MALARIA
-a protozoan disease transmitted by the bite of infected female Anopheles mosquitoes
-the most important of the parasitic diseases of humans
ETIOLOGY & PATHOGENESIS
-6 species of the genus Plasmodium cause nearly all malarial infections in humans:
P. falciparum, P. vivax, P. ovale (curtisi & wallikeri), P. malariae, P. knowlesi (the monkey
malaria parasite)
Intrahepatic/Pre Erythrocytic Schizogony
-begins a period of asexual reproduction
-a single sporozoite may produce from 10,000 to >30,000 daughter merozoites
-swollen infected liver cells eventually burst >> discharge the motile merozoites into the
bloodstream & invade RBCs to become trophozoites (multiply 6-20fold q48h (P. knowlesi,
q24h; P. malariae, q72h)
-If parasites reach densities of ~50/uL of blood (~100 M parasites in the blood of an adult)
>> the symptomatic stage of the infection begins
P. vivax & P. ovale: a proportion of the intrahepatic forms do not divide immediately but
remain inert for a period ranging from 2 weeks to >=1 yr
-dormant forms called hypnozoites (the cause of relapses that characterize infection w/ these
species)
Attachment of merozoites to RBC is mediated via a complex interaction with several specific
erythrocyte surface receptors
-P. falciparum merozoites bind to erythrocyte binding antigen 175 and glycophorin A & other
glycophorins
-Merozoite reticulocyte-binding protein homologue 5 (PfRh5): plays a critical role binding to
red cell basigin (CD147, EMMPRIN)
-P. vivax binds to receptors on young red cells; Duffy blood-group antigen Fya or Fyb
plays an important role in invasion
-P. knowlesi also invade the Duffy- positive human RBCs preferentially
First few hrs of intraerythrocytic development:
-small 'ring forms' of different malaria species appear similar under light microscopy
-as the trophozoites enlarge >> species-specific characteristics become evident >> malaria
pigment (hemozoin) becomes visible & the parasite assumes an irregular or ameboid
shape
By the end of intraerythrocytic life cycle:
-parasite has consumed ⅔ of the RBC's hemoglobin & has occupied most of the cell (now
called schizont)
-multiple nuclear divisions taken place (schizogony/merogony)
-the infected RBC then ruptures to release 6-30 daughter merozoites (each capable of
invading a new RBC & repeats the cycle)
-some of the blood stage parasites develop into morphologically distinct, longer-lived sexual
forms (gametocytes)
P. falciparum: a delay of several asexual cycles precedes this switch to gametocytogenesis
Female gametocytes typically outnumber males by 4:1
After being ingested in the blood meal of a biting female Anopheles mosquito >> male & female
gametocytes fuse to form a zygote in the insect's midgut
-this zygote mature into an ookinete (w/c penetrates and encysts in the mosquito's gut wall)
>> results in oocyst expands by asexual division u ntil it bursts to liberate myriad motile
sporozoites >> migrate in the hemolymph to the salivary gland of the mosquito to await
inoculation into another human at the next feed, thus completing the life cycle
EPIDEMIOLOGY
-malaria occurs throughout most of the tropical regions
P. falciparum: predominates in Africa, New Guinea and Hispaniola (i.e. Dominican Republic
& Haiti)
P. vivax: more common in Central & South America
-these two have approx equal prevalence on the Indian subcontinent & in eastern Asia &
Oceania
P. malariae: found in most endemic areas, esp throughout sub-Saharan Africa (but it much
less common)
P. ovale: relatively unusual outside of Africa
P. knowlesi: common in the island of Borneo, and to a lesser extent, elsewhere in Southeast
Asia (where the main hosts, long-tailed & pig-tailed macaques are found)
Principal Determinants of the epidemiology of malaria:
1. Number (density)
2. Human-biting habits
3. Longevity of the anopheline mosquito vectors
-transmission of malaria is directly proportional to the
● density of the vector,
● square of the number of human bites per day per mosquito,
● tenth power of the probability of the mosquito's surviving 1 day
Mosquito longevity: important determinant of malaria transmissibility
Parasite life cycle that takes place w/n mosquito (from gametocyte ingestion to
inoculation (sporogony)): lasts 8-30 days, depending on ambient temperature
In order to transmit malaria, the mosquito must survive for >7 days
Sporogony not completed at cooler temperatures or at high altitudes (<16C/ <60.8F for P.
