MALARIA
Overview
- Protozoan disease (Plasmodium)
- Transmitted by Anopheles mosquitoes
- Causing 1-3 million deaths each yr
- Has been eliminated from US, Canada, Europe, Russia. But has resurged
in many part of tropics
Etiology and Pathogenesis
Life Cycle
1. Mosquito Stage
- Female Anopheles mosquito bites human and transmits sporozoites into
the bloodstream
2. Human Stage
a. Exo Erythrocytic Stage asymptomatic
- Sporozoites migrate through blood to liver
- Invade hepatocytes and divide to form Multinucleated Schizonts
* Atovaquone-proguanil and primaquine against hepatic stage
schizonts
* P. Vivax and P. Ovale form latent hypnozoites in hepatocytes, which
cause relapses of malaria long after initial infection Primaquine is
effective
- Schizonts rupture and release merozoites into circulation where invade
RBC
b. Erythrocytic Stage
- Merozoites Early trophozoite (ring forms) Trophozoite
Multinucleated Schizonts cause rupture of RBC releasing
merozoites back into circulation and infect other RBC
*Artemisins, atovaquone-proguanil, doxycycline, mefloquine,
choloroquine interrupt this process within RBC
* Primaquine active against schizonts of P. Vivax, but not P. falciparum
- Some merozoites differentiate into male or female gametocytes
taken up by mosquito infect another host
- Within RBC parasites digest Hb breakdown is hemozoin (formed in
food vacuole)
- Parasites inside RBC also derive energy from anaerobic glycolysis to
glucose to lactic acid hypoglycaemia and lactic acidosis
- Parasites also cause RBC membrane less deformable hemolysis and
haemolytic anemia by spleen. Enlarged spleen also cause
thrombocytopenia
- Hemozoin & remnants of cell membrane phagocytised by circulating
macrophages stimulating immune cascade
- Free heme also released into peripheral bood endothelial activation
- Immune stimulated Release TNF suppresses hematopoiesis
Species of Plasmodium
1. Plasmodium Falciparum
- Tertian fever (every 48 hrs). But in P. Falciparum almost continuous
- Deadliest of all (malignant). Why?
a. P. Falciparum able to infect RBC of any age high parasite burdens
and profound anemia. The other only infect new & old RBC
b. P. Falciparum produces PfEMPI (P. Falciparum Erythrocyte Membrane
Protein) form ‘knobs’ on surface of RBC. PfEMP I binds to ligands
on endothelial cells, including CD36, thrombospondin, VCAM-1,
ICAM-1 and E-selectin. This causes infected RBC to clump together
(rosetting) and stick to endothelial cells lining small blood vessels
(sequestration) block blood flow.
Brain: Poor perfusion ischemia cerebral malaria main
cause of death in children
Kidneys: ATN + renal failure
Intestines: Ischemia + ulceration
Placenta: Intrauterine growth retardation
c. P. Falciparum stimulates production of high levels of cytokines
TNF, IFN-γ, IL-1 suppress hematopoiesis (anemia), increase fever,
increase NO, induce expression of endothelial receptors for PfEMP1
(increasing sequestration)
2. Plasmodium Vivax
- Benign tertian malaria (48 hr fever cycle)
- Has hypnozites dormant, can cause relapse
- Mortality rate low
- P. Vivax is major cause of morbidity in early infancy
- Splenic rupture is rare complication
3. Plasmodium Ovale
- Benign tertian malaria (48 hr fever cycle)
- Also have the dormant hypnozites stage
4. Plasmodium Malariae
- Quartan malaria (72 hr cycle)
- Can be chronic. Parasitemia can exist years or more with or without
symptoms (recurrence can happen more than 40 yrs after known
exposure)
- Chronic P. Malariae in children has mixed IgM and IgG basement
membrane immune complex nephropathy nephrotic syndrome
most die within 2 yrs can be cured with early recognition & tx
Epidemiology
- Occurs throughout most of tropical regions
- P. Falciparum causing largest burden of disease followed by P. Vivax
- P. Falciparum predominates in Africa, New Guinea, Hispaniola (Haiti &
Dominican Republic)
- P. Vivax is more common in Americas and Western Pacific
