Food allergies are immunologically mediated adverse reactions to foods.

Any food protein can

trigger an allergic response, and allergic reactions to a large number of foods have been
documented; however, only a small group of foods account for most of these reactions. Eggs,
milk, peanuts, soy, fish, shellfish, tree nuts, and wheat are the foods most often implicated.

Essential update: Omalizumab may reduce treatment time in patients with

multiple food allergies
A pair of recent studies indicates that oral immunotherapy can be used to desensitize patients
with multiple food allergies and that the asthma medication omalizumab (Xolair) can be used to
reduce treatment time.[1, 2, 3]
In the first trial, a proof-of-concept study involving 15 subjects with peanut-only allergies and 25
with multiple allergies, oral immunotherapy using multiple food allergens simultaneously was
shown to be feasible and safe. In the second study, 16 weeks of adjunctive omalizumab was used
to shorten the time course of multi oral immunotherapy in 25 subjects with at least 2 food
allergies. Maintenance dose in the second study was reached at a median of 18 weeks, 67 weeks
earlier than in the first study without omalizumab. The majority of reactions (94%) were mild.

Signs and symptoms

Signs and symptoms of food-induced anaphylaxis can include the following:

Oropharyngeal pruritus
Angioedema (eg, laryngeal edema)
Stridor
Dysphonia
Cough
Dyspnea
Wheezing
Nausea
Vomiting
Diarrhea
Flushing
Urticaria
Angioedema
Ocular injection, ocular pruritus, conjunctival edema, periocular swelling
Nasal congestion, nasal pruritus, rhinorrhea, and sneezing
Abdominal pain
Feeling of impending doom
Cardiovascular collapse

Necessary elements of a thorough medical history include the following:

Complete list of all foods suspected of causing symptoms

Manner in which the food was prepared (cooked, raw, added ingredients)

Minimum quantity of food exposure required to cause the symptoms

Reproducibility of symptoms on exposure to the food
Personal or family history of other allergic disease
Factors that can potentiate a food-allergic reaction (eg, exercise,[4] nonsteroidal antiinflammatory drugs [NSAIDs], or alcohol)

In addition, obtain a thorough description of each reaction, including the following:

Route of exposure (ingestion, skin contact, inhalation) and dose

Timing of symptom onset in relation to food exposure
All observed symptoms and each ones severity
Duration of the reaction
Treatment provided and clinical response to treatment
Most recent reaction

Physical examination findings are most useful for the following:

Assessing nutritional status, growth parameters, and signs of other allergic disease
Helping to rule out other conditions that may mimic food allergy

See Clinical Presentation for more detail.

Diagnosis
Laboratory studies that may be helpful include the following:

Specific immunoglobulin E (IgE) antibody testing: Positive results primarily denote

sensitization and may not confirm clinical allergy; specific laboratory tests for some food
hypersensitivities are not available
Peripheral serum measurements of eosinophils or total IgE concentrations: Results
support but do not confirm the diagnosis; normal values do not exclude the diagnosis
Basophil histamine-release assays: These are limited primarily to research settings and
have not been shown to be diagnostically useful in clinical settings

Skin testing includes the following approaches:

Prick and puncture testing: This is the most common screening test for food allergy;
negative predictive accuracy exceeds positive predictive accuracy (>90% vs < 50%)
Intradermal testing: Generally avoided, because of the risk of inducing a systemic
reaction
Patch testing: Appears promising, but additional studies are needed

Diet-related diagnostic measures may be helpful, as follows:

Diet diary
Elimination diet (may be used for diagnostic as well as therapeutic purposes)

Food challenge confirmation of food allergy (may be open; single-blind; or double-blind,

placebo-controlled)

See Workup for more detail.

Management
There are currently no curative therapies for food allergy. The only proven treatment is strict
elimination of the offending food allergen and avoidance of any contact with it. A properly
managed, well-balanced elimination diet includes the following elements:

Education of patients and families regarding how to read food labels properly and
identify common words used for indicating the presence of the food allergen of concern
Avoidance of cross-contact (eg, through shared utensils or fryers) of allergens with
otherwise safe foods during meal preparation
Elimination of only those foods that are confirmed as provoking allergic reactions; both
obvious and hidden sources of food allergens (eg, medications and cosmetics) must be
considered
Consideration of potential exposures by route other than ingestion (eg, skin contact or
inhalation)
Anticipation of potential candidates for food allergen cross-reactivity (eg, eggs with
chicken or cow milk with beef)[5]
Avoidance of high-risk situations where accidental or inadvertent ingestion of food
allergens can occur (eg, buffets or picnics)

