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UNCOMPLICATED MALARIA
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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.
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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.
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SEVERE (COMPLICATED) MALARIA
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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
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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.
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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.
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Infections caused by any species of Plasmodium can result in hemolysis, some degree of anemia, splenic enlargement, and, occasionally, splenic rupture.
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The very young, the elderly, and pregnant women are at greatest risk of developing complications when infected with P. falciparum.13 Additional risk factors for severe malaria include an immunocompromised state, asplenia, failure to take appropriate chemoprophylaxis, refusal of or delay in seeking medical care, and late or erroneous diagnosis.14
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The diagnosis of malaria rests on a history of potential exposure in a malarious area, clinical symptoms, signs, and competent microscopic examination of well-prepared thick and thin blood films (Figure 158-2). Diagnosis based on clinical features alone has very low specificity and results in overtreatment.1
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The three major questions to be answered by the blood smear are as follows: (1) Is there evidence of malaria? (2) If so, what is the density of parasitemia (correlates with prognosis)? (3) What species of malaria is responsible for the infection and, in particular, is P. falciparum present? Clues to the diagnosis of P. falciparum infection include the presence of small ring forms with double-chromatin dots within the erythrocyte, multiple infected rings in individual red blood cells, a paucity (usually absence) of mature trophozoites and schizonts on smear, and infected erythrocytes that are not enlarged and that have cytoplasm without basophilic stippling. In some (but not all) cases, gametocytes may be seen; in P. falciparum infection, these have a diagnostic crescent shape (banana shape). Parasite densities above 4% of erythrocytes are rare in malaria due to nonfalciparum species. Obtain smears daily to assess the efficacy of drug treatment.
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P. knowlesi is usually misdiagnosed as the less aggressive P. malariae, because the two are identical under light microscopy and require polymerase chain reaction for differentiation. Any patient coming from Asia with a high parasite burden resembling P. malariae should be assumed to be harboring P. knowlesi.4
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Place a small drop of blood (5 μL) on a microscope slide, spread it evenly to a diameter of ~1 cm, allow it to dry, and then stain, without initial fixation, with Fields or Giemsa stain. Record the result as the number of parasites seen per oil-immersion field (for an approximate indication of density) or per 200 white cell nuclei counted (a more accurate density of parasites can then be calculated once the WBC count is known). A thick blood film contains several layers of red cells (which are lysed by the staining procedure), allowing parasitemias down to ~40/μL to be detected by an expert microscopist.
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A standard hematologic blood smear (fixed with methanol and stained with Giemsa) allows a single sheet of intact red cells to be scrutinized for the percentage of red cells parasitized, from which the number of parasites per microliter can be calculated when the red cell count is known. Because the red cells are not destroyed, a thin film allows both parasite and red cell morphology to be examined, enabling more confident identification of the species of plasmodium. A thin film may fail to detect a parasitemia with a density below ~1000/μL, but it is more useful than a thick film for counting very heavy infections.
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A long and careful search for parasites is necessary before a film is declared "negative." In early infection, especially infection due to P. falciparum, in which mature-stage parasitized erythrocytes are sequestered from the bloodstream, parasitemia may be undetectable even in a competently read thick blood film. In highly suspicious cases, failure to detect parasitemia is not an indication to withhold therapy. If parasites are not seen in the stained thin smear, a thick smear must be done. If parasites are not seen on the first thick film, obtain repeat thick smears at least twice daily for as long as malaria remains a suspected diagnosis or until the patient is better. The first smear is positive in >90% of cases.15
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ADDITIONAL DIAGNOSTIC TECHNIQUES
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Newer techniques for rapid diagnosis and speciation include quantitative buffy coat fluorescent microscopy and rapid diagnostic tests (dipstick bedside tests) to detect parasite antigens (BinaxNOW®, ParaSight-F®) or to detect the parasite enzyme lactate dehydrogenase (OptiMal).16 Sensitivity of rapid tests is excellent for P. falciparum malaria with high parasitemia levels, but poor for nonfalciparum malaria, and sensitively drops with lower parasitemia levels. Polymerase chain reaction–based techniques to detect parasite DNA are more sensitive than microscopy and are valuable for research studies but are rarely available for routine clinical purposes.
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ADDITIONAL LABORATORY STUDIES
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Nonspecific laboratory features of malaria include normochromic normocytic anemia with findings suggestive of hemolysis, a normal or mildly depressed total leukocyte count, thrombocytopenia, an elevated erythrocyte sedimentation rate, mild abnormalities in liver and renal functions, and a biologic false-positive Venereal Disease Research Laboratory test. In severe P. falciparum malaria, there may be hypoglycemia, severe anemia, hyperlactatemia, electrolyte disturbances, or evidence of acute renal failure or disseminated intravascular coagulation.