Key points

Introduction

Malaria causes substantial morbidity and mortality in many of the most resource-limited areas of the world. In addition, malaria is a threat to travelers to endemic areas and should be considered in the evaluation of any traveler returning from a malaria-endemic region presenting with fever. Malaria infection can rapidly develop into severe disease that can be fatal. Prompt, effective treatment is critical to limiting these complications. Understanding the species-specific epidemiology and drug-resistance patterns in the geographic area where infection was acquired guides treatment. This review contains an overview of the epidemiology and pathogenesis of malaria with a focus on components relevant to treating malaria in nonendemic areas. Guidance for treatment and management of malaria in returned travelers is provided.

Introduction

Malaria causes substantial morbidity and mortality in many of the most resource-limited areas of the world. In addition, malaria is a threat to travelers to endemic areas and should be considered in the evaluation of any traveler returning from a malaria-endemic region presenting with fever. Malaria infection can rapidly develop into severe disease that can be fatal. Prompt, effective treatment is critical to limiting these complications. Understanding the species-specific epidemiology and drug-resistance patterns in the geographic area where infection was acquired guides treatment. This review contains an overview of the epidemiology and pathogenesis of malaria with a focus on components relevant to treating malaria in nonendemic areas. Guidance for treatment and management of malaria in returned travelers is provided.

Cause and pathogenesis

Malaria is caused by infection with Plasmodium parasites. Five species cause disease in humans: Plasmodium falciparum , Plasmodium vivax , Plasmodium malariae , Plasmodium ovale , and Plasmodium knowlesi. Infection is spread by the bite of a female Anopheles mosquito and has obligatory human and mosquito stages of the life cycle. The species of Anopheles mosquitoes responsible for Plasmodium transmission has a broad geographic distribution. Typically, Anopheles bite from dusk to dawn. However, exact biting patterns vary based on specific species.

The life cycle of the 5 Plasmodium species is similar, apart from the dormant stages of P vivax and P ovale :

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  Sporozoites are inoculated into humans by an Anopheles mosquito and immediately invade hepatocytes.

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  Asexual replication takes place initially in the liver, leading to the release of thousands of merozoites per infected hepatocyte into the blood. This release occurs 1 to 2 weeks after the bite of the infectious mosquito.

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  Blood stage infection causes clinical disease.

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  Merozoites invade erythrocytes, undergo asexual reproduction, and then rupture out of the erythrocyte, allowing the daughter merozoites to continue the cycle of invasion and replication.

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  Some blood stage parasites develop into male and female gametocytes, the stage that is responsible for transmission to the mosquito.

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  For the infection to be transmitted, a female Anopheles mosquito must ingest erythrocytes containing male and female gametocytes.

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  Sexual reproduction takes place in the mosquito midgut where the gametocytes mature into gametes, merge to form a zygote, and then develop into an ookinete.

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  Ookinetes invade the mosquito stomach wall and develop into oocysts, which rupture and release sporozoites.

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  Sporozoites migrate to the mosquito salivary gland and may infect another human during the mosquito’s next blood meal.

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  Of note, in P vivax and P ovale , dormant stages, called hypnozoites, may remain quiescent in the liver of the infected human for weeks to years from the initial infection, leading to onset of clinical symptoms or relapses of infections much later. Treatment specifically targeting these dormant stages is required to completely clear infections with P vivax and P ovale.

Malarial disease results from multiple complex parasite-host interactions during the asexual, blood stage of infection. Clinical manifestations of disease are related to parasite modification of the erythrocyte and parasite-induced inflammation.

Plasmodium pathogenesis can be divided into inflammation, anemia, and end-organ damage. Inflammation is caused by the downstream effects of parasite metabolism and erythrocyte rupture, and, in P falciparum , parasite sequestration. Splenic macrophages and monocytes release large amounts of proinflammatory cytokines in response to phagocytosis of hemozoin, a toxic metabolite from the parasite digestion of heme, and other erythrocyte remnants. Proinflammatory cytokines in turn give rise to (1) the systemic inflammatory response syndrome, (2) edema and inflammation in perivascular tissues in end organs due to disruption of endothelial basal lamina and extravasation, and (3) increased expression of adhesion molecules and increased sequestration of parasitized erythrocytes.