Adherence to avoidance measures notwithstanding, accidental or inadvertent ingestions may

occur and lead to a reaction. Strategies for dealing with such a reaction include the following:

Creation of a concise written emergency management plan (see www.foodallergy.org),

copies of which should be available in appropriate places (eg, daycare, schools, work
locations, and college dormitory advisors)
Use of medical identification jewelry indicating food allergies
Ensuring that the patient has an emergency contact number available
Provision of anticipatory guidance measures (eg, educating the patient about potential
sources of accidental exposure)

Emergency medications include the following:

Injectable epinephrine: This is the drug of choice for initial management of a foodinduced anaphylactic reaction; the patient should have self-injectable epinephrine readily
available at all times and should be properly trained in its use
Antihistamines
Bronchodilators
Histamine-2 blockers
Corticosteroids
Intravenous fluids

Glucagon

In severe anaphylaxis, ventilatory and circulatory support may be needed.

Oral or sublingual immunotherapy appears to be a promising therapeutic option for the future.[6, 7]
See Treatment and Medication for more detail.

Background
Food allergies are immunologically mediated adverse reactions to foods. Such allergies can
result in disorders with an acute onset of symptoms following ingestion of the triggering food
allergen (eg, anaphylaxis), as well as in chronic disorders (eg, atopic dermatitis). Symptoms
observed in a food-induced anaphylactic reaction may involve the skin, gastrointestinal tract, and
respiratory tract. (See Pathophysiology, Etiology, and Presentation.)[8]
Any food protein can trigger an allergic response, and allergic reactions to a large number of
foods have been documented; however, only a small group of foods account for most of these
reactions. Eggs, milk, peanuts, soy, fish, shellfish, tree nuts, and wheat are the foods most often
implicated in allergic reactions that have been confirmed in well-controlled, blinded food
challenges (medically supervised, gradual test feedings) . Sesame appears to be an emerging
allergen. (See Etiology and Workup.)
Investigations of near-fatal or fatal anaphylactic reactions following food ingestion reveal that
most are caused by peanuts, tree nuts, and shellfish, although milk has been increasingly
reported. (See Workup.)[9]
Adverse reactions to food that are not immune mediated are not considered to be food allergies.
An example is lactose intolerance, which is caused by a deficiency of lactase. Adverse reactions
to foods can also occur from toxic (eg, bacterial food poisoning) or pharmacologic (eg, caffeine)
effects.

Pathophysiology
Although anaphylaxis can occur without skin symptoms, cutaneous reactions are the most
common clinical manifestations of an allergic reaction to a 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.

Atopic dermatitis
Controversy surrounds the role of food allergy in the pathogenesis of atopic dermatitis.[10] Studies
show that among patients with moderate chronic atopic dermatitis, 35-40% have IgE-mediated
food allergy.[11, 12] Food-specific IgE-mediated and cellular mechanisms appear responsible for
chronic eczematous inflammation.

Removal of a specific food allergen may lead to reduction or resolution of clinical symptoms in
affected patients; reintroduction of the food may then exacerbate the atopic dermatitis if it is
food-responsive.[13, 14] Reintroduction of a suspected food allergen should be performed under
medical supervision because, in some instances, initial reintroduction of the food after a period
of dietary elimination has resulted in more significant symptoms than were observed when the
food was regularly ingested.[15]
Prophylactic studies show that avoiding particular foods (eg, cow milk, eggs, peanuts) helps to
delay the onset of atopic dermatitis.[16]
In a study of 619 exclusively breastfed infants, those with atopic dermatitis were significantly
more likely to be sensitized to foods.[17, 18] In addition, a strong association between the severity of
the dermatitis and sensitization was observed, and positive associations between atopic
dermatitis and specific foods (egg, cows milk, and peanut) were found.
In addition to skin-prick testing against cow's milk, egg, cod fish, wheat, sesame, and peanut,
infants in the study were screened for filaggrin loss-of-function (FLG) gene mutations.[18] FLG
mutations were significantly associated with incidence of atopic dermatitis and higher median
transepidermal water loss relative to dermatitis severity. Although children with atopic dermatitis
were significantly more likely to be sensitized to foods, this effect was not related to FLG
mutation inheritance.

Celiac disease
Celiac disease is the result of an immune response to gluten proteins in grain.

