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Malaria Diagnosis and Treatment
General Considerations
Malaria is preventable by taking chemoprophylaxis and using mosquito avoidance measures ( Chapter 6 ). However, healthcare providers should be knowledgeable about the work-up of malaria, as it is not uncommon for a returned traveler to present with fever. When a patient presents with fever, healthcare providers working in malaria-free areas might not consider malaria in the differential diagnosis, especially since this disease can mimic other illnesses, such as influenza or gastroenteritis. However, undiagnosed and untreated malaria can progress rapidly to death. Therefore, healthcare workers must obtain a travel history from patients who present with fever. All febrile patients who have traveled to a malaria-endemic area should be rapidly evaluated for malaria. Patients at risk for malaria most commonly come from one of the following groups:
- 1.
Visitors, immigrants, and refugees from a malaria-endemic area
- 2.
Travelers, regardless of duration of stay (e.g., tourist, business traveler, expatriate), especially first- and second-generation immigrants returning to their countries of origin to visit friends and relatives
- 3.
Military personnel assigned abroad.
Other groups in which malaria infrequently occurs include:
- 1.
Recipients of blood transfusions or organ or tissue transplant
- 2.
Infants of mothers who have lived or traveled in an endemic area (congenital infections)
- 3.
Injection drug users (parenteral transmission)
- 4.
Residents of non-endemic areas where local transmission might occur from undiagnosed imported infections. For example, Greece and Jamaica, both malaria non-endemic, had outbreaks originating from imported cases of malaria between 2011-2013 and 2006-2011, respectively.
Etiology
Malaria is a vector-borne protozoan parasite infection spread from person to person in endemic areas by female mosquitoes of the genus Anopheles. Four species of malaria regularly cause disease in humans, including Plasmodium falciparum , P. vivax , P. ovale , and P. malariae. P. knowlesi , a cause of malaria in long-tailed macaques, also naturally infects humans in Southeast Asia, most notably in Malaysia.
Presentation
Epidemiology
In 2013 there were approximately 198 million cases of malaria worldwide, and 500,000 deaths, mostly in children in sub-Saharan Africa. Malaria is endemic in most tropical areas of the world ( Fig. 21.1 ). Transmission of malaria can vary within a country and is affected by multiple factors, such as season, altitude, and urbanization. Migration and travel can potentially introduce malaria to previously malaria-free areas where the mosquito vector is present. Drug resistance is an increasing problem. Chloroquine-resistant P. falciparum is widespread, and there are very few areas (e.g., Central America west of the Panama Canal, the Dominican Republic, and Haiti) where chloroquine can still effectively treat falciparum malaria. Multidrug-resistant P. falciparum is present in parts of Southeast Asia, and chloroquine-resistant P. vivax is found in parts of Indonesia and Papua New Guinea. Resistance to sulfadoxine-pyrimethamine (Fansidar®) is also widespread.
Malaria endemicity and antimalarial drug resistance can change over time, so healthcare providers should always refer to the most up-to-date information when giving advice to a traveler or when managing malaria. A list of countries and their malaria-related information can be found in “Health Information for International Travel” (the “Yellow Book”), a publication prepared by the Centers for Disease Control and Prevention (CDC) and available online ( http://www.cdc.gov/travel/ ). Reports from the field by way of returned travelers, the news media, and other nonmedical news sources should be confirmed by checking official postings from the CDC ( www.cdc.gov/travel or www.CDC.gov/malaria ) and World Health Organization ( http://www.who.int ).
Pathogenesis
Natural Life Cycle
After inoculation of the malaria parasites (sporozoites) during feeding by a female anopheline mosquito, the sporozoites invade the liver parenchymal cells within minutes, and then replicate during an asymptomatic incubation period (pre-erythrocytic schizogony) that can last between 1 and 3 weeks but can be as long as a year ( P. vivax ). Relapsing species, P. vivax and P. ovale , can form hypnozoites in the liver, a dormant stage that can cause relapses weeks to months after the initial infection. Eventually, the hepatic schizonts rupture and parasites (merozoites) are released into the bloodstream, where red blood cells are rapidly infected (erythrocytic stage) ( Fig. 21.2 ).
- 1.
The merozoites mature in infected red cells, and early stages are called trophozoites, resembling signet rings. The blood-stage infection causes the symptoms and signs of malaria.
- 2.
Most trophozoites undergo asexual division within the red cells to form a schizont, or ball of new merozoites. During this process, the erythrocyte's hemoglobin is consumed. Eventually the cell bursts, liberating new merozoites that invade new red cells. For P. falciparum , P. vivax , and P. ovale , the duration of the asexual life cycle is 48 hours, for P. malariae 72 hours, and for P. knowlesi 24 hours.
- 3.
After asexual reproduction some merozoites will develop into sexual forms of the parasite called gametocytes. These transmissible stages are ingested by another feeding anopheline mosquito, fuse in the mosquito's midgut to form a zygote, develop in the wall of the gut, and then migrate to the mosquito's salivary gland to complete the cycle.
