CHAPTER : 1

INTRODUCTION

1.1. BACKGROUND:
The word malaria is derived from two Italian words mal:bad, aria:air (bad air), it was so named
because of association of disease with bad or foul air from swamps and marshy soil particularly
at night (1). Malaria is a common acute or chronic febrile infection (2). It is the main cause of
morbidity and mortality in malaria endemic areas (3). lt occurs as endemic as well as epidemic
patterns. It is described as endemic when constantly occurs for several successive years in an
area, and epidemic when occassinal rise occur in its incidence (4).
Human malarial parasite belong to genus Plasmodium. It is an obligate intracellular parasite,
only four out of hundred species are infectious to human. These are ;
1. Plasmodium falciparum

2. Plasmodium vivax

3. Plasmodium malariae

4. Plasmodium ovale (5)

P.falciparum is the most virulent form and prevalent in tropical areas. P.vivax is widely
distributed and most common while P.ovale is the most rare species. P.malarias is widely
distributed but having spotty distribution. It is less common then P.palcifarum and P.vivax (6).
Most of the deaths are caused by P.falciparum, it is the most severe cause of infection while
other species cause less severe infection.
Malaria is an infection of global importance. It is the most prevalent infection of humans
worldwide and present in about 105 countries (7). Over 40% of the world population live in
malaria endemic areas. About 1.5 to 2.7 million deaths and 300 to 500 million cases occur each
year but exact number is unknown. 90% deaths occurs in sub-Saharan Africa, children less
than five years of age are mostly affected. 60% of malarial deaths occurs in 20% poorest
population of the world (8). P.falciparum is predominant in Haiti, New Guinea and Dominican
Republic. P.falciparum and P.vivax both are endemic to Mexico, North Africa, Central and
South America and Asia (9). Except Africa P.malariae is present in many regions but rare.
P.ovale is restricted to West Africa where it is the second most prevalent species after
P.palcifarum.

1.2. HISTORY:
In medical books of ancient Indian, Chinese and Assryian civilisation seasonal intermittent
fever with chill and shiver was studied and is believed to have been malaria.
In 18 century the name malaria was given in Italy. Alphonse Laveran a French army surgeon
in Algeria discover specific agent of malaria in 1880. In 1886 the asexual development of
parasite in RBC's was identified by Golgi in Italy. Method of staining of malarial parasite in
blood film was established by Romanowsky in Russia in 1891. Three species of malarial
parasite (i.e P.falciparum, P.vivax and P.malariae) infecting human was discovers in Italy
between 1886 and 1890 while P.ovale was identified in 1992. Ronald Ross in Secunderabad
India studied the developing stage of parasite in mosquito in 1897 and thus the transmission of
the disease was established. For their discoveries both Ross(1902) and Laveran(1907) won the
noble prize (10). In 1948 Cyril Granham discoverd that the malarial parasite develop in the
liver before entering in blood stream while dormant stage in liver was demonstrated by
Wohciech Krotsoki in 1982 (11).

1.3. BIOLOGY:
1.3.1. CLASSIFICATION:
Kingdom ------------- Protista
Subkingdom --------- Protozoa
Phylum -------------- Apicomplexa
Class ------------------ Sporozoasida
Order ----------------- Eucoccidiorida
Family ---------------- Plasmodiidae
Genus ---------------- Plasmodium
Species --------------- falciparum, malariae, ovale, vivax (12)

1.3.2. LIFE CYCLE:

Malarial parasite passes its life cycle in two hosts; definitive host is female Anophlese while
intermediate host is human. The life cycle of Plasmodium is consist of two phases; asexual
phase occurring in human while sexual phase occurs in female Anophlese mosquito.

Asexual phase: This phase is also known as schizogony (schizo:to split, gone:generation).
In humans schizogony occurs in two places, in liver cells (exo- erythrocytic schizogony) and
in red blood cells (erythrocytic schizogony). The infective form of parasite is sporozoites, these
are present in salivary gland of mosquito and enter in human blood capillaries when mosquito
bites human. Usually 10 to 15 sporozoites are injected at a time. In exo- erythrocytic cycle
through blood stream sporozoites reach the liver and infect liver cells. They undergo several
nuclear division and form daughter nuclei sorrounded by cytoplasm, this stage is known as
schizonts. Mature schizonts varies in size from 24-60 micron meter in diameter in different
species of human malarial parasites. Mature schizonts are multinucleate having 2000 to 50,000
uninucleate merozoites, Schizonts rupture and release merozoites into the blood stream. (In
P.vivax and P.ovale a dormant stage hypnozoites (hypnos: sleep) are present in liver cells some
of these are activated, released in blood stream and cause relapses by infecting RBC's (even
years later). In erythrocytic cycle the merozoites released by schizonts infect RBC's. In RBC's
the merozoites losses their organelles and appear as rounded bodies known as trophozoites,
they enlarges in size and shows amoeboid movement. At this stage they are known as schizont,
it contain 8-32 merozoites. Schizont bursts and release merozoites, some of merozoites develop
into sexual erythrocytic stage gametocyte. Clinical manifestation of disease occur at this stage
of life cycle