<21C/ <69.8F for P. falciparum)
vivax &
PATHOPHYSIOLOGY & HOST RESPONSE
-all stages of parasite's devt are evident on peripheral-blood smears
P. vivax & P. ovale: marked predilection for young RBCs
P. malariae: for old cells
P. falciparum: invade erythrocytes of all age, associated with very high parasite densities
P. knowlesi: dangerous high parasite densities may occur, due to shorter (24hr) asexual life
cycle
Host responds to malaria infection
>> activate nonspecific defense mechanism
Spleen: removal of both parasitized & uninfected RBCs, removes damaged ring-form
parasites (process known as pitting) & returns the once-infected erythrocytes to circulation w/
shortened survival
-material released induce monocyte/macrophage activation and release of proinflammatory
cytokines>> causes fever & other pathologic effects
● Temperatures of >=40C (104F) damage mature parasites
● In untreated infections >> effect of such temp is to further synchronize the parasitic
cycle >> production of regular fever spikes & rigors
● These regular fever patterns (quotidian, daily; tertian, q2days; quartan, q 3days)
-Both humoral & cellular immunity are necessary for protection (immune individuals have
polyclonal increase in serum levels of IgM, IgG & IgA)
-Antibodies to parasite antigens can limit in vivo replication of the parasite
P. falciparum: most important antigens is the surface adhesin (variant protein family of
pFemP1)
-Passive transfer of IgG from immune adults reduced levels of parasitemia in children
● Passive transfer of maternal antibody contributes to the partial protection of infants from
severe malaria in the first months of life
● This complex immunity to disease declines when a person lives outside an endemic area
for several months or longer
Several factors that retard the development of cellular immunity to malaria:
1. Absence of major histocompatibility antigens on the surface of infected RBCs (which
precludes direct T cell recognition)
2. Malaria antigen-specific immune unresponsiveness
3. Enormous strain diversity of malarial parasites (w/ ability of the parasite to express
variant immunodominant antigens on the erythrocyte surface)
CLINICAL FEATURES:
-First symptoms are nonspecific: lack of a sense of well being, headache, fatigue,
abdominal discomfort & muscle aches followed by fever
(prominence of headache, chest pain, abdominal pain, cough, arthralgia, myalgia or diarrhea
suggest another dx)
● Myalgia may be prominent (not severe like dengue fever, muscles are not tender as in
leptospirosis/typhus)
● Nausea, vomiting, orthostatic hypotension are common
● Classic malarial paroxysms (fever spikes, chills & rigors occur at regular intervals:
relatively unusual & suggest infection (relapse) w/ P. vivax or P. ovale
● Fever is usually irregular at first (temp of nonimmune children & individuals often rises
above 40C (104F), w/ accompanying t achycardia & sometimes delirium
● Childhood febrile convulsions (generalized seizures may herald the devt of
encephalopathy >> cerebral malaria)
● Most pts with uncomplicated infections > fewer abnormal PE: fever, malaise, mild
anemia & palpable spleen (in nonimmune w/ acute malaria, the spleen takes several
days to become palpable)
● Slight enlargement of the liver is common (particularly among young children)
● Mild jaundice (common among adults), may develop in pts with uncomplicated malaria
& usu resolves over 1-3 weeks
● Not associated with rash
● Petechial hemorrhages in the skin or mucous membranes develop rarely
LABORATORY FINDINGS:
● Anemia: normochromic, normocytic is usual
● Normal leukocyte count (elevated in severe infections)
● Slight monocytosis, lymphopenia, & eosinopenia, w/ reactive lymphocytosis &
eosinophilia in weeks after acute infection
