224: MALARIA Gametocytes
• Blood-stage parasites differentiate into sexual forms: male
Overview and female gametocytes.
• Malaria is a protozoan disease transmitted by the bite of • Female gametocytes outnumber males 4:1.
infected female Anopheles mosquitoes. • In mosquito:
• One of the most important parasitic diseases of humans. o Male gametocyte → exflagellation → 8 male
• Endemic in 87 countries, affecting ~3 billion people. gametes → fuse with female → zygote →
• Global burden (2019): ookinete → oocyst → sporozoites migrate to
o 229 million cases salivary glands → infect next human host.
o 409,000 deaths (~1100 deaths/day)
• Mortality declined between 2000–2015 due to control Epidemiology
programs but has since risen. • Geographic distribution: most tropical regions.
• Eliminated from the US, Canada, Europe, and Russia >50 • Species prevalence:
years ago. o P. falciparum: Africa, New Guinea, Hispaniola
• Resurgence in many tropical areas between 1970–2000. o P. vivax: Central/South America, Southeast Asia
• Control efforts: o P. malariae: sub-Saharan Africa, less common
o Improved access to diagnosis o P. ovale: primarily Africa (<1% of isolates)
o Effective treatments o P. knowlesi: Borneo and Southeast Asia (macaque
o Insecticide-treated bed nets hosts)
• Threats: • Endemicity classification:
o Drug resistance o Hypoendemic: <10%
o Insecticide resistance o Mesoendemic: 11–50%
• Malaria remains a burden on endemic communities, a threat o Hyperendemic: 51–75%
o Holoendemic: >75%
to non-endemic countries, and a danger to travelers.
• Transmission types:
Etiology and Pathogenesis o Stable: frequent, year-round infection →
Causative Agents premunition in adults
• Six main human-infecting Plasmodium species: o Unstable: low/erratic transmission → symptomatic
disease at all ages
o P. falciparum: most deaths; severe disease
o P. vivax: relapsing malaria; severe illness possible • Epidemics: occur in unstable transmission areas due to
o P. ovale (two species: curtisi, wallikeri): relapsing environmental, social, or control failures.
malaria
o P. malariae: slower life cycle; less common Pathophysiology
o P. knowlesi (Southeast Asia): monkey malaria; can Erythrocyte Changes
be severe • RBC invasion → hemoglobin digestion → hemozoin
o Occasional monkey parasites: P. simium (South formation.
America), P. cynomolgi (Southeast Asia) • RBC membrane altered → exposure of antigens, decreased
Life Cycle deformability.
• Transmission begins when an infected female Anopheles • P. falciparum: knobs form → PfEMP1 → cytoadherence →
mosquito inoculates sporozoites into human blood. sequestration in vital organs (brain, placenta).
• Sporozoites travel to the liver → invade hepatocytes → • Rosetting and agglutination → microvascular obstruction →
undergo preerythrocytic schizogony → produce 10,000– pathogenesis of severe malaria.
30,000 merozoites per sporozoite. • Non-falciparum species: no significant sequestration;
• Merozoites released into bloodstream → invade red blood predilection for young (vivax, ovale) or old (malariae) RBCs.
cells (RBCs) → trophozoites → multiply every 48 h (species- Host Response
specific: P. knowlesi 24 h, P. malariae 72 h). • Spleen: clears parasitized/uninfected RBCs, removes
• Symptomatic phase: ~50 parasites/µL of blood (~100 damaged parasites (“pitting”).
million total in adults). • Fever and cytokine release from monocyte/macrophage
• Hypnozoites (P. vivax & P. ovale): dormant liver forms activation.
causing relapses (2 weeks–≥1 year). • Genetic protection:
RBC Invasion o HbAS (sickle cell trait), HbC, HbE → reduce
• P. falciparum: parasite growth or cytoadherence
o Erythrocyte binding antigen 175 → glycophorin A o α-thalassemia, ovalocytosis → protect against
o EBL140 → glycophorin C severe disease
o PfRh5 → CD147 (basigin) o G6PD deficiency → partial protection
• P. vivax: binds developing erythrocytes via Duffy antigen • Immunity:
(Fya/Fyb) o Premunition: infection without illness
• P. knowlesi: prefers Duffy-positive RBCs o Species- and strain-specific
• Early ring forms appear similar; trophozoites show species- o Requires both humoral and cellular immunity
specific morphology and hemozoin. o Maternal antibodies provide partial infant protection
• Schizonts: RBC nearly fully occupied → ruptures →
Clinical Features
releases 6–30 merozoites.
