Malaria: Parasite Biology

• Malaria remains a leading parasitic disease causing mortality worldwide, with young children and pregnant women being the most affected populations.
• Chronic malaria can lead to anemia, impairing physical and mental growth in children, and contributing to maternal morbidity and mortality during pregnancy.
• The UN's Millennium Development Goal 6 aims to reduce the burden of HIV/AIDS, malaria, and other diseases, including reducing malaria incidence and mortality.
• Malaria is a curable disease if treated promptly and adequately, and is caused by parasites of the genus Plasmodium, transmitted by Anopheles mosquitoes.
• Medically important Plasmodium species include P. falciparum, P. vivax, P. ovale, and P. malariae, with P. knowlesi recently identified as a fifth species affecting humans.
• P. knowlesi is typically a parasite of long-tailed macaques, but can infect humans working near forests, with cases reported in Southeast Asia and the Philippines.

Parasite Biology

• The asexual cycle of Plasmodium in humans involves schizogony, leading to merozoite formation, and gametogony, producing gametocytes.
• The sexual cycle in mosquitoes involves sporogony, which results in the formation of sporozoites.
• Humans get infected when sporozoites, injected by Anopheles mosquitoes, travel to the liver and initiate exo-erythrocytic schizogony, producing merozoites that then infect red blood cells.
• Some P. vivax and P. ovale merozoites form dormant hypnozoites in the liver, which can reactivate years later, while other species do not.
• Within red blood cells, merozoites transform into ring forms, then trophozoites, and finally schizonts, which rupture and release merozoites to infect more cells.
• Some merozoites differentiate into microgametocytes (male) or macrogametocytes (female), which are ingested by mosquitoes.
• In the mosquito gut, male gametocytes produce microgametes that fertilize macrogametes, forming zygotes that develop into ookinetes and then oocysts.
• Oocysts produce sporozoites that migrate to the mosquito's salivary glands and can be injected into a new human host.
• The entire developmental cycle in the mosquito takes 8 to 35 days, influenced by ambient temperature.
• Early trophozoites are ring-shaped, trophozoites have ameboid cytoplasm, and schizonts contain multiple merozoites.
• Gametocytes fill the red blood cell, are round to banana-shaped, with microgametocytes having lighter and macrogametocytes darker blue cytoplasm.

Pathogenesis and Clinical Manifestations

• The pre-patent period, or the time from sporozoite injection to parasite detection, ranges from 11 days to 4 weeks, depending on the Plasmodium species.

• The incubation period, from sporozoite injection to symptom onset, lasts 8 to 40 days, influenced by species, sporozoite dose, host immunity, and chemoprophylaxis history.

• Prodromal symptoms of malaria include weakness, aching, loss of appetite, nausea, vomiting, and chills.

• Classical malaria paroxysms consist of a cold stage with shivering, a hot stage with fever, headache, and confusion, and a sweating stage with defervescence.

• P. falciparum has a 48-hour erythrocytic cycle while P. vivax and P. ovale have paroxysms on alternate days and P. malariae have paroxysms every 72 hours, termed quartan malaria

• P. knowlesi causes fever in a quotidian pattern and does not relapse due to the lack of an exoerythrocytic stage.

• Non-falciparum species infect erythrocytes of certain ages, with P. vivax and P. ovale infecting young cells and P. malariae infecting aging cells, limiting parasitemia to less than 3%.

• P. falciparum and P. knowlesi infect erythrocytes of all ages, leading to higher parasitemia and increased severity.

• Attack severity depends on the parasite species and strain, geographic origin, host age, genetics, immunity, health, nutrition, and prior treatments.

• Recrudescence is the renewal of clinical features from persistent undetectable asexual parasitemia as relapse is renewed asexual parasitemia after the blood contains no detectable parasites.

• Pathological processes in malaria result from the erythrocytic cycle, causing reduced red blood cell deformability due to changes in the cytoskeleton, membrane stiffness, and cytoplasmic viscosity

• Infected erythrocytes develop "knobs" containing proteins like rosettins, riffins, histidine-rich proteins (HRP), and PfEMP-1, important for cytoadhesion which is induced by febrile temperatures

• Hemoglobin digestion in infected cells results in hematin production, and soluble P. falciparum antigens stimulate pro- and anti-inflammatory cytokine release.

• Glycosylphosphatidyl inositol (GPI) moieties on the surface antigens act like endotoxins, stimulating monocytes to release tumor necrosis factor (TNF), causing malarial fever.

• Altered red cell membranes and the host’s immune response lead to altered blood flow, altered biochemistry, anemia, and tissue hypoxia.

• Severe malaria can cause impaired consciousness, cerebral dysfunction, severe hemolytic anemia, and hyperbilirubinemia.

• Cerebral malaria leads to symmetric encephalopathy, retinal hemorrhage, bruxism, and mild neck stiffness and prompt treatment leads to recovery.

• Respiratory findings in severe malaria include altered pulmonary function, pneumonitis, non-cardiogenic pulmonary edema, and ARDS, with a high mortality rate

• Acute renal failure (ARF) occurs in up to 60% of severe falciparum malaria cases, defined by elevated serum creatinine and low urine output.

