen mostly
over the folds, bony protuberances, and forehead.
 Lesions are eczematous and exudative. Pallor of the face is
common; erythema and scaling occur around the eyes. Dennie-
Morgan folds (e.g., increased folds below the eye) are often seen.
Flexural creases, particularly the antecubital and popliteal fossae,
and buttock-thigh creases are often affected.
 Excoriations and crusting are common. The crusting with AD should not be
confused with infection because both may manifest oozing and crusting.
 164

Fig. 15. Eczematous and Fig. 16. Popliteal fossae lesions

exudative lesions in infancy in childhood

Adulthood
 Lesions become more diffuse with underlying background
of erythema. The face is commonly involved and is dry and scaly.
 Xerosis is prominent.
 Lichenification may be present.
 Brown macular ring around the neck is typical but not
always present. It represents localized deposition of amyloid.
Three types of skin lesions exist.
o Acute
Intensely pruritic erythematous papules and vesicles overlying
erythematous skin; frequently associated with extensive
excoriations and erosions accompanied by serous exudates
o Subacute
Erythema, excoriation, and scaling
o Chronic
Thickened plaques of skin, accentuated skin markings
(lichenification), fibrotic papules (prurigo nodularis); possible
coexistence of all 3 types of lesions in chronic AD
Skin features of atopic dermatitis
• Lichenification: thick, leathery skin resulting from constant
scratching and rubbing
• Lichen simplex: refers to a thickened patch of raised skin that
results from repeat rubbing and scratching of the same skin area
• Papules: small, raised bumps that may open when scratched,
becoming crusty and infected
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• Ichthyosis: dry, rectangular scales on the skin, commonly on the

lower legs and shins
• Keratosis pilaris: small, rough bumps, generally on the face, upper
arms, and thighs. These are also described as gooseflesh or chicken
skin and may have a small coiled hair under each bump.
• Hyper linear palms: increased number of skin creases on the palms
• Urticaria: hives (red, raised bumps), often after exposure to
allergen, at the beginning of flares, or after exercise or hot bath
• Cheilitis: inflammation of the skin on and around the lips
• Atopic pleat (Dennie-Morgan fold): extra fold of skin that
develops under the eye
• Dark circles under the eyes: may result from allergies and atopy
• Hyperpigmented eyelids: eyelids that have become darker in color
from inflammation or hay fever
• Prurigo nodules also called "picker's warts" are not really warts at
all. These are small thickened bumps of skin caused by repeated
picking of the same skin site
Diagnostic criteria
Until Hanifin and Rajka developed diagnostic criteria for the
diagnosis of AD in 1980, no standardized methods were available to
make the diagnosis. Since then, numerous other experts have
developed different criteria suitable for their own environment, and
varying with age. The original criteria of Hanifin and Rajka have been
modified many times. Efforts to develop practical clinical criteria have
not been successful, and those available are not suitable for all
geographic areas and age groups. The lack of good chemical marker for
diagnosing the disease is an enormous obstacle to the study of AD.
Diagnostic criteria for AD, proposed by Hanifin and Rajka (1980)
and largely adopted by the American Academy of Allergy, Asthma, and
Immunology. Appropriate cases must have at least 3 major
characteristics and at least 3 minor characteristics.
Major characteristics include the following:
 Pruritus
 Typical morphology and distribution (e.g., flexural
lichenification and linearity in adults, facial and extensor
involvement in infants and young children)
 Chronic or chronically relapsing dermatitis
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 Personal or family history of atopy (e.g., asthma, allergic

rhinoconjunctivitis, AD)
Minor characteristics are as follows:
 Xerosis (dry skin)
 Ichthyosis/palmar hyperlinearity/keratosis pilaris
 Hand and/or foot dermatitis
 Cheilitis
 Nipple eczema
 Susceptibility to cutaneous infection (e.g., with
Staphylococcus aureus, herpes simplex virus (HSV), other
viruses, warts, molluscum, dermatophytes)
 Erythroderma
 Immediate type I skin test response
 Elevated total serum IgE
 Peripheral blood eosinophilia
 Perifollicular accentuation
 Pityriasis alba
 Early age of onset
 Impaired cell-mediated immunity
 Recurrent conjunctivitis
 Orbital darkening
 Orbital fold (e.g., Dennie pleat, Morgan fold)
 Anterior neck folds
 Keratoconus
 Anterior subcapsular cataracts
 Sensitivity to emotional factors
 Food intolerance
 Pruritus with sweating
 Intolerance of wool
 White dermographism
A firm diagnosis of AD depends on excluding conditions such as
scabies, allergic contact dermatitis, seborrheic dermatitis (SD),
cutaneous lymphoma, ichthyosis, psoriasis, immunodeficiency, and
other primary disease entities.
Differential diagnosis.
A number of diseases may be confused with AD. Scabies can
present as pruritic skin disease, although distribution in the genital and
 167

axillary areas, presence of linear lesions, as well as skin scrapings may

help to differ it from AD. It is especially important to recognize that
adult who presents with eczematous dermatitis with no history of
childhood eczema and without other atopic features may have contact
dermatitis. In particular, contactant should be considered in those
patients whose AD does not respond to appropriate therapy. Typical
distribution for suspected contactant may be suggestive. However,
allergic contact dermatitis (ACD) complicating AD may appear as acute
flare of the underlying disease, rather than the more typical
vesiculobullous eruption.
In older adults with diffuse, pruritic, eczematous eruption,
cutaneous T-cell lymphoma also needs to be ruled out. In such cases,
biopsies should be obtained from three separate sites, because histology
may show spongiosis and cellular infiltrate similar to AD. In addition,
eczematous rash suggestive of AD has been reported with HIV. Platelet
count for thrombocytopenia helps exclude Wiskott-Aldrich syndrome,
and testing to rule out other immunodeficiencies may be helpful.
Laboratory Studies
No chemical marker for the diagnosis of AD is known. Laboratory
testing is seldom necessary. A swab of infected skin may help with the
isolation of specific organism and antibiotic sensitivity. Scraping to
exclude tinea corporis is occasionally helpful.
Elevated serum IgE levels and peripheral blood eosinophilia occur
in most individuals with AD, and these findings may be useful in
confirming the atopic status of suspected cases. The presence of serum
IgE directed against the cell wall of S. aureus is observed in hyper-IgE
syndrome and AD.
Common infections that mimic or complicate AD can be tested for
as follows: conduct a Tzanck smear for HSV, a potassium hydroxide
preparation for dermatophytes, and Gram stain for bacterial infections.
Prick skin testing to common allergens can help identify specific triggers
of AD.
RAST and ELISA in vitro tests identify serum IgE directed toward
specific allergens.
Histologic Findings
Biopsy shows acute, subacute, or chronic dermatitis, but no
specific findings are demonstrated.
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Complicating features
1. Infections.
Patients with AD have increased susceptibility to infection or
colonization with variety of organisms.
Viral infections include Herpes simplex and molluscum
contagiosum. This suggests that the T cell associated cytokine
abnormalities seen in AD may enhance viral infections. Rarely, patients
can have generalized dissemination of H. simplex, termed eczema
herpetic or Kaposi varicelliform eruption. Systemic antiviral therapy
with acyclovir and hospitalization may be required. It is worth
remembering that mollusk is a contagious disease, and although it often
resolves spontaneously, it can spread and school-aged children need to
be treated or their lesions need to be covered. Treatment options include
cryotherapy, blistering agents, or curettage.
Fungal infections can also cause AD to flare. Malassezia furfur
(Pityrosporum ovale) is lipophilic yeast and IgE antibodies against M.
furfur have been found predominantly in patients with head and neck
dermatitis. The potential importance of M. furfur as well as other
dermatophyte infections is further supported by the reduction in clinical
severity of AD in patients treated with antifungal agents. Occasionally,
resistant cheilitis or fissures may respond to antifungal therapy.
Bacterial infections, particularly Staphylococcus aureus, are
frequent in patients with AD. S. aureus is found in more than 90% of
AD skin lesions. In contrast, only 5% of healthy subjects harbor this
organism. The importance of S. aureus is supported by the observation
that even AD patients without superinfection show reduction in severity
of skin disease when anti-staphylococcal antibiotic is added to their
treatment regimen. Although recurrent staphylococcal pustulosis can be
significant problem in AD, invasive S. aureus infections occur rarely
and should raise the possibility of immunodeficiency such as hyper-IgE
syndrome.
2. Hand dermatitis.
Patients with AD often have nonspecific hand dermatitis. This is
frequently irritant in nature and aggravated by repeated wetting,
especially in the occupational setting.
3. Ocular problems.
Ocular complications associated with AD can lead to significant
morbidity. Atopic keratoconjunctivitis is always bilateral and symptoms
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include itching, burning, tearing, and copious mucoid discharge. It is

frequently associated with eyelid dermatitis and chronic blepharitis, and
may result in visual impairment from corneal scarring. Vernal
conjunctivitis is severe bilateral recurrent chronic inflammatory process
of the upper eyelid conjunctiva, usually occurring primarily in younger
patients. It has marked seasonal incidence often in the spring. The
associated intense pruritus is exacerbated by exposure to irritants, light,
or sweating. Examination of the eye reveals papillary hypertrophy or
“cobblestoning” of the upper inner eyelid surface. Keratoconus is
conical deformity of the cornea believed to result from persistent
rubbing of the eyes in patients with AD and allergic rhinitis. Anterior
subcapsular cataracts may develop during adolescence or early adult life.
4. Psychological issues.
Patients with AD have been characterized as having high levels of
anxiety and problems in dealing with anger and hostility, which can
exacerbate the illness. Stress or frustration, in turn, can precipitate itch–
scratch cycle. In some cases, scratching is associated with significant
secondary gain or with strong component of habit. In addition, severe
disease can have significant impact on patients' self-esteem and social
interactions.
TREATMENT
Patients with atopic dermatitis do not usually require emergency
therapy, but they may visit the emergency department for treatment of
acute flares caused by eczema herpetic and bacterial infections.
Identification and elimination of exacerbating factors.
Patients with AD have lowered threshold of irritant responsiveness
and need to avoid irritants including detergents, soaps, and chemicals.
Cleansers with minimal defatting activity and neutral pH should be used
rather than soaps, especially after exposure to chlorine. Air temperatures
at home and work should be temperate to minimize sweating. In
addition, non-sensitizing sunscreens should be used to prevent sunburn.
Avoidance of foods confirmed by controlled challenges results in
clinical improvement. In dust mite allergic individuals, environmental
control measures aimed at reducing dust mite allergen loads (e.g., use of
dust mite-proof covers for pillows and mattresses and washing sheets in
hot water) have been shown to improve AD in patients allergic to dust
mite allergen.
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Depending on the climate, patients usually benefit from 5-minute,

lukewarm baths followed by the application of moisturizer such as white
petrolatum. Frequent baths with the addition of emulsifying oils (1
capful added to lukewarm bath water) for 5-10 minutes hydrate the skin.
The oil keeps the water on the skin and prevents evaporation to the
outside environment. In infants, 3 times a day is not great burden; in
adults, once or twice a day is usually all that can be achieved. Leave the
body wet after bathing. Advise patients to apply emollient such as
petrolatum or Aquaphor all over the body while wet, to seal in moisture
and allow water to be absorbed through the skin. The ointment spreads
well on wet skin. The active ingredient should be applied before the
emollient.
Steroid therapy
Topical steroids are currently the mainstay of treatment. In
association with moisturization, responses have been excellent.
Ointment bases are preferred, particularly in dry environments. Steroids
are discontinued when lesions disappear and are resumed when new
patches arise.
Limitations to topical steroid therapy
• Efficacy (do they work as they should?)
• Skin side effects
• Atrophy
• Telangiectasia
• Striae
• Perioral dermatitis
• Risk of cataracts and glaucoma
• Cushing syndrome and growth retardation

General. Topical corticosteroids have been the mainstay of

treatment for AD. They reduce inflammation and pruritus and are
effective for both the acute and chronic phases of the disease. They
impact multiple resident and infiltrating cells primarily through
suppression of inflammatory genes. Topical corticosteroids are available
in potencies ranging from extremely low to high (Table 15).
Choosing the appropriate compound. Use of particular drug should
depend on the severity and distribution of the skin lesions. Patients
should be informed of the strength of topical corticosteroid they are
given and the potential side effects. Patients often make the mistake of
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assuming that the potency of their prescribed corticosteroid is based

solely on the percent noted after the compound name (e.g., believing that
hydrocortisone 2.5% is more potent than betamethasone dipropionate
0.05%) and may apply the preparations incorrectly. In general, the
lowest potency corticosteroid that is effective should be used, although
using topical corticosteroid that is too low in potency may result in
persistence or worsening of AD. In such cases, step-care approach with
mid- or high-potency preparation (although usually not to eczema of the
face, axillae, or groin) followed by low-potency preparation may be
more successful. Often, patients are only prescribed high-potency
corticosteroid and told to discontinue use after period of time, which can
result in rebound flaring of the AD, similar to what is often seen with
oral corticosteroid therapy. Occasionally, therapy-resistant lesions may
respond to potent topical corticosteroid under occlusion, although this
approach should be used with caution and reserved primarily for eczema
of the hands or feet.

