Malaria 2017: Update on the Clinical Literature and Management

Abstract

Purpose of Review

Malaria is a prevalent disease in travelers to and residents of malaria-endemic regions. Health care workers in both endemic and non-endemic settings should be familiar with the latest evidence for the diagnosis, management and prevention of malaria. This article will discuss the recent malaria epidemiologic and medical literature to review the progress, challenges, and optimal management of malaria.

Recent Findings

There has been a marked decrease in malaria-related global morbidity and mortality secondary to malaria control programs over the last few decades. This exciting progress is tempered by continued levels of high transmission in some regions, the emergence of artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia, and the lack of a highly protective malaria vaccine. In the United States (US), the number of travelers returning with malaria infection has increased over the past few decades. Thus, US health care workers need to maintain expertise in the diagnosis and treatment of this infection.

Summary

The best practices for treatment and prevention of malaria need to be continually updated based on emerging data. Here, we present an update on the recent literature on malaria epidemiology, drug resistance, severe disease, and prevention strategies.

Introduction

Plasmodium infections continue to cause significant morbidity and mortality for residents of and travelers to endemic areas. This protozoan parasite is transmitted through the bite of an anopheles mosquito and remains an important public health threat. There are a number of challenges in the identification and management of malaria. The diagnosis of malaria can be elusive as the presenting symptoms are non-specific, and a delay in diagnosis can result in poor outcomes. The selection of an antimalarial regiment is dependent on the species, origin of infection, and severity of illness. Determination of appropriate treatment is further complicated by the dynamic geographic distribution of antimalarial drug resistance. Finally, newly reported breakthroughs in the pathogenesis and treatment of severe disease should inform best management practices. This review of the malaria literature highlights current clinical and public health issues and discusses the evidence to guide best practices for the diagnosis, treatment, and prevention of malaria (Table 1).

Table 1 Summary of important recent findings in the clinical literature and practical implications

Global Malaria Epidemiology: Successes and Challenges

There has been a remarkable decrease in malaria transmission in Africa over the past 15 years, due to large investments in malaria control programs across the continent [1, 2•]. Between 2000 and 2015, there has been an estimated 50% decrease in prevalence and a 40% decrease in the incidence of clinical disease from Plasmodium falciparum infection based on an innovative model informed by field data (Fig. 1) [3•]. This translates to a reduction in death across sub-Saharan Africa with an estimated decrease of 57% (95% uncertainty interval, 46 to 65) in the rate of malaria deaths, from 12.5 per 10,000 population in 2000 to 5.4 per 10,000 population in 2015 [4•]. The scaling up of multipronged interventions including the use of insecticide-treated bednets (ITNs), indoor residual spraying (IRS), seasonal malaria chemoprevention, rapid malaria diagnostics, and treatment with artemisinin combination therapy have all contributed to infection reduction [5]. However, some regions in Africa continue to have high transmission and mortality rates, a finding associated with low use of preventative and treatment interventions [2•, 4•]. The identification of specific regions with high malaria disease rates allows targeted scaling up of malaria control efforts in these areas, to further decrease the global burden of malaria related morbidity and mortality.

Fig. 1

Reduction in malaria prevalence between 2000 and 2015 in Africa. Estimated prevalence of malaria infection in children 2–10 years of age from Bhatt et al. [3•]. Maps are freely available from the Malaria Atlas Project ( http://www.map.ox.ac.uk/ ) under the Creative Commons Attribution 3.0 Unsupported License

Epidemiology of Returning Travelers to the US with Malaria

The number of returning travelers to the US with malaria has been increasing over the past few decades, with 1727 cases reported in 2013 [6•]. Of those who reported purpose of travel, 70% were visiting friends or relatives (VFR) in the endemic area. The vast majority of infections were acquired in Africa (82%), followed by travel to Asia (11%), and the remaining cases from Central America, the Caribbean, South America, Oceania, and Greece. Almost every state in the US reported at least one case in 2013. Thus, health care facilities that evaluate returning travelers from malaria endemic areas with fever should be able to provide a rapid diagnosis and treatment of malaria.

Children are likely to be underdiagnosed with traveler’s malaria compared to adults. A retrospective review of 95 children and adults hospitalized for traveler’s malaria between 2005 and 2012 was carried out in the Bronx [7]. P. falciparum infection was responsible for 86% of infections, 83% of patients were VFR and 18% had severe malaria. Children were more likely to have been seen previously by a health care worker and not diagnosed with malaria compared to adults (43 vs 13%, p = 0.002). The under diagnosis of malaria in children may be due to their significantly higher rate of gastrointestinal symptoms as compared to adults, which mimic common pediatric illnesses such as viral gastroenteritis. As malaria can present with diverse and non-specific symptoms, a diagnostic test should be a priority in all febrile travelers with a history of visiting a malaria-endemic area.

