Figure 200.1 (A and B) Malaria-endemic countries of the Western and Eastern Hemispheres. (Courtesy of the Centers for Disease Control and Prevention, 2014.)
Clinical aspects
Fever in a patient who has recently traveled to an area endemic for malaria should be considered a medical emergency. The minimum incubation period is generally considered to be 7 days after inoculation, and of greatest concern is the patient who has traveled to a P. falciparum endemic area within 2 months of presentation, since an incubation period of 2 to 4 weeks is typical for falciparum malaria. Presentation several months to 1 year after departing an endemic region is also possible, particularly when infected with P. vivax or P. ovale, since infection with these species can result in a dormant liver stage. Patients with falciparum malaria can also present months after exposure, as the use of prophylaxis or presence of semi-immunity can modify or delay the onset. For these reasons, febrile patients who have traveled to a malarious region in the preceding year should be ruled out for malaria, regardless of prophylaxis history.
Malaria transmission occurs when a malaria-infected female Anopheles mosquito inoculates sporozoites into a human host. Initially, infected persons are asymptomatic as the sporozoites enter the bloodstream and travel to the liver where maturation occurs in hepatocytes. Malaria symptoms begin when merozoite forms are released into the bloodstream, and the erythrocytic stage begins. In this stage, merozoites infect erythrocytes and replicate within them, resulting in rupture and further merozoite release. Symptom severity typically depends on the percentage of erythrocytes infected and the presence or absence of partial immunity due to previous infection.
Initial symptoms are nonspecific and include fever, chills, malaise, anorexia, headaches, and myalgias. Cough, abdominal pain, and diarrhea may also be present. The illness may resemble numerous other febrile syndromes including enteric fever, dengue fever, influenza, meningitis, and septicemia, so a high index of suspicion for malaria is critical, even when an alternate diagnosis appears more likely. Although regular periodicity of fever is classically described, this is unlikely early in the disease course and may not be seen at all, particularly with falciparum malaria.
Severe falciparum malaria is a multiorgan system disease. Infected erythrocytes adhere to vascular endothelium cells, resulting in sequestration, circulatory obstruction, and inflammation in the affected organ. Complications include severe anemia, jaundice, thrombocytopenia, hypoglycemia, pulmonary edema, acute respiratory distress syndrome (ARDS), renal failure, and disseminated intravascular coagulation (DIC). Seizures, impaired consciousness, and coma may result from hypoglycemia or suggest the presence of cerebral malaria. Even with treatment, the case-fatality rate of severe malaria is 15% to 20%. Lactic acidosis suggests a worse prognosis. Nonimmune pregnant woman are at higher risk for severe disease, as well as preterm birth and fetal loss. Among travel-associated cases in nonendemic countries, patients over 65 years old have the worst outcomes. Though P. vivax typically causes uncomplicated malaria, severe P. vivax malaria can occur. However, since severe disease is most associated with falciparum malaria and mixed infection with multiple species is possible, severe disease in a patient diagnosed with non-falciparum malaria should raise the possibility of coexisting falciparum malaria.
P. vivax and P. ovale infections can also result in a dormant hypnozoite liver stage which requires special consideration for treatment and prophylaxis. Patients carrying hypnozoites are asymptomatic until the infection reactivates, resulting in a relapsed infection.
Diagnosis
Prompt and accurate diagnosis is critical in malaria management. The diagnostic gold standard is examination of Giemsa-stained thick and thin blood smears. Thick smears are highly sensitive and can detect parasites in patients with low parasitemia levels that might be missed in thin smears. However, thin smears are best for speciation, quantification of parasites (i.e., percent of erythrocytes parasitized), and assessment of treatment response. If the initial blood smears are negative, they should be repeated at 12- to 24-hour intervals for a total of three sets before considering the disease ruled out. When expertise to prepare or examine thick smears is not immediately available, thin blood smears alone are better than none at all, since a negative thin smear suggests a high parasitemia infection is unlikely. Wright’s stain, which is typically used in clinical laboratories for peripheral blood smears, is not optimal for blood parasites; however, it can be helpful when Giemsa staining is unavailable.
A number of rapid diagnostic tests (RDTs) are available for malaria diagnosis when blood smears are not readily available. These tests rely on the detection of Plasmodium spp. antigens, including histidine-rich protein 2 (HRP2) and parasite lactate dehydrogenase. These tests can be highly sensitive and specific for falciparum malaria. However, test performance can vary widely among different kits and false results can occur if instructions on use and storage are not strictly followed. Nonetheless, RDTs can be important in situations where microscopy is not feasible or timely.