Table 15. Classification of antiinflammatory

activity of topical corticosteroids
Activity International name Trade name
Very strong Clobetasol* Dermovate*
Strong Mometasone furoate Elocom, Elomet, Elosalic
Fluticasone furoate* Cutivate*, Flutivate*
Betamethasone dipropionate* Celestoderm*
Fluocinolone acetonide* Synalar *, Synaflan*, Flucinar*
Methylprednisolone Advantan
aceponate
Averages Flumetasone* Lorinden*
Triamcinolone* Ftorocort*
Alclometasone Afloderm
Hydrocortisone butyrate Locoid
Weak Hydrocortisone acetate Unguentum Hydrocortisoni
Prednisolone Unguentum Prednisoloni
* - fluorinated corticosteroids, are not recommended in pediatric practice
 Very strong (class IV in Europe, class I in the USA);
 Strong (class III in Europe, class II and III in the USA);
 Averages (class II in Europe, class IV and V in the USA);
 Weak (class I in Europe, class VI and VII in the USA).
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Choosing the appropriate vehicle. The vehicle that the product is

formulated in can alter the potency of the steroid and move it up or
down in this classification.
Topical steroids are available in variety of bases including
ointments, creams, lotions, solutions, gels, sprays, foam, oil, and even
tape. Ointments are most occlusive, have the fewest additives, provide
better delivery of the medication, and decrease evaporative losses.
During periods of excessive heat or humidity, creams may be better
tolerated than ointments because the increased occlusion may cause
itching or folliculitis. In general, however, creams and lotions, while
easier to apply, may be less effective and can contribute to xerosis.
Solutions can be used on the scalp or other hirsute areas, although the
alcohol in them can be quite irritating when used on inflamed or
excoriated lesions. Ingredients used to formulate the different bases may
be irritating to individual patients and may cause sensitization.
Other practical considerations. Inadequate prescription size often
contributes to poor compliance and suboptimal outcome, especially in
patients with generalized disease. In addition, dispensing the prescribed
medication in larger can result in significant cost savings for the patient.
It is worth remembering that approximately 30 grams of medication are
needed to cover the entire body of average adult. The fingertip unit
(FTU), defined as the amount of topical medication that extends from
the tip to the first joint on the palmar aspect of the index finger, has been
proposed as measure for applying topical corticosteroids. It takes
approximately 1 FTU to cover the hand or groin, 2 FTUs for the face or
foot, 3 FTUs for arm, 6 FTUs for the leg, and 14 FTUs for the trunk.
Always avoid placing emollient either under or over area of topical
steroid application, as this will reduce the effectiveness of the steroid.
Side effects of topical corticosteroids are infrequent with low- to
medium-potency topical corticosteroids when used appropriately, even
when applied for extended periods of time. More potent topical steroids
cause thinning of the skin most commonly. Several weeks of topical
corticosteroid (especially, fluorinated) application can lead to decrease
in collagen and elastin synthesis and subsequent skin fragility, dermal
atrophy, striae, telangiectasia, purpura, and poor wound healing. In
addition, hypopigmentation, secondary infections, and acneiform
eruptions may occur. Local side effects are most likely to occur on the
face and on the intertriginous areas, and therefore only low-potency
corticosteroids should be used in these areas on a routine basis. Perioral
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dermatitis may also occur with the chronic use of topical corticosteroids
on the face and is characterized by erythema, scaling, and follicular
papules and pustules that occur around the mouth, alar creases, and
sometimes on the upper lateral eyelids.
Systemic side effects are extremely rare with topical
corticosteroids. However, prolonged use of high- and super-high-
potency compounds, especially if used under occlusion, may cause
systemic side effects and should therefore be used judiciously.
Oral corticosteroids. The use of oral corticosteroids should be
avoided in chronic disease. Although patients may experience rapid and
dramatic relief with oral corticosteroids, this is all too often followed by
rebound flaring of the dermatitis. Short courses of prednisolone are
occasionally used with the introduction of other treatment measures.
Gradual tapering of the oral corticosteroid and intensification of topical
skin care may decrease the occurrence of rebound exacerbations that can
occur with systemic corticosteroid use.
Antiinfective therapy.
Antibacterial therapy. Systemic antibiotics may be necessary to
treat AD secondarily infected with S. aureus. Cephalosporins or other
antibiotics given for 7 to 10 days are usually effective. Long-term
maintenance antibiotic therapy should be avoided because it may result
in colonization by resistant organisms. The topical anti-staphylococcal
antibiotic mupirocin (Bactroban) applied three times daily to affected
areas for 7 to 10 days can be used to treat localized areas of
involvement. In patients found to have positive nasal cultures for S.
aureus, treatment with nasal preparation of mupirocin twice daily for 5
days may reduce nasal carriage of S. aureus. Although antibacterial
cleansers have been shown to be effective in reducing bacterial skin
flora, they can be irritating to the skin of atopic patients.
Antiviral therapy. Patients with disseminated eczema herpetic, also
referred to as Kaposi varicelliform eruption, usually require treatment
with systemic acyclovir. Recurrent cutaneous herpetic infections can be
suppressed with a prophylactic oral antiviral.
Antifungal therapy. Superficial dermatophytosis and P. ovale can
be treated with topical or rarely systemic antifungal drugs. Subset of
patients with AD may respond to course of empiric treatment with
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antifungal agents. However, the clinical significance of fungi as an

etiologic factor in AD remains unresolved.
Nowadays, pharmaceutical market shows combined preparations,
which consist of corticosteroids, antifungal, antibiotics in different
compositions. For example, Lotrisone contains clotrimazole (antifungal)
and beclomethasone dipropionate (high-potency corticosteroid).
Immunosupressores
Tacrolimus (Prograf) is immunomodulator that acts as calcineurin
inhibitor. Stinging sensation may occur following application, but this
can be minimized by applying the medication only when the skin is dry.
The burning usually disappears within 2-3 days. Tacrolimus is ointment
and is indicated for moderate-to-severe AD. It is indicated for children
older than 2 years.
Pimecrolimus (Elidel) 1% is produced in cream base for use twice
a day; it is indicated for mild AD in persons older than 2 years and is
particularly useful on the face.
These agents are much more expensive than corticosteroids and
should only be used as second-line therapy.
Antihistamines
Pruritus is the cardinal symptom of AD and even partial reduction
can result in significant improvement in quality of life for patients with
severe disease. In general, antihistamines do not have large effect on
pruritis associated with AD. First generation antihistamines appear to be
most useful because of their tranquilizing effects, and can be dosed
primarily in the evening to avoid daytime drowsiness. In patients with
very severe pruritus and sleep disruption, the tricyclic antidepressant
doxepin (which has both histamine H1- and H2-receptor binding affinity
and long half-life) may be given in the evening. Treatment of AD with
topical antihistamines and local anesthetics should be avoided because
of potential sensitization.
Other treatments,
Probiotics have been explored as therapeutic option for the
treatment of AD. The rationale for their use is that bacterial products
may induce immune response of the Th1 series instead of Th2 and could
therefore inhibit the development of allergic IgE antibody production.
This research has yet to be proven.
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Phototherapy – UV-A, UV-B, combination of both, psoralen plus

UV-A (PUVA), or UV-B1 (narrow-band UV-B) therapy may be used.
Long-term adverse effects of skin malignancies in fair-skinned
individuals should be weighed against the benefits.
In patients with severe disease, and particularly in adults,
methotrexate, azathioprine, cyclosporine, and mycophenolate mofetil
have been used with success.
Ketotifen (calcium channel blocker) may be effective.
Nonmedical efforts
Clothing should be soft next to the skin. Cotton is comfortable and
can be layered in winter.
Cool temperatures, particularly at night, are helpful because
sweating causes irritation and itch.
Humidifier (cool mist) prevents excess drying and should be used
in both winter, when the heating dries the atmosphere, and in the
summer, when air conditioning absorbs the moisture from the air.
Clothes should be washed in a mild detergent with no bleach or
fabric softener.
Prevention
Since there is no cure for atopic eczema, treatment should mainly
involve discovering the triggers of allergic reactions and learning to
avoid them.
Diet: Originally controversial, the association of food allergy with
atopic dermatitis has now been clearly demonstrated. Many common
food allergens can trigger allergic reaction: such as milk, nuts, cheese,
tomatoes, wheat, yeast, soy, and corn. Many of these allergens are
common ingredients in grocery store products (especially corn syrup,
which is sugar substitute). Specialty health food stores often carry
products that do not contain common allergens. If a child avoids these
allergens early on, the frequency of reactions to this later in life is
decreased significantly. Breastfeeding is the best way to avoid these
problems, but if that is unavailable, then hydrolysed formulas are
preferred to cow's milk.
Environment and Lifestyle: Since dust is very common allergen
and irritant, adults with AD should likely avoid smoking, as well as the
inhalation of dust in general. The dander from the fur of dogs and cats
may also trigger inflammatory response. It is common misconception
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that simply removing animal from room will prevent allergic reaction
from occurring. Room must be completely free of animal dander in
order to prevent allergic reaction. Anger, stress, and lack of sleep are
also factors that are known to aggravate skin syndrome. Excessive heat
(especially with humidity) and coldness are known to provoke
outbreaks, as well as sudden and extreme temperature swings.
Atopic dermatitis and quality of life
Despite the symptoms caused by atopic dermatitis, it is possible for
people with the disorder to maintain high quality of life. The keys to
improved quality of life are education, awareness, and developing a
partnership among the patient, family, and doctor.
Education of patients and their families is essential component of
successful management of chronic illness such as AD. Adequate time
and teaching materials are necessary to provide effective education,
because most patients or parents will forget or confuse the skin care
recommendations given them without written instructions. For many
patients, written step-care treatment plan will lead to improved outcomes
and this should be reviewed and adjusted at follow-up visits.
When a child has atopic dermatitis, the entire family situation may
be affected. It is important that families have additional support to help
them to cope with the stress and frustration associated with the disease.
The child may be fussy and difficult and often is unable to keep from
scratching and rubbing the skin. Distracting the child and providing as
many activities that keep the hands busy are the key but requires much
effort and work on the part of the parents or caregivers. Another issue
family’s face is the social and emotional stress associated with
disfigurement caused by atopic dermatitis. The child may face difficulty
in school or other social relationships and may need additional support
and encouragement from family members.
Adults with atopic dermatitis can enhance their quality of life by
caring regularly for their skin and being mindful of other effects of the
disease and how to treat them. Adults should develop skin-care regimen
as part of their daily routine, which can be adapted as circumstances and
skin conditions change. Stress management and relaxation techniques
may help decrease the likelihood of flares due to emotional stress.
Developing network of support that includes family, friends, health
professionals, and support groups or organizations can be beneficial.
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Chronic anxiety and depression may be relieved by short-term

psychological therapy.
Recognizing the situations when scratching is most likely to occur
may also help. For example, many patients find that they scratch more
when they are idle. Structured activity that keeps their hands occupied
may prevent further damage to the skin. Occupational counseling also
may be helpful to identify or change career goals if job involves contact
with irritants or involves frequent hand washing, such as kitchen work or
auto mechanics.
For estimation of clinical symptoms gravity now most widely use
scales SCORAD (Scoring Atopic Dermatitis), EASY (Eczema Area and
Severity Index), SASSAD (SixAreaSixSignAtopic Dermatitis Severity
Score).
The scale SCORAD is most often used, which considers
prevalence of dermal process (A), intensity of clinical implications (B)
and subjective symptoms (C).

