Malaria, Trypanosomes & Leishmania

Plasmodium: life cycle and species

Life cycle. A female Anopheles mosquito injects sporozoites into the blood during a bite.

Hypnozoites and relapse. P. vivax and P. ovale can leave dormant hypnozoites in hepatocytes. Blood-stage drugs such as chloroquine and artemisinins do not reach them, so infection relapses weeks to months later. Relapse differs from recrudescence, the return of blood-stage parasites that survived inadequate therapy. Primaquine (14 days) or single-dose tafenoquine eradicates hypnozoites; both are oxidants that hemolyze G6PD-deficient RBCs, so G6PD activity is tested first, and both are avoided in pregnancy because the fetus's G6PD status is unknown.

Fever periodicity. When schizont rupture is synchronized, patients have paroxysms of shaking chills, high fever, and drenching sweats: every 48 hours with P. vivax and P. ovale (tertian), every 72 hours with P. malariae (quartan), and irregularly with P. falciparum. P. malariae can also cause an immune-complex nephrotic syndrome.

Falciparum malaria and host resistance

The smear. P. falciparum invades RBCs of every age, so parasitemia can climb very high; more than 5% signals severe disease. Thin smears show many small rings, often several in one cell and some hugging the membrane, plus crescent (banana-shaped) gametocytes. Mature trophozoites and schizonts are rarely seen because they have left the circulation.

Sequestration. Infected RBCs develop surface knobs displaying PfEMP1, which binds endothelial receptors such as ICAM-1 and CD36. Parasitized cells therefore stick in capillaries and venules, escape splenic clearance, and obstruct flow. In the brain this produces cerebral malaria (impaired consciousness, seizures, coma); in the placenta it causes maternal anemia, low birth weight, and fetal loss.

Severe malaria. Beyond cerebral malaria, look for severe anemia (hemolysis of infected and uninfected cells plus splenic clearance), hypoglycemia, lactic acidosis, acute kidney injury, blackwater fever (massive intravascular hemolysis with dark hemoglobinuria), ARDS or pulmonary edema, and shock. Hypoglycemia has three sources: parasite glucose use, failing gluconeogenesis, and quinine-stimulated insulin release, so check glucose in any obtunded patient. IV artesunate is first-line.

Inherited resistance. P. vivax merozoites enter RBCs through the Duffy antigen (DARC); many people of West African descent are Duffy-negative and resist vivax. Sickle cell trait, G6PD deficiency, and α- and β-thalassemia protect against severe falciparum malaria. This heterozygote advantage (balanced polymorphism) explains why these alleles are common where malaria has long been endemic.

Diagnosis and antimalarial drugs

Blood smears. Giemsa-stained smears remain the standard. The thick smear lyses RBCs and concentrates parasites, making it the more sensitive test for detection; the thin smear preserves RBCs, so it identifies species and measures percent parasitemia. Negative smears are repeated every 12–24 hours for three sets. Rapid tests detect antigens such as histidine-rich protein 2 (HRP-2). The brown malaria pigment (hemozoin) in parasites is polymerized heme.

Babesia microti (Ixodes tick, northeastern US) also forms intraerythrocytic rings and is worst in asplenic patients, but it makes Maltese-cross tetrads and lacks hemozoin and gametocytes.

Choosing therapy. Uncomplicated falciparum malaria from chloroquine-resistant regions is treated with an artemisinin combination such as artemether-lumefantrine, or with atovaquone-proguanil. Severe malaria gets IV artesunate, which lowers mortality compared with quinine; patients are watched for delayed hemolysis 1–3 weeks later. Vivax or ovale malaria gets a blood-stage drug plus primaquine or tafenoquine.

Trypanosomes

African trypanosomiasis. Trypanosoma brucei gambiense (West and Central Africa) causes chronic illness over months to years; T. b. rhodesiense (East Africa) is acute. Both are spread by tsetse fly bites. A painful chancre forms at the bite. In the hemolymphatic stage fevers come in waves, because the parasite repeatedly switches its variant surface glycoprotein (VSG) coat and escapes each round of antibody; posterior cervical lymphadenopathy (Winterbottom sign) and hepatosplenomegaly accompany them. In the CNS stage, patients develop daytime somnolence with nighttime insomnia, personality change, and finally coma and death.

Diagnosis and treatment. Trypomastigotes are seen in blood, lymph node aspirate, or CSF, and lumbar puncture stages the disease. Suramin (rhodesiense) or pentamidine (gambiense) treats the blood stage but does not reach the CNS. CNS disease classically requires melarsoprol, an arsenical that can cause a fatal reactive encephalopathy; less toxic eflornithine-based regimens and oral fexinidazole have largely replaced it for gambiense disease.

Chagas disease. T. cruzi is endemic in rural Latin America. Triatomine (reduviid, "kissing") bugs bite exposed skin, often the face, at night and defecate while feeding; scratching rubs trypomastigotes into the bite or conjunctiva. Transfusion, organ transplantation, congenital spread, and contaminated food or drink also transmit it, so donated blood is screened. The acute phase may bring fever, lymphadenopathy, hepatosplenomegaly, myocarditis, a chagoma at the bite, or Romaña sign (painless unilateral eyelid and periorbital swelling).

Chronic Chagas disease. Years to decades later, a minority develop organ damage as intracellular amastigotes and inflammation destroy myocytes and neurons. The heart shows dilated cardiomyopathy with an apical aneurysm and mural thrombus (embolic stroke), right bundle branch block with left anterior fascicular block, ventricular arrhythmias, and sudden death. Loss of myenteric (Auerbach) plexus ganglion cells causes megaesophagus with achalasia-like dysphagia and megacolon with severe constipation. Chronic infection is diagnosed by serology. Benznidazole or nifurtimox works best in acute infection and in children and is avoided in pregnancy.

Leishmania

Biology. Phlebotomine sandflies inject flagellated promastigotes, which macrophages engulf. Inside the phagolysosome they become small oval amastigotes with a nucleus and a rod-shaped kinetoplast but no external flagellum, and they multiply there. Th1 immunity with IFN-γ–activated macrophages controls infection; when it fails (HIV, malnutrition), disease spreads to the viscera. Macrophages packed with amastigotes (Leishman-Donovan bodies) resemble Histoplasma-laden macrophages, but Histoplasma yeast lack a kinetoplast.

Visceral leishmaniasis (kala-azar). Caused by L. donovani and L. infantum in South Asia, East Africa, Brazil, and the Mediterranean. Months of fever and weight loss are accompanied by massive splenomegaly with hepatomegaly, pancytopenia, hypergammaglobulinemia, and grayish skin darkening ("kala-azar" means black fever). Untreated disease is usually fatal. Amastigotes are found in splenic or bone marrow aspirates, and rK39 antibody tests support the diagnosis. Liposomal amphotericin B is first-line; oral miltefosine is an alternative but is teratogenic.

Cutaneous and mucocutaneous leishmaniasis. Cutaneous disease comes from L. major and L. tropica in the Middle East and Afghanistan and from L. mexicana and L. braziliensis in Latin America, classically in soldiers and travelers. A painless papule at the bite enlarges into an ulcer with a raised, indurated, volcano-like border and heals over months with a scar. L. braziliensis can later spread to the nose and mouth, destroying the nasal septum, palate, and lips (mucocutaneous leishmaniasis, espundia), which always needs systemic therapy. Treatment options include pentavalent antimony (sodium stibogluconate), amphotericin B, and miltefosine.