Malaria, a protozoan disease transmitted by the bite of the Anopheles mosquito, is one of mankind’s most feared and serious afflictions. It is a leading cause of morbidity and mortality in many tropical areas of the world, especially in Africa. Approximately 55% of the world’s population is exposed to the infection, which exerts its toll mainly on the young and the pregnant. Malaria is endemic or sporadic throughout most of the tropics and subtropics below an altitude of 1500 m, excluding the Mediterranean littoral, the United States, and Australia. Malaria is perhaps the most significant disease acquired through international travel to the tropics.

Five species of the genus Plasmodium infect humans: Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium falciparum, and Plasmodium knowlesi. In 2012, there were an estimated 207 million cases of symptomatic malaria worldwide (80% of which occurred in Africa), with about 627,000 deaths, 90% of which occurred in Africa, and with nearly 77% of those occurring in young children.¹ The great majority of malaria deaths are due to P. falciparum infections, although both P. vivax and P. knowlesi can also cause fatal disease.

The incidence of malaria has decreased dramatically in some countries in recent years as a result of intensive control efforts (e.g., South Africa), but elsewhere there has been little change, and some areas have experienced increases or epidemics (e.g., Algeria, Venezuela). In the United States, more cases of imported malaria were identified in 2011 than in any year since 1971.² Obstacles to successful reduction of malaria worldwide include human factors (poverty, war, inadequate international cooperation), capacities of the mosquito vector (changing temperatures, insecticide resistance) and parasite characteristics (antimalarial drug resistance).

In an area of intense transmission, most malaria infections occur in children, who gradually acquire a considerable degree of immunity. In such areas, a high percentage of children may have asymptomatic parasitemia (malaria infection), and illness due to malaria (malaria disease) is commonly mild and only occasionally severe or life threatening. Nevertheless, the absolute burden of mortality is large because nearly all children are infected. Adults in such areas rarely develop severe or fatal disease.

By contrast, malaria due to P. falciparum is a medical emergency in a nonimmune host of any age, because the infection, if untreated, is likely to progress and to become life threatening. Once a P. falciparum infection has reached the stage of severe disease, there is a 5% to 30% risk of a fatal outcome, even if optimal treatment is then begun. The early clinical features of malaria are nonspecific, and malaria can mimic many other infections. A diagnosis of malaria must be considered in any person returning from the tropics with an unexplained febrile illness and must be considered in any resident in the tropics who develops a fever.

Malaria transmission occurs in large areas of Central and South America, the Caribbean, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania. Certain species may predominate in a given geographic area.³ For example, P. vivax is more common in the Indian subcontinent, whereas P. falciparum is the most prevalent form in Africa, Haiti, and New Guinea. P. knowlesi has been found in several countries in southeast Asia, including Malaysia, Myanmar (Burma), Thailand, the Philippines, and Singapore.⁴

The risk of contracting malaria varies considerably between regions. In 2011, the Centers for Disease Control and Prevention reported 1925 cases of malaria among persons in the United States.² Of 1655 imported cases where the region of acquisition was known, 1144 (69%) were acquired in Africa (63% of these in West Africa), 363 (22%) in Asia (68% of these in India), 104 (6.3%) in the Caribbean and Central America, 35 (2%) in South America, and 7 (<1%) in Oceania. P. falciparum accounted for 49% and P. vivax for 22% of all cases (although in many cases, the parasite species was not identified). Thus, almost half of all cases of malaria, including the majority of cases due to P. falciparum, were acquired from travels in West Africa, despite the fact that for every traveler to sub-Saharan Africa, at least 10 travelers visit potential malarious areas of Asia and South America each year. Complications developed in 14% of the reported cases of malaria identified in the United States in 2011, and five patients died (1.8% of the 275 severe cases).