A. Prevalence of dermal
process – the area of the damaged
skin (%) which count by "a nine"
rule (Fig. 17). For estimation also
it is possible to use "a palm" rule
(the area of a palmar surface of a
brush accept peer 1 % of all
surface of skin).
B. For definition of intensity
of clinical implications count up
expression of 6 signs: Fig. 17. "A nine" rule
o redness (erythema),  Head and neck 9%
o swelling  Upper limbs 9% each
 Lower limbs 18% each
(edema/papule),
 Anterior trunk 18%
o oozing / crusting,  Back 18%
o excoriations,  1% each for genitals, each palm
o lichenification, and the back of each hand.
o xeroderma (dryness).
Each sign estimate from 0 to 3 points (0 - is absent, 1 - it is weakly
expressed, 2 - is expressed moderately, 3 - is expressed sharply;
fractional value are not supposed). Estimation of symptoms make on
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skin site where they are as much as possible expressed (Fig. 18). The
total sum of points can be from 0 (dermal lesions are absent) to 18 (the
maximum intensity of all symptoms). The same site of the damaged skin
can be used for estimation of expression of any quantity of symptoms.
C. Subjective symptoms – itch of skin and dream disturbance –
estimate at children who are at age over 7 years. The patient or his
parents is offered to specify point within 10-centimetric ruler,
corresponding, in their opinion, degree of itch and the dream
disturbances, averaged for last 3 days. The score of subjective symptoms
can be from 0 to 20.

Redness: 1; Swelling: 0; Redness: 2; Swelling: 1; Redness: 1; Swelling: 1;

Oozing: 0; Scratching: 0; Oozing: 1; Scratching: 1; Oozing: 1; Scratching: 3;
Lichenification: 1; Lichenification: 1; Lichenification: 3;
Dryness: 1. Dryness: 1. Dryness: 1.
Fig. 18. Atopic dermatitis: intensity scoring.

The general estimation count under the formula: А/5 + 7В/2 + C.

The total sum of points on scale SCORAD can make from 0 (clinical
implications of lesion of skin are absent) to 103 (as much as possible
expressed implications of atopic dermatitis).
Although symptoms of atopic dermatitis can be very difficult and
uncomfortable, the disease can be successfully managed. People with
atopic dermatitis, as well as their families, can lead healthy, normal
lives. Long-term management may include treatment with allergist to
control internal allergies and dermatologist to monitor the skin-care
component.

Questions for self-control:

1. Enumerate of atopic dermatitis triggers.
2. Name criteria of atopic dermatitis diagnosis.
3. Describe peculiarities of atopic dermatitis in infants, children, and
adults.
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4. Characterize the treatment of atopic dermatitis.

5. Characterize topical steroids in therapy of atopic dermatitis.
6. Characterize the principles of lifestyle care.

CONTACT DERMATITIS

Contact dermatitis is any inflammatory reaction of the skin that

results from direct contact with offending agent. Most cases of contact
dermatitis can be classified as allergic contact dermatitis (ACD) or non-
allergic (irritant) contact dermatitis (ICD). Additional type of contact
dermatitis includes photodermatitis.
Pathophysiology. The main pathologic feature of contact
dermatitis is intercellular edema of the epidermis. This initial reaction
may result in intraepidermal vesicle and bulla formation in acute cases
and papules, scaling, and lichenification in chronic cases. Within the
dermal layer, various cells congregate around the dilated capillaries to
aid in inflammatory response.
Allergic contact dermatitis affects only individuals previously
sensitized to the contactant. It represents delayed (cell-mediated, type
IV) hypersensitivity reaction and classically requires several hours to
complete the cascade of cellular immunity before symptoms manifest.
ICD results from direct injury to the skin. It affects individuals
exposed to specific irritants and generally produces stinging or burning
sensation within seconds of exposure. Alternatively, extended exposure
to mild irritant can cause chronic form of ICD. In this case, dryness
precipitates erythematous state, which ultimately leads to cracking and
the formation of painful fissures.
Most cases of contact dermatitis are easily treated, but cases with
unrecognized etiology can result in long-term morbidity. In rare cases,
epidermal contact with allergen results in IgE-mediated immediate
hypersensitivity reaction causing anaphylactic shock. Anaphylactic
shock, if untreated, can result in death. Contact dermatitis can present
concomitantly with chemical burns, which can be life-threatening,
depending on the severity of exposure.
Low humidity and cold temperatures increase incidence of contact
dermatitis. One notable contrast to this is ICD due to cement exposure,
which is more common in the summer in hot and humid areas.
Women are at highest risk following childbirth. The female-to-
male ratio is 2:1.
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ACD is most common during adulthood, but it affects all ages. A

frequent cause of ACD in elderly patients is topical medication. ICD
affects very young and very old patients more severely. The most
common cause of ICD in infants is diaper dermatitis.
Clinical implications
In allergic contact dermatitis, lesions appear within 24-96 hours of
exposure to the allergen. The main symptom, in addition to the lesion, is
pruritus. Location of the dermatitis is helpful in identifying the cause.
Most heavily contaminated areas break out first, followed by areas of
lesser exposure. In more severe ACD reactions, lesions can form in
adjacent areas of the skin that never had direct contact with the
offending agent.
Irritant contact dermatitis is divided into 2 types.
 Mild irritants require prolonged or repeated exposure before
inflammation is noted.
 Strong irritants (e.g., strong acids, alkalis) can produce
immediate reactions similar to thermal burns.
Unlike ACD, ICD will only erupt in areas of the skin that have had
direct contact with the irritant.
Photodermatitis is diagnosed by the presence of lesions limited to
sun-exposed body areas. Burning is the primary complaint in phototoxic
reactions. Pruritus is the main complaint in photoallergic reactions. Skin
contact with photosensitizing agents found in some plants (notably
limes) followed by ultraviolet (UV) irradiation can precipitate type of
photodermatitis called phytophotodermatitis.
Most cases of contact dermatitis have similar appearance
regardless of the mechanism or cause of inflammation. Inflammatory
responses can be categorized into acute, subacute, and chronic phases. In
all phases, key feature is localization to the area of contact.
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Fig. 19. Acute contact dermatitis. Fig. 20. Chronic contact dermatitis
Acute contact dermatitis presents with bright red edematous skin.
In moderate-to-severe cases, clear fluid-filled vesicles or bulla appear
(Fig. 19). As the lesions break, skin becomes exudative and weeps clear
fluid. In acute ICD, these lesions and surrounding erythema are sharply
demarcated and located in the distribution of the area of contact.
Subacute contact dermatitis is characterized by the formation of
papules instead of the vesicles more typical of the acute phase.
Additionally, less edema is seen in the subacute phase. Dry scales are
sometimes seen.
Chronic contact dermatitis presents with scaling, skin fissuring,
and lichenification but only minimal edema (Fig. 20). Excoriations can
also be observed.

Allergic contact dermatitis

Contributing factors include allergen concentration, duration of
exposure, and presence of other skin diseases. Repeated exposures to
ACD-inducing allergen tend to cause incrementally more severe
reactions (Table 16).

Table 16. The most widespread contactants

substance source
Nickel ornaments, buttons, zipper, spectacle frame
Cobalt ornaments, stomatologic materials and
prostheses
Chrome cement, decolourants, tattoo
Formaldegyde shampoo, cosmetics, deodorant
Paraphenylene colouring agent in hair-dyes, cloths, gum,
diamine photographic chemicals
Ethylene diamine conserving agent in creams, colours, gum,
antifreeze
Thiuram rubber goods, hair-dyes
Colophony polyrole, Emplastrum, lacquer
Parabens preservatives in cosmetics, creams
Epoxy resin glue, polyvinylchloride products
Lanolinum cosmetic agents, creams
Vegetable Toxicodendron genus (e.g., poison ivy, poison
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allergens oak, poison sumac); and various plants which

are part of cosmetic agents, creams, medicines
Topical medicines antibiotics, anesthetics, etc.

Irritant contact dermatitis

Irritant produces direct local cytotoxic effect on the cells of the
epidermis, with subsequent inflammatory response in the dermis. The
most common site is the hand. Individuals with atopic dermatitis have
inborn constitutional skin weakness. The risk of developing irritant
contact dermatitis is particularly high in individuals with eczema
affecting the hands. Although irritant contact dermatitis is caused mostly
by chemicals (e.g., acids, alkalis, solvents, oxidants), plants (e.g., hot
peppers, garlic, tobacco) have also been implicated. Severity of the
reaction is related to the amount and duration of exposure to the irritant.
Most cases of ICD are acute in onset, in which symptoms develop
within seconds of exposure.
Common irritants
• Water
• Skin cleansers
• Industrial cleaning agents
• Acids and alkalis
• Oils and organic solvents
• Oxidizing and reducing agents
• Plants
• Animal products
• Miscellaneous
Clinical effects of irritants
• Dermatitis
• Ulcerations
• Acneiform rashes
• Miliaria
• Disorders of pigmentation
• Alopecia
• Urticaria
• Granulomas
Alternatively, prolonged exposure to low-level irritant can lead to
chronic ICD. Soaps and prolonged exposure to water, often due to
occupational soaking of the hands, are typical causes of chronic ICD.
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Contact dermatitis on the thigh of recreational jogger after long

run. This individual noted running through shrubs, which likely caused
the rash. The linear plaques and confluent vesicles and papules on the
inferior aspect of the thigh are common presentation of thus dermatitis.
Photodermatitis
Irradiation of certain substances by ultraviolet light results in the
transformation of the substance into allergens (photoallergic) or irritants
(phototoxic). Common example of this is phytophotodermatitis, in
which phototoxic reaction occurs after skin that has been in contact with
citrus fruit (or another plant contact) is exposed to sunlight. This
exposure to sun chemically alters previously benign agent in citrus
(called furocoumarin or psoralen) into skin allergen. Many plant families
are known to cause phototoxic response. Besides citrus, these plant
families include mulberry (figs) and Umbelliferae (parsnip, celery).
Medications (particularly sulfa drugs, thiazides, and tetracycline) have
also been implicated in photodermatitis.
Clinical differences
Properly differentiating between irritant and allergic contact
dermatitis will rarely change initial therapy, but it may aid in the
identification of the offending agent and prevent reinjury. Telling
allergic contact dermatitis apart from irritant contact dermatitis can be
very difficult.
ICD can occur secondary to the first lifetime exposure to agent,
whereas ACD requires initial sensitization to offending antigen before
inflammatory reaction can occur. ICD is dose-dependent and has
threshold of exposure below which no reaction will occur. Following
prior sensitization, ACD can occur after any amount of contact with
antigen. It appears immediately in irritant contact dermatitis, but
sometimes in allergic contact dermatitis the rash does not appear for 1-2
days after the exposure. Additionally, ICD only occurs in the discreet
areas of direct contact with the offending chemical, whereas ACD can
involve the surrounding skin and other tissues.
Skin may papule, or may be raised red rash, sometimes in pattern
that points to the offending agent. Skin will itch and perhaps burn.
Irritant contact dermatitis tends to be more painful than itchy. Irritant
contact dermatitis often affects the hands, which have been exposed by
resting in or dipping into container (sink, pail, tub) containing the
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irritant. Once reaction starts, it may take as long as 4 weeks to resolve

completely.
Panniculitis (cellulitis) should be excluded. On physical
examination, both contact dermatitis and cellulitis can present with
poorly marginated areas of erythema and occasionally edema. Cellulitis
can be best differentiated by taking focused patient history. Furthermore,
cellulitis can cause pain, in contrast to the pruritic quality of ACD.
Finally, cellulitis can be associated with fever, malaise, local
lymphadenopathy, and leukocytosis; none of these findings are
consistent with contact dermatitis. If skin blistering has occurred, herpes
zoster as well as herpes simplex and impetigo should also be considered.
Disease to differentiate with
 Bites, Insects  Herpes Simplex
 Cellulites  Herpes Zoster
 Atopic Dermatitis,  Herpetic Whitlow
 Exfoliative Dermatitis,  Impetigo
 Erysipelas  Scabies
 Erythema Multiforme  Vulvovaginitis
 Psoriasis

Diagnostics
No chemical marker for the diagnosis of ACD and ICD is known.
Laboratory testing is seldom necessary. A swab of infected skin may
help with the isolation of specific organism and antibiotic sensitivity.
In case of ACD dermatologist or allergist applies multiple potential
allergens into the skin of the patient (skin tests). The presence of
erythema, papules, or vesicles can indicate positive test.
Pathologic findings obtained from biopsy specimens include
intercellular edema and bulla.
Treatment
Main principles of Self-Care
Avoid touching the trigger. Washing with soap and cool water can
remove or inactivate most of the offending substance, if it is done
immediately after exposure. If blistering develops, cold moist
compresses applied for 30 minutes 3 times a day are helpful. Calamine
lotion and cool oatmeal baths may relieve itching.
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Medications
The definitive treatment of both ICD and ACD is the identification
and removal of any potential causal agents. Topical soaks with cool tap
water, Burow solution (1:40 dilution), saline (1 tsp/pint), or silver nitrate
solution (25.5%). Lukewarm water baths (antipruritic), Emollients (e.g.,
white petrolatum, Eucerin) may be beneficial chronic cases. Large
vesicles may benefit from therapeutic drainage (but not removing the
vesicle tops). These lesions should then be covered with dressing soaked
in Burow solution.
Corticosteroid may be prescribed to combat inflammation in
localized area. This medication may be applied to skin as cream or
ointment. If the reaction covers relatively large portion of the skin or is
severe, corticosteroid that is taken as pills or as injection may be
prescribed.
Prescription antihistamines may be given if nonprescription
strengths are not adequate also can be given to relieve itching. Do not
apply antihistamine lotions to the skin, because patient may have
allergic contact dermatitis from the lotion itself.
Prevention
If the patient knows what causes the dermatitis, avoid that trigger.
If the patient cannot avoid the trigger altogether, take steps to protect
skin from the trigger. Wearing protective clothing such as long sleeves,
long pants, and gloves helps protect the skin from allergens and irritants.
Protection is especially important at industrial site, but it is also
important when working outdoors where you could come in contact with
plants from the poison ivy family as well as with lawn and garden
chemicals, cleaning solvents, and other toxic substances. Take care to
avoid poison ivy, poison oak, and poison sumac when enjoying the
outdoors. If the patient does become exposed, wash the area
immediately with soap and cool water to prevent rash from developing.

