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