Sexual phase: This phase is also known as sporogonic cycle. The gametocytes are ingested
by female Anopheles mosquito with blood meal, they set free in midgut. The macrogametes
(female gamete) is fertilised by microgametes (male gamete) and form zygotes. The zygotes
whose are initially motionless become motile and known as ookinetes. It penetrate the midgut
wall and develop into oocyst. Mature oocyst bulges in body cavity of mosquito which bursts
and release sporozoites in body cavity from where they find way to salivary gland of mosquito.
The mosquito is knows infective if it bites human the life cycle is begins again. Depend upon
environmental temperature and species this cycle is completed in 1-4 weeks (13).
Table 1.1 : Features of Human Malarial Parasite
P. vivax P. ovale P. falciparum P. malariae
Exoerythrocytic 8 days 9 days 5-6 days 15 days
cycle
Erythrocytic 2 days 2 days 2 days 3 days
cycle
Merozoites per 10,000 15,000 30,000 2000
schizont
RBC preference Young cells Young cells All age cells Young cells
(13).

Fig 1.1: Life Cycle Of Human Malarial Parasite (14).

1.4. TYPES OF MALARIA
There are three types of malaria.
1. Benign Malaria
2. Benign Quartan
3. Malignant Tertian Malaria

1.4.1 BENGIN MALARIA

It is caused by P. vivax and P. ovale with a fever every second day followed by anemia and
splenomegaly. Vomiting, nausea and headache are common. In man the duration of
developmental cycle is 48 hours.

1.4.2. BENGIN QUARTAN

It is caused by P. malariae with a fever every third day. It cause infection of many years
duration and having 72 hours developmental cycle.

1.4.3. MALAGNANT TERTIAN MALARIA

It is caused by P. falciparum and is more serious and fatal type of infection. It has 40-48
hours cycle of development. When not treated properly dangerous complications develop.
The term pernicious malaria has been applied to complex life-threating complications. These
maybe present in different forms;
a) Cerebral Malaria: In malignant malaria it is the most common cause of death. It is
characterized by paralysis, hyperpyrexia and coma. The death ratio is 15% in children
and 20% in adults who develop cerebral malaria.
b) Algid Malaria: It is characterized by peripheral circulatory failure, surgical shocks
with cold clammy skin. Patient may also develop abdominal pain, vomiting, diarrhea,
and profound shock.
c) Septicemic Malaria: It is characterized by high continuous fever with involvement of
various organs, leading to multiorgan failure. Death occurs in 80% of the cases.
Congenital malaria and transfusion malaria is caused by any of four species of
malarial parasites (15,16,17).

1.5. TRANSMISSION OF MALARIA

Malaria is transmitted by the bite of an infective female Anopheles mosquito; it can also be
transmitted as a result of blood transfusion, or by unsterilized needles. The Infective
mosquitoes insert sporozoites into the bloodstream during feeding. These sporozoites infect:
(a) The liver cells. (b) where they undergo asexual reproduction (exoerythrocytic
schizogony), producing schizonts. (c) In 6 to 14 days (sometimes longer), the schizonts
rupture, releasing merozoites into the bloodstream. (d) Merozoites occupy red blood cells and
undergo a second phase of asexual reproduction (erythrocytic schizogony), developing into
rings. (e) trophozoites. (f) and finally blood stage schizonts. (g) The schizonts rupture,
destroying the red blood cell and releasing more merozoites into the bloodstream, starting
another cycle of asexual development and multiplication.
This erythocytic cycle will continue until the infected individual is treated successfully,
producing an immune response that clears the infection, or dies. During this cycle, sexual
forms called gametocytes are produced and can be ingested by a mosquito during a blood
meal. Sexual reproduction occurs in the mosquito. Sporozoites are formed, which migrate to
the salivary glands, making the mosquito infective to humans.
The duration of events in the life cycle of malaria parasites and the number of merozoites
produced during schizogony vary by species. In addition, two species of malaria, P.
vivax and P. ovale, have a form, “hypnozoites”, that can persist in the liver for months to
years, causing periodic relapses of peripheral parasitemia and illness (18).