Questions for self-control:

1. Enumerate ACD and ICD triggers.
2. Describe peculiarities of ACD, ICD, and photodermatitis.
3. Characterize treatment of ACD and ICD.
4. Characterize the principles of lifestyle care.

LATEX ALLERGY
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Latex allergy – the disease caused by sensibilization to latex.

Latex, plant rubber, is milky juice of macrotherm Hevea
brasiliensis families Euphorbiaceae. Many plants effecting latex are
known, but industrial and commercial value was gained by this type.
13 allergens of natural latex which possess larger or smaller
allergenic activity are characterized at the moment, but exact quantity
(full list) of allergens for today is not known.
The latex allergy is one of the actual problems of the up-to-date
allergology. It is bound to wide utilization of subjects containing latex in
life during last 15-20 years: children's dummies, balloons, toys,
condoms, underwear, gloves, catheters, drainages, rubber tooth
prostheses, endotracheal tubes, clysters, surgical gloves and others.
The problem of latex allergy becomes also complicated becouse
latex allergens have cross-reactions with allergens of some foodstuff
(similar epitopes to latex proteins and some types of nutrition), and also
with pollen allergens.
The product possessing cross reactivity with latex
– Bananas, – potato, – chestnuts,
– avocado, – papaya, – persian walnuts,
– kiwi, – plum, – tomatoes,
– peaches, – cherry, – shrimps, etc.
– citrus, – wild strawberry,
– guava, – apricot,

Sensibilization paths at latex allergy

 aerogenic (inhalation), at inhalation of the latex particles getting
to air for the account of latex powder with which coat gloves
from within and outside
 direct contact to skin (during diaphoresis some proteins are
solved and inpoured through cutaneous coverings)
 parenteral path (patients with frequent catheterization of pots at
repeated operations and intravenous introductions of drugs
through catheter)
 cross sensibilization.
Risk groups on latex allergy development:
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1. medical staff professionally contacting with products from latex

(surgeons, procedural and operational staff nurses,
stomatologists, gynecologists and other specialities);
2. health care workers;
3. workers of rubber industry occupied on effecting of latex and
products from it;
4. workers of the food-processing industry (for the account of
presence of blanket epitopes at latex proteins and some views of
nutrition);
5. patients with atopic diseases, first of all suffering, atopic
dermatitis, pollinosis and food allergy;
6. patients with urogenital anomalies, spina bifida,
meningomielocele;
7. patients, suffering from the diseases demanding frequent
surgical interventions.
Provoking factors of response development to latex are frequent
washing of arms and operation with chemical reagents. The important
role in the development of latex allergy is played by presence of such
concomitant diseases, as eczema or dermatitis.
Kinds of the responses arising at contact to latex
 allergic
o I type – IgE dependent
o IV type – cellular-mediated
 non allergic (latex as irritant)
Clinical implications of latex allergy depend on a kind of
sensibilization, can arise in some seconds till 24 hours and are
characterized by diversity of symptoms from local (contact dermatitis)
before serious system reactions (atopic dermatitis, local and generalized
urticaria, Quincke's edema, rinoconjunctival and bronchoobstructive
syndromes, anaphylactic shock).
 188

Fig. 21. Allergic

contact dermatitis
after latex gloves
using.

Contact dermatitis from latex gloves in health care worker. Note

the sharp demarcations at the perimeter of the contact area (Fig 21).
Diagnostics
Diagnosis of latex allergy is based on the data of the anamnesis,
clinic, laboratory tests spotting latex-specific IgE and response of target
cells of allergic response (mast cells and basophils), and also skin
(application or prik-tests) tests with latex allergen, in need of
provocative tests.
Treatment
Like most types of contact dermatitis, the most important treatment
is identification and avoidance of the offending agent. Medication is
prescribed depending on clinical implications of latex allergy
(dermatitis, urticaria, bronchial asthma or anaphylactic shock).

Questions for self-control:

1. Enumerate latex dermatitis causing factors.
2. Name risk groups on latex allergy development
3. Name ways of sensibilization to latex allergen
4. Name clinical symptoms at latex allergy.
5. What is the feature of latex allergy diagnostics?

ALLERGIC CONJUNCTIVITIS

The ocular surface may exhibit a wide variety of immunologic

responses that may result in conjunctival and corneal inflammation.
Allergic conjunctivitis may be divided into 5 major subcategories.
Seasonal allergic conjunctivitis (SAC) and perennial allergic
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conjunctivitis (PAC) are commonly grouped together. Vernal

keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and
giant papillary conjunctivitis (GPC) constitute the remaining subtypes of
allergic conjunctivitis.
Seasonal and perennial allergic conjunctivitis
Since conjunctiva is a mucosal surface similar to the nasal mucosa,
the same allergens that trigger allergic rhinitis may be involved in the
pathogenesis of allergic conjunctivitis. Common airborne antigens,
including pollen, grass, and weeds, may provoke the symptoms of acute
allergic conjunctivitis, such as ocular itching, redness, burning, and
tearing. The main distinction between SAC and PAC, as implied by the
name, is the timing of symptoms. Individuals with SAC typically have
symptoms of acute allergic conjunctivitis for defined period of time, that
is, in spring, when the predominant airborne allergen is tree pollen; in
summer, when the predominant allergen is grass pollen; or in fall, when
the predominant allergen is weed pollen. Typically, persons with SAC
are symptom-free during the winter months in cooler climates because
of the decreased airborne transmission of these allergens.
In contrast, individuals with PAC may have symptoms that last the
whole year; thus, PAC may not be caused exclusively by seasonal
allergens, although they may play a role. Other common household
allergens, such as dust mite, cockroaches, and pet dander, may be
responsible for the symptoms of PAC.
Vernal keratoconjunctivitis
VKC is chronic bilateral inflammation of the conjunctiva,
commonly associated with personal and/or family history of atopy. More
than 90% of patients with VKC exhibit one or more atopic conditions,
such as asthma, eczema, or seasonal allergic rhinitis. VKC is typically
recognized as type I hypersensitivity reaction, evidence has been found
that supports some involvement of type IV hypersensitivity reaction.
Atopic keratoconjunctivitis
AKC is bilateral inflammation of conjunctiva and eyelids, which
has strong association with atopic dermatitis. It is also type I
hypersensitivity disorder with many similarities to VKC, yet AKC is
distinct in number of ways. Approximately 3% of the population is
afflicted with atopic dermatitis, and, of these, approximately 25% have
ocular involvement.
Giant papillary conjunctivitis
 190

GPC is immune-mediated inflammatory disorder of superior tarsal

conjunctiva. As the name implies, the primary finding is the presence of
"giant" papillae, which are typically greater than 0.3 mm in diameter. It
is believed that GPC represents immunologic reaction to variety of
foreign bodies, which may cause prolonged mechanical irritation to the
superior tarsal conjunctiva. Although contact lenses (hard and soft) are
the most common irritant, ocular prostheses, extruded scleral buckles,
and exposed sutures following previous surgical intervention may
precipitate GPC.
Clinical implication
Perhaps the most important feature in the clinical history is the
symptom of itching. Without itching, the diagnosis of allergic
conjunctivitis is suspect.
Seasonal and perennial allergic conjunctivitis
Classic signs of allergic conjunctivitis include injection of
conjunctival vessels as well as varying degrees of chemosis
(conjunctival edema) and eyelid edema (Fig 22).
The conjunctiva often has milky appearance due to obscuration of
superficial blood vessels by edema within the substantia propria of the
conjunctiva. Edema is generally believed to be the direct result of
increased vascular permeability caused by release of histamine from
conjunctival mast cells.
Fig. 22.
Allergic conjunctivitis
(bilateral epiphora,
redness, eyelids edema)

Vernal keratoconjunctivitis
VKC may be subdivided into 2 varieties, as follows: palpebral and
limbal. The classic conjunctival sign in palpebral VKC is the presence of
giant papillae. They most commonly occur on the superior tarsal
conjunctiva; usually, the inferior tarsal conjunctiva is unaffected. Giant
papillae assume a flattop appearance, which often is described as
"cobblestone papillae." In severe cases, large papillae may cause
mechanical ptosis.
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Ropy mucous discharge may be present, which commonly is

associated with tarsal papillae. Large numbers of eosinophils are present
in the discharge.
The limbal form of VKC commonly occurs in dark-skinned
individuals, such as those from Africa or India. As the name implies,
papillae tend to occur at the limbus and have thick gelatinous
appearance. They commonly are associated with multiple white spots
(Horner-Trantas dots), which are collections of degenerated epithelial
cells and eosinophils. Horner-Trantas dots are transient, with each
appearance rarely lasting more than 1 week.
While corneal vascularization is rare, the cornea may be affected in
variety of ways. Punctate epithelial keratopathy (PEK) may be due to the
toxic effect of inflammatory mediators released from the conjunctiva
and may be precursor of the characteristic shield ulcer, which is
pathognomonic of VKC. As the areas of PEK coalesce, they may result
in frank epithelial erosion resulting in shield ulcer, which is typically
shallow with white irregular epithelial borders. Although the
pathogenesis of shield ulcer is not well understood, major factor in
promoting development may be chronic mechanical irritation from the
giant tarsal papillae. Some evidence suggests that the major basic protein
released from eosinophils may promote ulceration.
Another type of corneal involvement is vernal pseudogerontoxon,
which is degenerative lesion in the peripheral cornea resembling corneal
arcus. Keratoconus may be seen in chronic cases, which may be
associated with chronic eye rubbing.
Atopic keratoconjunctivitis
AKC may affect eyelid skin and lid margin, conjunctiva, cornea,
and lens. Skin of the eyelids may exhibit eczematous dermatitis with
dry, scaly, and inflamed skin. Lid margins may show meibomian gland
dysfunction and keratinization. Staphylococcal colonization of eyelid
margins is very common and may result in blepharitis. Conjunctiva may
show chemosis and typically papillary reaction, which is more
prominent in the inferior tarsal conjunctiva, in contrast to that seen in
vernal keratoconjunctivitis.
Hyperplasia of limbal regions may result in gelatinous thickening,
similar to the limbal variant of VKC, and Horner-Trantas dots also may
be present, although rarely. Fibrosis or scarring of the conjunctiva may
result in shortened fornix or symblepharon formation with chronic
inflammation. Corneal involvement ranges from punctate epithelial
 192

keratopathy early in the course of the disease, to neovascularization,

stromal scarring, and possibly ulceration. There is strong association
between herpes simplex viral keratitis and AKC.
Another corneal finding, which may be associated with AKC, is
keratoconus, which may stem from chronic eye rubbing. Characteristic
lenticular changes in AKC include anterior or posterior subcapsular
cataract formation. Lens opacities are usually bilateral and present in the
second decade of life but progress very slowly. There may be
association with the long-term use of topical corticosteroids. Note that
there is increased incidence of retinal detachment following surgical
removal of cataracts in patients with atopic dermatitis; the exact
mechanism is unknown.
Giant papillary conjunctivitis
Examination of superior tarsal conjunctiva reveals the presence of
large cobblestone papillae, which are generally 0.3 mm or greater in
diameter and, in severe cases, may cause mechanical ptosis of the upper
lid. Three zones of superior tarsal conjunctiva were described. Zone 1 is
located closest to the fornix and is the most inferior portion of the tarsal
conjunctiva seen when the upper eyelid is everted. Zone 3 is located
closest to the eyelid margin. Zone 2 is located between zone 1 and zone
3. GPC associated with localized irritant, such as exposed suture or
filtering bleb, is typically localized to the area overlying these inciting
lesions. Another clinical sign of GPC may be chronic bulbar
conjunctival injection and inflammation due to prolonged and persistent
use of contact lenses.
Laboratory Studies
Seasonal and perennial allergic conjunctivitis
Superficial conjunctival scrapings may help to establish the
diagnosis by revealing eosinophils, but only in the most severe cases,
since eosinophils are typically present in the deeper layers of the
substantia propria of the conjunctiva. Therefore, the absence of
eosinophils on conjunctival scraping does not rule out the diagnosis of
allergic conjunctivitis.
Many investigators have described measurement of tear levels of
IgE, histamine, and tryptase, as indicators of allergic activity.
Additionally, skin testing by allergist may provide definitive
diagnosis and pinpoint the offending allergen(s). Also provocative
 193

conjunctival test is made with any home, epidermal allergens and pollen
for diagnostics of allergic conjunctivitis (Fig. 23).