Pathophysiology
Each of the species has a variable incubation period (the interval between infection and the onset of clinical illness). Incubation periods can be as short as 1 week (rare) or between 2 and 4 weeks (more common), but they can be much longer for vivax or ovale malaria or if the infection is suppressed by partial adherence to chemoprophylaxis. The erythrocytic stage of the infection is associated with spiking fevers and chills, but relapsing fever is not necessarily seen. Fever and illness are caused by the release of proinflammatory cytokines (particularly tumor necrosis factor) and other inflammatory mediators. Cytokines are responsible for many features of severe malaria, but microvascular obstruction is the primary pathologic process. The pathology of severe falciparum malaria is associated with the sequestration of infected red cells in the microvasculature of vital organs. Thus, the pathologies of sepsis and severe malaria are different.
Falciparum malaria may progress rapidly to parasitize a large number of erythrocytes, with severe systemic consequences of multiple organ failure and death unless treated immediately. P. falciparum infections are potentially lethal for several reasons:
- 1.
Each blood-stage schizont liberates up to 32 merozoites when it ruptures, potentially infecting many red blood cells quickly.
- 2.
P. falciparum causing severe malaria parasitizes circulating red cells of all ages (in contrast to P. vivax , which tends to infect young cells only, and P. malariae , which has a predilection for older cells).
- 3.
Erythrocytes containing mature forms of P. falciparum stick to the endothelium of capillaries and post-capillary venules (cytoadherence). The resulting sequestration results from the interaction between antigenically variant parasite-derived adhesive proteins expressed on the surface of infected erythrocytes and specific receptors on the vascular endothelium. In addition, the deformability of both parasitized and uninfected erythrocytes is markedly reduced in severe malaria. The subsequent interference with microcirculatory flow and regional metabolism is most evident in the brain, resulting in cerebral malaria, but also occurs in the other vital organs. Sequestration accounts for the frequently observed discrepancy between the peripheral parasite count and disease severity and also explains the relative rarity with which mature trophozoites and schizonts are seen in the peripheral blood in falciparum malaria.
Although malaria can be severe with P. vivax , P. ovale , and P. malariae infections, clinical attacks are less likely to be fatal because cytoadherence and sequestration do not occur with these species of malaria. For P. vivax and P. ovale infections, the hypnozoite, or dormant, stage can cause relapses weeks to months after the initial infection.
Immunity to Malaria
The immune response to malaria infections is incomplete, and frequent repeated attacks are required to induce a degree of protective immunity, which is rapidly lost if the individual leaves the endemic area. Acquired immunity is specific for both the species of malaria and the particular strain(s) causing the infection. The development of immunity to P. falciparum is gained at the expense of a high mortality in children living in areas of heavy transmission. For this reason, severe malaria is a disease of childhood in these areas, and adults who have gained protective immunity are less likely to develop severe manifestations, so long as they continue to be exposed via more infected mosquito bites. Without this boosting effect, immunity will wane in time. Thus, in contrast to adult residents of areas of heavy malaria transmission, non-immune travelers—including immigrants—of all ages coming from areas without malaria to malaria-endemic areas are vulnerable to developing severe and potentially fatal infections.
Clinical Features
The symptoms and signs of malaria are nonspecific and are most commonly fever, chills, myalgias, and headache. Malaria may present as febrile seizures in children or coma (cerebral malaria). It may be mistaken for infectious hepatitis when jaundice is prominent, for pneumonia when there is respiratory distress, or for enteric infections with fever, vomiting, abdominal pain, and diarrhea. Furthermore, malaria may exist in a patient with other acute travel-related illnesses. Therefore, clinicians should suspect and test for malaria in all febrile patients who traveled to a malaria-endemic area.
Malaria is typically classified as either uncomplicated or severe. Indicators for severe malaria are listed in Table 21.1 . Patients need to have only one of these indicators to have severe malaria; however, patients with severe malaria usually meet multiple criteria.
TABLE 21.1
Criteria for Severe Malaria
Malaria is severe if one or more of the following is present:
|
Hyperparasitemia is defined as more than 5% erythrocytes parasitized. All patients with malaria should have their percent parasitemia calculated at the time of diagnosis, as it is not uncommon for hyperparasitemia to be the only factor that categorizes the patient as having severe malaria requiring parenteral medicine; early initiation of parenteral treatment prior to the development of clinical complications can improve the chances of prompt and complete recovery.
Cerebral malaria can present with either focal or generalized neurologic features, most commonly, altered mental status, seizures (especially in children), or coma. It must be distinguished from other causes of fever and altered consciousness (e.g., bacterial or viral meningoencephalitis).
Acute kidney injury results from acute tubular necrosis. Some patients may develop brisk hemolysis and hemoglobinuric renal failure (“blackwater fever”).
Acute respiratory distress syndrome (ARDS), defined as respiratory distress from pulmonary inflammation and characterized by severe hypoxemia with bilateral pulmonary infiltrates on radiograph, is associated with a high mortality. ARDS can occur with all species of malaria. Respiratory distress in patients with malaria can also be due to metabolic acidosis, iatrogenic volume overload from overly aggressive fluid resuscitation resulting in pulmonary edema, transfusion-related lung injury, and secondary nosocomial pneumonia.
