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Malaria Cures and Treatments
Malaria is a mosquito-carried disease. The insect carries a parasite, and when the insect bites a host, it is transmitted. Malaria is a serious disease that requires medical care. Your doctor can provide information on malaria disease prevention and treatment as well.
Malaria in Mosquitoes
Malaria is usually carried by infected female mosquitoes of the Anopheles family. When the insect bites a human, the parasite enters the person’s bloodstream via the mosquito’s saliva. The parasite then travels to the human hosts liver where it matures to adulthood and reproduces. Malaria can vary in severity based on the species of parasite the human is infected with. Doctors use blood samples under a microscope or antigen-based rapid diagnostic tests to diagnose malaria.
Malaria Risks in Different Countries
Malaria is found throughout the world in more than 100 countries; however, some countries are at more risk of the disease than others due to the climate conditions that breed mosquitoes, such as high humidity and moisture. The top six countries with the highest malaria burden include Nigeria, Democratic Republic of the Congo, United Republic of Tanzania, Uganda, Mozambique and Cote d’Ivoire, as stated by the World Health Organization (WHO). South East Asia, India, Indonesia and Myanmar are also high burden areas.
Malaria Symptoms
Symptoms of malaria start as flu-like symptoms. The symptoms tend to appear within eight to 25 days following infection or bite. Symptoms appear as shaking chills, profuse sweating, nausea, headaches, high fever, abdominal pains and issues such as vomiting and diarrhea. Other symptoms can vary and include muscle pain, convulsions and bloody stools. If you are displaying any of these symptoms and have recently been to a mosquito-infested area, it is important to seek medical attention immediately.
Complications from Malaria can be life-threatening and include swelling of blood vessels within the brain, fluid build-up in the lungs, which causes breathing issues or pulmonary edema. Complications can also result in organ failure, severe anemia and low blood sugar. If you are experiencing any complications, it is imperative to seek treatment immediately as complications can lead to coma or even death.
Considerations for Traveling
If you are planning to travel to a known malaria-burden country, it is important to take some precautions. Avoid mosquito bites altogether by choosing the proper repellents or by wearing and using nets and bed nets, as suggested by the Center for Disease Control and Prevention (CDC). Be sure to wear hats and proper clothing, such as pants and long-sleeved shirts. There are also medicines available to prevent malaria if you are bitten.
Malaria Treatments
Once diagnosed with malaria, your doctor will likely put you on a regiment of drugs including antiparasitics and antibiotics. Your doctor may also prescribe you a separate antiparasitic that can help prevent any relapses. The treatment chosen is dependent on the country the malaria was contracted along with the species of the parasite. For serious or complicated cases, the doctor will likely give the medication via an intravenous infusion until you show signs of improvement, per the CDC. Expect to be treated for about two weeks. Severe or complicated cases can take up to four weeks for malaria cure and treatment.
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- Korean J Parasitol
- v.47(2); 2009 Jun
Malaria Diagnosis: A Brief Review
Noppadon tangpukdee.
1 Critical Care Research Unit, Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand.
Chatnapa Duangdee
2 Diagnostic Laboratory Unit, Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand.
Polrat Wilairatana
3 WHO Collaborating Center for Clinical Management of Malaria, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Srivicha Krudsood
Malaria is a major cause of death in tropical and sub-tropical countries, killing each year over 1 million people globally; 90% of fatalities occur in African children. Although effective ways to manage malaria now exist, the number of malaria cases is still increasing, due to several factors. In this emergency situation, prompt and effective diagnostic methods are essential for the management and control of malaria. Traditional methods for diagnosing malaria remain problematic; therefore, new technologies have been developed and introduced to overcome the limitations. This review details the currently available diagnostic methods for malaria.
INTRODUCTION
Malaria, sometimes called the "King of Diseases", is caused by protozoan parasites of the genus Plasmodium . The most serious and sometimes fatal type of malaria is caused by Plasmodium falciparum . The other human malaria species, P. vivax , P. ovale , P. malariae , and sometimes P. knowlesi can cause acute, severe illness but mortality rates are low. Malaria is the most important infectious disease in tropical and subtropical regions, and continues to be a major global health problem, with over 40% of the world's population exposed to varying degrees of malaria risk in some 100 countries. It is estimated that over 500 million people suffer from malaria infections annually, resulting in about 1-2 million deaths, of whom 90% are children in sub- Saharan Africa [ 1 ]. The number of malaria cases worldwide seems to be increasing, due to increasing transmission risk in areas where malaria control has declined, the increasing prevalence of drugresistant strains of parasites, and in a relatively few cases, massive increases in international travel and migration [ 2 ]. The need for effective and practical diagnostics for global malaria control is increasing [ 3 ], since effective diagnosis reduces both complications and mortality from malaria. Differentiation of clinical diagnoses from other tropical infections, based on patients' signs and symptoms or physicians' findings, may be difficult. Therefore, confirmatory diagnoses using laboratory technologies are urgently needed. This review discusses on the currently available diagnostic methods for malaria in many settings, and assesses their feasibility in resource-rich and resource-poor settings.