Uncomplicated Malaria
, • Initial symptoms nonspecific: headache, fatigue, malaise, • P. vivax: reduces birth weight (~110 g), more in multigravida.
abdominal discomfort, myalgia, fever.
• Classic paroxysms (fever, chills, rigors) rare; more common Malaria in Children
in P. vivax/P. ovale. • Most malaria deaths (>400,000/year) occur in young African
• Non-immune patients: fever >40°C, tachycardia, sometimes children.
delirium. • Complications: convulsions, coma, hypoglycemia, metabolic
• Children: febrile convulsions possible; generalized seizures acidosis, severe anemia.
with P. falciparum. • Less common: deep jaundice, oliguric AKI, pulmonary
• Physical findings: mild anemia, splenomegaly, occasional edema.
hepatomegaly, mild jaundice. • Deep breathing often due to metabolic acidosis, not cardiac
• Rash: absent. failure.
Severe Falciparum Malaria • Children respond well to treatment.
• Mortality rises when >2% RBCs infected or organ dysfunction
occurs. Transfusion Malaria
• Major manifestations: cerebral malaria, severe anemia, • Transmission: blood transfusion, needlestick, organ
hypoglycemia, acidosis, renal failure, pulmonary edema, transplantation.
hematologic abnormalities, liver dysfunction. • Short incubation due to absence of preerythrocytic stage.
Cerebral Malaria • Clinical management similar to natural infections; primaquine
• Diffuse symmetric encephalopathy; coma, abnormal not required for vivax/ovale.
behavior, seizures.
• Funduscopic findings: retinal hemorrhages, opacification,
papilledema, cotton wool spots.
Chronic Complications of Malaria
• Children: ~10% have residual neurologic deficits; adults <3%.
Hyperreactive Malarial Splenomegaly (HMS)
Hypoglycemia
• Occurs in residents of malaria-endemic areas with chronic or
• Due to hepatic failure, increased glucose consumption, and
repeated infections.
quinine-induced hyperinsulinemia.
• Pathophysiology
• Particularly severe in children and pregnant women.
o Abnormal immunologic response to repeated
Acidosis
malaria.
• Hyperlactatemia, accumulation of organic acids → poor
o Massive splenomegaly and hepatomegaly.
prognosis.
o Marked elevations in serum IgM and malarial
• Causes: anaerobic glycolysis in sequestered tissues, lactate antibody titers.
from parasites, impaired clearance. o Hepatic sinusoidal lymphocytosis; peripheral B-cell
Noncardiogenic Pulmonary Edema lymphocytosis in Africa.
• Mortality >80% in adults; can occur in vivax malaria with o Production of cytotoxic IgM antibodies to CD8+ T
usual recovery. cells, antibodies to CD5+ T cells.
Renal Impairment o Increased CD4+/CD8+ T-cell ratio.
• Acute kidney injury, often acute tubular necrosis. o Uninhibited B-cell IgM production → cryoglobulin
• Early dialysis improves survival. formation → lymphoid hyperplasia →
Hematologic Abnormalities splenomegaly.
• Anemia: accelerated RBC removal, schizogony, ineffective • Clinical features
erythropoiesis. o Abdominal mass or dragging sensation.
• Blackwater fever: massive hemolysis, sometimes associated o Occasional sharp abdominal pains (perisplenitis).
with G6PD deficiency. o Anemia and varying degrees of pancytopenia
• Thrombocytopenia common; DIC rare. (hypersplenism).
Liver Dysfunction o Sometimes no detectable parasites in peripheral
• Mild hemolytic jaundice common; severe jaundice in P. blood.
falciparum. o High susceptibility to respiratory and skin infections;
• Liver failure does not occur in isolation. risk of sepsis.
Other Complications • Management
• HIV/AIDS, malnutrition, helminth infections exacerbate o In endemic areas: antimalarial chemoprophylaxis—
severity. usually effective.