Dermatitis herpetiformis
This is a form of non-IgE cell-mediated hypersensitivity related to celiac disease. It is a blistering
skin disorder that manifests clinically with a chronic and intensely pruritic rash with a
symmetrical distribution. Elimination of gluten from the diet usually leads to resolution of skin
symptoms.

IgE-mediated gastrointestinal food allergy

These food allergy reactions include immediate hypersensitivity reactions and the pollen-food
allergy syndrome (oral allergy syndrome). Specific gastrointestinal symptoms include nausea,
vomiting, abdominal pain, and cramping. Diarrhea is found less frequently.

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 a
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.[19]

This syndrome is caused by cross-reactivity between certain pollen and food allergens. 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, peach or hazelnut.

Mixed IgE/non-IgE gastrointestinal food allergy (eosinophilic esophagitis and

gastroenteritis)
Symptoms vary according to location of the eosinophilia. Typical symptoms include postprandial
nausea, abdominal pain, and a sensation of early satiety. Eosinophilic esophagitis may manifest
as reflux symptoms and dysphagia; food impaction can occur as well. Children may experience
weight loss or failure to thrive.[20]
A complete blood count (CBC) 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 to establish the presence of eosinophils in the affected segment of the gut.
While a dense eosinophil infiltrate may be seen anywhere from the lower esophagus through the
large bowel, involvement is patchy and variable.
Eosinophilic esophagitis is characterized by symptoms related to esophageal dysfunction, such as
dysphagia and pain, and histologically by eosinophil-predominant inflammation. Pathologically,
1 or more biopsy specimens must show a peak of 15 or more eosinophils per high power field.
Alternative explanations (eg, reflux) for symptoms/histopathologic abnormalities should be
excluded.
An elemental (no potential allergens) or oligoantigenic diet (a diet that removes common
allergenic foods) and trials of food elimination may be required to determine the role of foods in
a patient's condition. Eosinophilic esophagitis does not respond to acid blockade therapy.
In addition to diet therapy (or in place of diet therapy), treatment with anti-inflammatory
medications (eg, corticosteroids) may be needed. Eosinophilic esophagitis appears to be a
chronic disease and fibrosis and stricture formation could occur. Updated diagnostic and
treatment approaches have been proposed.[21]

NonIgE-mediated gastrointestinal food allergy

Food proteininduced enterocolitis syndrome (FPIES) typically manifests in the first few months
of life with severe projectile vomiting, diarrhea, and failure to thrive.[22] Cow milk and soy protein
formulas are usually responsible for these reactions. However, solid foods may also trigger these
reactions, especially rice and oats.[23]
When the allergen is removed from the diet, symptoms resolve. Reexposure prior to resolution
results in a delayed (2h) onset of vomiting, lethargy, increase in the peripheral blood
polymorphonuclear leukocyte count, and, later, diarrhea. Hypotension and methemoglobinemia
may occur.
Infants with FPIES who are chronically ingesting the allergen typically appear lethargic, wasted,
and dehydrated. The presentation may mimic sepsis. An oral food challenge may establish the

diagnosis but is not always needed if the history is clear. No other definitive diagnostic tests are
available.
Breastfed infants may have mucus and blood in their stool, attributed to food allergens ingested
by the mother, primarily cow milk. This allergic proctocolitis does not typically lead to anemia
and is not associated with vomiting or poor growth. Maternal exclusion of the allergen resolves
the bleeding. Eosinophilic inflammation of the rectum is noted if a biopsy is performed.[24]
Additional causes of bleeding (eg, infection, fissures) should be considered.

Upper and lower respiratory tract reactions

Upper respiratory reactions typically include nasal congestion, sneezing, nasal pruritus, or
rhinorrhea. They are usually observed in conjunction with ocular, skin, or gastrointestinal
symptoms. IgE-mediated pulmonary symptoms may include laryngeal edema, cough, or
bronchospasm.

Asthma
The role of food allergy in the pathogenesis of asthma is a controversial area of investigation.[25]
At the National Jewish Center for Immunology and Respiratory Medicine, 67 (24%) of the 279
children with a history of food-induced asthma were documented to have a positive result after a
blinded food challenge, which included wheezing. Interestingly, only 5 (2%) of these patients
had wheezing as their only objective adverse symptom.[26]
In a related report, 320 children with atopic dermatitis undergoing blinded food challenges at
Johns Hopkins Hospital were monitored for respiratory reactions. Overall, 34 (17%) of 205
children with positive results from food challenges developed wheezing as part of their reaction.
Therefore, a conservative estimate is that 5-10% of patients with asthma have food-induced
allergy symptoms.[27]
In a pediatric case-controlled study comparing 19 children who required ventilation for an
exacerbation of asthma and 38 control subjects matched by sex, age, and ethnicity, coincident
food allergy was found to be independently associated with life-threatening asthma.[28]
In summary, food allergy appears to be a very uncommon trigger of chronic asthma. Food
allergy is also an uncommon trigger of chronic allergic rhinitis.