The anemia caused by Plasmodium infection is multifactorial. Asexual reproduction in infected erythrocytes leads directly to hemolysis. Moreover, intraerythrocytic parasites decrease erythrocyte deformability, leading to increased hemolysis and splenic clearance, compounded by splenic sequestration in P falciparum infection. Hematopoiesis, which would normally compensate for hemolysis, is suppressed by tumor necrosis factor-alpha released during infection.

End organ damage due to P falciparum infection is mediated by cytoadherence of infected erythrocytes, also referred to as sequestration. Intraerythrocytic parasites produce proteins that are expressed on the surface of infected erythrocytes and lead to binding to a variety of cell types. Binding of parasitized erythrocytes in the microvasculature along with uninfected erythrocytes, inflammatory cells, and platelets leads to partial blood flow obstruction, breakdown of the endothelium, and inflammation that causes end organ damage. Sequestered erythrocytes can be found in any organ. Sequestration in the brain leads to the clinical syndrome of cerebral malaria described in later discussion. Sequestration in the placenta leads to the adverse birth outcomes associated with malaria during pregnancy. Sequestration also removes parasites from the circulation, preventing splenic clearance during one phase of parasite replication and permitting on-going infection.

Epidemiology

Although rarely encountered in the United States, malaria causes approximately 45% of the world’s population to be at risk of infection. P falciparum and P vivax are the most common causes of human malaria and have distinct geographic distributions, as in Fig. 1 . P malariae is found in a similar distribution as P falciparum ; P ovale is primarily found in West Africa, but cases have been reported in other sub-Saharan African countries. The limited cases of P knowlesi , a primarily nonhuman primate parasite, are reported in Southeast Asia.

Spatial distribution of P falciparum ( A ) and P vivax ( B ) endemicity in 2010. Prevalence rates are presented in different populations and different scales based on species. The P falciparum map ( A ) shows the prevalence rate in 2 to 10 year olds (PfPR) and ranges from 0% to 70%; see color scale on map. The P vivax map ( B ) shows the prevalence rate in 1 to 99 year olds (PvPR) and ranges from 0 to greater than 7%. Shaded areas have unstable transmission (<0.1%), and hatched areas have greater than 90% prevalence of Duffy antigen negativity. Duffy antigen is required for the invasion of P vivax into the erythrocyte and is absent in some African populations. These maps are open source and made available by the Malaria Atlas Project ( http://www.map.ox.ac.uk/map/ ) under the Creative Commons Attribution 3.0 Unported License.

( Reproduced from [ A ] Gething PW, Patil AP, Smith DL, et al. A new world malaria map: plasmodium falciparum endemicity in 2010. Malar J 2011;10:378; and [ B ] Gething PW, Elyazar IRF, Moyes CL, et al. A long neglected world malaria map: plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis 2012;6(9):e1814.)

Worldwide over the last 15 years, there has been a 60% decrease in the malaria death rate due to increased availability of preventive measures, such as bed nets, and effective new diagnostics and treatments. Since 2007 when the World Health Organization (WHO) endorsed a global commitment to eradicate malaria, 5 countries have been declared malaria free (United Arab Emirates, Morocco, Turkmenistan, Armenia, and Sri Lanka), and 26 more are poised for elimination by 2020. Despite this progress, in 2015, it is estimated that there were still 214 million new cases of malaria and 438,000 deaths. The vast majority of morbidity and mortality occur in sub-Saharan Africa, where the heaviest burden of disease is shouldered by children less than 5 years of age. Further progress is threatened by the spread of drug and insecticide resistance, the need for new tools for malaria control in areas that have not reduced transmission with current interventions, and the continued demand for a global financial commitment to the goal of eradication.