Microscopy provides speciation and parasite quantification and the CDC provides educational material for diagnostic procedures for malaria, including a telediagnostic service [8]. However, adequate microscope equipment and expertise may not be readily available. Rapid diagnostic tests are excellent alternatives and in many settings outperform microscopy for the diagnosis of malaria. These tests are less reliable for non-falciparum malaria and are less sensitive than microscopy; however, they have provided a key diagnostic resource for both malaria control programs worldwide and for US health care facilities. Updated information on the use and evaluation of rapid diagnostic tests is available at http://www2.wpro.who.int/sites/rdt/home.htm.

Diagnosis and Treatment of Severe Malaria

Clinical and laboratory criteria are used to establish the diagnosis of severe malaria, which requires aggressive treatment, particularly for travelers who often have no immunity [9•]. There were 270 travelers in the US diagnosed with severe malaria in 2013, with 233 (86%) cases due to P. falciparum [6•]. The severe disease criteria for these travelers included renal failure, severe anemia, and/or cerebral malaria. Severe cerebral edema and brainstem herniation was reported in some of the malarial deaths in this case series. The striking phenomena of brain swelling was recently described in detail in a large cohort of Malawian children with cerebral malaria (CM) where high rates of brain swelling had the greatest association with death (adjusted OR 7.5 (95% 2.1–26.9)) and associated with brainstem herniation [6•, 10]. High rates of brain swelling are associated with elevated levels of inflammatory cytokines and lipid metabolites of the phospholipase A2 pathway, although the mechanisms of this complication are not understood [11]. The optimal adjunctive therapy to treat CM-related brain swelling remains to be determined.

The majority of travelers with severe malaria in the US in 2013 were treated appropriately with quinidine (55%) and intravenous artesunate (16%), as both drugs are recommended for treatment of severe malaria [6•]. Although parenteral therapy is the standard of care for severe malaria, 30% of patients were treated with an oral antimalarial regimen [6•]. Furthermore, some of the severe malaria deaths were associated with a delay in diagnosis. Best practice management of severe malaria requires a rapid diagnosis, intravenous antimalarial therapy, and supportive care as needed.

Quinidine (a stereoisomer of quinine) is the only FDA-approved treatment for severe malaria in the US; however, its availability is decreasing as newer generation antiarrhythmic drugs are being used. The CDC can provide artesunate as an alternative treatment for severe malaria, if the patient fulfills eligibility criteria [12]. Excellent outcomes with the use of intravenous artesunate for severe or complicated malaria was recently reported through a retrospective case series of 102 patients treated in the US which included a 7-day follow-up period. They found that artesunate was indeed commonly requested due to lack of quinidine availability and that artesunate is a safe and clinically beneficial alternative to quinidine [13]. However, it is important to recognize that a late hemolytic complication can occur after the use of intravenous artesunate. Post-artemisinin delayed hemolysis (PADH) occurs at least 7 days after the first dose of intravenous artesunate and is defined as a decrease of ≥10% hemoglobin in the setting of a haptoglobin <0.1 g/L and an increase in lactate dehydrogenase (LDH) of >390 U/L. Some patients with PADH require blood transfusions and experts suggest that patients who receive intravenous artesunate for severe malaria should be tested for hemolysis weekly for 4 weeks after treatment [14, 15].

Changing Patterns of Antimalarial Resistance

Artemisinins remain the mainstay of therapy and are used in combination with a second agent to forestall drug resistance [9•]. Artemisinins are superior to quinine for severe disease to prevent death: are available in parenteral, oral, and rectal formulations; and have the additional benefit of clearing gametocytes, the transmissible form of malaria [9•]. One potential threat to the large reduction in malaria prevalence is the emergence of artemisinin resistance in Southeast Asia. P. falciparum resistance to artemisinin was first reported in Southeast Asia a decade ago and now has become prevalent in regions of Cambodia, Vietnam, Laos, Thailand, Myanmar, and China [16•]. To date, it does not appear that artemisinin resistance has spread outside these regions, based on a recent worldwide survey of artemisinin genotypic resistance [16•]. In order to treat patients in regions with artemisinin-resistant isolates, the duration of antimalarial therapy should be extended from 3 to 6 days, which has been associated with cure rates up to 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days in regions that had high failure rates with the 3-day course [17]. Future studies will need to determine the durability of this strategy. Strategies to contain artemisinin resistance include adding a dose of primaquine to the treatment course, which is more effective at killing gametocytes, to further reduce the prevalence of these drug-resistant transmissible forms within a population [9•].