• Bacteremia (~6% children, <1% adults), often Salmonella o In non-endemic areas: antimalarial treatment
spp. advised.
o Rarely, refractory cases may evolve into clonal
Malaria in Pregnancy lymphoproliferative disorders resembling
• Early pregnancy: fetal loss. hematologic malignancy.
• High transmission areas: low birth weight (~170 g), increased Quartan Malarial Nephropathy
infant mortality. • Caused by chronic/repeated P. malariae infections (possibly
• HIV co-infection → higher maternal parasite density, other species).
congenital malaria risk. • Pathophysiology
• Unstable transmission areas: severe infections, anemia, o Soluble immune complex-mediated glomerular
hypoglycemia, pulmonary edema, fetal death. injury → nephrotic syndrome.
, o Histology: focal/segmental glomerulonephritis with o Not useful for acute diagnosis.
capillary basement membrane splitting. Laboratory Findings in Acute Malaria
o Electron microscopy: subendothelial dense • Normochromic, normocytic anemia.
deposits. • Leukocyte count: usually normal; may increase in severe
o Immunofluorescence: deposits of complement, Ig, infection.
and sometimes P. malariae antigens. • Mild monocytosis, lymphopenia, eosinopenia; reactive
o Prognosis: lymphocytosis/eosinophilia post-infection.
▪ Coarse-granular, IgG3 deposits with • Thrombocytopenia (~10⁵/μL).
selective proteinuria → better prognosis. • Elevated ESR, plasma viscosity, CRP, acute-phase proteins.
▪ Fine-granular, IgG2 deposits with • Severe infection: prolonged PT/PTT, reduced antithrombin III,
nonselective proteinuria → worse metabolic acidosis, electrolyte disturbances, elevated
prognosis. BUN/creatinine, bilirubin, liver enzymes.
• Management • Hypergammaglobulinemia in immune/semi-immune
o Rarely reported today. individuals.
o Poor response to antimalarials, glucocorticoids, or • Urinalysis: usually normal.
cytotoxic drugs.
• CSF (cerebral malaria): normal or slightly elevated
Burkitt’s Lymphoma and Epstein-Barr Virus (EBV)
protein/cell count.
• Strong association between childhood Burkitt’s lymphoma,
EBV infection, and high P. falciparum transmission. Treatment of Malaria
• Mechanism Severe Malaria
o Chronic P. falciparum malaria → expansion of • First-line treatment: IV or IM artesunate.
EBV-infected B cells in germinal centers.
• Artesunate advantages:
o Deregulates activation-induced cytidine deaminase
o Rapid, safe, effective; no dose adjustment in
→ DNA damage → c-myc translocations →
liver/renal dysfunction.
lymphoma.
o Approved for pregnant women.
• Alternative: artemether or quinine if artesunate unavailable.
Diagnosis of Malaria
o Quinine: IV infusion with loading dose; risk of
General Principles
hypotension; monitor plasma levels.
• Malaria is not a clinical diagnosis.
• Supportive care:
• Fever in or from endemic areas → confirm via blood smear
o Frequent monitoring (parasite count, hematocrit,
or rapid diagnostic test (RDT).
glucose).
• If blood smear negative by an experienced microscopist → o Hypoglycemia: IV dextrose infusion.
malaria very unlikely. o Convulsions: IV or rectal benzodiazepines.
Demonstration of the Parasite o Fluid management: careful to avoid pulmonary
• Definitive diagnosis: visualization of asexual forms in edema or renal impairment.
peripheral blood. o Blood transfusion: consider Hct <20%; in children,
• Preferred stains: Giemsa (pH 7.2), Field’s, Wright’s, Hb <4 g/dL.
Leishman’s. o Renal failure: early hemofiltration or hemodialysis.
• Fluorescent staining: acridine orange—rapid detection in o Pulmonary edema/ARDS: oxygen, diuretics,
low parasitemia; species identification not possible. positive-pressure ventilation if needed.
• Blood films o Avoid ineffective or harmful adjuncts: high-dose
o Thin smear: fixed with methanol; counts parasitized steroids, urea, dextran, heparin, mannitol.
RBCs per 1000 RBCs. Uncomplicated Malaria
o Thick smear: unfixed; concentrates parasites 40– • P. falciparum / P. knowlesi: ACT.
100×; counts parasites per WBC or estimated via • P. vivax, P. ovale, P. malariae: chloroquine or ACT.