Fig. 23. Positive

conjunctival provocative test
(Allergen is instilled in the left
eye, indifferent solution
(negative control) – in the
right eye).

Vernal keratoconjunctivitis
Conjunctival scrapings of the superior tarsal conjunctiva and of
Horner-Trantas dots show abundance of eosinophils. Conjunctival
biopsy reveals that there are large numbers of mast cells within the
substantia propria. Histochemical analysis of mast cells present in VKC
reveals neutral proteases tryptase and chymase. There is enhanced
fibroblast proliferation, which leads to deposition of collagen within the
substantia propria resulting in conjunctival thickening. B and T
lymphocytes are present locally, which combine to produce IgE.
Specific IgE and IgG as well as the inflammatory mediators such as
histamine and tryptase have been isolated from tears of patients with
VKC.
Atopic keratoconjunctivitis
Conjunctival scrapings of patients with AKC may demonstrate the
presence of eosinophils, although the number is not as significant as that
seen in VKC. Additionally, free eosinophilic granules, which are seen in
VKC, are not seen in AKC. Mast cells also may be found within the
substantia propria of the conjunctiva in greater numbers. There is
increased amount of IgE in the tears of patients with AKC.
Giant papillary conjunctivitis
Histologic findings in GPC consist of cellular infiltration of the
conjunctiva by a number of cell types. Plasma cells, lymphocytes, mast
cells, eosinophils, and basophils have been identified within the
substantia propria. Mast cells also may be found in the epithelium.
Tear levels of immunoglobulin, especially IgE and tryptase also
are elevated. It is believed that the stimulus for development of GPC is
 194

immunologic reaction to specific antigen in predisposed individuals.

Mechanical trauma to the conjunctiva may be contributing factor.
Medical Care
Seasonal and perennial allergic conjunctivitis
Pharmacologic intervention may help alleviate the symptoms of
acute allergic conjunctivitis. Various classes of medication may be
effective against the symptoms of acute allergic conjunctivitis; each is
directed at specific point in the inflammatory and allergic cascade.
Artificial tear substitutes provide barrier function and help to
improve the first-line defense at the level of conjunctival mucosa. These
agents help to dilute various allergens and inflammatory mediators that
may be present on the ocular surface, and they help flush the ocular
surface of these agents.
Systemic and/or topical antihistamines may be given to relieve
acute symptoms due to interaction of histamine at ocular H1 and H2
receptors. While systemic antihistamines often relieve ocular allergic
symptoms, patients may experience systemic adverse affects, such as
drowsiness and dry mouth.
Topical antihistamines competitively and reversibly block
histamine receptors and relieve itching and redness but only for short
time. These medications do not affect other proinflammatory mediators,
such as prostaglandins and leukotrienes, which remain uninhibited. A
number of topical antihistamines are available, including epinastine
(Elestat) and azelastine (Optivar). Both are potent antihistamines that
have rapid onset and are effective in relieving the signs and symptoms of
allergic conjunctivitis.
Vasoconstrictors are available either alone or in conjunction with
antihistamines to provide short-term relief of vascular injection and
redness. These pharmacologic agents are ineffective against severe
ocular allergies and against other more severe forms of allergic
conjunctivitis, such as atopic and vernal disease.
Common mast cell stabilizers include cromolyn sodium,
nedocromil (Alocril), and ketotifen (Zaditor) are mast cell stabilizers and
inhibit histamine release.
Nonsteroidal anti-inflammatory drugs act on the cyclooxygenase
metabolic pathway and inhibit production of prostaglandins and
thromboxanes. They have no role in blocking mediators formed by the
lipoxygenase pathway, such as leukotrienes.
 195

Corticosteroids remain one of the most potent pharmacologic

agents used in the treatment of ocular allergy. They act at the first step of
the arachidonic acid pathway by inhibiting phospholipase, which is
responsible for converting membrane phospholipid into arachidonic
acid. By preventing the formation of arachidonic acid, corticosteroids
effectively block both cyclooxygenase and lipoxygenase pathways, in
contrast to NSAIDs, which act only on the cyclooxygenase pathway.
Corticosteroids do have limitations, including ocular adverse effects,
such as delayed wound healing, secondary infection, elevated intraocular
pressure, and formation of cataract. In addition, the anti-inflammatory
and immunosuppressive affects are nonspecific.
Vernal keratoconjunctivitis
Various pharmacologic agents may be used to provide varying
degrees of relief. Mucolytic agents, such as acetylcysteine, may help
minimize the discharge and provide temporary relief. Vasoconstrictors
may reduce hyperemia but are not effective in severe cases on long-term
basis. Similarly, topical antihistamines have no significant long-term
benefit.
Mast cell stabilizers are perhaps the mainstay of treatment of VKC
and are safe for long-term use. However, topical corticosteroids
generally become necessary for most patients with significant
symptoms. Systemic steroids may be used but generally are not
necessary for moderate cases of VKC.
In some cases topical cyclosporine (Restasis) may be effective in
reducing some of the signs and symptoms of VKC without adverse
effects. Treatment of corneal shield ulcer may require antibiotic-steroid
ointments.
Atopic keratoconjunctivitis
Treatment of patients with AKC is similar to that of VKC, in that it
includes controlling the environment and avoiding allergens and may
require topical and systemic medications to provide symptomatic relief.
As with VKC, topical vasoconstrictors and antihistamines may provide
very limited, short-term relief; they are not the mainstay of treatment.
As with VKC, topical mast cell stabilizers and topical
corticosteroids provide significant relief of symptoms. Mast cell
stabilizers have to be used for several weeks prior to seeing clinical
effect, and, in the interim, topical steroids used in a pulsed fashion may
help to control symptoms. Systemic antihistamines that are specific for
 196

H1 histamine receptors have been found to be helpful. Systemic steroids

rarely are required, except in cases of vision-threatening complications.
Systemic cyclosporine, which has been shown to be effective in the
treatment of atopic dermatitis, has shown promise in controlling ocular
inflammation in AKC. Postulated mechanism of action is inhibition of
the ability of T lymphocytes to produce interleukin 2 (IL-2), which is
responsible for recruiting and activating new T cells. However, as with
any systemic therapy, adverse effects may be significant; therefore,
monitoring of serum levels and renal function is essential.
Concomitant herpes simplex virus infection should be treated with
either topical or oral antiviral agents as needed.
Subset of patients with recalcitrant and debilitating AKC may
benefit from plasmapheresis, if had hyperimmunoglobulinemia E.
Giant papillary conjunctivitis
Goal of treatment in GPC is resolution of symptoms and
restoration of functional use of contact lenses or ocular prosthetics.
Pharmacologic treatment of GPC includes the use of mast cell
stabilizers, topical corticosteroids, and antihistamines similar to that in
the other immunologic conjunctival disorders discussed previously. As
always, care must be taken when using topical corticosteroids; pulsed
regimen is recommended to minimize adverse reactions.
In severe cases of keratoconjunctivitis surgical care is
recommended.
Also for treatment of allergic conjunctivitis can be recommended
ASIT.

Questions for self-control:

1. Characterize etiopathogenesis of allergic conjunctivitis.
2. Name clinical signs of different types of allergic conjunctivitis.
3. Characterize diagnostics of allergic conjunctivitis.
4. Name differential diagnostics of allergic conjunctivitis.
5. Characterize allergic conjunctivitis treatment.

ALLERGIC RHINITIS

Rhinitis is defined as inflammation of the nasal membranes and is

characterized by symptom complex that consists of any combination of
the following: sneezing, nasal congestion, nasal itching, and rhinorrhea.
The eyes, ears, sinuses, and throat can also be involved. Allergic rhinitis
 197

is the most common cause of rhinitis. It is extremely common condition,

affecting approximately 20% of the population. While allergic rhinitis is
not life-threatening condition, complications can occur and the condition
can significantly impair quality of life.
The causes of allergic rhinitis may differ depending on whether the
symptoms are seasonal, perennial, or sporadic/episodic. Some patients
are sensitive to multiple allergens and can have perennial allergic rhinitis
with seasonal exacerbations. While food allergy can cause rhinitis,
particularly in children, it is rarely cause of allergic rhinitis in the
absence of gastrointestinal or skin symptoms.
Seasonal allergic rhinitis is commonly caused by allergy to
seasonal pollens and outdoor molds.
Pollens (tree, grass, and weed)
Tree pollens, which vary by geographic location, are typically
present in high counts during the spring, although some species produce
their pollens in the fall. Common tree families associated with allergic
rhinitis include birch, oak, maple, cedar, olive, and elm.
Grass pollens also vary by geographic location. Most of the
common grass species are associated with allergic rhinitis, including
Kentucky bluegrass, orchard, redtop, timothy, vernal, meadow fescue,
Bermuda, and perennial rye. A number of these grasses are cross-
reactive, meaning that they have similar antigenic structures (e.g.,
proteins recognized by specific IgE in allergic sensitization).
Consequently, person who is allergic to one species is also likely to be
sensitive to a number of other species. The grass pollens are most
prominent from the late spring through the fall but can be present year-
round in warmer climates. In much of southern Africa, the most
common pollens are the grass pollen. Examples of common grass
pollens found in this region include rye grass, Bermuda grass, kikuyu
grass, etc. The grass flowering seasons in South Africa can be relatively
long (up to 10 months due to the warm climate) and thus induce
hypersensitive reactions throughout much of the year.
Weed pollens also vary geographically. Many of the weeds, such
as short ragweed, which is common cause of allergic rhinitis in much of
the United States, are most prominent in the late summer and fall. Other
weed pollens are present year-round, particularly in warmer climates.
Weeds are not thought to be as important in Southern Africa. Common
weeds associated with allergic rhinitis include short ragweed, western
ragweed, pigweed, sage, yellow dock, sheep sorrel, English plantain.
 198