DIAGNOSIS OF MALARIA
Prompt and accurate diagnosis is critical to the effective management of malaria. The global impact of malaria has spurred interest in developing effective diagnostic strategies not only for resource-limited areas where malaria is a substantial burden on society, but also in developed countries, where malaria diagnostic expertise is often lacking [ 4 , 5 ]. Malaria diagnosis involves identifying malaria parasites or antigens/products in patient blood. Although this may seem simple, the diagnostic efficacy is subject to many factors. The different forms of the 5 malaria species; the different stages of erythrocytic schizogony, the endemicity of different species, the interrelation between levels of transmission, population movement, parasitemia, immunity, and signs and symptoms; drug resistance, the problems of recurrent malaria, persisting viable or non-viable parasitemia, and sequestration of the parasites in the deeper tissues, and the use of chemoprophylaxis or even presumptive treatment on the basis of clinical diagnosis, can all influence the identification and interpretation of malaria parasitemia in a diagnostic test.
Malaria is a potential medical emergency and should be treated accordingly. Delays in diagnosis and treatment are leading causes of death in many countries [ 6 ]. Diagnosis can be difficult where malaria is no longer endemic for healthcare providers unfamiliar with the disease. Clinicians may forget to consider malaria among the potential diagnoses for some patients and not order the necessary diagnostic tests. Technicians may be unfamiliar with, or lack experience with, malaria, and fail to detect parasites when examining blood smears under a microscope. In some areas, malaria transmission is so intense that a large proportion of the population is infected but remains asymptomatic, e.g., in Africa. Such carriers have developed sufficient immunity to protect them from malarial illness, but not infection. In such situations, finding malaria parasites in an ill person does not necessarily mean that the illness is caused by the parasites. In many malaria-endemic countries, the lack of resources is a major barrier to reliable and timely diagnosis. Health personnel are undertrained, underequipped, and underpaid. They often face excessive patient loads, and must divide their attention between malaria and other equally severe infectious diseases, such as tuberculosis or HIV/AIDS.
CLINICAL DIAGNOSIS OF MALARIA
A clinical diagnosis of malaria is traditional among medical doctors. This method is least expensive and most widely practiced. Clinical diagnosis is based on the patients' signs and symptoms, and on physical findings at examination. The earliest symptoms of malaria are very nonspecific and variable, and include fever, headache, weakness, myalgia, chills, dizziness, abdominal pain, diarrhea, nausea, vomiting, anorexia, and pruritus [ 7 ]. A clinical diagnosis of malaria is still challenging because of the non-specific nature of the signs and symptoms, which overlap considerably with other common, as well as potentially life-threatening diseases, e.g. common viral or bacterial infections, and other febrile illnesses. The overlapping of malaria symptoms with other tropical diseases impairs diagnostic specificity, which can promote the indiscriminate use of antimalarials and compromise the quality of care for patients with non-malarial fevers in endemic areas [ 8 - 10 ]. The Integrated Management of Children Illness (IMCI) has provided clinical algorithms for managing and diagnosing common childhood illnesses by minimally trained healthcare providers in the developing world having inappropriate equipment for laboratory diagnosis. A widely utilized clinical algorithm for malaria diagnosis, compared with a fully trained pediatrician with access to laboratory support, showed very low specificity (0-9%) but 100% sensitivity in African settings [ 11 , 12 ]. This lack of specificity reveals the perils of distinguishing malaria from other causes of fever in children on clinical grounds alone. Recently, another study showed that use of the IMCI clinical algorithm resulted in 30% over-diagnosis of malaria [ 13 ]. Therefore, the accuracy of malaria diagnosis can be greatly enhanced by combining clinical-and parasite-based findings [ 14 ].
LABORATORY DIAGNOSIS OF MALARIA
Rapid and effective malaria diagnosis not only alleviates suffering, but also decreases community transmission. The nonspecific nature of the clinical signs and symptoms of malaria may result in over-treatment of malaria or non-treatment of other diseases in malaria-endemic areas, and misdiagnosis in non-endemic areas [ 15 ]. In the laboratory, malaria is diagnosed using different techniques, e.g. conventional microscopic diagnosis by staining thin and thick peripheral blood smears [ 16 ], other concentration techniques, e.g. quantitative buffy coat (QBC) method [ 15 ], rapid diagnostic tests e.g., OptiMAL [ 17 , 18 ], ICT [ 19 ], Para-HIT-f [ 10 ], ParaScreen [ 20 ], SD Bioline [ 21 ], Paracheck [ 22 ], and molecular diagnostic methods, such as polymerase chain reaction (PCR) [ 23 , 24 ]. Some advantages and shortcomings of these methods have also been described, related to sensitivity, specificity, accuracy, precision, time consumed, cost-effectiveness, labor intensiveness, the need for skilled microscopists, and the problem of inexperienced technicians.