Therapy
The increasing prevalence of drug-resistant plasmodia has complicated malaria treatment. In addition to widespread CRPF, mefloquine-resistant P. falciparum is endemic in several Southeast Asian countries, and strains of P. vivax resistant to drugs including chloroquine and primaquine have emerged. In contrast, drug resistance has not been described in P. ovale or P. malariae. When species identification is uncertain in a patient with malaria, clinicians should treat for the worst-case scenario, i.e., infection caused by CRPF. Malaria acquired while taking prophylaxis should not be treated with the same medication used for prophylaxis. Recommended drug regimens for treatment in the United States are listed in Table 200.1. Since effective malaria therapy requires consideration of the infecting species and local resistance patterns, clinicians are strongly advised to review current recommendations and to seek diagnostic assistance when needed. Suspected or confirmed malaria should always be treated with the assistance of an infectious diseases or tropical medicine specialist when available. Updated country guides and detailed US treatment recommendations are available from the Centers for Disease Control and Prevention (CDC), either online (www.cdc.gov/malaria/index.html) or by phone through the CDC Malaria Hotline (1–770–488–7788 or 1–855–856–4713 toll free, weekdays 9AM–5PM; or 1–770–488–7100 for emergency consultation after hours).
| Clinical severity/species | Resistance | Recommended treatments for adults1 | Recommended pediatric treatments1 |
|---|---|---|---|
| Uncomplicated P. falciparum or species not identified NOTE: If an unidentified species is subsequently determined to be P. vivax or P. ovale, addition of primaquine therapy is indicated to prevent relapse, see below | Chloroquine-resistant or unknown | Atovaquone-proguanil: Adult tablet = 250 mg atovaquone/100 mg proguanil 4 adult tablets daily × 3 d | Atovaquone-proguanil: Pediatric tablet = 62.5 mg atovaquone/25 mg proguanil Adult tablet = 250 mg atovaquone/100 mg proguanil 5–8 kg: 2 ped tabs daily × 3 d 9–10 kg: 3 ped tabs daily × 3 d 11–20 kg: 1 adult tab daily × 3 d 21–30 kg: 2 adult tabs daily × 3 d 31–40 kg: 3 adult tabs daily × 3 d >40 kg: 4 adult tabs daily × 3 d |
| Artemether–lumefantrine: One tablet = 20 mg artemether/120 mg lumafantrine Three-day treatment with total of 6 oral doses based on weight. Initial dose is followed by second dose 8 h later, then 1 dose BID for the following 2 days. 5–<15 kg:1 tab/dose 15–<25 kg: 2 tab/dose 25–<35 kg: 3 tabs/dose ≥35 kg: 4 tabs/dose | |||
| Quinine sulfate: 542 mg base (=650 mg salt) PO TID × 3 or 7 days2 PLUS one of the following: Doxycycline: 100 mg PO BID × 7 d OR Tetracycline: 250 mg PO QID × 7 d OR Clindamycin: 20 mg base/kg/day PO divided tid × 7 d | Quinine sulfate: 8.3 mg base/kg (=10 mg salt/kg) PO TID × 3 or 7 days2 PLUS one of the following: Doxycycline3: 2.2 mg/kg PO BID × 7 d OR Tetracycline3: 25 mg/kg/day PO divided QID × 7 d OR Clindamycin: 20 mg base/kg/day PO divided tid × 7 d | ||
| Mefloquine4: 684 mg base (=750 mg salt) PO as initial dose, followed by 456 mg base (=500 mg salt) PO given 6–12 h after initial dose | Mefloquine4: 13.7 mg base/kg (=15 mg salt/kg) PO as initial dose, followed by 9.1 mg base/kg (=10 mg salt/kg) PO given 6–12 h after initial dose | ||
| Uncomplicated P. falciparum or species not identified acquired in area with no chloroquine resistance P. malariae (all regions) P. knowlesi (all regions) NOTE: If an unidentified species is subsequently determined to be P. vivax or P. ovale, addition of primaquine therapy is indicated to prevent relapse, see below | Chloroquine-sensitive | Chloroquine phosphate: 600 mg base (=1000 mg salt) PO immediately, followed by 300 mg base (=500 mg salt) in 6, 24, and 48 h | Chloroquine phosphate: 10 mg base/kg (=16.7 mg salt/kg) PO immediately, followed by 5 mg base/kg (=8.3 mg salt/kg) PO at 6, 24, and 48 h |
| Hydroxychloroquine: 620 mg base (=800 mg salt) PO immediately, followed by 310 mg base (=400 mg salt) in 6, 24, and 48 h | Hydroxychloroquine: 10 mg base/kg (=12.9 mg salt/kg) PO immediately, followed by 5 mg base/kg (=6.5 mg salt/kg) at 6, 24, and 48 h | ||
| Uncomplicated P. vivax or P. ovale6 | Chloroquine-sensitive6 | Chloroquine phosphate or hydroxychloroquine (doses as above) PLUS Primaquine phosphate5: 30 mg base (=52.6 mg salt) PO qd × 14 d | Chloroquine phosphate or hydroxychloroquine (doses as above) PLUS Primaquine phosphate5: 0.5 mg base/kg (=0.8 mg salt/kg) PO qd × 14 d |
| Severe malaria (usually P. falciparum) | All resistance profiles | Quinidine gluconate:
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