Food-induced pulmonary hemosiderosis (Heiner syndrome)

This is a 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 a nonIgE hypersensitivity process.

Etiology

Food allergies are primarily the result of immune responses to food proteins. (Allergic reactions
to non-protein food additives are uncommon.[29] ) Normally, noninflammatory immune responses
develop to ingested foods in a process called oral tolerance.[30, 31] For reasons that remain unclear,
but likely include environmental and genetic factors, tolerance may be abrogated, leading to
adverse immune responses.
While sensitization (eg, development of an immunoglobulin E [IgE] immune response) to an
allergen has been primarily assumed to occur from ingestion, this may not always be the case.
For example, oral allergy syndrome (pollen-food related syndrome) describes an allergic
response to specific raw fruits or vegetables that share homologous proteins with pollens; the
initial route of sensitization is respiratory exposure to pollen proteins rather than oral exposure to
food proteins. The skin may be another potential route of sensitization.[32]

IgE antibody-mediated responses

IgE antibodymediated responses are the most widely recognized form of food allergy and
account for acute reactions. Patients with atopy produce IgE antibodies to specific epitopes
(areas of the protein) of one or more food allergens. These antibodies bind to high-affinity IgE
receptors on circulating basophils and tissue mast cells present throughout the body, including in
the skin, gastrointestinal tract, and respiratory tract.
Subsequent allergen exposure binds and cross links IgE antibodies on the cell surface, resulting
in receptor activation and intracellular signaling that initiates the release of inflammatory
mediators (eg, histamine) and synthesis of additional factors (eg, chemotactic factors, cytokines)
that promote allergic inflammation. 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 acute allergic reactions to
food.

Cell-mediated responses
Cell-mediated responses to food allergens may also mediate allergic responses, particularly in
disorders with delayed or chronic symptoms. For example, food proteininduced enterocolitis
syndrome (FPIES), a gastrointestinal food allergy, appears to be mediated by T-cell elaboration
of the cytokine tumor necrosis factor (TNF)-alpha.[33] Persons with atopic dermatitis that flares
with ingestion of milk have been noted to have T cells that, in vitro, express the homing receptor
cutaneous lymphocyte antigen, which is thought to home the cell to the skin and mediate the
response.[34] Celiac disease is the result of an immune response to gluten proteins in grains.

Characteristics of food allergens

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, such as
peanut Ara h1, Ara h2, and Ara h3; chicken egg white Gal d1, Gal d2, and Gal d3; soybean-Gly
m1; fish-Gad c1; and shrimp-Pen a1.

Closely related foods frequently contain allergens that cross-react immunologically (ie, lead to
the generation of specific IgE antibodies detectable by skin prick or in vitro testing) but less
frequently cross-react clinically.[5] Delayed allergic reactions to meat proteins have been
attributed to reactions to carbohydrate moieties.[35]

Risk factors
Risk factors or associations for fatal food-induced anaphylaxis include: (1) the presence of
asthma, especially in patients with poorly controlled disease; (2) previous episodes of
anaphylaxis with the incriminated food; (3) a failure to recognize early symptoms of
anaphylaxis; and (4) a delay or lack of immediate use of epinephrine to treat the allergic
reaction.[36, 9] Teenagers and young adults appear to be overrepresented in registries of food
allergy fatalities and present a special risk group.

Epidemiology
General surveys report that as many as 25-30% of households consider at least 1 family member
to have a food allergy.[37, 38] However, this high rate is not supported by controlled studies in
which oral food challenges are used to confirm patient histories.[39, 40]
Comprehensive studies that include oral food challenges are few in number. Considering allergy
to milk, egg, peanut, and seafood in a meta-analysis of 6 international studies using oral food
challenges, estimated rates of 1-10.8% were obtained.[41]
In a meta-analysis including allergy to fruits and vegetables (excluding peanut), only 6
international studies included oral food challenges, and estimates of allergy varied widely from
0.1-4.3% for fruits and tree nuts to 0.1-1.4% for vegetables to under 1% for wheat, soy, and
sesame.[42]