Microscopic diagnosis using stained thin and thick peripheral blood smears (PBS)
Malaria is conventionally diagnosed by microscopic examination of stained blood films using Giemsa, Wright's, or Field's stains [ 25 ]. This method has changed very little since Laverran's original discovery of the malaria parasite, and improvements in staining techniques by Romanowsky in the late 1,800s. More than a century later, microscopic detection and identification of Plasmodium species in Giemsa-stained thick blood films (for screening the presenting malaria parasite), and thin blood films (for species' confirmation) remains the gold standard for laboratory diagnosis [ 26 ]. Malaria is diagnosed microscopically by staining thick and thin blood films on a glass slide, to visualize malaria parasites. Briefly, the patient's finger is cleaned with 70% ethyl alcohol, allowed to dry and then the side of fingertip is picked with a sharp sterile lancet and two drops of blood are placed on a glass slide. To prepare a thick blood film, a blood spot is stirred in a circular motion with the corner of the slide, taking care not make the preparation too thick, and allowed to dry without fixative. After drying, the spot is stained with diluted Giemsa (1 : 20, vol/vol) for 20 min, and washed by placing the film in buffered water for 3 min. The slide is allowed to air-dry in a vertical position and examination using a light microscope. As they are unfixed, the red cells lyse when a water-based stain is applied. A thin blood film is prepared by immediately placing the smooth edge of a spreader slide in a drop of blood, adjusting the angle between slide and spreader to 45° and then smearing the blood with a swift and steady sweep along the surface. The film is then allowed to air-dry and is fixed with absolute methanol. After drying, the sample is stained with diluted Giemsa (1 : 20, vol/vol) for 20 min and washed by briefly dipping the slide in and out of a jar of buffered water (excessive washing will decolorize the film). The slide is then allowed to air-dry in a vertical position and examined under a light microscope [ 27 ]. The wide acceptance of this technique by laboratories all around the world can be attributed to its simplicity, low cost, its ability to identify the presence of parasites, the infecting species, and assess parasite density-all parameters useful for the management of malaria. Recently, a study showed that conventional malaria microscopic diagnosis at primary healthcare facilities in Tanzania could reduce the prescription of antimalarial drugs, and also appeared to improve the appropriate management of non-malarial fevers [ 16 ]. However, the staining and interpretation processes are labor intensive, time consuming, and require considerable expertise and trained healthcare workers, particularly for identifying species accurately at low parasitemia or in mixed malarial infections. The most important shortcoming of microscopic examination is its relatively low sensitivity, particularly at low parasite levels. Although the expert microscopist can detect up to 5 parasites/µl, the average microscopist detects only 50-100 parasites/µl [ 28 ]. This has probably resulted in underestimating malaria infection rates, especially cases with low parasitemia and asymptomatic malaria. The ability to maintain required levels of in malaria diagnostics expertise is problematic, especially in remote medical centers in countries where the disease is rarely seen [ 29 ]. Microscopy is laborious and ill-suited for high-throughput use, and species determination at low parasite density is still challenging. Therefore, in remote rural settings, e.g. peripheral medical clinics with no electricity and no health-facility resources, microscopy is often unavailable [ 30 ].
QBC technique
The QBC technique was designed to enhance microscopic detection of parasites and simplify malaria diagnosis [ 31 ]. This method involves staining parasite deoxyribonucleic acid (DNA) in micro-hematocrit tubes with fluorescent dyes, e.g. acridine orange, and its subsequent detection by epi-fluorescent microscopy. Briefly, finger-prick blood is collected in a hematocrit tube containing acridine orange and anticoagulant. The tube is centrifuged at 12,000 g for 5 min and immediately examined using an epi-fluorescent microscope [ 27 ]. Parasite nuclei fluoresces bright green, while cytoplasm appears yellow-orange. The QBC technique has been shown to be a rapid and sensitive test for diagnosing malaria in numerous laboratories settings [ 15 , 32 - 35 ]. While it enhances sensitivity for P. falciparum , it reduces sensitivity for non-falciparum species and decreases specificity due to staining of leukocyte DNA [ 36 ]. Recently, it has been shown that acridine orange is the preferred diagnostic method (over light microscopy and immunochromatographic tests) in the context of epidemiologic studies in asymptomatic populations in endemic areas, probably because of increased sensitivity at low parasitemia [ 37 ]. Nowadays, portable fluorescent microscopes using light emitting diode (LED) technology, and pre-prepared glass slides with fluorescent reagent to label parasites, are available commercially [ 38 ]. Although the QBC technique is simple, reliable, and user-friendly, it requires specialized instrumentation, is more costly than conventional light microscopy, and is poor at determining species and numbers of parasites.