● Reduced platelet count (usu ~10^5/uL)
● Elevated ESR (erythrocyte sedimentation rate, plasma viscosity, & levels of
C-reactive protein & other acute-phase proteins
● Severe infections: may accompany prolonged PT & PTT & severe thrombocytopenia
● Reduced antithrombin III levels in mild infection
● Uncomplicated malaria: normal plasma concentrations of electrolytes, BUN &
creatinine
DIAGNOSIS:
The dx of malaria rests on the demonstration of asexual forms of the parasite in stained
peripheral-blood smears
-Thick & thin blood smears: to confirm dx & identify species of infecting species
-If microscopy is not available: rapid test should be performed
● Molecular dx by PCR amplification of parasite nucleic acid: more sensitive than
microscopy or rapid diagnostic tests for detecting malaria parasites & defining malarial
species (used in reference centers in endemic areas)
● Serologic dx w/ either indirect fluorescent antibody or enzyme-linked
immunosorbent assays: useful for screening of prospective blood donors & useful as a
measure of transmission intensity in future
TREATMENT:
*WHO recommends artemisinin-based combination therapy (ACT) as first-line treatment
for uncomplicated falciparum m alaria in malaria endemic areas
P. falciparum & P. knowlesi: treated with an artemisinin-based combination
P. vivax, P. malariae, & P. ovale: treated with an artemisinin-based combination or oral
chloroquine (total dose, 25 mg of base/kg)
-ACT regimens now recommended are safe and effective in adults, children & pregnant women
Five ACT regimens are currently recommended by WHO:
● Artemether-lumefantrine
● Artesunate-mefloquine
● Dihydroartemisinin- piperaquine
● Artesunate-sulfadoxine-pyrimethamine
● Artesunate-amodiaquine
Low malaria transmission areas: a single dose of primaquine (0.25 mg/kg) should be
added to ACT
-Pregnant women should not be given primaquine
-3day ACT regimens are all well tolerated but mefloquine is associated with increased rates
of vomiting & dizziness
2nd line tx for recrudescence ff 1st therapy:
● A different ACT regimen may be given
● Another alternative 7-day course of either artesunate or quinine plus tetracycline,
doxycycline or clindamycin
● Tetracycline & doxycycline cannot be given to pregnant women after 15 weeks of
gestation or to children <8yo
Oral quinine: extremely bitter, regularly produces cinchonism comprising tinnitus, high-tone
deafness, nausea, vomiting & dysphoria
*pt should be monitored for vomiting after 1hr after the administration of any oral antimalarial
drug (if there is vomiting, the dose should be repeated)
Symptom-based tx: tepid sponging & acetaminophen (paracetamol) >> lowers fever,
reduce pt propensity to vomit
*Thick blood films should be checked again 1&2 days later to exclude the dx
*Non immune pts receiving tx for malaria should have daily parasite count performed until
the thick films are negative
(If the level of parasitemia does not fall below 25% of the admission value in 72h or if
parasitemia has not cleared by 7 days, DRUG RESISTANCE is likely & regimen should be
changed)
To eradicate persistent liver stages & prevent relapse: primaquine (0.5 mg of base/kg in
East Asia & Oceania & 0.25 mg/kg elsewhere) should be given for 14 days to pts with P.
vivax or P. ovale
PREVENTION: PERSONAL PROTECTION AGAINST MALARIA
● Avoidance of exposure to mosquitoes at their peak feeding times (usually dusk to dawn)
● The use of insect repellents containing 10-35% DEET (or if DEET is unacceptable, 7%
picaridin)
● Suitable clothing
● Insecticide-treated bed nets (ITNs) or other insecticide- impregnated materials
● Widespread use of bed nets treated w/ residual pyrethroids reduces the incidence of
malaria in areas where vectors bite indoors at night