WBC count of 8000/μL. • ACT regimens (WHO recommended):
• Interpretation notes o Artemether-lumefantrine
o Examine 100–200 fields before declaring negative. o Artesunate-mefloquine
o Low-density parasitemia in endemic areas may be o Dihydroartemisinin-piperaquine
asymptomatic. o Artesunate-sulfadoxine-pyrimethamine
• Rapid Diagnostic Tests (RDTs) o Artesunate-amodiaquine
o Detect PfHRP2, lactate dehydrogenase, or o Artesunate-pyronaridine
aldolase. • Low-dose primaquine (0.25 mg/kg) for P. falciparum
o Some differentiate P. falciparum vs. P. vivax. gametocytes in low-transmission areas.
o PfHRP2 may remain positive weeks post-infection. • Second-line therapy: different ACT or 7-day
o Limitation: do not quantify parasitemia. artesunate/quinine plus tetracycline/doxycycline/clindamycin.
• Molecular diagnosis Radical Cure (Relapse Prevention)
o PCR is more sensitive than microscopy/RDT. • P. vivax / P. ovale:
o Useful for species identification and epidemiologic o Primaquine: 0.25–0.5 mg/kg daily for 14 days
surveys. (G6PD testing required).
• Serology o Tafenoquine (single dose) where available;
o Screening of blood donors or population-level quantitative G6PD test needed.
transmission studies.
, • Pregnant women: suppressive chloroquine prophylaxis until o Insecticide resistance and mosquito behavior
delivery; radical cure postpartum. changes.
o Limited resources and infrastructure.
Management of Complications • Vaccines:
• Acute renal failure: restrict fluids; early renal replacement o RTS,S/AS01: 35–40% protection in African
therapy. children; deployed in Ghana, Kenya, Malawi.
• Pulmonary edema / ARDS: elevate head, oxygen, diuretics, o Other vaccines (irradiated live sporozoite, placental
ventilation if needed. malaria-targeted) under development.
• Hypoglycemia: IV dextrose; monitor frequently. • Prevention relies primarily on vector control and drug
• Sepsis: consider broad-spectrum antibiotics if deterioration strategies.
during treatment.
• Other complications:
o Spontaneous bleeding → fresh blood, IV vitamin K.
o Convulsions → benzodiazepines.
o Aspiration pneumonia → oxygen, IV antimicrobials,
pulmonary toilet.
Malaria Prevention
Personal Protection
• Avoid mosquito exposure at peak feeding times (dusk to
dawn).
• Use insect repellents (10–35% DEET, or 7% picaridin),
suitable clothing.
• Use ITNs or insecticide-impregnated materials.
Chemoprophylaxis
• Drugs depend on local resistance patterns.
• Effective agents against resistant P. falciparum: atovaquone-
proguanil, doxycycline, mefloquine.
• Pregnant women:
o Mefloquine safe in 2nd/3rd trimesters.
o Chloroquine and proguanil safe, but limited use.
• Travelers: start 2 days–2 weeks before travel; continue 4
weeks after departure (except causal prophylaxis drugs like
atovaquone-proguanil or primaquine).
• IPT (Intermittent Preventive Treatment):
o Pregnancy (IPTp): sulfadoxine-pyrimethamine per
antenatal visit.
o Infancy (IPTi): sulfadoxine-pyrimethamine at 2, 3, 9
months.
• Seasonal Malaria Chemoprevention (SMC): monthly
amodiaquine + sulfadoxine-pyrimethamine in children 3–59
months during rainy season.
Specific Drugs for Prophylaxis
• Atovaquone-proguanil: daily; effective, well tolerated; not
recommended if GFR <30 mL/min.
• Mefloquine: weekly; generally safe; avoid in psychiatric
disorders, seizures, cardiac conduction issues.
• Doxycycline: daily; avoid in children <8 and pregnant
women.
• Chloroquine: safe in pregnancy; limited P. falciparum use
due to resistance.
• Primaquine: 0.5 mg/kg daily; G6PD testing required.
Global Considerations
• Main control tools:
o Insecticide-treated bed nets (ITNs).
o Artemisinin-based combination therapy (ACTs).
• Challenges to eradication:
o High mosquito population density and breeding
sites.
o Resistance to ACTs in P. falciparum.