Rapid diagnostic tests (RDTs)
Since the World Health Organization (WHO) recognized the urgent need for new, simple, quick, accurate, and cost-effective diagnostic tests for determining the presence of malaria parasites, to overcome the deficiencies of light microscopy, numerous new malaria-diagnostic techniques have been developed [ 39 ]. This, in turn, has led to an increase in the use of RDTs for malaria, which are fast and easy to perform, and do not require electricity or specific equipment [ 40 ]. Currently, 86 malaria RDTs are available from 28 different manufacturers [ 41 ]. Unlike conventional microscopic diagnosis by staining thin and thick peripheral blood smears, and QBC technique, RDTs are all based on the same principle and detect malaria antigen in blood flowing along a membrane containing specific anti-malaria antibodies; they do not require laboratory equipment. Most products target a P. falciparum -specific protein, e.g. histidine-rich protein II (HRP-II) or lactate dehydrogenase (LDH). Some tests detect P. falciparum specific and pan-specific antigens (aldolase or pan-malaria pLDH), and distinguish non- P. falciparum infections from mixed malaria infections. Although most RDT products are suitable for P. falciparum malaria diagnosis, some also claim that they can effectively and rapidly diagnose P. vivax malaria [ 21 , 42 , 43 ]. Recently, a new RDT method has been developed for detecting P. knowlesi [ 44 ]. RDTs provide an opportunity to extend the benefits of parasite-based diagnosis of malaria beyond the confines of light microscopy, with potentially significant advantages in the management of febrile illnesses in remote malaria-endemic areas. RDT performance for diagnosis of malaria has been reported as excellent [ 14 , 19 , 20 , 22 , 45 - 47 ]; however, some reports from remote malaria-endemic areas have shown wide variations in sensitivity [ 36 , 40 , 48 ]. Murray and co-authors recently discussed the reliability of RDTs in an "update on rapid diagnostic testing for malaria" in their excellent paper [ 49 ]. Overall, RDTs appears a highly valuable, rapid malaria-diagnostic tool for healthcare workers; however it must currently be used in conjunction with other methods to confirm the results, characterize infection, and monitor treatment. In malaria-endemic areas where no light microscopy facility exists that may benefit from RDTs, improvements are required for ease of use, sensitivity for non-falciparum infection, stability, and affordability. The WHO is now developing guidelines to ensure lot-to-lot quality control, which is essential for the community's confidence in this new diagnostic tool [ 41 ]. Because the simplicity and reliability of RDTs have been improved for use in rural endemic areas, RDT diagnosis in non-endemic regions is becoming more feasible, which may reduce time-to-treatment for cases of imported malaria [ 30 ].
Serological tests
Diagnosis of malaria using serological methods is usually based on the detection of antibodies against asexual blood stage malaria parasites. Immunofluorescence antibody testing (IFA) has been a reliable serologic test for malaria in recent decades [ 50 ]. Although IFA is time-consuming and subjective, it is highly sensitive and specific [ 51 ]. The literature clearly illustrates the reliability of IFA, so that it was usually regarded as the gold standard for malarial serology testing [ 47 ]. IFA is useful in epidemiological surveys, for screening potential blood donors, and occasionally for providing evidence of recent infection in non-immunes. Until recently, it was a validated method for detecting Plasmodium -specific antibodies in various blood bank units, which was useful for screening prospective blood donors, so avoiding transfusion-transmitted malaria [ 52 , 53 ]. In France, for example, IFA is used as a part of a targeted screening strategy, combined with a donor questionnaire [ 54 ]. The principle of IFA is that, following infection with any Plasmodium species, specific antibodies are produced within 2 wk of initial infection, and persist for 3-6 months after parasite clearance. IFA uses specific antigen or crude antigen prepared on a slide, coated and kept at -30℃ until used, and quantifies both IgG and IgM antibodies in patient serum samples. Titers > 1 : 20 are usually deemed positive, and < 1 : 20 unconfirmed. Titers > 1 : 200 can be classified as recent infections [ 27 ]. In conclusion, IFA is simple and sensitive, but time-consuming. It cannot be automated, which limits the number of sera that can be studied daily. It also requires fluorescence microscopy and trained technicians; readings can be influenced by the level of training of the technician, particularly for serum samples with low antibody titers. Moreover, the lack of IFA reagent standardization makes it impractical for routine use in blood-transfusion centers, and for harmonizing inter-laboratory results.