In the United States, there has been a consistent increase the number of cases of malaria reported to the US Centers for Disease Control and Prevention (CDC) since 1973. In 2013, 1727 cases were reported. All infections in which origin was determined (99.6%) were acquired abroad. Most occurred in US residents, and 17% occurred in children (age <18 years). Severe malaria, infection associated with end organ damage, was more common in children less than 5 year old compared with older children and adults. However, none of the 10 deaths caused by malaria in the United States were among children.

Susceptibility to infection

In nonendemic and low transmission areas, all individuals are at risk of infection. In highly endemic settings, primarily some areas in sub-Saharan Africa, multiple malaria infections lead to the development of partial immunity. As children in these areas have repeated exposure to malaria infection, they become less likely to experience clinical disease. By adulthood, individuals in high transmission settings may still become infected, but the parasite load is lower and there is very low risk of clinical disease. Sterilizing immunity, complete prevention of infection, does not occur. Moreover, the duration of acquired immunity is not life-long: if individuals from endemic areas are no longer exposed to infection for as little as a year, they are at risk of disease upon repeat exposure. Many cases of malaria in the United States occur when individuals from endemic countries return home to visit friends and relatives. These individuals may not realize that their immunity has decayed, making them again susceptible to high-density infection and disease.

Hemoglobinopathies alter susceptibility to malaria infection and disease. Sickle cell trait (HbAS) is estimated to afford 90% protection from severe disease, 75% protection from hospitalization with malaria, but no protection from asymptomatic infection. This protection contributes to the persistence of HbS in African populations given the decreased life expectancy of homozygotes. Protection is also seen with hemoglobin C and alpha-thalassemia and beta-thalassemia. However, it is important to recognize that individuals with any of these hemoglobinopathies can still get malaria and have severe manifestations.

History and physical

During medical evaluation of patients with fever, taking a travel history and considering malaria are critical. Malaria should be suspected in any case of documented or history of fever and residence in or travel to malaria-endemic areas. Key malaria-related questions to ask on history include the following:

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  Has the patient traveled to a malaria-endemic area? Which species are present in that region? The geographic region determines the possibility of malaria infection and the most likely species, risk of severe disease, and treatment choice based on geographic patterns of antimalarial drug resistance. See the CDC Travelers’ Health Web site ( http://wwwnc.cdc.gov/travel ) for details on malaria epidemiology by country.

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  When did exposure occur? The time from the bite of an infected mosquito until presentation with clinical illness of P faliciparum is typically 10 to 14 days but may be as short as 7 days and as long as 30 days. Presentation with clinical illness may be delayed in those with partial immunity or who were taking incomplete or ineffective prophylaxis. P malariae may persist at low levels for long periods of time, up to years. Because of their dormant stages, P vivax and P ovale may present months to years after initial infections. Three to 6 weeks after the initial infectious bite is the most common period for relapse of P vivax infection obtained in tropical areas, and most relapses have occurred by 6 months. Relapse may occur 6 to 12 months after P vivax infection obtained in subtropical or temperate climates.

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  Has the patient used antimalarials in the last 1 to 2 months? Drugs recently used for treatment or prophylaxis should not be used for treatment of clinical illness. Among individuals living in or emigrating from endemic areas, it is important to know if they were treated for malaria in the last 1 to 2 months, what drug was used, and if treatment was completed. Among travelers, it is important to know if they were taking malaria prophylaxis, what drug was used, and what their adherence was. Note that taking prophylaxis, even as recommended, does not definitively exclude malaria diagnosis.

Other groups in which Plasmodium infection should be considered in health care include asymptomatic immigrants (refugees, international adoptees, and others) from endemic areas. See the section on “Screening and Treatment of immigrants from malaria endemic areas” in later discussion.