1.6. SIGN AND SYMPTOMS :

The symptoms of malaria develop within 10 days - 4 weeks following the infection.
Symptoms may not develop for several months some cases. Some malarial parasites can enter
the body but will be inactive for long periods of time.
Malaria is classified as uncomplicated or complicated.
1.6.1. Uncomplicated malaria

The most common symptoms are

 fever and chills,

 headaches,
 nausea and vomiting, and
 general weakness and body ache.

The classic description of a malaria attack (which is rarely observed), would be a six- to 12-
hour period of cold and shivering alternating with fever and headaches and then a stage
of sweating and tiredness (sometimes divided into the cold and hot stage).
As these symptoms are very nonspecific, it is important to evaluate if the patient has risk
factors for malaria (usual travel in endemic areas).

1.6.2. Complicated or severe malaria

This occurs when malaria affects different body systems.

 Severe anemia (due to destruction of red blood cells)

 Kidney failure
 Cerebral malaria -- seizures, unconsciousness, abnormal behavior, or confusion
 Cardiovascular collapse
 Low blood sugar (in pregnant women after treatment with quinine) (19,20).

1.7. DIAGNOSIS:
There are two ways to diagnose malaria in humans;
1.7.1 CLINICAL DIAGNOSIS: It is based on clinical criteria (sign and symptoms).It is
inaccurate, unreliable and have very low specificity.
1.7.2 PARASITOLOGICAL DIAGNOSIS:

The most commonly used parasitological diagnostic method is light microscopy (blood
smears). In case of microscopy thick and thin blood smear should be done to check for parasite
preferably when the patient is febrile. For examination of blood smear stained by Romanowsky
stain preferably Giesma's make the diagnosis accurate. To determine the presence of parasite
in blood Giesma stained " thick" smear are done; thus all the species and stages of development
will be examined. Thin smears are used to estimate the number of RBC's infected and to
identify the Plasmodium species. On the thin smear more than one species may be detected.
Other lab tests that may be helpful in diagnosis are a complete blood count to check for anaemia
or presence of other infection, and blood glucose test to check for hypoglycaemic and liver
function test. New tests such as Polymerase Chain Reaction tests (PCR) and Rapid Diagnostic
tests (RDTs) can be supplemented but not yet replace microscopy(21,22,23,24)

1.8. TREATMENT:
The malaria depends upon the infecting Plasmodium species the severity of infection and the
geographical area of acquisition (which affect the like-hood of drug resistance). The treatment
should be started immediately after diagnosis of malaria. A course of chloroquine for treatment
of P. vivax (except that acquired in Guinea) and P. ovale infection which is followed by 14
days of primaquine treatment to eradicate hypnozoites( a dormant stage in liver) and prevent
relapses of disease. The strains of malarial parasites (P. vivax and P. falciparum) are reported
which are chloroquine and primaquine resistant and require alternative therapies for treatment.
For chloroquine resistant strains from mefloquine alone may be used, it is not well tolerable
and combination therapy using halofantrine or quinine- doxycycline or atovaquone plus
proguanil is preferred. Chloroquine and amodiaquine are effective against gametocytes of P.
vivax, P. ovale and P. malariae but not mature gametocytes of P. falciparum (25,26).

1.8. PROPHYLAXIS:
To reduce exposure night biting Anopheles mosquito avoid outdoors activities after dusk. If
it is not possible than long- sleeved shirt and pant are advised (weather permitting). If the
sleeping environment is not secured from mosquitoes a permithrin- impregnated bed nets is
recommended. Mospel may be used for extra protection. Due to increased risk of serve malaria
and adverse pregnancy outcomes women who are pregnant or likely to became Pregnant are
advised to avoid travel to malaria endemic areas. A helpful acronym ABCD for remembering
is provided by WHO for malarial risk reduction: Awarness (of main symptoms, incubation
period, risks), bite precautions (avoidance of mosquito between dusk and dawn), Chen option
to axis (antimalarial drugs to suppress infection where appropriate) and diagnosis (immediately
seek treatment/ diagnosis if fever develop one week or more after entering an area where there
is risk of malaria, and for months after return). In travellers malaria is preventable. If travellers
experience fever during or after travel, especially within the first two months after returning
homes, the travellers must be told to seek medical attention immediately. All travelers to
malaria endemic areas, including expatriates of such areas, should receive pretravel counseling
from a travel medicine centre or from a qualified health care providers (27,28).

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