Malaria

Overview

Malaria is a protozoan disease caused by Plasmodium species, transmitted through the bite of female Anopheles mosquitoes. It remains one of the most serious infectious diseases globally - the WHO estimated over 200 million cases and more than 600,000 deaths in 2020, with the vast majority occurring in sub-Saharan Africa, primarily in children. - Robbins & Kumar Basic Pathology

Causative Species

Five Plasmodium species infect humans:

Species	Fever Cycle	Severity	Notes
P. falciparum	Every 48 hrs (tertian)	Most severe - high fatality	Responsible for cerebral malaria; near-universal chloroquine resistance
P. vivax	Every 48 hrs (tertian)	Mild-moderate	Has liver hypnozoites; infects only reticulocytes
P. ovale	Every 48 hrs	Mild	Has liver hypnozoites
P. malariae	Every 72 hrs (quartan)	Mild	Associated with nephrotic syndrome
P. knowlesi	Every 24 hrs	Virulent - can be fatal	Simian malaria (Southeast Asia); morphologically resembles P. malariae

All humans are the only natural reservoir. - Murray & Nadel's Respiratory Medicine

Life Cycle & Pathogenesis

Life cycle of P. falciparum showing hepatic and erythrocytic stages

Hepatic (pre-erythrocytic) stage - clinically silent:

Infected Anopheles mosquito injects sporozoites into the bloodstream
Two surface proteins - thrombospondin-related adhesive protein and circumsporozoite protein - bind heparan sulfate proteoglycans on hepatocytes
Sporozoites enter hepatocytes and differentiate into merozoites (incubation: 1-4 weeks)
Infected hepatocytes rupture, releasing merozoites into blood
In P. vivax and P. ovale, some sporozoites remain dormant as hypnozoites in the liver (responsible for relapses months to years later)

Erythrocytic stage - causes clinical disease:

A lectin-like molecule on merozoites binds sialidated glycophorin on red cells, allowing entry into a digestive vacuole
Intraerythrocytic organisms become trophozoites, then differentiate into:
- Gametocytes - restart the cycle in the mosquito
- Schizonts - express PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1) as knob-like extensions on the RBC surface
PfEMP1 binds ICAM-1, VCAM-1, and CD36 on endothelium, causing parasitized RBCs to sequester in capillary beds - this is the key mechanism of severe disease
Schizonts eventually lyse RBCs, releasing merozoites in "showers," causing paroxysmal fever

Robbins & Kumar Basic Pathology

Morphology & Pathological Changes

Hemolytic anemia - destruction of infected (and uninfected) RBCs
Hematin (malarial pigment) - brown pigment derived from hemoglobin degradation; deposits in spleen, liver, lymph nodes, bone marrow
Splenomegaly - often massive, due to hyperplasia of mononuclear phagocytes; occasional hepatomegaly
Cerebral malaria - small brain vessels engorged and occluded by PfEMP1-adherent parasitized RBCs - Robbins & Kumar Basic Pathology

Clinical Features

Classic presentation:

Episodic shaking chills and fever coinciding with merozoite release ("malarial paroxysm")
- Every 24 hrs: P. knowlesi
- Every 48 hrs: P. vivax, P. ovale, P. falciparum
- Every 72 hrs: P. malariae
- Note: periodic fever is unreliable, especially in P. falciparum
Hemolytic anemia (universal)
Headache, myalgia, malaise, nausea

Features of severe malaria (P. falciparum):

Cerebral malaria - convulsions, coma, rapid deterioration (death within days-weeks)
Blackwater fever - massive intravascular hemolysis, hemoglobinemia, hemoglobinuria, jaundice, renal failure
Thrombocytopenia
Acute kidney injury
Acute lung injury / ARDS - diffuse bilateral opacities on CXR; can occur even after several days of treatment; noncardiogenic pulmonary edema
Multiorgan failure (especially in non-immune patients)
Hypoglycemia

High-risk groups: children, pregnant women, non-immune travelers - Murray & Nadel's Respiratory Medicine

Genetic Protection

Malaria has exerted profound evolutionary selective pressure on humans. Erythrocyte defects most prevalent in malaria-endemic regions include:

Sickle cell trait (HbAS) - protects against severe falciparum malaria
Thalassemia
G6PD deficiency
Pyruvate kinase deficiency
Murray & Nadel's Respiratory Medicine

Diagnosis

Method	Notes
Thick blood smear (gold standard)	Detects presence of parasites; repeat after 8 hours if initial smear negative
Thin blood smear	Species identification by morphology
Rapid Diagnostic Test (RDT)	Point-of-care antigen detection; available for P. falciparum and P. vivax; antigen can persist after infection, reducing specificity
PCR	Reference labs only; not commercially available

Only ring forms of P. falciparum are seen in peripheral blood (mature forms sequester in microvasculature)
Parasitemia >10% = sign of severe disease
P. vivax parasitemias are lower (infects reticulocytes only)
Murray & Nadel's Respiratory Medicine

Treatment

Uncomplicated malaria:

P. vivax, P. ovale, P. malariae, P. knowlesi: Chloroquine (still effective)
P. falciparum: Artemisinin-based Combination Therapy (ACT) - P. falciparum is nearly universally chloroquine-resistant
P. vivax / P. ovale: Add primaquine (after checking G6PD status) to eliminate liver hypnozoites and prevent relapse

Severe malaria:

IV artesunate - treatment of choice (as of 2019 in the US, available via CDC Malaria Hotline: 855-856-4713)
IV quinine is still used outside the US
Artesunate resistance is an emerging problem, particularly in Southeast Asia (manifested by slower parasite clearance)

Supportive care:

Careful fluid balance (prevent pulmonary edema)
Correction of hypoglycemia
Oxygenation support
Antibiotics if concurrent bacterial sepsis
Exchange transfusion is no longer recommended (insufficient evidence)
Murray & Nadel's Respiratory Medicine

Prevention

Insecticide-treated bed nets (ITNs)
Antimalarial prophylaxis for travelers (options: atovaquone-proguanil, doxycycline, mefloquine, chloroquine in sensitive areas)
Larval control - removal of stagnant water (mosquito breeding sites)
RTS,S/AS01 vaccine (Mosquirix) - contains sporozoite antigens; partial protection; approved by WHO for use in children in sub-Saharan Africa; expected to prevent thousands of fatal cerebral malaria cases
A history of prophylaxis does not rule out malaria; subtherapeutic levels or resistant organisms can still cause disease - Robbins & Kumar Basic Pathology

Key Summary Points

Feature	P. falciparum	P. vivax / P. ovale	P. malariae	P. knowlesi
Fever cycle	48 hrs	48 hrs	72 hrs	24 hrs
Relapse from hypnozoites	No	Yes	No	No
Chloroquine sensitivity	Resistant	Sensitive	Sensitive	Sensitive
Key complication	Cerebral malaria, ARDS	Relapsing fever	Nephrotic syndrome	Severe disease
Treatment	ACT + IV artesunate (severe)	Chloroquine + primaquine	Chloroquine	Chloroquine

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