MOLECULAR DIAGNOSTIC METHODS
As mentioned above, traditional malaria diagnostic methods remain problematic. New laboratory diagnostic techniques that display high sensitivity and high specificity, without subjective variation, are urgently needed in various laboratories. Recent developments in molecular biological technologies, e.g. PCR, loop-mediated isothermal amplification (LAMP), microarray, mass spectrometry (MS), and flow cytometric (FCM) assay techniques, have permitted extensive characterization of the malaria parasite and are generating new strategies for malaria diagnosis.
PCR technique
PCR-based techniques are a recent development in the molecular diagnosis of malaria, and have proven to be one of the most specific and sensitive diagnostic methods, particularly for malaria cases with low parasitemia or mixed infection [ 55 ]. The PCR technique continues to be used extensively to confirm malaria infection, follow-up therapeutic response, and identify drug resistance [ 27 ]. It was found to be more sensitive than QBC and some RDTs [ 56 , 57 ]. Concerning with the gold standard method for malaria diagnosis, PCR has shown higher sensitivity and specificity than conventional microscopic examination of stained peripheral blood smears, and now seems the best method for malaria diagnosis [ 55 ]. PCR can detect as few as 1-5 parasites/µl of blood (≤ 0.0001% of infected red blood cells) compared with around 50-100 parasites/µl of blood by microscopy or RDT. Moreover, PCR can help detect drug-resistant parasites, mixed infections, and may be automated to process large numbers of samples [ 58 , 59 ]. Some modified PCR methods are proving reliable, e.g., nested PCR, real-time PCR, and reverse transcription PCR, and appear to be useful second-line techniques when the 96 Korean J Parasitol. Vol. 47, No. 2: 93-102, June 2009 results of traditional diagnostic methods are unclear for patients presenting with signs and symptoms of malaria; they also allow accurate species determination [ 58 , 60 - 62 ]. Recently, the PCR method has become widely accepted for identifying P. knowlesi infections [ 63 - 65 ]. Although PCR appears to have overcome the two major problems of malaria diagnosis-sensitivity and specificity- the utility of PCR is limited by complex methodologies, high cost, and the need for specially trained technicians. PCR, therefore, is not routinely implemented in developing countries because of the complexity of the testing and the lack of resources to perform these tests adequately and routinely [ 66 ]. Quality control and equipment maintenance are also essential for the PCR technique, so that it may not be suitable for malaria diagnosis in remote rural areas or even in routine clinical diagnostic settings [ 67 ].
LAMP technique
The LAMP technique is claimed to be a simple and inexpensive molecular malaria-diagnostic test that detects the conserved 18S ribosome RNA gene of P. falciparum [ 68 ]. Other studies have shown high sensitivity and specificity, not only for P. falciparum , but also P. vivax , P. ovale and P. malariae [ 69 , 70 ]. These observations suggest that LAMP is more reliable and useful for routine screening for malaria parasites in regions where vector-borne diseases, such as malaria, are endemic. LAMP appears to be easy, sensitive, quick and lower in cost than PCR. However, reagents require cold storage, and further clinical trials are needed to validate the feasibility and clinical utility of LAMP [ 30 ].
Microarrays
Publication of the Plasmodium genome offers many malaria-diagnostic opportunities [ 71 , 72 ]. Microarrays may play an important role in the future diagnosis of infectious diseases [ 73 ]. The principle of the microarrays technique parallels traditional Southern hybridization. Hybridization of labeled targets divided from nucleic acids in the test sample to probes on the array enables the probing of multiple gene targets in a single experiment. Ideally, this technique would be miniaturized and automated for point-of-care diagnostics [ 23 ]. A pan-microbial oligonucleotide microarray has been developed for infectious disease diagnosis and has identified P. falciparum accurately in clinical specimens [ 74 ]. This diagnostic technique, however, is still in the early stages of development [ 30 ].
Flow cytometry has reportedly been used for malaria diagnosis [ 75 - 77 ]. Briefly, the principle of this technique is based on detection of hemozoin, which is produced when the intra-erythrocytic malaria parasites digest host hemoglobin and crystallize the released toxic heme into hemozoin in the acidic food vacuole. Hemozoin within phagocytotes can be detected by depolarization of laser light, as cells pass through a flow-cytometer channel. This method may provide a sensitivity of 49-98%, and a specificity of 82-97%, for malarial diagnosis [ 78 , 79 ], and is potentially useful for diagnosing clinically unsuspected malaria. The disadvantages are its labor intensiveness, the need for trained technicians, costly diagnostic equipment, and that false-positives may occur with other bacterial or viral infections. Therefore, this method should be considered a screening tool for malaria.