Sex- and age-related demographics

Among children, males appear to be more affected; among adults, females are more frequently
affected.[43] The prevalence of food allergies has been estimated to be 5-6% in infants and
children younger than 3 years and 3.7 % in adults.[44]
However, variations in prevalence have been reported according to method used (self report,
testing, physician evaluation), geographic region, and foods included in the assessment.[45] US
data from an Internet-based study found that as many as 8% of children were reported to have
food allergy.[46]
Studies in the United States and the United Kingdom indicate a rise in peanut allergy among
young children in the past decade.[43, 47] One study showed an increase of peanut allergy in
children from 0.4% in 1997 to 0.8% in 2002.[43] Studies from Canada and the United Kingdom
indicate allergy rates to peanut of over 1% in children.[48, 49]
A report from the US Centers for Disease Control and Prevention (CDC) indicated an 18% rise
in food allergies among US children since the 1990s.[50]

Based on available studies, estimations of the rate of food allergies in children have been
summarized as follows for common food allergens[44] :

Cow milk - 2.5%

Eggs - 1.3%
Peanuts - 0.8%
Wheat - 0.4%
Soy - 0.4%

Children exposed to 3 or more courses of antibiotics between the ages of 7 and 12 months have a
significantly (nearly 2-fold) increased risk of developing food allergies, according to a
retrospective case-control study of more than 1100 children diagnosed with food allergy before
the age of 3 and 6433 control subjects.[6] Antibiotics used included penicillin (54%),
cephalosporins (21%), macrolides (18%), and sulfonamides (7%). The researchers controlled for
asthma, atopic dermatitis, and eczema, which are associated with an increased risk of food
allergy.[6]

Prognosis
In general, most infants and young children outgrow or become clinically tolerant of their food
hypersensitivities. Specifically, most "outgrow" allergies to milk, egg, soy and wheat. Allergies
to peanut, tree nuts, fish, and shellfish are more persistent.[51]
Population-based studies generally show that 85% of young children outgrow their allergy to
milk or egg by age 3-5 years.[51] However, studies reported from a referral center showed more
persistence of egg, milk, and soy allergies, with only about 50% of patients resolving these
allergies by age 8-12 years.[52, 53, 54] Children continued to lose their allergy into adolescent years.
About 20% of infants and young children experience resolution of their peanut allergy by the
time they reach school age.
Children with non-IgEmediated food allergies, such as proctocolitis and enterocolitis, typically
resolve their food allergy in the first years of life.[55] Allergic eosinophilic esophagitis appears to
be a persistent disorder.[56]

Morbidity and mortality

Severe anaphylactic reactions, including death, can occur following the ingestion of food.[36, 9]
Fatalities result from severe laryngeal edema, irreversible bronchospasm, refractory hypotension,
or a combination thereof.
Peanuts, tree nuts, fish, and shellfish are the foods most often implicated in severe food-induced
anaphylactic reactions, although anaphylactic reactions to a wide variety of foods have been
reported. Fatalities caused by reactions to milk have increasingly been noted.[9]

Patient Education

Preparation
Patients should always carry a self-injectable device with epinephrine that has been properly
stored and is current (ie, not expired). Ensure that the patient receives proper training regarding
when and how to use the injection device. Patients should also have an H1-blocker medication
(again, properly stored and not expired) in a syrup or chewable tablet form available. In addition,
patients should be instructed to obtain immediate medical assistance (eg, call 911) in the event of
anaphylaxis.
Caregivers of children should be instructed on identification and treatment of allergic and
anaphylactic reactions.

Avoidance of allergens
Complete avoidance of the offending food allergen is the best strategic approach and the only
proven therapy once the diagnosis of food hypersensitivity is established. Therefore, patients
with food allergies should be taught to recognize relevant food allergens that must be eliminated
from their diet.
Instruct the patient about the proper reading of food labels and the need to inquire about food
ingredients when dining out. If the patient is in doubt about a food or food ingredient, suggest
avoidance of the food in question. Educate patients about the potential for food allergens to be
present in medications and cosmetics.

Support groups
Inform patients with food allergies how to identify and use support groups. One such
organization is the Food Allergy and Anaphylaxis Network.