- Both equal in Indian subcontinent, Eastern Asia, and Oceania
- P. Malaria uncommon sub Saharan Africa
- P. Ovale less common and unusual outside Africa
Determinants of epidemiology
- Number (density), human biting habits (indoor or outdoor) and longevity
of the Female Anopheline mosquito
- Eg. An. Gambiae in Africa effective as vector as long lived, occur in
high densities in tropical climates, breed readily, rest and bite within
dwellings, and bite human in preference to other animals
Clinical presentation of Malaria
1. After Anopheles female bite sphorozites go to liver within 1 to 2 hrs
Asymptomatic for 12 – 35 days (exo erythrocytic stage)
2. Symptoms manifest when merozoites released from ruptured RBC
- 3 successive stages:
a. 15-60 Minute Cold Stage
shivering + feeling of cold
b. 2-6 hr Hot Stage
Fever
Flushed, dry skin
Headache
Nausea/vomiting
c. 24 Hr Sweating Stage
Fever drops rapidly
Rapid thready pulse
Polyuria
Poor Px if:
Altered consciousness with or without seizures
Respiratory distress
Circulatory collapse
Metabolic acidosis
Renal failure, hemoglobinuria (‘blackwater fever’ intravascular
hemolysis leading to Hburia)
Hepatic failure
Coagulopathy with or without disseminated intravascular coagulation
Severe anemia
Hypoglycemia
Physical findings: Pallor, petechiae, jaundice, hepatosplenomegaly
Lab findings:
- parasitemia > 5-10% of neutrophil contain malaria pigment
- Normochromic normocytic Anemia
- Thrombocytopenia
- Coagulopathy
- Elevated transaminases (ALT or AST) liver damage
- Elevated BUN/creatinine
- Acidosis
- Hypoglycemia
Thick & Thin Blood Films
- Thin films are similar to usual blood films and allow species
identification, because the parasite's appearance is best preserved in
this preparation.
- Thick screen a larger volume of blood and are about eleven times
more sensitive than the thin film picking up low levels of infection
is easier on the thick film, but the appearance of the parasite is much
more distorted and therefore distinguishing between the different
species can be much more difficult
MALARIA DRUGS
Drugs that kill parasite in blood Schizonticides
- For acute attack act on erythrocytic stage
1. Quinine
MOA:
- Inhibit Plasmodium’s Haem Polymerase (wh/ breaks down Hb to
haemozoin. Free Haem is also toxic to plasmodium)
- Interferes with DNA or RNA syntheses
- Increase intravascular pH
AE: Cinchonism (tinnitus, headache, nausea, vomiting, blurry vision)
2. Mefloquine
MOA:
- Forms toxic complexes with free haem damages membranes
AE:
- Neuropsychiatric disorders (avoid in depressed, schizophrenic,
psychological ill), GIT, giddiness, confusion, insomnia
3. Chloroquine widespread resistance, still remains effective for P.
Ovale, P. Malariae, and in most regions P. Vivax
Drugs for radical cure (to remove hypnozoites) Tissue Schizonticide
- Act on parasites in liver in P. Ovale and P. Vivax eliminating
hypnozoites
- Also destroy gametocytes in P. Falciparum
- Drugs: Primaquine and Tafenoquine
Drugs that prevent transmission Gametocides
- Primaquine, Proguanil, Pyrimethamine, Artermisinin all have
‘additional action’ of destroying gametocytes preventing transmission
Prophylactic drugs
- Block link between pre-erythrocytic and erythrocytic by killing
parasites when out from liver
1. Doxycyline Tetracycline AB inhibits protein synthesis
(bacteriostatic)
2. Pyrimethamine with sulfodoxine (Fansidar) Folate antagonist
3. Artemisinin reacts with iron from Hb to produce ROS
4. Malarone combination of Atovaquone + Proguanil
Atovaquone blocks parasite mitochondrial electron transport chain
Proguanil inhibits parasite DHFR
PREVENTION
1. Vector Control: Insect repellent, protective clothing, insecticide
impregnated bed nets (permethrin), elimination of breeding site, avoid
dusk/dawn and dark clothing/perfume
2. Prophylactic chemotherapy
-Drug used usually:
o Atovaquone+Proguanil (Malarone)
o Doxycyline
o Mefloquine