P. knowlesi is a zoonosis. Macaques (old world monkeys) are the natural host. Members of the Anopheles leucosphyrus groups are equally attracted to humans and monkeys, which has given rise to human cases. The forest fringe habitat of this mosquito will hopefully limit the spread of this species of parasite.⁵

Resistance of P. falciparum to chloroquine has been widespread for many years.⁶ Strains of P. falciparum have since become resistant to other chemotherapeutic agents, including pyrimethamine-sulfadoxine (no longer recommended as first-line treatment; can be used in pregnancy), quinine, mefloquine, and doxycycline.⁷ Widespread mefloquine-resistant strains of P. falciparum have been seen in parts of Thailand, Myanmar (Burma), Cambodia, and China. Of greatest current concern is the observation in Cambodia and in parts of Thailand that parasites are slower to respond to artemisinin therapy than a few years ago.⁸ There has not yet been evidence of impaired cure rates with artemisinin therapy, but worldwide vigilance is required to track the continuing efficacy of this important class of drugs. Resistance of P. vivax to chloroquine has also been identified in Southeast Asia.⁹

The organism is transmitted primarily by the bite of an infected female Anopheles mosquito, which requires a blood meal every 3 to 4 days to nourish its eggs. This vector is most frequently found in tropical and subtropical regions below 1500 m (5000 ft) above sea level. Plasmodial sporozoites are injected into the host’s bloodstream during the mosquito’s blood meal and are carried through the bloodstream to the liver. Within hours, the hepatic parenchymal cells are invaded, and asexual reproduction of the parasite begins (pre-erythrocytic schizogony or exoerythrocytic stage). After thousands of daughter merozoites have been formed within a hepatocyte (amplification cycle), the cell ruptures, releasing daughter merozoites into the circulation, where they rapidly invade erythrocytes to begin the erythrocytic stage of the asexual cycle. In P. vivax and P. ovale infection, a portion of the intrahepatic forms are not released, but remain dormant as hypnozoites, which can reactivate after months or years to cause clinical relapses.

Once merozoites enter the erythrocytic stage, they do not reinvade the liver. A merozoite matures within the erythrocyte, feeding on hemoglobin and enlarging until it divides into about a score of daughter merozoites to form a schizont. Eventually, the infected erythrocyte lyses, merozoites are released, and these invade uninfected red blood cells, continuing and amplifying the infection.

A portion of the merozoites develop into sexual forms (gametocytes). Upon ingestion by another feeding Anopheles mosquito, male and female gametocytes undergo sexual reproduction within the vector’s gut and migrate as infective sporozoites to her salivary glands. To maximize her blood meal, the mosquito injects her next victim with saliva containing an anticoagulant, which introduces the malarial infection. The rate at which parasites replicate and migrate in the mosquito is temperature dependent; at average environmental temperatures below about 15°C (59°F), the cycle does not complete before the death of the mosquito, and malaria transmission cannot occur.

The clinical signs of malaria first appear during the erythrocytic stage. The rupture of schizont-containing erythrocytes triggers an array of host cytokine responses, giving rise to fever and other features of the malarial illness. Because fever slows the rate of schizont formation, early-stage parasites tend to catch up with more mature stages, and therefore over time, schizont rupture may become synchronous, giving rise to the periodic fever characteristic of untreated malaria. Such periodicity rarely has time to develop when malaria is treated promptly with efficacious drugs.

Each species of Plasmodium has specific characteristics, including typical morphologic forms and selective red blood cell tropism (Table 158-1). Many of these characteristics are responsible for important pathophysiologic consequences.

Anemia can develop rapidly with P. falciparum infection because the percentage of erythrocytes parasitized can be overwhelming (erythrocytes of all ages are susceptible to invasion) and because the lifespan of uninfected erythrocytes is also reduced, while bone marrow erythropoiesis is slowed or halted. P. falciparum asexual parasites transport to the red cell surface proteins that can adhere to host endothelial receptors, resulting in the sequestration of mature parasites in the microvasculature of many tissues and organs. Sequestration may be enhanced by the impaired deformability of infected erythrocytes and consequent slowing of blood flow through microvessels. Sequestration benefits parasites by keeping them away from the spleen, but additional consequences for the host include metabolic deprivation and/or impaired perfusion of tissues, processes that are believed to contribute to many of the syndromes characteristic of severe falciparum malaria. Acidosis, for example, results from tissue hypoxia, to which sequestration, hypotension, and severe anemia may all contribute. Hypoglycemia occurs largely due to impaired hepatic gluconeogenesis, possibly enhanced by the consumption of glucose by actively metabolizing parasites and the diversion of glucose for the host’s anaerobic glycolysis. Sequestration accounts for the paucity of observed mature parasites in the peripheral smear of patients infected with P. falciparum.

Although nearly all malaria transmission is mediated by mosquito vectors, plasmodia of any species may also be transmitted by transfusion of infected blood, by needlestick accident, or across the placenta from mother to fetus. In these cases, an exoerythrocytic phase is absent, and hypnozoites of P. vivax or P. ovale cannot develop.