Plasmodium vivax

P. vivax is the most prevalent human malaria, has a prolonged liver phase (hypnozoite), and can occasionally cause severe disease [18•]. P. vivax is generally sensitive to chloroquine; however, reports of chloroquine resistance have been emerging and resistance is well established in Indonesia and Oceania. A meta-analysis to determine the global extent of chloroquine resistance evaluated 129 clinical trials and 26 case reports [19•]. Studies of drug failure in P. vivax are complicated by the hypnozoite-induced relapse (which relapse typically after 1 month or longer after the primary infection), which could be misclassified as a drug resistant parasite. Thus, in this meta-analysis, they reported recurrences occurring within 1 month of a treated infection; in addition, they highlighted studies that documented recurrences occurring in the presence of adequate blood concentrations of chloroquine, in order to provide robust evidence of drug resistance. Chloroquine resistance was present in 58 study sites (53%). Microscopic clearance of parasitemia by day 3 of treatment was found to be a highly predictive marker of P. vivax chloroquine sensitivity. Currently, the WHO recommends either artemisinin combination therapy or chloroquine as first-line treatment for Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, or Plasmodium knowlesi [9•]. A reasonable strategy for treatment of travelers with P. vivax is to treat with chloroquine and follow daily smears. If the patient is from a known chloroquine-resistant area, then treatment with artemisinin combination therapy is appropriate. In both cases, treatment should be followed with a course of primaquine if they have a normal glucose-6-phosphate dehydrogenase (G6PD) level to treat the hypnozoite phase and prevent relapse.

The hypnozoite stages of P. vivax serves as a silent reservoir, to perpetuate transmission within a population. Primaquine clears the liver stage; however, the limitations of primaquine are the need for a 14 day course, the risk of hemolysis in patients with G6PD deficiency, and reports of drug failure at 15 mg/day dose regimen [20]. A single dose of tafenoquine has been tested as an alternative liver-stage antimalarial and there is evidence that this single dose may be more effective than 14 days of primaquine to prevent relapses at 6 months of follow-up (RR 0.29, (95% CI 0.10–0.84) [21]. The availability of a safe and single-dose therapy to clear hypnozoites could have a major impact on individual care and P. vivax control and eradication programs. Additional, large sample size data on the risk of tafenoquine-induced hemolysis in patients with G6PD deficiency and safety/efficacy in children and pregnant women are needed.

Plasmodium knowlesi

P. knowlesi is a zoonotic malaria that is notable for a 24-h life cycle, its association with severe disease, and challenges in diagnosis. A large focus of P. knowlesi malaria was identified in Malaysia over a decade ago, and P. knowlesi has since become their most prevalent malaria with ongoing transmission in additional Southeast Asian countries [22, 23•]. P. knowlesi can be misdiagnosed as the typically benign P. malarie due to the histological similarities of the trophozoite and schizont stages by microscopy. Rapid diagnostic tests have only limited sensitivity and specificity for P. knowlesi. This species can result in severe disease, partially due to its association with hyperparasitemia. Of note, the severe disease criteria of hyperparasitemia for this species is >100,000/uL, which is lower than that of P. falciparum [9•].

P. knowlesi is the only major zoonotic Plasmodium infection of humans, where macaques serve as the reservoir and transmit infection to humans via infected mosquitoes; infections transmitted between human hosts through an anopheles mosquito do not occur. The existence of an animal reservoir may make elimination of P. knowlesi more challenging [24]. The optimal treatment strategies are being tested in clinical trials. Both artesunate–mefloquine and chloroquine were found to be highly efficacious for the treatment of P. knowlesi in Malaysia in an open-label randomized controlled trial. However artensuate–mefloquine resulted in a more rapid parasite clearance and shorter time to fever resolution [25].

Preventative Measures

Mass Drug Administration

One approach to reduce transmission that is being revisited by malaria control practitioners is the implementation of Mass Drug Administration (MDA). MDA is the distribution of a curative dose of an antimalarial drug to an entire population without first testing for infection. MDA has had mixed successes in the past and its role as part of a malaria control campaign has been debated. Recently, the WHO Malaria Policy Advisory Committee updated their recommendations to consider the use of MDA in the settings of low transmission approaching elimination, in regions with multi-drug resistance as a component of malaria elimination and as part of an immediate response to malaria epidemics [26, 27]. A cluster-randomized controlled trial in Southern Province, Zambia, was used to assess the short-term impact of two rounds of dihydroartemisinin plus piperaquine MDA compared with no MDA. They found an 87% relative reduction in infection prevalence (adjusted OR, 0.13; 95% CI, 0.02–0.92; p = 0.04) after accounting for confounding factors [28]. Importantly, the reduction in infection prevalence only occurred in the lower transmission setting, with no effect in the high transmission region. More studies are underway in to further identify the role and efficacy of MDA in a malaria control programs.