Automated blood cell counters (ACC)
An ACC is a practical tool for malaria diagnosis [ 80 ], with 3 reported approaches. The first used a Cell-Dyn® 3500 apparatus to detect malaria pigment (hemozoin) in monocytes, and showed a sensitivity of 95% and specificity of 88%, compared with the gold-standard blood smear [ 81 ]. The second method also used a Cell-Dyn® 3500, and analyzed depolarized laser light (DLL) to detect malaria infection, with an overall sensitivity of 72% and specificity of 96% [ 82 ]. The third technique used a Beckman Coulter ACC to detect increases in activated monocytes by volume, conductivity, and scatter (VCS), with 98% sensitivity and 94% specificity [ 83 ]. Although promising, none of the 3 techniques is routinely available in the clinical laboratory; further studies are required to improve and validate the instrument and its software. The accuracy these methods promise, for detecting malaria parasites, mean ACC could become a valuable and routine malaria-diagnostic laboratory method.
Mass spectrophotometry
A novel method for in vitro detection of malaria parasites, with a sensitivity of 10 parasites/µl of blood, has been reported recently. It comprises a protocol for cleanup of whole blood samples, followed by direct ultraviolet laser desorption mass spectrometry (LDMS). For malaria diagnosis, the principle of LDMS is to identify a specific biomarker in clinical samples. In malaria, heme from hemozoin is the parasite-specific biomarker of interest. LDMS is rapid, high throughput, and automated. Compared with the microscopic method, which requires a skilled microscopist and up to 30-60 min to examine each peripheral blood smear, LDMS can analyze a sample in < 1 min [ 84 ]. However, the remote rural areas without electricity are inhospitable for existing high-tech mass spectrometers. Future improvements in equipment and techniques should make this method more practicable.
Recently, other reliable malaria-diagnostic tests have been developed and introduced, and some tests are commercially available, for example, enzyme linked immunosorbent assay (ELISA)/enzyme immunoassay (EIA) [ 50 , 54 , 85 ], latex agglutination assay [ 86 ], and cultivation of live malaria parasites [ 87 , 88 ]. Post-mortem organ diagnoses, by investigating malaria parasites in tissue autopsy, e.g. liver and spleen [ 89 ], kidney [ 90 ] and brain [ 91 ], have also been described. However, parasite culture, molecular techniques, serology techniques and pathobiological diagnostic techniques, although sometimes useful in research laboratories, are not practical or appropriate for the routine clinical diagnosis of malaria. Table 1 summarizes of modalities and issues for consideration in malaria diagnosis.
Summary of modalities and issues for consideration in malaria diagnosis
PBS, peripheral blood smears; QBC, quantitative buffy coat; RDTs, rapid diagnostic tests; PCR, polymerase chain reaction; LAMP, loop-mediated isothermal amplification; FCM, flow cytometry; ACC, automated blood cell counter; MS, mass spectrometry; LDMS, laser desorption mass spectrometry.
Conventional microscopic examination of peripheral thick and thin blood smears remains the gold standard for malaria diagnosis. Although this method requires a trained microscopist, and sensitivity and specificity vary compared with recent technical advances, it is inexpensive and reliable. Quick and convenient RDTs are currently implemented in many remote settings, but are costly and need improved quality control. Serological tests are useful for epidemiological surveys, but not suitable for the diagnosis of acute malaria. Molecular-biological techniques are appropriate for research laboratories; they can be used to identify the development of drug-resistance, are useful for species identification, and also for quantifying parasite density with low parasitemia. Finally, the level of malaria endemicity, the urgency of diagnosis, the experience of the physician, the effectiveness of healthcare workers, and budget resources, are all factors influencing the choice of malaria-diagnostic method.
ACKNOWLEDGEMENTS
The authors thank Dr. Kevin C. Kain, of the McLaughlin Center for Molecular Medicine, University of Toronto, Canada, and Dr. Yaowalark Sukthana, Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, for their advice. Thanks to Mr. Paul Adams for editing the English language.
The authors declare no conflict of interest.
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Malaria 2017: Update on the Clinical Literature and Management
- Johanna P. Daily 1
Current Infectious Disease Reports volume 19 , Article number: 28 ( 2017 ) Cite this article
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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.
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.
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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 ).
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.
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.
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.
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.
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The author acknowledges Dr. Lin Hwei Chen and Dr. Margaret Aldrich for their critical reviews of the manuscript.
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Daily, J.P. Malaria 2017: Update on the Clinical Literature and Management. Curr Infect Dis Rep 19 , 28 (2017). https://doi.org/10.1007/s11908-017-0583-8
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Malaria rapid diagnostic tests: literary review and recommendation for a quality assurance, quality control algorithm.