• Blood-stage parasites differentiate into sexual forms: male
Overview and female gametocytes.
• Malaria is a protozoan disease transmitted by the bite of • Female gametocytes outnumber males 4:1.
infected female Anopheles mosquitoes. • In mosquito:
• One of the most important parasitic diseases of humans. o Male gametocyte → exflagellation → 8 male
• Endemic in 87 countries, affecting ~3 billion people. gametes → fuse with female → zygote →
• Global burden (2019): ookinete → oocyst → sporozoites migrate to
o 229 million cases salivary glands → infect next human host.
o 409,000 deaths (~1100 deaths/day)
• Mortality declined between 2000–2015 due to control Epidemiology
programs but has since risen. • Geographic distribution: most tropical regions.
• Eliminated from the US, Canada, Europe, and Russia >50 • Species prevalence:
years ago. o P. falciparum: Africa, New Guinea, Hispaniola
• Resurgence in many tropical areas between 1970–2000. o P. vivax: Central/South America, Southeast Asia
• Control efforts: o P. malariae: sub-Saharan Africa, less common
o Improved access to diagnosis o P. ovale: primarily Africa (<1% of isolates)
o Effective treatments o P. knowlesi: Borneo and Southeast Asia (macaque
o Insecticide-treated bed nets hosts)
• Threats: • Endemicity classification:
o Drug resistance o Hypoendemic: <10%
o Insecticide resistance o Mesoendemic: 11–50%
• Malaria remains a burden on endemic communities, a threat o Hyperendemic: 51–75%
o Holoendemic: >75%
to non-endemic countries, and a danger to travelers.
• Transmission types:
Etiology and Pathogenesis o Stable: frequent, year-round infection →
Causative Agents premunition in adults
• Six main human-infecting Plasmodium species: o Unstable: low/erratic transmission → symptomatic
disease at all ages
o P. falciparum: most deaths; severe disease
o P. vivax: relapsing malaria; severe illness possible • Epidemics: occur in unstable transmission areas due to
o P. ovale (two species: curtisi, wallikeri): relapsing environmental, social, or control failures.
malaria
o P. malariae: slower life cycle; less common Pathophysiology
o P. knowlesi (Southeast Asia): monkey malaria; can Erythrocyte Changes
be severe • RBC invasion → hemoglobin digestion → hemozoin
o Occasional monkey parasites: P. simium (South formation.
America), P. cynomolgi (Southeast Asia) • RBC membrane altered → exposure of antigens, decreased
Life Cycle deformability.
• Transmission begins when an infected female Anopheles • P. falciparum: knobs form → PfEMP1 → cytoadherence →
mosquito inoculates sporozoites into human blood. sequestration in vital organs (brain, placenta).
• Sporozoites travel to the liver → invade hepatocytes → • Rosetting and agglutination → microvascular obstruction →
undergo preerythrocytic schizogony → produce 10,000– pathogenesis of severe malaria.
30,000 merozoites per sporozoite. • Non-falciparum species: no significant sequestration;
• Merozoites released into bloodstream → invade red blood predilection for young (vivax, ovale) or old (malariae) RBCs.
cells (RBCs) → trophozoites → multiply every 48 h (species- Host Response
specific: P. knowlesi 24 h, P. malariae 72 h). • Spleen: clears parasitized/uninfected RBCs, removes
• Symptomatic phase: ~50 parasites/µL of blood (~100 damaged parasites (“pitting”).
million total in adults). • Fever and cytokine release from monocyte/macrophage
• Hypnozoites (P. vivax & P. ovale): dormant liver forms activation.
causing relapses (2 weeks–≥1 year). • Genetic protection:
RBC Invasion o HbAS (sickle cell trait), HbC, HbE → reduce
• P. falciparum: parasite growth or cytoadherence
o Erythrocyte binding antigen 175 → glycophorin A o α-thalassemia, ovalocytosis → protect against
o EBL140 → glycophorin C severe disease
o PfRh5 → CD147 (basigin) o G6PD deficiency → partial protection
• P. vivax: binds developing erythrocytes via Duffy antigen • Immunity:
(Fya/Fyb) o Premunition: infection without illness
• P. knowlesi: prefers Duffy-positive RBCs o Species- and strain-specific
• Early ring forms appear similar; trophozoites show species- o Requires both humoral and cellular immunity
specific morphology and hemozoin. o Maternal antibodies provide partial infant protection
• Schizonts: RBC nearly fully occupied → ruptures →
Clinical Features
releases 6–30 merozoites.