Outdoor molds
Atmospheric conditions can affect the growth and dispersion of a
number of molds; therefore, their airborne prevalence may vary
depending on climate and season. For example, Alternaria and
Cladosporium are particularly prevalent in the dry and windy conditions.
Their dispersion often peaks on sunny afternoons. They are virtually
absent when snow is on the ground in winter, and they peak in the
summer months and early fall. Aspergillus and Penicillium can be found
both outdoors and indoors (particularly in humid households), with
variable growth depending on the season or climate. Their spores can
also be dispersed in dry conditions.
Perennial allergic rhinitis is typically caused by allergens within
the home but can also be caused by outdoor allergens that are present
year-round. In warmer climates, grass pollens can be present throughout
the year. In some climatic zones, individuals may be symptomatic due to
trees and grasses in warmer months and molds and weeds in winter.
House dust mites Two major house dust mite species are associated
with allergic rhinitis. These are Dermatophagoides farinae and
Dermatophagoides pteronyssinus. These mites feed on organic material
in households, particularly the skin that is shed from humans and pets.
They can be found in carpets, upholstered furniture, pillows, mattresses,
comforters, and stuffed toys. While they thrive in warmer temperatures
and high humidity, they can be found a year-round in many households.
On the other hand, dust mites are rare in arid climates.
Pets Allergy to indoor pets is common cause of perennial allergic
rhinitis. Cat and dog allergies are encountered most commonly in allergy
practice, although allergy has been reported to occur with most of the
furry animals and birds that are kept as indoor pets.
Cockroaches While cockroach allergy is most frequently
considered a cause of asthma, particularly in the inner city, it can also
cause perennial allergic rhinitis in infested households.
Sporadic allergic rhinitis, intermittent brief episodes of allergic
rhinitis, is caused by intermittent exposure to allergen. Often, this is due
to pets or animals to which person is not usually exposed. Sporadic
allergic rhinitis can also be due to pollens, molds, or indoor allergens to
which a person is not usually exposed. While allergy to specific foods
can cause rhinitis, an individual affected by food allergy usually has
some combination of gastrointestinal, skin, and lung involvement as
well. In this situation, the historic findings usually suggest association
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with particular food. Watery rhinorrhea occurring shortly after eating

may be vasomotor (and non allergic) in nature, mediated via the vagus
nerve. This is often called gustatory rhinitis.
Occupational allergic rhinitis, which is caused by exposure to
allergens in the workplace, can be sporadic, seasonal, or perennial.
People who work close to animals (e.g., veterinarians, laboratory
researchers, farm workers) might have episodic symptoms when
exposed to certain animals, daily symptoms while at the workplace, or
even continual symptoms (which can persist in the evenings and
weekends with severe sensitivity due to persistent late-phase
inflammation). Some workers who may have seasonal symptoms
include farmers, agricultural workers (exposure to pollens, animals,
mold spores, and grains), and other outdoor workers. Other significant
occupational allergens that may cause allergic rhinitis include wood
dust, latex (due to inhalation of powder from gloves), acid anhydrides,
glues, and psyllium (e.g., nursing home workers who administer it as
medication).
Mechanisms of allergic rhinitis
Allergic rhinitis involves inflammation of the mucous membranes
of the nose, eyes, eustachian tubes, middle ear, sinuses, and pharynx.
The nose is involved invariably, and other organs are affected in certain
individuals. Inflammation of the mucous membranes is characterized by
complex interaction of inflammatory mediators but ultimately is
triggered by IgE-mediated response to extrinsic protein. The tendency to
develop allergic, or IgE-mediated reactions to extrinsic allergens
(proteins capable of causing an allergic reaction) is of genetic character.
First type mediators via various actions, ultimately lead to the
symptoms of rhinorrhea (e.g., nasal congestion, sneezing, itching,
redness, tearing, swelling, ear pressure, postnasal drip). Mucous glands
are stimulated, which leads to increased secretions. Vascular
permeability is increased, leading to plasma exudation. Vasodilation
occurs, leading to congestion and pressure. Sensory nerves are
stimulated, leading to sneezing and itching. All these events can occur
within some minutes; hence, this reaction is called the early, or
immediate, phase of the reaction. During the period of 4-8 hours, these
mediators, through complex interplay of events, lead to the recruitment
of other inflammatory cells, such as neutrophils, eosinophils,
lymphocytes, and macrophages in the mucosa. This results in continued
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inflammation, termed the late-phase response. The symptoms of the late-

phase response are similar to those of the early phase, but less sneezing
and itching and more congestion and mucus production tend to occur.
The late phase may persist for hours or days. Systemic effects, including
fatigue, sleepiness, and malaise, can occur from the inflammatory
response. These symptoms often contribute to impaired quality of life.

Classification of Allergic rhinitis

according to the course:
1. light intermittent of disease
2. light persistent course
3. medium persistent course
4. serious persistent course
according to the causes
1. Seasonal allergic rhinitis (also known as hay fever )
2. Perennial (year-round) allergic rhinitis

Diagnostic of allergic rhinitis

History Obtaining a detailed case history is important in the
evaluation of allergic rhinitis. Important elements include evaluation of
the nature, duration, and course time of the symptoms; possible trigger
factors for the symptoms; response to medications; comorbid conditions;
family history of allergic diseases; environmental exposures;
occupational exposures; and effects on quality of life.
Because allergic rhinitis has significant genetic component,
positive family history for atopy makes the diagnosis more likely. In
fact, greater risk of allergic rhinitis exists if both parents are atopic than
if one parent is atopic. However, the cause of allergic rhinitis appears to
be multifactorial, and person with no family history of allergic rhinitis
can develop allergic rhinitis.
The age of onset of symptoms and whether the symptoms have
been present continuously since the onset. While the onset of allergic
rhinitis can occur well in adulthood, most patients develop the
symptoms by the age of 20.
Patients with allergic rhinitis may have other atopic conditions
such as asthma or atopic dermatitis. Among the patients with allergic
rhinitis, 20% also have symptoms of asthma. Uncontrolled allergic
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rhinitis may cause worsening of asthma or even atopic dermatitis.

Explore this possibility when obtaining the patient history.
Thorough history taking of environmental exposures helps to
identify specific allergic triggers. This should include investigation of
risk factors of exposure to perennial and season allergens.
Response to treatment with antihistamines supports the diagnosis
of allergic rhinitis, although sneezing, itching, and rhinorrhea associated
with nonallergic rhinitis can be also improved with antihistamines.
Response to intranasal corticosteroids supports the diagnosis of allergic
rhinitis, although some cases of nonallergic rhinitis (particularly the
nonallergic rhinitis with eosinophils syndrome [NARES]) are also
improved with nasal steroids.
Physical
The symptoms that can be associated with allergic rhinitis include
sneezing, itching (of nose, eyes, ears, palate), rhinorrhea, postnasal drip,
congestion, anosmia, headache, earache, tearing, red eyes, eye swelling,
cough, fatigue, drowsiness, and malaise.
The physical examination should be focused on the nose, but
examination of facial features, eyes, ears, oropharynx, neck, lungs, and
skin is also important. Look for the physical findings that may be
consistent with a systemic disease that is associated with rhinitis.
General facial features
 "Allergic shiners" are dark circles around the eyes and are related
to vasodilation or nasal congestion.
 "Nasal crease" is horizontal crease across the lower half of the
bridge of the nose that is caused by repeated upward rubbing of the tip
of the nose by the palm of the hand (e.g., the "allergic salute").
Nose
Nasal examination is best accomplished by means of nasal
speculum or otoscope with nasal adapter. In a specialist's office, rigid or
flexible rhinolaryngoscope may be used. The mucosa of the nasal
turbinates may be swollen (boggy) and have pale, bluish-gray color.
Some patients may have predominant erythema of the mucosa, which
can also be observed with rhinitis medicamentosa, infection, or
vasomotor rhinitis. While pale, boggy, blue-gray mucosa is typical for
allergic rhinitis, mucosal examination findings cannot definitively
distinguish between allergic and nonallergic causes of rhinitis (Fig. 24).
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Fig. 24. Rhinoscopy of

allergic rhinitis (rhinorrhea,
rhinedema)

Thin and watery secretions are frequently associated with allergic

rhinitis, while thick and purulent secretions are usually associated with
sinusitis; however, thicker, purulent, colored mucus can also occur in
allergic rhinitis.
The nasal septum should be examined for any deviation or septal
perforation, which may be present due to chronic rhinitis, granulomatous
disease, cocaine abuse, prior surgery, topical decongestant abuse, or,
rarely, topical steroid overuse.
The nasal cavity should be observed for other masses such as
polyps or tumors. Polyps are firm gray masses that are often attached by
stalk, which may not be visible. After spraying topical decongestant,
polyps do not shrink, while the surrounding nasal mucosa does shrink.
Ears, eyes, and oropharynx
Perform otoscopy to look for tympanic membrane retraction, air-
fluid levels, or bubbles. Performing pneumatic otoscopy is to look for
abnormal tympanic membrane mobility. These findings can be
associated with allergic rhinitis, particularly if eustachian tube
dysfunction or secondary otitis media is present.
Ocular examination may reveal the injection and swelling of the
palpebral conjunctivae, with excess tear production. Dennie-Morgan
lines (prominent creases below the inferior eyelid) are associated with
allergic rhinitis.
The term "cobblestoning" is used to describe streaks of lymphoid
tissue on the posterior pharynx, which is commonly observed with
allergic rhinitis. Tonsillar hypertrophy can also be observed.
Malocclusion (overbite) and high-arched palate can be observed in
patients who breathe thtough their mouths excessively. Leaking nasal
secretions into the larynx can lead to cough.
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Any of systemic diseases that may cause rhinitis are sarcoidosis,

hypothyroidism, immunodeficiency, ciliary dyskinesia syndrome, other
connective tissue diseases.
Sinusitis occurs quite frequently. Other possible complications
include otitis media, sleep disturbance or apnea, dental problems
(overbite), and palatal abnormalities. The treatment plan must be
different if one of these complications is present. Nasal polyps occur in
association with allergic rhinitis, although whether allergic rhinitis
actually causes polyps remains unclear. Polyps may not respond to
medical treatment and might predispose patient to sinusitis or sleep
disturbance (due to congestion).
Laboratory studies
Elevated eosinophil count supports the diagnosis of allergic
rhinitis, but it is neither sensitive nor specific for the diagnosis. The
results can sometimes be helpful when combined with other factors.
While patients with allergic rhinitis are more likely to have
elevated total IgE level than the normal population, this test is neither
sensitive nor specific for allergic rhinitis. Therefore, this test is not
generally used alone to establish the diagnosis of allergic rhinitis, but the
results can be helpful in some cases when combined with other factors.
The amount of specific IgE produced to particular allergen
approximately correlates with the allergic sensitivity to that substance.
Allergy testing
Allergy skin tests (immediate hypersensitivity testing) are in vivo
method of determining immediate (IgE-mediated) hypersensitivity to
specific allergens. Sensitivity to virtually all the allergens that cause
allergic rhinitis can be determined with skin testing. If skin tests show
poor positive results provocative tests are carried out.
Medical Care
The management of allergic rhinitis consists of 3 major categories
of treatment, (1) environmental control measures and allergen
avoidance, (2) pharmacological management, and (3) immunotherapy.
Environmental control measures and allergen avoidance: These
involve both the avoidance of known allergens and avoidance of
nonspecific, or irritant, trigger factors. Consider environmental control
measures, when possible, in all cases of allergic rhinitis.
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The majority of clinical signs of rhinitis is stopped by reception of

H1 receptors antagonists. Antihistamine drugs of the 2nd generation
(dezloratadine, Acrivastine, Cetirizine, Ebastine, Loratadine,
fexophenadine), possessing a slight sedation, have powerful effect on
rhinitis symptoms (a sneezing, a burning sensation in nasal cavity, a
rhinorrhea).
Antihistamines for local usage (azelastin hydrocholoride,
Levocabastine hydrochloride) are characterized by quick start action.
They reduce rhinorrhea and sneezing, react to ophthalmic symptoms and
can be applied in light and medium forms of allergic rhinitis.
Membranostabilizators are presented by Cromolyn sodium
(lomuzole, cromosol, etc. – nasal spray). Their effect on allergic rhinitis
is low enough, and dosage regimen is also inconvenient (4-6 times a
day). On the other hand, they are safe and deprived of side effects.
Topical corticosteroids have found the application in treatment of
allergic rhinitis as well. Topical corticosteroids reduce nasal
hyperreactivity, actively depress inflammation of the mucous. Their
effect manifests in 6-12 hours and reaches maximum in some days.
These are highly effective drugs of the first choice for treatment of
allergic rhinitis with moderately expressed or persistent symptoms.
These drugs owing to features of pharmacokinetics can to be used at
very low risk of development of systemic effects.
Topical corticosteroids as nasal spray
 Beclomethasone dipropionate (Beconase, Alanase, Vancenase),
 Fluticasone propionate is marketed as Flonase (USA and Canada)
Flixonase (EU, South Africa, Israel and Brazil). Teva markets
fluticasone propionate as Nasofan in Italy.
 Fluticasone furoate is marketed by GlaxoSmithKline as Veramyst
(US) and Avamys (Australia, Canada, EU, South Africa and
Mexico). It is marketed under the name "Furamist" in India by
Cipla.
 Flunisolide (AeroBid, Nasalide, Nasarel);
 Budesonide is marketed by AstraZeneca as a nasal spray under the
brand name Rhinocort; in Denmark, as Rhinosol;
 Mometasone furoate (Nasonex).