1. Introduction
2. histidine-rich protein ( hrp2 ), 3. limitation: genetic variation, 4. limitation: persistent positivity and poor role as a test of treatment, 5. prozone and empiric treatment for severe cases, 6. low parasitemia, 8. aldolase, 9. binaxnow tm, 10. evaluation of rdts and regional recommendations, 11. quality assurance/quality control (qa/qc) recommendation, 12. emerging diagnostic technologies, 13. conclusions, author contributions, institutional review board statement, conflicts of interest, disclosures.
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Kavanaugh, M.J.; Azzam, S.E.; Rockabrand, D.M. Malaria Rapid Diagnostic Tests: Literary Review and Recommendation for a Quality Assurance, Quality Control Algorithm. Diagnostics 2021 , 11 , 768. https://doi.org/10.3390/diagnostics11050768
Kavanaugh MJ, Azzam SE, Rockabrand DM. Malaria Rapid Diagnostic Tests: Literary Review and Recommendation for a Quality Assurance, Quality Control Algorithm. Diagnostics . 2021; 11(5):768. https://doi.org/10.3390/diagnostics11050768
Kavanaugh, Michael J., Steven E. Azzam, and David M. Rockabrand. 2021. "Malaria Rapid Diagnostic Tests: Literary Review and Recommendation for a Quality Assurance, Quality Control Algorithm" Diagnostics 11, no. 5: 768. https://doi.org/10.3390/diagnostics11050768
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Open Access
Peer-reviewed
Research Article
Comparison of diagnostic performance between conventional and ultrasensitive rapid diagnostic tests for diagnosis of malaria: A systematic review and meta-analysis
Roles Conceptualization, Data curation, Formal analysis, Methodology, Software, Writing – original draft, Writing – review & editing
* E-mail: [email protected]
Affiliations Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran, Department of Biology, Faculty of Natural and Computational Sciences, Woldia University, Woldia, Ethiopia
Roles Supervision, Writing – review & editing
Affiliations Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran, Centers for Research of Endemic Parasites of Iran (CREPI), Tehran University of Medical Sciences, Tehran, Iran
Roles Methodology, Software
Affiliations Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran, Department of Medical Parasitology and Mycology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
- Yonas Yimam,
- Mehdi Mohebali,
- Mohammad Javad Abbaszadeh Afshar
- Published: February 10, 2022
- https://doi.org/10.1371/journal.pone.0263770
- Reader Comments
Successful malaria treatment, control and elimination programs require accurate, affordable, and field-deployable diagnostic tests. A number of studies have directly compared diagnostic performance between the new ultrasensitive rapid diagnostic test (us-RDT) and conventional rapid diagnostic test (co-RDT) for detecting malaria. Thus, we undertook this review to directly compare pooled diagnostic performance of us-RDT and co-RDT for detection of malaria.
PubMed, Web of Science, Scopus, Embase, and ProQuest were searched from their inception until 31 January 2021 accompanied by forward and backward citations tracking. Two authors independently assessed the quality of included studies by RevMan5 software (using the QUADAS-2 checklist). Diagnostic accuracy estimates (sensitivity and specificity and others) were pooled using a random-effect model and 95% confidence interval (CI) in Stata 15 software.
Fifteen studies with a total of 20,236 paired co-RDT and us-RDT tests were included in the meta-analysis. Molecular methods (15 studies) and immunoassay test (one study) were used as standard methods for comparison with co-RDT and us-RDT tests. The pooled sensitivity for co-RDT and us-RDT were 42% (95%CI: 25–62%) and 61% (95%CI: 47–73%), respectively, with specificity of 99% (95%CI: 98–100%) for co-RDT, and 99% (95%CI: 96–99%) for us-RDT. In asymptomatic individuals, the pooled sensitivity and specificity of co-RDT were 27% (95%CI: 8–58%) and 100% (95%CI: 97–100%), respectively, while us-RDT had a sensitivity of 50% (95%CI: 33–68%) and specificity of 98% (95%CI: 94–100%). In low transmission settings, pooled sensitivity for co-RDT was 36% (95%CI: 9 76%) and 62% (95%CI: 44 77%) for us RDT, while in high transmission areas, pooled sensitivity for co RDT and us RDT were 62% (95%CI: 39 80%) and 75% (95%CI: 57–87%), respectively.
The us-RDT test showed better performance than co-RDT test, and this characteristic is more evident in asymptomatic individuals and low transmission areas; nonetheless, additional studies integrating a range of climate, geography, and demographics are needed to reliably understand the potential of the us-RDT.