Untreated, inadequately treated, or frequent malaria may lead to sequelae mediated by immunologic mechanisms, including massive splenomegaly with consequent hypersplenism, and glomerulonephritis leading to a nephrotic syndrome (attributed, without strong evidence, mainly to P. malariae infection). Thrombocytopenia (rarely sufficient to cause bleeding) is invariable in acute symptomatic malaria.

INCUBATION PERIOD

The incubation period between infection and symptoms varies with the species of parasite (Table 158-1). In the nonimmune, symptoms begin after an incubation period ranging from 7 days to several weeks or more. Incomplete suppression of disease by partially active chemoprophylaxis and partial immunity can prolong the incubation period to months or even years. For U.S. residents who developed malaria associated with travels abroad during 2011, disease became evident within 1 month after arrival home in 95% of P. falciparum cases, but in only 52% of P. vivax cases. The interval between arriving in the United States and becoming ill was between 3 and 12 months in 46% of P. vivax cases and 5% of P. falciparum cases. Six patients (0.6% overall) became ill more than 1 year after returning to the United States.²

UNCOMPLICATED MALARIA

The clinical hallmark of malaria is fever, with a prodrome of malaise, myalgia, headache, and chills.¹⁰ In some patients, chest pain, cough, abdominal pain, or arthralgias may be prominent. Early symptoms are nonspecific and can easily be confused with a viral syndrome such as influenza or hepatitis or with bacterial sepsis. In a nonimmune individual, the illness usually progresses to include chills, followed by high-grade fever accompanied by nausea, orthostatic dizziness, and extreme weakness. After several hours, the fever abates and the patient develops diaphoresis and becomes exhausted. If the infection is untreated, the paroxysms of malaria—chills and fever followed by diaphoresis—may over time begin to occur at nearly regular intervals that correspond to the length of the asexual erythrocytic cycles (Table 158-1). The classic paroxysms of malaria are often lacking in malaria due to P. falciparum or in persons who received some form of chemoprophylaxis. The findings upon physical examination are also not specific for malaria. Most patients appear acutely ill with high fever, tachycardia, and tachypnea. Splenomegaly and abdominal tenderness are common. The liver may or may not be enlarged. Clinical signs that point to a diagnosis other than (or in addition to) malaria include lymphadenopathy and a maculopapular or petechial skin rash.

In children growing up in a malarious area, attributing an illness to malaria is particularly difficult because many children carry parasites without being unwell and because symptoms and signs of both mild and severe malaria are nonspecific.¹¹ In these circumstances, the higher the parasite density in the peripheral blood, the greater is the likelihood that malaria is the cause of the illness.

SEVERE (COMPLICATED) MALARIA

Malaria is described as severe or complicated when it includes one or more of the following syndromes in the context of a plasmodial infection, usually due to P. falciparum: coma with or without seizures (“cerebral malaria”), prostration, severe anemia, acidosis, hypoglycemia, acute renal failure, acute respiratory distress syndrome, pulmonary edema, jaundice, intravascular hemolysis, shock, and disseminated intravascular coagulation. The percentage of malaria cases imported to the United States that were classified as severe increased significantly from 18% of 1691 cases in 2010 to 22% of 1925 cases in 2011.²

Complications of malaria can develop rapidly in untreated P. falciparum infection or may supervene early in the course of treatment. Occasionally, one or more complications may constitute the presenting illness, when correct diagnosis may be both difficult and critically important. A patient with severe malaria is at risk of dying even with optimal case management. Case fatality rates range between 5% and 30% in patients receiving treatment for severe malaria according to the complications present and their intensity.

When cerebral malaria is suspected, meningitis or encephalitis must be either excluded or treated, and the clinician must decide whether a lumbar puncture is safe. At lumbar puncture, the opening pressure is usually raised in children and normal in adults. The fluid is normal in appearance and on routine tests. In children in P. falciparum–endemic areas, asymptomatic parasitemia is common, so it is difficult to be sure that an illness is due to malaria. In a child with coma and parasitemia, the presence of a recently identified retinopathy (Figure 158-1) greatly strengthens confidence that malaria is the cause of the syndrome.¹² Among those who recover from cerebral malaria, up to 1 in 5 children and up to 1 in 20 adults may be left with, or may later develop, neurologic sequelae.