Early detection and treatment

Educate patients regarding recognition of the early signs and symptoms of a food-induced
allergic reaction, and provide them with a written management plan for successfully dealing with
these reactions.
Write a specific list of clinical signs and symptoms to look for if a reaction may be occurring,
and include a clear management plan. An excellent example of such a plan is available on the
Food Allergy and Anaphylaxis Network Web site.
Demonstrate to the patient and family how to actually administer medications, especially
injectable epinephrine, in the event of an allergic reaction. To accomplish this, use demonstration
trainer devices in the clinic setting. Reinforce that if injectable epinephrine is administered, the
patient must be immediately evaluated in a medical setting.
For patient education information, see the Allergies Center, as well as Food Allergy and Severe
Allergic Reaction (Anaphylactic Shock).
Proceed to Clinical Presentation

Infectious mononucleosis was first described by Sprunt and Evans in the Bulletin of the Johns
Hopkins Hospital in 1920.[1] They described the clinical characteristics of Epstein-Barr virus
(EBV) infectious mononucleosis. At the time, their article was entitled "Mononuclear
leukocytosis in reaction to acute infection (infectious mononucleosis)," because the causative
organism, EBV, had yet to be described.
Since the 1800s, infectious mononucleosis has been recognized as a clinical syndrome consisting
of fever, pharyngitis, and adenopathy. The term glandular fever was first used in 1889 by
German physicians and was termed Drsenfieber. The association between infectious
mononucleosis and EBV was described in the late 1960s.

Pathophysiology
EBV is transmitted via intimate contact with body secretions, primarily oropharyngeal
secretions. EBV infects the B cells in the oropharyngeal epithelium. The organism may also be
shed from the uterine cervix, implicating the role of genital transmission in some cases. On rare
occasion, EBV is spread via blood transfusion.
Circulating B cells spread the infection throughout the entire reticular endothelial system (RES),
ie, liver, spleen, and peripheral lymph nodes. EBV infection of B lymphocytes results in a
humoral and cellular response to the virus. The humoral immune response directed against EBV
structural proteins is the basis for the test used to diagnose EBV infectious mononucleosis.
However, the T-lymphocyte response is essential in the control of EBV infection; natural killer
(NK) cells and predominantly CD8+ cytotoxic T cells control proliferating B lymphocytes
infected with EBV.
The T-lymphocyte cellular response is critical in determining the clinical expression of EBV
viral infection. A rapid and efficient T-cell response results in control of the primary EBV
infection and lifelong suppression of EBV.
Ineffective T-cell response may result in excessive and uncontrolled B-cell proliferation,
resulting in B-lymphocyte malignancies (eg, B-cell lymphomas).
The immune response to EBV infection is fever, which occurs because of cytokine release
consequent to B-lymphocyte invasion by EBV. Lymphocytosis observed in the RES is caused by
a proliferation of EBV-infected B lymphocytes. Pharyngitis observed in EBV infectious
mononucleosis is caused by the proliferation of EBV-infected B lymphocytes in the lymphatic
tissue of the oropharynx.

Epidemiology
Frequency
United States

EBV infectious mononucleosis is a common cause of viral pharyngitis in patients of all ages, but
it is particularly frequent in young adults. In the United States, approximately 50% of the
population seroconverts before age 5 years, with much of the rest seroconverting in adolescence

or young adulthood. Approximately 12% of susceptible college-aged young adults convert each
year, half of whom develop acute infectious mononucleosis.
International

See United States.

Mortality/Morbidity

Patients with EBV infection who present clinically with infectious mononucleosis invariably
experience accompanying fatigue. Fatigue may be profound initially but usually resolves
gradually in 3 months. Some patients experience prolonged fatigue and, after initial recovery,
enter a state of prolonged fatigue without the features of infectious mononucleosis.
Mortality and morbidity rates due to uncomplicated primary EBV infectious mononucleosis are
low. The rare cases of attributed mortality are usually related to spontaneous splenic rupture.
Splenic rupture may be the initial presentation of EBV mononucleosis.
Most cases of EBV infectious mononucleosis are subclinical, and the only manifestation of EBV
infection is a serological response to EBV surface proteins discovered with EBV serological tests.
Airway obstruction and central nervous system (CNS) mononucleosis are also responsible for
increased morbidity in infectious mononucleosis. Selective immunodeficiency to EBV, which
occurs in persons with X-linked lymphoproliferative syndrome, may result in severe, prolonged,
or even fatal infectious mononucleosis.
Hepatic necrosis caused by extensive EBV proliferation in the RES of the liver is the usual cause
of death in affected males. EBV is the main cause of malignant B-cell lymphomas in patients
receiving organ transplants.
Most instances of posttransplant lymphoproliferative disorder (PTLD) are associated with EBV.
EBV in PTLD is acquired from an EBV-positive donor organ. The likelihood of PTLD is directly
proportional to the degree of immunosuppressive drugs administered to the transplant patient.
Depending on the intensity, rapidity, and completeness of the T-lymphocyte response,
malignancy may result if EBV-induced B-lymphocyte proliferation is uncontrolled. Hodgkin
disease and non-Hodgkin lymphoma (NHL) may result. Other EBV-related malignancies include
oral hairy leukoplakia in patients with HIV infection.
Leiomyomas and leiomyosarcomas in immunocompromised children, nasopharyngeal
carcinoma, and Burkitt lymphoma are among other neoplasms caused by EBV.