The physical examination and initial laboratory evaluation should be used to determine the likelihood of malaria, evaluate other conditions on the differential, and determine the disease severity if malaria is likely (see Box 2 and the section, “Assessing severity”). General physical examination should be performed with specific attention to the following organ systems:

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  Ophthalmologic: Check for conjunctival pallor indicative of anemia. If seizures, altered consciousness, or other concern for cerebral malaria, consider dilated funduscopic examination by an ophthalmologist to evaluate for retinal hemorrhages, areas of retinal opacification, papilledema, cotton wool spots, or decolorization of retinal vessels.

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  Pulmonary: Note tachypnea, which may be related to pulmonary complications (manifested by crepitation) or to metabolic acidosis (manifested by the characteristic acidotic breathing pattern).

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  Cardiac: Note tachycardia, which could be related to fever, increased cardiac output demand due to anemia, or shock. Assess capillary refill and extremity temperature variation.

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  Gastrointestinal: Palpate for splenomegaly.

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  Neurologic: Calculate Glasgow Coma Score if altered mental status and monitor for deterioration. Monitor for seizures. Assess for nuchal rigidity and photophobia, which would suggest meningitis rather than cerebral malaria.

Differential diagnosis

Because the symptoms of malaria are nonspecific, the differential diagnosis is broad. Specific alternative diagnoses are listed in Box 1 .

Diagnosis

Malaria has the potential to be fatal. In cases where the index of suspicion is high, treatment can be started before testing results are available or even before they are performed, so that there is no delay in therapy. If presumptive treatment is initiated, diagnostic specimens should still be obtained.

Blood smear and detection by microscopy are considered the gold standard for laboratory confirmation of malaria. Thick and thin smears should be read. The CDC provides details on preparation and interpretation. Briefly, smears are stained with either Wright’s or ideally Giemsa stain. The thick smear is the most sensitive measure to detect low-density infection because it allows the microscopist to review a large volume of blood and is read for detection of infection. The thin smear, which allows greater resolution of the red blood cell morphology and the parasite, is used for determining the Plasmodium species and quantifying the specific parasite density. The later features are important for treatment and monitoring decisions. If the initial blood smears are negative but Plasmodium infection remains on the differential, 2 additional smears should be obtained at 12- to 24-hour intervals. Blood smears and trends in parasite quantification are also useful in following response to treatment (see later discussion).

Antigen-detecting rapid diagnostics tests (RDTs) are increasingly available for diagnosis of malaria in both resource-limited and nonendemic settings. The tests are generally cassette- or card-based lateral flow immunochromatographic assays that appear much like a pregnancy test. Labeled antibodies detect 1 of 3 Plasmodium antigens that may or may not be species specific depending on the test. Up-to-date information on the tests available, their mechanisms, and performance characteristics can be found on the WHO Foundation for Innovative New Diagnostics Web site.

Only one RDT is approved for use in commercial and hospital laboratories in the United States. The BinaxNOW test (Alere Inc, Waltham, MA, USA) detects one antigen that is specific for P falciparum and another that is found in all human Plasmodium species. The sensitivity of detecting P falciparum and non- P falciparum infection in US or Canadian hospitals has ranged from 72% to 100% depending on the study. This RDT is specifically less sensitive for the detection of P malariae and low-density infections (<200 parasites per microliter). Sensitivity for detection of P knowlesi is low (29%). The current recommendations are that RDTs should be used in conjunction with blood smears. RDTs may significantly reduce the time required for preliminary diagnosis and, thus, are useful tools for initial diagnosis. Positive RDTs should be considered significant support of Plasmodium infection, but blood smears are required for confirmation, definitive species identification, and quantification. Negative RDTs should not eliminate consideration of malaria, especially if there has been recent treatment or infection is due to low-density or non- falciparum infections. Blood smears should be performed to exclude the diagnosis.

All cases of laboratory confirmed malaria should be reported to the state health department and to the CDC ( www.cdc.gov/malaria/report.html ).