Systemic corticosteroids stop all symptoms of rhinitis and even

recover sense of smell, but because of the numerous side effects are
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extremely seldom applied in treatment of allergic rhinitis, being

considered to be an agent of last hope.
Topical decongestants (oxymetazoline, xylomethazoline, etc.)
recover nasal breath, but their action on manifestations of AR is limited.
Vasohypertonic drugs can be applied only for a short course, their long
(over 10 days) use can result in the development of "a rebound
syndrome" and medicamental vasomotor rhinitis.
Oral decongestants (especially, pseudoephedrine) to lesser degree
react on nasal breath, but do not cause rebound. Short-term courses of
treatment by systemic decongestants do not result in the functional and
morphological changes in mucosa. The adverse events associated with
oral decongestants are dose-dependent and include irritability, dizziness,
headaches, tremor and insomnia. Oral decongestants should be given to
susceptible patients such as pregnant women and the elderly with
caution.
Allergen Specific Immunotherapy (desensitization): Considerable
body of clinical research has established the effectiveness of high-dose
allergy shots in reducing symptoms and medication requirements.
Success rates have been demonstrated to be as high as 80-90% for
certain allergens. It is a long-term process; noticeable improvement is
not often observed within 6-12 months, and, if helpful, therapy should
be continued for 3-5 years. Immunotherapy cannot be performed without
risk because severe systemic allergic reactions which can sometimes
occur. For these reasons, carefully consider the risks and benefits of
immunotherapy in each patient and weigh against the risks and benefits
of other management options.

Questions for self-control:

1. Characterize the etiopathogenesis of allergic rhinitis.
2. Characterize the allergic rhinitis history.
3. Name the clinical symptoms of allergic rhinitis.
4. What is the feature of allergic rhinitis diagnostics (seasonal and
perennial)?
5. What the principles of allergic rhinitis treatment (in the acute
phase and remission)?

BRONCHIAL ASTHMA
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Bronchial asthma (from the Greek άσθμα, ásthma, "panting") is

one of the most widespread and serious allergic diseases, entering the
so-called «a major three of allergic illnesses». The case rate of the
yielded pathology grows every year. Now not less than 6 % of the
population have bronchial asthma of this or that severity level. The
major alarm is caused by huge number of non taped cases of disease. As
a rule, tyese are easy shapes of a bronchial asthma which can hide from
diagnoses «an obstructive bronchitis» or it is simple «a chronic
bronchitis». The case rate among children is still high and in some
regions reaches up to 20 %. Among children, there are a great number of
patients with indeterminate diagnosis.
Bronchial asthma is the chronic inflammatory disease of
respiratory tracts associated with hyperreactivity of airway which results
in repeated episodes of a goose breathing, a dyspnea, constraint in a
breast or tussis, especially at night or early in the morning provided by
bronchospasm, mucous hypersecretion, and bronchi mucosa edema.
These symptoms are bound with spread, but variable obstruction of
respiratory tracts which is often reversible spontaneously or below the
influence of treatment (Global Strategy for Asthma Management and
Prevention, Global Initiative for Asthma (GINA), 2006, 2010). It affects
the bronchi, but not alveoli as in emphysema.
Etiologic classification
1. Allergic
 IgE-dependent
 IgE-independent
2. Nonallergic
3. Mixed (both allergic and nonallergic)
Depending on treatment effectiveness
1. Controlled (checked) asthma
2. Particulate checked asthma
3. Uncontrollable asthma
Asthma triggers may include:
 Tobacco smoke
 Infections such as colds, flu, or pneumonia
 Physical exercise
 Air pollution and toxins
 Weather, especially extreme changes in temperature
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 Drugs (such as aspirin, NSAID, and beta-blockers)

 Food additives
 Emotional stress and anxiety
 Singing, laughing, or crying
 Smoking, perfumes, or sprays
 Acid reflux
Allergic bronchial asthma is connected with allergens arriving at
inhalation path, more often: household (house dust, various types of
mites in it, library dust, feather and down of pillows), pollen, epidermal
(wool and dandruff of animals, pens of auks, feeds for fish, etc.), fungal
allergens. Food allergy as the cause of bronchial asthma occurs
extremely rarely, but is possible as well. For food allergy the cross
allergic responses in this case are more characteristic (e.g., allergens of
birch pollen and apple fruit). Dyspnea attacks can develop only in
available sensibilization.
Mechanisms of bronchial asthma
The pathophysiology of asthma is complex and involves airway
inflammation, intermittent obstruction, and bronchial hyperreactivity.
Immune mechanisms have been supposed to be involved in
bronchial asthma. Induction of specific hyperreactivity to allergen is
largely IgE mediated and is mast cell dependent. In addition to IgE, it is
recognized that CD4+ T lymphocytes and their cytokine products,
including interleukin (IL)-4, IL-5, and IL-13, are important in the
pathogenesis of asthma and the induction and/or maintenance of
bronchial asthma. Cytokines from activated CD4+ T lymphocytes,
differentiated toward Th2 profile, have been shown to be implicated in
the development of bronchial asthma. In particular, IL-4 and IL-13 seem
to regulate this response. After inhalation of allergen, CD4+ cells
infiltrate the airways, followed by accumulation and degranulation of
eosinophils and asthma occurs, which appears to depend totally on IL-5.
Mast cells have bystander role in the recruitment of eosinophils in
allergen inhalation but do not appear to be involved in bronchial asthma
(Fig. 25).
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Fig. 25. Scheme of bronchial asthma immune pathogenesis.

Airway hyperreactivity in asthma is an exaggerated response to

numerous exogenous and endogenous stimuli. The degree of airway
hyper responsiveness generally correlates with the clinical severity of
asthma.
The involved mechanisms include direct stimulation of airway
smooth muscle and indirect stimulation by pharmacologically active
substances from mediator-secreting cells such as mast cells or
nonmyelinated sensory neurons.
Airflow obstruction can be caused by variety of changes,
including:
 acute bronchoconstriction,
 airway edema,
 chronic mucous plug formation,
 airway remodeling.
Acute bronchoconstriction is the consequence of IgE-dependent
mediator release upon exposure to aeroallergens and is the primary
component of the early asthmatic response. Airway edema occurs 6-24
hours following allergen challenge and is referred to as the late
asthmatic response. Chronic mucous plug formation consists of exudate
of serum proteins and cell debris that may take weeks to resolve. Airway
remodeling is associated with structural changes due to long-standing
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inflammation and may profoundly affect the extent of reversibility of

airway obstruction (Fig. 26).

Fig. 26. Pathology of airways in bronchial asthma.

Signs and Symptoms of Bronchial Asthma

 Shortness of breath
 Chest tightness
 Wheezing
 Excessive coughing or cough that keeps awake at night
Bronchial Asthma diagnosing
Asthma tests include:
The most important tests are pulmonary function tests.
Spirometry Pulmonary function test (PFT) is performed to measure
breathing capacity. Spirometer is used.
Peak Expiratory Flow (PEF) Using a device called peak flow
meter, patient forcefully exhale into the tube to measure the force of air
which is exhaled out of lungs. Peak flow monitoring allows to control
the course of asthma at home.
Laboratory Studies
The serum IgE level is elevated only approximately half the time in
patients with allergic disease. Checking IgE level is not indicated in
most patients with asthma.
Sputum and serum eosinophilia tests are not routinely performed
or required for diagnosis. Decrease in sputum eosinophilia may suggest
 210

asthma control or responsiveness to inhaled steroids. Note that finding

of greater than 15% serum eosinophilia can indicate parasites, drug
allergies, or eosinophilic pulmonary disorders.
Exhaled nitric oxide may also predict airway inflammation and
asthmatic control but it is more expensive to measure.
In older patients, elevated serum brain natriuretic peptide (BNP)
level may help to suggest heart failure as a primary or contributing cause
of dyspnea and wheezing.
To determine specific allergen sensitivity in vitro RAST is very
useful in advising patients about allergen avoidance techniques.
Imaging Studies
Other Tests
Chest X-ray: These are taken only if pneumonia, large airway
lesions, or heart failure are suggested or if symptoms are atypical or
refractory to therapy, if a patient has unilateral or focal wheezing, or if
the patient has new adult-onset asthma.
Modified or limited sinus CT scans: Consider CT scans of the
sinuses if chronic sinusitis is suggested. About 65% of people with
severe asthma have concomitant sinusitis.
Chest CT scans: These are indicated in selected patients to help
exclude interstitial lung disease, bronchiectasis, bronchiolitis, or
infection.
Echocardiograms: These are performed if congestive heart failure
is suggested based on the history and physical examination findings.
Symptom improvement with asthma therapy is suggestive but not
diagnostic of asthma. Symptoms alone do not necessarily reflect asthma
severity. Infants may be treated empirically. In patients older than 5
years, objectively demonstrating reversible airflow obstruction with
pulmonary function tests is possible and essential.
o Obstruction is defined as ratio less than 70% of forced expiratory
volume per 1 second (FEV1) to forced vital capacity (FVC). FEV1
is normally greater than 80% of values predicted by age. Young
patients with supranormal FVC can sometimes have reduced
FEV1-to-FVC ratio without having obstructive lung disease.
o Reversibility can be shown by administering short-acting β2
agonist inhaler with resultant 10-12% and more than 200-mL
improvement in FEV1 or FVC. If there is no response, 2-3 weeks
of oral or inhaled corticosteroids may be required to demonstrate
improvement in airflow. Note that airways obstruction in some
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patients with chronic obstructive pulmonary disease may be

partially reversible.
o 15% fall in FEV1 after 6 minutes of running or other exercise can
be diagnostic of exercise-induced bronchospasm.
o 20% variation in the peak expiratory flow rate (PEFR) between
high and low values is highly suggestive of asthma, but formal
pulmonary function testing (as above) is recommended because the
PEFR is extremely effort-dependent.
o Asthma specialist can perform bronchoprovocation testing with
exercise, histamine, methacholine, or eucapnic voluntary
hyperventilation. The results from these tests have very high
negative predictive value and are useful for excluding the diagnosis
of asthma. The authors most commonly use challenge with
increasing doses of inhaled methacholine. 20% decline in FEV1
with methacholine concentration of 8 mg/mL or less is considered
to be positive (abnormal) test result. This testing should be avoided
during pregnancy because of the risk of precipitating asthma attack
and because methacholine is a class C drug.
Allergen-inhalation challenges can be performed in selected
patients but are not generally needed or recommended. This test requires
available allergen solution and specialized centers able to handle
potentially significant reactions. A negative test finding may allow
continued exposure to allergen (e.g., family pet); a positive test finding
can dramatically indicate that the patient should avoid particular
allergen. This test is often needed to help in diagnosis of occupational
asthma.
If restrictive or other lung disease is suggested by history, physical
examination, or pulmonary function testing findings, additional data
must be obtained, including complete lung volumes, respiratory muscle
strength, diffusion capacity, and high-resolution CT scan.
Perform barium swallow, endoscopy, or 24-hour pH probe helps to
diagnose gastroesophageal reflux disease (GERD) if a patient’s
condition is refractory to asthma therapy. Empiric medical therapy is
often tried without performing these tests, especially if a patient has the
symptoms of GERD.
Measure oxygenation (e.g., with pulse oximetry or arterial blood
gas testing) in selected patients.
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Sputum analysis results show creola bodies (e.g., bronchial

regenerative cells with nuclear atypia), Charcot-Leyden crystals (e.g.,
residual product of eosinophils), and Curschmann spirals (e.g.,
concentric layers of mucous and debris).
Skin testing to determine possible allergic reaction in the patient.
Testing is recommended for antigens to which the patient is exposed
rather than testing with standard panel. Skin test findings have very high
positive and negative predictive values; however, negative test finding
does not rule out the possibility that allergen has an impact on the
patient’s asthma. Conversely, positive test finding does not mean that
patient is exposed to allergen or that the patient will react to it in natural
exposure. Identification of allergen triggers can assist in formulating
environmental control strategy.
Histologic Findings The diagnosis of asthma is not made
histologically. However, autopsy and bronchoscopic biopsy findings
include mucus plugging, inflammatory cell infiltrates and debris,
vascular permeability, mucosal edema, and epithelial exfoliation.
Remodeling, consisting of hypertrophy of smooth muscle, squamous and
goblet cell metaplasia, mucous gland hypertrophy, and basement
membrane thickening due to collagen and other matrix protein
deposition, is present.

Clinical stages and severity of asthma attack are presented in the

table 17 and 18 (Guideline on the Management of Asthma).

Table 17. Clinical classification of asthma severity.