Age
Although primarily a disease of young adults, EBV infectious mononucleosis may occur from
childhood to old age.
Proceed to Clinical

Most patients with Epstein-Barr virus (EBV) infectious mononucleosis are asymptomatic
and, therefore, have few if any symptoms. Most adults (approximately 90%) show
serological evidence of previous EBV infection.
The incubation period of EBV infectious mononucleosis is 1-2 months. Many patients
cannot recall close contact with individuals with pharyngitis. Virtually all patients with

EBV infectious mononucleosis report fatigue and prolonged malaise. A sore throat is
second only to fatigue and malaise as a presenting symptom.
Fever is usually present and is low grade, but chills are relatively uncommon. Arthralgias
and myalgias occur but are less common than in other viral infectious diseases.
Nausea and anorexia, without vomiting, are common symptoms.
Various other symptoms have been described in patients with EBV infectious
mononucleosis, including cough, ocular muscle pain, chest pain, and photophobia.
Importantly, patients without CNS involvement experience no cognitive difficulties.
CMV infectious mononucleosis rarely involves the CNS.
Myalgias, which are uncommon, are rarely (if ever) severe
Physical findings in infectious mononucleosis should be viewed in terms of frequency
distribution and time course after clinical presentation.
Early signs include fever, lymphadenopathy, pharyngitis, rash, and/or periorbital edema.
Relative bradycardia has been described in some patients with EBV mononucleosis, but it
is not a constant finding.
Later physical findings include hepatomegaly, palatal petechiae, jaundice, uvular edema,
splenomegaly, and, rarely (1-2%), findings associated with splenic rupture.
CNS findings associated with EBV mononucleosis are rare but usually occur later in the
course of the illness.
Splenic tenderness may be present in patients with splenomegaly.
Pulmonary involvement is not a feature of EBV infectious mononucleosis.
The classic presentation of EBV infectious mononucleosis in children and young adults
consists of the triad of fever, pharyngitis, and lymphadenopathy.
Older adults and elderly patients with EBV infectious mononucleosis often have few
signs and symptoms referable to the oropharynx and have little or no adenopathy. Elderly
patients with EBV mononucleosis present clinically as having anicteric viral hepatitis.
Predictably, jaundice develops in less than 10% of young adults with EBV infectious
mononucleosis, but jaundice may occur in as many as 30% of affected elderly
individuals.
The pharyngitis due to EBV infectious mononucleosis may be exudative or nonexudative.
o Exudative pharyngitis is commonly confused with group A streptococcal
pharyngitis, which is complicated further by the fact that approximately 30% of
patients with EBV infectious mononucleosis have group A streptococcal carriage
of the oropharynx. The unwary physician may incorrectly conclude that a throat
culture or rapid test positive for group A streptococci in a patient with infectious
mononucleosis represents streptococcal pharyngitis.
o Nonexudative pharyngitis with or without tonsillar enlargement is common in
patients with EBV infectious mononucleosis and resembles viral pharyngitis.
o Patients with either exudative or nonexudative EBV infectious mononucleosis are
commonly colonized by group A streptococci.
Tonsillar enlargement is common, and massive tonsillar enlargement may be observed.
The term kissing tonsils is used to describe extreme enlargement of both tonsils in
patients with EBV infectious mononucleosis. Extreme tonsillar enlargement may result in
airway obstruction.

