Malaria and other tropical infections in the intensive care unit

Epidemiology

Malaria parasites are spread to humans by the bite of anopheline mosquitoes. Five species of Plasmodia commonly cause malaria in humans: Plasmodium falciparum , P. vivax , P. ovale , P. malariae, and P. knowlesi (see Table 123.2 ). Furthermore, recent evidence suggests that there may be distinct species of P. ovale. vivax. Simultaneous infections with multiple strains of P. falciparum are common in some areas of sub-Saharan Africa and also occur with P. vivax in Southeast Asia and Latin America.

The most prevalent and dangerous form of malaria is that due to P. falciparum . The risk of acquiring P. falciparum is highest in sub-Saharan Africa, in particular West Africa, and in New Guinea; moderate in India; and comparatively low in Southeast Asia and Latin America. There is increasing recognition that P. vivax, the second most common cause of malaria and previously considered to be benign, can also cause severe disease and death. ^, P. vivax malaria is especially frequent in travelers returning from Oceania, although the parasite exists in all malaria-endemic regions except Haiti and the Dominican Republic. ^, The dormant liver stage parasites (hypnozoites) that characterize P. vivax sometimes result in primary disease or relapse even years after infection. P. knowlesi is found in rainforests of Southeast Asia, including parts of Cambodia, China, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Viet Nam. ^, P. knowlesi is now the most common cause of malaria in Malaysia and parts of Indonesia. Although quite rare, deaths resulting from P. ovale or P. malariae infection have been reported. ^,

Although rare, malaria has been reported in persons without documented travel, usually resulting from the carriage of malaria-infected passengers (who may be asymptomatic) or anopheline mosquitoes on aircraft arriving from endemic areas. The parasite may then be secondarily transmitted by anopheline mosquitoes endemic in some industrialized countries, including the United States, Canada, and Southern Europe.

Pathophysiology

P. falciparum accounts for the vast majority of severe malaria because of (1) its ability to infect RBCs of all ages, resulting in overwhelming parasitemia (up to 70% of RBCs); (2) its induction of adherence of parasitized RBCs to the microvascular wall, with consequent obstruction; (3) its induction of severe metabolic derangements, both directly through glucose consumption and lactate production and indirectly through the induction of cytokines; and (4) the high prevalence of chloroquine and multidrug resistance to P. falciparum in many parts of the world (see Table 123.2 ). Unlike the other species of malaria, P. falciparum causes decreased RBC deformability and the production of small protrusions, or “knobs,” on parasitized RBC membranes that mediate their adhesion to the venular endothelium ( Fig. 123.2 ). These knobs are high-molecular-weight (>200 kD), strain-specific molecules displayed on the surface of infected RBCs. The best described of these is P. falciparum erythrocyte membrane protein 1 that plays a critical role in malaria pathogenesis, including in evasion of the host immune system. ^, The rupture of schizont-stage parasites exposes glycosylphosphatidylinositol anchors on the parasite and RBC surface that induce macrophages and other inflammatory cells to release a host of inflammatory mediators, including tumor necrosis factors, interleukin-1, and various kinins and reactive nitrogen intermediates. These cytokines play a role in up-regulation and activation of endothelial adhesion molecules such as ICAM-1 and E-selectin, enhancing cytoadherence of parasitized cells and mediating pathologic processes such as hypoglycemia, lactic acidemia, shock, gut mucosal damage, and increased permeability and neutrophil aggregation in the lung.

The sum total of this cascade is sequestration of parasitized RBCs in the microvasculature, where they are not only sheltered from removal but cause sluggish flow and obstruction, resulting in impaired oxygen delivery and organ dysfunction. ^, The most profound effects are usually on the cerebral capillaries, although a host of tissues may be affected, including the kidney, liver, spleen, placenta, intestine, lung, bone marrow, heart, and retina. Histopathologic changes are usually minimal, but ring hemorrhages and perivascular infiltrates sometimes develop at the sites of obstructed vessels, perhaps facilitated by thrombocytopenia because of splenic sequestration of platelets. Although subendocardial and epicardial hemorrhages have been noted at autopsy, myocarditis does not occur, and primary cardiac events are relatively rare in malaria.