Severity Symptom Nighttime Peak Variability
frequency symptoms expiratory of peak
flow rate or expiratory
FEV1 of flow rate
predicted or FEV1
Intermittent < once a week ≤ twice per ≥ 80% < 20%
month predicted
Mild > once a week > twice per ≥ 80% 20 – 30%
persistent but month predicted
< once per
day
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Moderate Daily > once per 60 – 80% > 30%

persistent week predicted
Severe Daily Frequently < 60% > 30%
persistent predicted

Table 18. Bronchial asthma attacks’ severity

Sign/Symptom Mild Moderate Severe Imminent
respiratory
arrest
Alertness May show Agitated Agitated Confused/
agitation Drowsy
Breathlessness On walking On talking Even at rest
Talks in Sentences Phrases Words
Wheeze Moderate Loud Loud Absent
Accessory Usually, Used Used
muscle not used
Respiratory rate Increased Increased Often > 30
(/min)
Pulse rate 100 100 – 120 > 120 < 60
(/min) (Bradycardia)
PaO2 Normal > 60 < 60,
possible
cyanosis
PaCO2 < 45 < 45 > 45

MEDICAL CARE
Current treatment protocols recommend preventive medications
such as inhaled corticosteroid, which helps to suppress inflammation and
reduces the swelling of the airways, in anyone who has frequent attacks
(more than twice a week) the best way to suppress bronchoconstriction
is to use short-acting bronchodilator If symptoms persist, additional
preventive drugs are added until the asthma is controlled. With the
proper use of preventive drugs, asthmatics can avoid the complications
that result from overuse of giving medications.
Asthmatics sometimes stop taking their preventive medication
when they feel fine and have no breathing problems. This often results
in further attacks, and there is no improvement for a long time.
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Preventive agents include the following.

Inhaled glucocorticoids are the most widely used of the preventive
medications and normally come as inhaler devices (beclomethasone,
budesonide, flunisolide, fluticasone, mometasone, and triamcinolone).
← Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and
zileuton).
← Mast cell stabilizers (cromoglicate, and nedocromil).
← Antimuscarinic/anticholinergic (ipratropium, oxitropium, and
tiotropium), which have mixed relieving and preventuve effect. (These
are rarely used in preventive treatment of asthma, except in patients who
do not tolerate β2-agonists.)
← Methylxanthines (theophylline and aminophylline), which are
sometimes suggested if sufficient control cannot be achieved with
inhaled glucocorticoids and long-acting β-agonists alone.
← Antihistamines, often used to treat allergic symptoms that may
underlie the chronic inflammation.
← Allergen-specific Immunotherapy may be recommended in some
cases where allergy is the suspected cause or trigger of asthma.
Depending on the allergen, it can be given orally or by injection.
Omalizumab, monoclonal antibodies against IgE; this can help
patients with severe allergic asthma that does not respond to other drugs
(only in case of laboratory proved rising of IgE level). However, it is
expensive and must be injected.
Methotrexate is occasionally used in some difficult-to-treat
patients.
← If chronic acid indigestion (GERD) contributes to patient's asthma,
it should also be treated, because it may prolong the respiratory problem.
Trigger avoidance As is common with respiratory disease,
smoking is believed to adversely affect asthmatics in several ways,
including an increased severity of symptoms, a more rapid decline of
lung function, and decreased response to preventive medications.
Automobile emissions are considered even more significant cause and
aggravating factor. Asthmatics who smoke or who live near arterial
roads typically require additional medications to help control their
disease. Furthermore, exposure of both non-smokers and smokers to
wood smoke, gas stove fumes and second-hand smoke is detrimental,
resulting in more severe asthma, more emergency room visits, and more
asthma-related hospital admissions. Smoking cessation and avoidance of
second-hand smoke is strongly encouraged in asthmatics.
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For those in whom exercise can trigger asthma attack (exercise-

induced asthma), higher levels of ventilation and cold, dry air tend to
exacerbate attacks. For this reason, activities in which a patient breathes
in large amounts of cold air, such as skiing and running, tends to be
worse for asthmatics, whereas swimming in indoor, heated pool, with
warm, humid air, is less likely to provoke response.
If asthmatic lives with smoker use of air filter or room air cleaner
is likely to be helpful. Secondhand smoke can worsen the symptoms.
The same is true for those with hay fever (allergic rhino sinusitis) or
COPD (emphysema or chronic bronchitis). Room air cleaners remove
small particles that are in the air near the air cleaner. However, room air
cleaners do not remove small allergen particles that are caused by local
disturbances, such as the microscopic house dust mite feces that
surround pillow when your head hits it or you turn over in bed. There
are several types of air filters available.
Treatment of bronchial asthma exacerbation
The specific medical treatment is recommended to patients with
asthma, It depends on the severity of their illness and the frequency of
their symptoms. Bronchodilators are recommended for short-term relief
in all patients. For those who experience occasional attacks, no other
medication is needed. For those with mild persistent disease (more than
two attacks a week), low-dose inhaled glucocorticoids or alternatively,
oral leukotriene modifier, mast-cell stabilizer, or theophylline may be
administered. For those who suffer from daily attacks, higher dose of
glucocorticoid in conjunction with long-acting inhaled β2-agonist may
be prescribed; alternatively, leukotriene modifier or theophylline may
substitute for the β2-agonist. In severe asthmatics, oral glucocorticoids
may be added to these treatments during severe attacks.
Symptomatic control of episodes of wheezing and shortness of
breath is generally achieved with short-acting bronchodilators. These are
typically provided in pocket-sized, metered-dose inhalers (MDIs). In
young sufferers, who may have difficulty with the coordination
necessary to use inhalers, or those with poor ability to hold their breath
for 10 seconds after inhaler use (generally the elderly), asthma spacer is
used. The spacer is a plastic cylinder that mixes the medication with air
in simple tube, making it easier for patients to receive full dose of the
drug and allows for the active agent to be dispersed into smaller, more
fully inhaled bits.
 216

Nebulizer which provides larger, continuous dose can also be used.

Nebulizers work by vaporizing dose of medication in saline solution into
steady stream of foggy vapour, which the patient inhales continuously
until the full dosage is administered. Nebulizers may be helpful to some
patients experiencing severe attack, babies and children. Such patients
may not be able to inhale deeply, so regular inhalers may not deliver
medication deeply into the lungs, even on repeated attempts. Since
nebulizer delivers the medication continuously, it is thought that the first
few inhalations may relax the airways enough to allow the following
inhalations to draw in more medication.
Relievers include:
Short-acting, selective β2-adrenoceptor agonists, such as
salbutamol (albuterol USAN), levalbuterol, terbutaline and bitolterol.
Tremors, the major side effect, have been greatly reduced by inhaled
delivery, which allows the drug to target the lungs specifically; oral and
injected medications are delivered throughout the body. There may also
be cardiac side effects at higher doses (due to β1 agonist activity), such
as elevated heart rate or blood pressure; with the advent of selective
agents, these side effects have become less common. Patients must be
cautioned against using these medicines too frequently, as with such use
their efficacy may decline, producing desensitization resulting in an
exacerbation of symptoms which may lead to refractory asthma and
death.
Anticholinergic medications, such as ipratropium bromide may be
used instead. They have no cardiac side effects and thus can be used in
patients with heart disease; however, they take up to an hour to achieve
their full effect and are not as powerful as the β 2-adrenoreceptor
agonists.
Inhaled glucocorticoids.
Preparations can be used in low, average and high doses (Table
18). They are usually supplied in the form of the dosed out aerosols or
powders for inhalation or in the form of solutions for inhalations through
Nebulizer.

Table 18. Doses of inhaled glucocorticoids for adults.

drug low doses, µg average doses, µg high doses, µg
Beclomethasone 200-500 500-1000 More than 1000
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Budesonide 200-400 400-800 More than 800

Flunisolide 500-1000 1000-2000 More than 2000
Fluticasone 100-250 250-500 More than 500

Beclomethasone dipropionate is in the form of inhaler (e.g. Clenil,

Qvar), there is a wide number of brands which are available.
Budesonide is under the brand name Pulmicort (in Israel, Budicort)
Fluticasone propionate – Flovent (USA, Canada), Flixotide (EU)
The medication is under the brand name Asmanex Twisthaler as
dry powder inhaler (DPI) for lower respiratory conditions.
Long-acting β2-agonists.
Long-acting bronchodilators (LABD) are similar in structure to
short-acting selective β2-adrenoceptor agonists, but have much longer
side chains resulting in 12-hour effect, and are used to give smoothed
symptomatic relief (used in the morning and at night). When patients
notice improved symptom control, these drugs do not replace the need
for routine preventers, and their slow onset means that short-acting
dilatators may still be required.
Currently available long-acting β2-adrenoceptor agonists include
salmeterol, formoterol (Oxis), bambuterol, and sustained-release oral
albuterol. Combinations of inhaled steroids and long-acting
bronchodilators are more widespread; the most common combination
currently in use is fluticasone/salmeterol (Advair in the United States,
and Seretide in the EU). Another combination is
budesonide/formoterol which is commercially known as Simbicort and
Foradil Combi.
Treatment of bronchial asthma is spent taking into account the
standards, the recommended GINA (Table 19).

Table 19. Supporting therapy protocols (GINA) 1

Step 1 Step 2 Step 3 Step 4 Step 5
Training of patients
The environment control
Short-acting β2-agonists, necessarily.
Plus one or Plus one or
Plus one of: Plus one of:
several of: several of:
Inhaled IGC low IGC IGC
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medial/high medial/high
glucocorticoids doses +
doses + doses +
(IGC) low Long-acting
Long-acting Long-acting β2-
doses β2-agonists 2
β2-agonists agonists
IGC
Leukotriene Leukotriene Leukotriene
medial/high
modifiers. modifiers. modifiers.
doses
IGC low
doses + Prolonged Systemic (oral)
Leukotriene theophylline glucocorticoids
modifiers.
IGC low
Omalizumab
doses +
(anti IgE
prolonged
antibody)
theophylline
1
- Guideline on the Management of Asthma
2
- there was information on the efficiency of the prolonged cholinolytics
comparable with β2-agonist (Peters SP, et al, 2010).

Emergency
When asthma attack is unresponsive to patient's usual medication,
other treatments are available to the physician or hospital:
 Oxygen to alleviate the hypoxia (but not asthma itself) that results
from extreme asthma attacks.
 Nebulized salbutamol or terbutaline often combined with
ipratropium, or with corticosteroids.
 Systemic steroids, oral or intravenous (prednisone, prednisolone,
methylprednisolone, dexamethasone, or hydrocortisone). Some
research has looked into alternative inhaled route.
 Other bronchodilators that are occasionally effective when the
usual drugs fail to affect:
– Intravenous salbutamol
– Nonspecific β-agonists, injected or inhaled (epinephrine,
isoetharine, isoproterenol, metaproterenol)
– Anticholinergics, IV or nebulized, with systemic effects
(glycopyrrolate, atropine, ipratropium)
– Methylxanthines (theophylline, aminophylline)
 219

– Inhalation anesthetics that have bronchodilatory effect

(isoflurane, halothane, enflurane)
– The dissociative anaesthetic ketamine, often used in
endotracheal tube induction
– Magnesium sulfate, intravenous
 Intubation and mechanical ventilation, for patients in or
approaching respiratory arrest.
 Heliox, mixture of helium and oxygen, may be used in hospital
setting. It has a more laminar flow than ambient air and moves
more easily through constricted airways.
Prognosis
The prognosis for asthmatics is good; especially for children with
mild disease. For asthmatics diagnosed during childhood, 54% will no
longer carry the diagnosis after decade. The extent of permanent lung
damage in asthmatics is unclear. Airway remodelling is observed, but it
is unknown whether these represent harmful or beneficial changes.
Although conclusions from studies are mixed, most studies show that
early treatment with glucocorticoids prevents or ameliorates decline in
lung function as measured by several parameters. For those who
continue to suffer from mild symptoms, corticosteroids can help the
majority to live their lives with few disabilities.

Questions for self-control:

1. List the factors contributing to development of BA.
2. Characterize the role of local protective factors of respiratory tracts
in BA pathogenesis.
3. List the mediators causing bronchial obstruction.
4. List clinical criteria of allergic BA.
5. Characterize methods of specific and nonspecific therapy of
allergic BA.
6. Characterize topical steroids in therapy of allergic asthma.
7. List indications and contraindications to carrying out ASIT at
allergic bronchial asthma.
220
 221

BIBLIOGRAPHY

1. Khaitov, R.M. Immunology: textbook. M.- 2008. - 256p.:il

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3. http://en.wikipedia.org
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