• Pregnant women infected are at higher risk of maternal death, anemia, fetal growth retardation, spontaneous abortion, stillbirth, and neonatal death.

• Falciparum malaria in young children is a medical emergency, causing complications like cerebral malaria, severe anemia, respiratory distress, and hypoglycemia.

• Repeated parasite exposures in endemic areas lead to specific immunity, restricting serious problems in young children.

• Poor prognostic factors in falciparum malaria include hyperparasitemia, mature schizonts, deep coma, respiratory distress, circulatory collapse, and age below 3 years.

• Other lab indicators of poor prognosis include low blood glucose, elevated serum enzymes, low hemoglobin, high blood urea and creatinine, and high plasma TNF concentrations.

Diagnosis

• Prompt and adequate diagnosis of malaria is necessary for effective management and to prevent life-threatening complications.
• Microscopic identification of malarial parasites in Giemsa- or Wright's-stained blood smears is still the gold standard for definitive diagnosis of malaria.
• Blood smears should be taken every 6 to 8 hours until diagnosis is made or confidently ruled out and smears should be obtained to monitor the response to treatment.
• Malaria rapid diagnostic tests (RDTs) use immunochromatographic methods to detect Plasmodium-specific antigens in finger prick blood samples.
• Target antigens include histidine-rich protein II (HRP II), Plasmodium lactate dehydrogenase (pLDH), and Plasmodium aldolase.
• RDTs can be performed in 15 to 30 minutes without electricity or special training and the main disadvantages are cost, the inability to quantify parasite density and the inability to distinguish between species
• Serologic tests like IHA, IFAT, and ELISA cannot differentiate between current and past infections, they are most helpful in epidemiologic studies
• PCR can enhance microscopic diagnosis, especially in low parasitemia and mixed infection cases.

Treatment

• Antimalarial drugs act on different phases of the malaria parasite's life cycle.
• Drugs can be classified into causal prophylactic, blood schizonticidal, tissue schizonticidal, gametocytocidal, hypnozoitocidal, and sporonticidal drugs.
• Main uses of antimalarial drugs are protective (prophylactic), curative (therapeutic), and preventive.
• The DOH Malaria Control Program (MCP) recommends artemisinin-based combination therapies (ACTs) for severe and uncomplicated falciparum malaria, replacing chloroquine.
• Recommended drug combinations include artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, and artesunate with sulfadoxine-pyrimethamine.
• For severe malaria, recommendation is artesunate intravenous (IV) injection or intramuscular (IM) injection, quinine IV or IM, or artemether IM
• Primaquine is recommended as it demonstrates added benefit to artemisinins in eliminating gametocytes as long as G6PD deficiency is considered.
• Vivax malaria remains sensitive to chloroquine and primaquine, however, resistance is prevalent and increasing in Indonesia, Peru, and Oceania.
• Resistance of P. malariae and P. ovale to antimalarials is not well characterized whilst infections with these species are still considered sensitive to chloroquine.
• Artemisinin and its derivatives produce rapid clearance of parasitemia and symptoms, particularly in areas of low to moderate endemicity.
• Quinine sulfate plus doxycycline or clindamycin serves as the second line drug when artemisinins are unavailable or are not working.
• Tetracycline is contraindicated in pregnant women and children below 8 years
• Drug resistance is graded according to asexual parasitemia patterns after treatment initiation.
• Early treatment failure (ETF) is classified by development of danger signs or severe malaria on Day 1, 2, or 3 when parasitemia is present
• Late treatment failure (LTF) is divided into late clinical failure and late parasitological failure.
• In cases of renal failure in severe malaria, dopamine may be administered and dialysis is indicated if the patient remains unresponsive.
• For control of seizures, diazepam or phenytoin may be given and the following are are not recommended: corticosteroids and anti-inflammatory agents
• Proper management of malaria also includes supportive measures especially if fluid replacement or blood transfusion is necessary as well as blood sugar monitoring and dextrose

Epidemiology

• Malaria is the world’s most important tropical parasitic disease and is linked to activities like road building, mining, logging, and new agricultural and irrigation projects.
• In 2010, the WHO reported an estimated 216 million cases of malaria and an estimated 655,000 malaria deaths occurred in 2010.
• In the Philippines, malaria has not been included among the 10 leading causes of morbidity since 2006, however has been decreasing, still, disease prevalence remains markedly high in Regions IV-B, Caraga, III, XII, and II.
• Principal malaria vector is Anopheles minimus var. flavirostris, a night biter,which prefers to breed in slow flowing, partly shaded streams.
• Malaria can also be transmitted through blood transfusion from infected donors and the malaria survey involves investigation of human hosts and insect vectors.

Prevention and Control

• Early diagnosis and prompt treatment of malaria are essential for malaria control.
• Personal protection measures include the use of insecticide-treated nets (ITNs) and long-lasting insecticide-treated nets (LLIN).
• Chemoprophylaxis may be protective to travelers who have no immunity to malaria such as chloroquine, mefloquine, doxycycline or atovaquone/proguanil.
• Strategies include proper vector control such as environmental modification, biological and chemical control.
• Ongoing research includes stable germline transformation of the Anopheles mosquito which involves inserting genes that will inhibit the development of the parasite in the mosquito.