Glucose levels fall in severe malaria infections as a result of increased metabolic demands by the host and parasites, and decreased gluconeogenesis. Hypoglycemia most commonly develops in women in late pregnancy and children with severe malaria, which is hazardous to the viability of the pregnancy. It is usually accompanied by lactic acidosis. Quinine stimulates pancreatic insulin secretion and is an important cause of hypoglycemia.
Severe anemia is defined as hemoglobin levels <7 g/dL. The hematocrit falls rapidly in severe malaria because of the accelerated clearance of both parasitized and unparasitized erythrocytes. The anemia is compounded by bone marrow dyserythropoiesis.
Another poor prognostic indicator is disseminated intravascular coagulation that presents as abnormal bleeding (e.g., petechiae, ecchymosis, bleeding from intravenous lines), thrombocytopenia, and abnormal clotting or coagulation laboratory values. Some degree of thrombocytopenia (at or even below 100,000/µL) is usually seen in all symptomatic malaria cases. Thrombocytopenia alone is not a criterion for severe malaria.
Patients with severe malarial infections are more vulnerable to bacterial infections, such as aspiration pneumonia and spontaneous septicemia with Gram-negative bacteria (particularly nontyphoidal salmonellae), especially in children.
Chronic malaria can manifest in residents of highly endemic areas who, through repeated infections, have developed some degree of immunity, resulting in few to no symptoms despite having parasites in their blood. This asymptomatic parasitemia is a major cause of chronic anemia, particularly in young children. Splenomegaly is also a reflection of repeated malaria attacks in children in endemic areas. Splenic rupture occasionally occurs as a complication of P. vivax infection in adults. Hyperreactive malarial splenomegaly (or “tropical splenomegaly syndrome”) is sometimes seen in adults in endemic areas and presents as hepatosplenomegaly, anemia, abnormal immunologic findings, and immunosuppression. This appears to reflect an exaggerated immune response to repeated infection. Nephrotic syndrome may develop in children chronically infected with P. malariae (“quartan nephropathy”).
Laboratory Diagnosis
The diagnosis of malaria is best made by the identification of malaria parasites on the peripheral blood smear. Preparation of thick and thin smears should be done immediately for any febrile patient living in or returning from a malarious area. Because parasitemia waxes and wanes with the parasite's life cycle, these smears should be performed at least three times, 12-24 hours apart, to achieve acceptable negative predictive value. Although Giemsa stains of the blood smear are preferred for determining speciation of the parasite, the modified Wright's stain used for the routine processing of blood smears in clinical hematology laboratories is adequate. Field's stain may also be used. Both thick and thin smears are first screened at low magnification, then examined using a 100× oil immersion objective for at least 300 fields, because symptoms of malaria can occur at lower parasite densities in nonimmune individuals.
Thick smears are much more sensitive than thin smears, but provide less information regarding the species and infection burden. The thick smear is first examined for presence of parasites. If parasites are present, the thin smear is used to determine the species of parasite, and the percent parasitemia, that is, the percentage of red blood cells infected. To quantify malaria parasites, between 500 and 2000 red blood cells should be examined. Both the species of malaria and the percent parasitemia are key pieces of information when selecting therapeutic options.
The CDC offers training workshops and web-based training on malaria diagnosis for laboratory personnel throughout the United States. DPDx also allows telediagnosis, where outside laboratories can email digital images of their microscopy findings to the CDC and receive same-day feedback from CDC staff ( http://www.cdc.gov/dpdx/contact.html ).
Rapid Diagnostic Test (RDT)
Immunochromatographic strip assays detect malarial antigens in finger-stick blood samples using test strips or cards impregnated with specific antibodies. These are based either on detection of P. falciparum histidine-rich protein 2 (HRP-2) or parasite lactate dehydrogenase isoenzymes or aldolase. Unlike microscopy, which requires a microscope and trained technician, RDTs can be used in places without a skilled microscopist. Only the BinaxNOW® Malaria Test is approved by the US Food and Drug Administration (FDA) for use in the United States. Disadvantages include the cost of the test kits, the inability to determine species of malaria and parasite load, and the potential lack of sensitivity at very low parasitemias. Therefore, use of RDTs should be reserved for situations where quality microscopy is not immediately available and should be followed as soon as possible by microscopy to confirm the results, determine the species, and calculate the parasitemia. Also, HRP-2 may persist in the blood for a number of weeks after an infection has been treated, so use of this test is not recommended to diagnose malaria in a symptomatic patient who has already received a treatment course of antimalarials. However, if a retrospective diagnosis is needed in an asymptomatic patient who treated him- or herself with antimalarials, the persistent positivity of the PfHRP-2 test is helpful.
Polymerase Chain Reaction (PCR)
PCR currently has limited use for the acute management of malaria: it is not widely available, and results are not timely. The advantage of PCR, however, is its ability to detect very low sub-microscopic parasitemias and to identify species; therefore, it can be used following microscopy to confirm the malaria species. All malaria cases diagnosed in the United States should have PCR confirmation of species. This service is available at the CDC free of charge ( www.CDC.gov/malaria ).
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