Uncomplicated Malaria
, • Initial symptoms nonspecific: headache, fatigue, malaise, • P. vivax: reduces birth weight (~110 g), more in multigravida.
abdominal discomfort, myalgia, fever.
• Classic paroxysms (fever, chills, rigors) rare; more common Malaria in Children
in P. vivax/P. ovale. • Most malaria deaths (>400,000/year) occur in young African
• Non-immune patients: fever >40°C, tachycardia, sometimes children.
delirium. • Complications: convulsions, coma, hypoglycemia, metabolic
• Children: febrile convulsions possible; generalized seizures acidosis, severe anemia.
with P. falciparum. • Less common: deep jaundice, oliguric AKI, pulmonary
• Physical findings: mild anemia, splenomegaly, occasional edema.
hepatomegaly, mild jaundice. • Deep breathing often due to metabolic acidosis, not cardiac
• Rash: absent. failure.
Severe Falciparum Malaria • Children respond well to treatment.
• Mortality rises when >2% RBCs infected or organ dysfunction
occurs. Transfusion Malaria
• Major manifestations: cerebral malaria, severe anemia, • Transmission: blood transfusion, needlestick, organ
hypoglycemia, acidosis, renal failure, pulmonary edema, transplantation.
hematologic abnormalities, liver dysfunction. • Short incubation due to absence of preerythrocytic stage.
Cerebral Malaria • Clinical management similar to natural infections; primaquine
• Diffuse symmetric encephalopathy; coma, abnormal not required for vivax/ovale.
behavior, seizures.
• Funduscopic findings: retinal hemorrhages, opacification,
papilledema, cotton wool spots.
Chronic Complications of Malaria
• Children: ~10% have residual neurologic deficits; adults <3%.
Hyperreactive Malarial Splenomegaly (HMS)
Hypoglycemia
• Occurs in residents of malaria-endemic areas with chronic or
• Due to hepatic failure, increased glucose consumption, and
repeated infections.
quinine-induced hyperinsulinemia.
• Pathophysiology
• Particularly severe in children and pregnant women.
o Abnormal immunologic response to repeated
Acidosis
malaria.
• Hyperlactatemia, accumulation of organic acids → poor
o Massive splenomegaly and hepatomegaly.
prognosis.
o Marked elevations in serum IgM and malarial
• Causes: anaerobic glycolysis in sequestered tissues, lactate antibody titers.
from parasites, impaired clearance. o Hepatic sinusoidal lymphocytosis; peripheral B-cell
Noncardiogenic Pulmonary Edema lymphocytosis in Africa.
• Mortality >80% in adults; can occur in vivax malaria with o Production of cytotoxic IgM antibodies to CD8+ T
usual recovery. cells, antibodies to CD5+ T cells.
Renal Impairment o Increased CD4+/CD8+ T-cell ratio.
• Acute kidney injury, often acute tubular necrosis. o Uninhibited B-cell IgM production → cryoglobulin
• Early dialysis improves survival. formation → lymphoid hyperplasia →
Hematologic Abnormalities splenomegaly.
• Anemia: accelerated RBC removal, schizogony, ineffective • Clinical features
erythropoiesis. o Abdominal mass or dragging sensation.
• Blackwater fever: massive hemolysis, sometimes associated o Occasional sharp abdominal pains (perisplenitis).
with G6PD deficiency. o Anemia and varying degrees of pancytopenia
• Thrombocytopenia common; DIC rare. (hypersplenism).
Liver Dysfunction o Sometimes no detectable parasites in peripheral
• Mild hemolytic jaundice common; severe jaundice in P. blood.
falciparum. o High susceptibility to respiratory and skin infections;
• Liver failure does not occur in isolation. risk of sepsis.
Other Complications • Management
• HIV/AIDS, malnutrition, helminth infections exacerbate o In endemic areas: antimalarial chemoprophylaxis—
severity. usually effective.
