MALARIA• causative agent = Plasmodium species• 40% of world’s population lives in

endemic areas• 3-500 million clinical cases per year• 1.5-2.7 million deaths (90% Africa)• known since antiquity

• early medical writings from India and China• Hippocrates usually credited (500 BC)• Laveran identified parasite (1880)• Ross demonstrated mosquito transmission

(1898)• Garnham described liver stage (1940’s)

Clinical Features• characterized by acute febrile attacks

(malaria paroxysms)• periodic episodes of fever alternating with

symptom-free periods• manifestations and severity depend on

species and host status• immunity, general health, nutritional state,

genetics• recrudescences or relapses can occur

over months or years• can develop severe complications

(especially P. falciparum)

•natural (sporozoites/Anopheles)•blood transfusions

• shorter incubation period• fatality risk (P. falciparum)• no relapses possible (vivax/ovale)

•syringe sharing•congenital

• relatively rare although placenta is heavily infected

Malaria Transmission

Pf Pv/Po PmPrepatent Period 6-9 d 8-12d 15-18dIncubation Period 6-25 d 8-27d 16d-8w

Prodromal Symptoms end of incubation period 2-3 days before 1st paroxysm includes: malaise, fatigue, lassitude,

headache, muscle pain, nausea, anorexia (i.e., flu-like symptoms)

can range from none to mild to severe

Febrile Attack (Malaria Paroxysm) periodic febrile episodes alternating with

symptom-free periods initially fever may be irregular before

developing periodicity may be accompanied by splenomegaly,

hepatomegaly (slight jaundice), anemia

cold stage• feeling of intense cold• vigorous shivering, rigor• lasts 15-60 min

hot stage• intense heat• dry burning skin• throbbing headache• lasts 2-6 hours

sweating stage• profuse sweating• declining temperature• exhausted, weak sleep• lasts 2-4 hours

• paroxysms associated with synchrony of merozoite release

• temperature is normal and patient feels well between paroxysms

• falciparum may not exhi-bit classic paroxysms• continuous fever• 24 hr periodicity

Malaria Paroxysm

tertian malariaquartan malaria

Karunaweera et al (1992) PNAS 89:3200

• TNF = tumor necrosis factor- ()• proinflammatory cytokine (produced

in response to malarial antigens?)

rigor

sweating

•may be accompanied by spleno-megaly, hepatomegaly (slight jaundice), hemolytic anemia

•P. falciparum can be lethal in non-immune (eg., children, expatriates)

•paroxysms become less severe and irregular as infection progresses

•semi-immune may exhibit little (1-2 days fever) or no symptoms

Other Features of the Paroxysms

Immunity• slow to develop• short lived

• ‘premunition’• non-sterilizing

• lower parasitemia• less symptoms

Anti-Parasite Immunity• immune response prevents

merozoite invasion, eliminates infected erythrocytes, etc.

Anti-Disease Immunity• eg., neutralization of exo-

antigens or toxic effects

Current Distribution of Malaria

• tropical and subtropical climates• formerly widespread in

temperate zones (ague)• 40% of worlds population live in

endemic regions

P. vivaxmost widespread, found in most endemic areas including some temperate zones

P. falciparumprimarily tropics and subtropics

P. malariaesimilar range as P. falciparum, but less common and patchy distribution

P. ovaleoccurs primarily in tropical west Africa

Distribution of Malarial Parasites

Stable or Endemic Malaria

• ~constant incidence over several years• includes seasonal transmission

• immunity and disease tolerance correlates with level of endemicity (especially adults)

Unstable or Epidemic Malaria

• periodic sharp increase in malaria• little immunity• high morbidity and mortality

Malaria Epidemiology

EndemicityLevels:• holo-• hyper-• meso-• hypo-

DateTested

% Incidence(smear/PCR)*

Sep 93 13% (2/8)Jan 94 19% (4/11) } 33% reported

symptomsApr 94 24% (8/11)Jun 94 19% (0/14) } no symptomatic

cases*Number of individuals testing positive by blood smearand PCR. PCR assay detects ~2.5 parasites/l (4-10Xmore sensitive than thick smears).

Roper et al (1996) AJTMH 54:325

• eastern Sudan (mesoendemic, seasonal)• rainy season June-Sept.• peak symptomatic malaria Oct.-Nov.

• followed cohort of 79 individuals using thick films and PCR (P. falciparum)

• susceptibility of anopheline species

• feeding habits• density• longevity• climatic factors

• temperature, humidity, rainfall, wind, etc

Mosquito Transmission

Anopheles

"Everything about malaria is so moulded by local conditions that it becomes a thousand epidemiological puzzles."

Hackett (1937)

Malaria ControlReduce Human-Mosquito Contact

• impregnated bed nets• repellants, protective clothing• screens, house spraying

Reduce Vector • environmental modificaton• larvacides/insecticides• biological control

Reduce Parasite Reservoir• diagnosis and treatment• chemoprophylaxis