Palatal petechiae of the posterior oropharynx distinguish infectious mononucleosis from

other causes of viral pharyngitis but do not distinguish it from group A streptococcal
pharyngitis, in which palatal petechiae may occur.
Uvular edema is an uncommon finding in infectious mononucleosis, but, if present, it is a
helpful sign in distinguishing EBV infectious mononucleosis from other causes of viral
pharyngitis or from group A streptococcal pharyngitis.
Early in the course of EBV infectious mononucleosis, patients may present with a
maculopapular generalized rash. The rash is faint and evanescent and rapidly disappears.
It is nonpruritic. This is a marked contrast to patients mistakenly diagnosed with
streptococcal pharyngitis who have been administered ampicillin or amoxicillin and then
develop a maculopapular rash as a drug reaction. Drug-induced rash is usually pruritic
and is prolonged, in contrast to the viral rash of EBV infectious mononucleosis. Patients
with EBV infectious mononucleosis who experience drug reactions to beta-lactams are
not allergic to these medications. Administration of beta-lactams after resolution of the
infection does not result in drug fevers or rashes.
Splenomegaly is a late finding in EBV infectious mononucleosis. Splenic enlargement
returns to normal or near normal usually within 3 weeks after the clinical presentation.
In rare cases, EBV infectious mononucleosis results in various unusual clinical
manifestations, including encephalitis, pancreatitis, acalculous cholecystitis, myocarditis,
mesenteric adenitis, myositis, and glomerular nephritis.
Neurologic syndromes due to EBV infectious mononucleosis include optic neuritis,
transverse myelitis, aseptic meningitis, encephalitis, meningoencephalitis, cranial nerve
(CN) palsies (particularly CN VII), and Guillain-Barr syndrome.
Although EBV-induced antibodies to RBC membranes may occur, clinical anemia is
uncommon with EBV infectious mononucleosis.
Leukocytosis, rather than leukopenia, is the rule in infectious mononucleosis.
Periorbital edema is an uncommon, and therefore fairly specific, physical finding in
infectious diseases.
o Bilateral periorbital edema not associated with generalized edema (eg, nephrotic
syndrome) suggests trichinosis, Kawasaki disease, allergic reactions, or bilateral
periorbital cellulitis.
o Unilateral periorbital edema suggests conditions such as thyrotoxicosis, retroorbital eye tumor, Chagas disease, insect sting, or unilateral conjunctivitis.
o EBV infectious mononucleosis is characterized by early and transient bilateral
upper-lid edema. In contrast to the disorders mentioned above, which are either
unilateral or bilateral and involve the periorbital area, with or without the eyelids,
the external eye involvement of EBV infectious mononucleosis is characterized
by bilateral upper-lid edema. This finding was first described by Hoagland and is
referred to as Hoagland sign. Hoagland noted the association of EBV infectious
mononucleosis in young military recruits with EBV infectious mononucleosis.
Hoagland sign may be detected when patients look in the mirror early in the
course of their illness or when the astute physician notices this early in the clinical
presentation. Hoagland sign is present for only the first few days of illness and
should not be sought later in the course of the infectious process.

Table 1. Differential Diagnoses of Infectious Mononucleosis (Open Table in a new window)

EpsteinBarr Virus
Fatigue
+++
Malaise
++
Mild sore throat
+
Early maculopapular rash
Early bilateral upper

eyelid edema
Unilateral localized
adenopathy
Bilateral posterior
+
cervical adenopathy
Tender hepatomegaly
+/Splenomegaly
+
WBC count
N*/

Elevated SGOT /SGPT ++

Atypical lymphocytes ( +
10%)
Thrombocytopenia
+/
Elevated IgM CMV titer Elevated IgM EBV
+
VCAII titer
Elevated IgM
toxoplasmosis titer
Elevated hepatitis (eg, A, B, D) IgM titer

Clinical Parameters
Symptoms

Signs

Laboratory
abnormalities

*Normal

Serum glutamic-oxaloacetic transaminase

Serum glutamic-pyruvic transaminase

Immunoglobulin M

Cytomegalovirus
+
+
+
-

Toxoplasmosis
+/+/-

Viral
Hepatitis
+
+
+/+/-

+/-

+/+/N/+
+

+/N
+/-

+++
-

+/+
-

+/-

II

Viral capsid antigen

The only predisposing risk factor for EBV infectious mononucleosis is close contact with
an individual infected with EBV.
EBV commonly persists in oropharyngeal secretions for months after clinical resolution
of EBV infectious mononucleosis.
Patients with congenital immunodeficiencies are predisposed to EBV-induced
lymphoproliferative disorders and malignancies.
Acquired immunodeficiencies due to the effects of immunosuppression (eg, PLDT) or
infectious disease-induced immunosuppression (ie, HIV) may predispose to oral hairy
leukoplakia or non-Hodgkin lymphoma.
Burkitt lymphoma has a distribution (ie, in Africa) that is the same as the distribution of
malaria. The geographic location predisposes to Burkitt lymphoma in children.