• Bacteremia (~6% children, <1% adults), often Salmonella o In non-endemic areas: antimalarial treatment
spp. advised.
o Rarely, refractory cases may evolve into clonal
Malaria in Pregnancy lymphoproliferative disorders resembling
• Early pregnancy: fetal loss. hematologic malignancy.
• High transmission areas: low birth weight (~170 g), increased Quartan Malarial Nephropathy
infant mortality. • Caused by chronic/repeated P. malariae infections (possibly
• HIV co-infection → higher maternal parasite density, other species).
congenital malaria risk. • Pathophysiology
• Unstable transmission areas: severe infections, anemia, o Soluble immune complex-mediated glomerular
hypoglycemia, pulmonary edema, fetal death. injury → nephrotic syndrome.
, o Histology: focal/segmental glomerulonephritis with o Not useful for acute diagnosis.
capillary basement membrane splitting. Laboratory Findings in Acute Malaria
o Electron microscopy: subendothelial dense • Normochromic, normocytic anemia.
deposits. • Leukocyte count: usually normal; may increase in severe
o Immunofluorescence: deposits of complement, Ig, infection.
and sometimes P. malariae antigens. • Mild monocytosis, lymphopenia, eosinopenia; reactive
o Prognosis: lymphocytosis/eosinophilia post-infection.
▪ Coarse-granular, IgG3 deposits with • Thrombocytopenia (~10⁵/μL).
selective proteinuria → better prognosis. • Elevated ESR, plasma viscosity, CRP, acute-phase proteins.
▪ Fine-granular, IgG2 deposits with • Severe infection: prolonged PT/PTT, reduced antithrombin III,
nonselective proteinuria → worse metabolic acidosis, electrolyte disturbances, elevated
prognosis. BUN/creatinine, bilirubin, liver enzymes.
• Management • Hypergammaglobulinemia in immune/semi-immune
o Rarely reported today. individuals.
o Poor response to antimalarials, glucocorticoids, or • Urinalysis: usually normal.
cytotoxic drugs.
• CSF (cerebral malaria): normal or slightly elevated
Burkitt’s Lymphoma and Epstein-Barr Virus (EBV)
protein/cell count.
• Strong association between childhood Burkitt’s lymphoma,
EBV infection, and high P. falciparum transmission. Treatment of Malaria
• Mechanism Severe Malaria
o Chronic P. falciparum malaria → expansion of • First-line treatment: IV or IM artesunate.
EBV-infected B cells in germinal centers.
• Artesunate advantages:
o Deregulates activation-induced cytidine deaminase
o Rapid, safe, effective; no dose adjustment in
→ DNA damage → c-myc translocations →
liver/renal dysfunction.
lymphoma.
o Approved for pregnant women.
• Alternative: artemether or quinine if artesunate unavailable.
Diagnosis of Malaria
o Quinine: IV infusion with loading dose; risk of
General Principles
hypotension; monitor plasma levels.
• Malaria is not a clinical diagnosis.
• Supportive care:
• Fever in or from endemic areas → confirm via blood smear
o Frequent monitoring (parasite count, hematocrit,
or rapid diagnostic test (RDT).
glucose).
• If blood smear negative by an experienced microscopist → o Hypoglycemia: IV dextrose infusion.
malaria very unlikely. o Convulsions: IV or rectal benzodiazepines.
Demonstration of the Parasite o Fluid management: careful to avoid pulmonary
• Definitive diagnosis: visualization of asexual forms in edema or renal impairment.
peripheral blood. o Blood transfusion: consider Hct <20%; in children,
• Preferred stains: Giemsa (pH 7.2), Field’s, Wright’s, Hb <4 g/dL.
Leishman’s. o Renal failure: early hemofiltration or hemodialysis.
• Fluorescent staining: acridine orange—rapid detection in o Pulmonary edema/ARDS: oxygen, diuretics,
low parasitemia; species identification not possible. positive-pressure ventilation if needed.
• Blood films o Avoid ineffective or harmful adjuncts: high-dose
o Thin smear: fixed with methanol; counts parasitized steroids, urea, dextran, heparin, mannitol.
RBCs per 1000 RBCs. Uncomplicated Malaria
o Thick smear: unfixed; concentrates parasites 40– • P. falciparum / P. knowlesi: ACT.
100×; counts parasites per WBC or estimated via • P. vivax, P. ovale, P. malariae: chloroquine or ACT.