Chemoprophylaxis

P. falciparum infection during pregnancy can result in infection of the placenta to compromise its normal functions and therefore result in premature delivery and fetal loss. Intermittent preventative therapy, starting in the second trimester with sulfadoxine–primethamine (SP) has been used to prevent maternal malaria; however, its efficacy has diminished due to the development of SP resistance [9•]. Artemisinin combination therapies have been studied as an alternative prophylactic strategy. In one region of Kenya with high transmission and SP resistance, a study showed that intermittent preventive treatment with dihydroartemisinin–piperaquine compared to SP was associated with a lower incidence of malaria infection during pregnancy (192·0 vs 54·4 events per 100 person-years; incidence rate ratio [IRR] 0·28, 95% CI 0·22–0·36; p < 0·0001) [29]. Ultimately, the best antimalarial regiments and strategies to prevent malaria during pregnancy will depend on local SP resistance rates and transmission intensity.

Seasonal malaria prophylaxis with SP plus amodiaquine to children under 5 years of age in moderate to high transmission areas of Africa reduces infection and is recommended by the WHO [9•]. In some regions, older children bear a large burden of disease from malaria and potentially could also benefit from seasonal malaria prophylaxis. A large study of chemoprevention in children under the age of 10 years in Senegal, found that SP-amodiaquine significantly reduced the incidence of malaria and severe malaria, and that this protection extended to subjects greater than 5 years of age [30]. These data suggest that seasonal chemoprophylaxis could contribute to reducing disease in older children.

Vaccine

An effective vaccine against malaria has been a long sought goal. A vaccine that targets the sporozoite stage of P. falciparum (RTS,S/AS01) has demonstrated protection in children in Africa. The RTS,S/ASO1 vaccine (4 doses) was associated with rates of protection against clinical malaria of 36.3% (95% confidence interval [CI], 31.8 to 40.5) among children 5 to 17 months of age and 25.9% (95% CI, 19.9 to 31.5) among young infants (6 to 12 weeks) (n = 15,459) [31]. This protection wains over time and in a 7-year follow-up subanalysis of 5–17 months of age subjects receiving three doses, children in regions of high transmission had higher-than-average infection with malaria parasites [32]. This malaria rebound may occur because protection against the sporozoite stage prevents blood-stage infections and thus vaccine recipients have less immunity to blood-stage parasite antigens. The WHO recently announced a study of the vaccine’s protective efficacy in the context of routine use in children aged 5–17 months old, using the four-dose regiment in Ghana, Kenya, and Malawi [33, 34]. Additional malaria vaccine candidates that target additional stages of the life cycle are in clinical development [35•]. Continued investments from public sources and philanthropy will be critical to advance the vaccine agenda forward.

Resources

The WHO Guidelines for the treatment of malaria—third edition is an excellent and comprehensive resource on malaria [9•]. This updated document provides detailed background on a range of clinical topics and their recommendations are accompanied by a quality of evidence rating. Some of the updated guidelines in 2015 include the recommendation of IV artesunate for a pregnant woman with severe disease in all stages of pregnancy, the first-line use of artemisinin combination therapy (or chloroquine) for non-falciparum malarias and the use of primaquine during treatment of active infections with artemisinin combination therapies to reduce transmissible forms in patients with P. falciparum infection in low-transmission regions. The CDC also provides a critical and outstanding resource to US health care workers for the prevention and management of travelers malaria [36•]. Their 24-h hotline provides expert guidance on diagnosis and treatment of malaria and the CDC can provide intravenous artesunate as indicated. They can be reached via the CDC Malaria Hotline (770–488-7788) from 9:00 a.m. to 5:00 p.m. Eastern Time. For emergency consultation after hours, call 770–488-7100 and request to speak with a CDC Malaria Branch Clinician.

Conclusions

There have been tremendous strides in controlling and decreasing malaria infections worldwide. Experts in diagnostics, drug development, disease modeling, clinical research, vaccine development and others have moved the field forward due to investments by committed donors. The march toward further reduction in transmission and possible elimination will require continued efforts and resources. For now, malaria remains an important infectious disease in endemic regions and for travelers, and best practices for malaria control and management will continue to evolve.