In P. falciparum infection, acute pulmonary hypertension can be precipitated by nitric oxide consumption by free plasma hemoglobin released from intravascular hemolysis. Endothelial injury leading to increased alveolar permeability and noncardiogenic pulmonary edema also contributes. Autopsy studies have shown increased markers of endothelial activation (vWF and ANG-2) in patients with acute malaria-associated respiratory distress syndrome (MA-ARDS) compared with infected and uninfected controls. Interstitial edema and inflammatory cell infiltrates are seen at autopsy, but sequestration of parasitized RBCs in the lung is not common. There is evidence, however, that P. falciparum erythrocyte membrane protein 1 interaction with host endothelial cell receptors (e.g., ICAM-1 and endothelial protein C receptor) plays a role in cytoadherence and pathogenesis of MA-ARDS.

Parasitemia usually reaches a lower level in P. vivax infection because of a strong predilection for reticulocytes. Chronic exposure to P. vivax parasites may be sufficient to destroy the new reticulocytes and, over time, to reduce the population of mature RBCs, thereby contributing to severe anemia. This, combined with a lack of cytoadhesive properties of the infected cells, results in reduced microvascular obstruction and suggests different pathogenetic mechanisms to severe infection. ^, The main pathogenesis of P. vivax is the result of higher cytokine production and endothelial activation caused by an increased guanine-cytosine DNA content in its genome and a higher associated content of Toll-like receptor 9-stimulating GpG motifs.

The returned traveler exposed to P. vivax for a short period will rarely present with a severe or fatal infection unless there is an underlying condition. However, in endemic regions, children with prolonged P. vivax infection resulting from frequent exposures and relapsing infections from the liver hypnozoites can present with profound anemia with subsequent high morbidity and mortality, particularly in the presence of malnutrition and other causes of anemia. P. vivax anemia is exacerbated by splenic removal of uninfected RBCs, which occurs at a higher proportion compared with P. falciparum, although the removal mechanism is not well understood. ^{, ,}

In P. vivax infection, a cytokine-mediated inflammatory response in the pulmonary microvessels leads to increased alveolar permeability and fluid buildup. Because of a lower parasitic biomass, the effect of the hemolysis-associated nitric oxide depletion on pulmonary pressures is minimal. ^, There is greater inflammatory and endothelial activation per parasite in P. vivax compared with P. falciparum infections, and this likely contributes to MA-ARDS in the absence of other risk factors specific to P. falciparum . In addition to the acute hemolytic destruction of parasitized RBCs, the more chronic processes of removal of parasitized cells from circulation by the spleen and cytokine inhibition of erythropoiesis may contribute.

Clinical presentation

Malaria classically produces three stages of symptoms that progress over an 8- to 12-hour period, comprising a “paroxysm.” These correspond and are attributable to the period of schizont rupture and appearance of ring forms (merozoites) in the blood, accompanied by the release of numerous host inflammatory mediators. The paroxysm classically begins suddenly with a “cold stage” in which the patient experiences rigors and chills, often accompanied by headache, nausea, and vomiting. Intense peripheral vasoconstriction may result in pale, goosepimpled skin and cyanosis of the lips and nail beds. Within a few hours, the “hot stage” ensues, with high fever, flushed skin, throbbing headache, and palpitations. The paroxysm concludes with the “defervescent stage,” consisting of a drenching sweat and resolution of the fever. The exhausted patient often then sleeps. Clinical deterioration with P. falciparum usually appears 3–7 days after onset of fever.

Although a classic periodicity is described for the different malaria species (see Table 123.2 ), this occurs only when the infection has persisted untreated long enough to allow for synchronization of schizont rupture. Furthermore, schizont rupture tends to be asynchronous in P. falciparum and in most primary infections of any Plasmodium species. Therefore malaria may often result in persistently spiking fevers difficult to distinguish from fever produced by many other infections, and the absence of a classic paroxysm and periodicity should not be used to exclude the diagnosis. Paroxysms may be accompanied by cough, sore throat, myalgias, back pain, postural hypotension, abdominal pain, nausea, vomiting, diarrhea, and weakness. These flulike symptoms are more common in children and may lead to misdiagnoses. Rash and lymphadenopathy are not typical of malaria and suggest another diagnosis.