WBC count of 8000/μL. • ACT regimens (WHO recommended):
• Interpretation notes o Artemether-lumefantrine
o Examine 100–200 fields before declaring negative. o Artesunate-mefloquine
o Low-density parasitemia in endemic areas may be o Dihydroartemisinin-piperaquine
asymptomatic. o Artesunate-sulfadoxine-pyrimethamine
• Rapid Diagnostic Tests (RDTs) o Artesunate-amodiaquine
o Detect PfHRP2, lactate dehydrogenase, or o Artesunate-pyronaridine
aldolase. • Low-dose primaquine (0.25 mg/kg) for P. falciparum
o Some differentiate P. falciparum vs. P. vivax. gametocytes in low-transmission areas.
o PfHRP2 may remain positive weeks post-infection. • Second-line therapy: different ACT or 7-day
o Limitation: do not quantify parasitemia. artesunate/quinine plus tetracycline/doxycycline/clindamycin.
• Molecular diagnosis Radical Cure (Relapse Prevention)
o PCR is more sensitive than microscopy/RDT. • P. vivax / P. ovale:
o Useful for species identification and epidemiologic o Primaquine: 0.25–0.5 mg/kg daily for 14 days
surveys. (G6PD testing required).
• Serology o Tafenoquine (single dose) where available;
o Screening of blood donors or population-level quantitative G6PD test needed.
transmission studies.
, • Pregnant women: suppressive chloroquine prophylaxis until o Insecticide resistance and mosquito behavior
delivery; radical cure postpartum. changes.
o Limited resources and infrastructure.
Management of Complications • Vaccines:
• Acute renal failure: restrict fluids; early renal replacement o RTS,S/AS01: 35–40% protection in African
therapy. children; deployed in Ghana, Kenya, Malawi.
• Pulmonary edema / ARDS: elevate head, oxygen, diuretics, o Other vaccines (irradiated live sporozoite, placental
ventilation if needed. malaria-targeted) under development.
• Hypoglycemia: IV dextrose; monitor frequently. • Prevention relies primarily on vector control and drug
• Sepsis: consider broad-spectrum antibiotics if deterioration strategies.
during treatment.
• Other complications:
o Spontaneous bleeding → fresh blood, IV vitamin K.
o Convulsions → benzodiazepines.
o Aspiration pneumonia → oxygen, IV antimicrobials,
pulmonary toilet.
Malaria Prevention
Personal Protection
• Avoid mosquito exposure at peak feeding times (dusk to
dawn).
• Use insect repellents (10–35% DEET, or 7% picaridin),
suitable clothing.
• Use ITNs or insecticide-impregnated materials.
Chemoprophylaxis
• Drugs depend on local resistance patterns.
• Effective agents against resistant P. falciparum: atovaquone-
proguanil, doxycycline, mefloquine.
• Pregnant women:
o Mefloquine safe in 2nd/3rd trimesters.
o Chloroquine and proguanil safe, but limited use.
• Travelers: start 2 days–2 weeks before travel; continue 4
weeks after departure (except causal prophylaxis drugs like
atovaquone-proguanil or primaquine).
• IPT (Intermittent Preventive Treatment):
o Pregnancy (IPTp): sulfadoxine-pyrimethamine per
antenatal visit.
o Infancy (IPTi): sulfadoxine-pyrimethamine at 2, 3, 9
months.
• Seasonal Malaria Chemoprevention (SMC): monthly
amodiaquine + sulfadoxine-pyrimethamine in children 3–59
months during rainy season.
Specific Drugs for Prophylaxis
• Atovaquone-proguanil: daily; effective, well tolerated; not
recommended if GFR <30 mL/min.
• Mefloquine: weekly; generally safe; avoid in psychiatric
disorders, seizures, cardiac conduction issues.
• Doxycycline: daily; avoid in children <8 and pregnant
women.
• Chloroquine: safe in pregnancy; limited P. falciparum use
due to resistance.
• Primaquine: 0.5 mg/kg daily; G6PD testing required.
Global Considerations
• Main control tools:
o Insecticide-treated bed nets (ITNs).
o Artemisinin-based combination therapy (ACTs).
• Challenges to eradication:
o High mosquito population density and breeding
sites.
o Resistance to ACTs in P. falciparum.