Citation: Yimam Y, Mohebali M, Abbaszadeh Afshar MJ (2022) Comparison of diagnostic performance between conventional and ultrasensitive rapid diagnostic tests for diagnosis of malaria: A systematic review and meta-analysis. PLoS ONE 17(2): e0263770. https://doi.org/10.1371/journal.pone.0263770
Editor: Michelle L. Gatton, Quensland University of Technology, AUSTRALIA
Received: May 4, 2021; Accepted: January 26, 2022; Published: February 10, 2022
Copyright: © 2022 Yimam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Alongside the scale-up of malaria prevention and treatment interventions, tremendous progress has made in reducing global malaria cases incidence and malaria deaths, such that between 2000 and 2015, malaria incidence rates fell 41% globally, malaria mortality rates were reduced by 62% and 17 countries eliminated malaria [ 1 ]. Bolstered by these remarkable gains, Global Technical Strategy for malaria (2016–2030) develops goals to eliminate malaria by 2030 from at least 35 countries in which malaria was transmitted in 2015 and reduce global malaria incidence by 90% compared to 2015 [ 2 ]. In this context, active malaria case detection are a key component and this requires diagnostic tools capable of detecting low parasitemic infections in low endemicity regions and asymptomatic infections in high transmission settings [ 3 ].
Microscopic examination of peripheral blood smear for the presence of Plasmodium parasite remains the mainstay of malaria diagnosis; nonetheless, it has low sensitivity for detecting low- density parasitemia [ 4 – 6 ]. Also, microscopy needs trained personnel and sufficient laboratory reagents and equipment [ 7 ]. While nucleic acid amplification-based diagnostic tests can diagnose low-density infection, they are impractical for use in resource-constrained settings due to the need for sophisticated laboratory facilities, high-cost and highly trained staff [ 8 ]. Conventional malaria rapid diagnostic tests (co-RDTs) are easy to use, low-cost, rapid, and field deployable tool for the detection of malaria antigens, but co-RDTs have limitation for the detection of low density and asymptomatic malaria infections [ 9 ]. For successful malaria control and elimination, routine surveillance of low-density infections is crucial and this requires highly sensitive and field- deployable tests [ 3 ].
New malaria detection test, such as Alere™ Ultra-sensitive Malaria Ag P . falciparum RDT (us-RDT) test, has been recently developed for the detection of low malaria parasite density [ 10 ]. This us-RDT test, similar to many co-RDT tests, is designed in an immunochromatographic strip platform to detect histidine-rich protein 2(HRP2), but with improved analytical sensitivity (i.e. a detection threshold lower than co-RDTs) [ 11 ]. Various studies have assessed diagnostic performance of us-RDT and co-RDT for the detection of malaria in the same study population [ 12 – 16 ]. These studies demonstrated a wild discrepancy in the magnitude of us-RDT performance compared to co-RDT; considerable studies highlighted us-RDT outperform co-RDT with different magnitudes [ 12 , 13 , 15 , 17 ], whereas one single study found no difference in sensitivity of us-RDT compared to co-RDT [ 16 ]. A systematic review and meta-analysis was carried out recently [ 18 ]; however, this meta-analysis had missed studies [ 10 , 12 , 19 , 20 ] and did not evaluate diagnostic accuracy of us-RDT and co-RDT in relation to malaria transmission settings. Therefore, this review was conducted to establish summary estimates of us-RDT diagnostic performance compared to co-RDT, taking into account missed studies and malaria transmission settings.
This systematic review and meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses of Diagnostic Test Accuracy studies (PRISMA-DTA) guidelines and Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy [ 21 ]. PRISMA Checklist is presented in Supplementary information ( S1 Checklist ).
Data sources and searches
We systematically searched the following databases; PubMed, Web of Science, Scopus, Embase, and ProQuest, from the earliest available dates of indexing through 31 January 2021. The searches were restricted to the English language. The search strategies were based on all possible combinations of the following Medical Subject Headings (MeSH) terms and keywords; ’’Infection, Plasmodium ’’, ’’Plasmodium Infections’’, ’’malaria’’, ’’ultra-sensitive’’, ’’ultrasensitive’’, ’’highly-sensitive’’, ’’ highly sensitive’’, ’’high-sensitive’’, ’’high sensitive’’, ’’diagnosis’’, ’’ rapid diagnostic test’’, ’’detection ’’, ’’rapid diagnosis’’, and ’’rapid test ’’. Additionally, we manually secerned reference lists of eligible studies and relevant reviews and forward citations tracking using Google Scholars. When there were incomplete data for the 2x2 table, we contacted the corresponding authors through email. The description of the exact search is available in S1 File .
Eligibility criteria and studies selection
In this study, we included studies that fulfill the following criteria; i) original studies that directly compare diagnostic test accuracy us-RDT and co-RDT in the same population, (ii) studies directly compare diagnostic test accuracy of us-RDT and co-RDT with reference standard tests, (iii) studies that contain data for 2X2 table completion (True Positive (TP), False Positive (FP), False Negative (FN), True Negative (TN)). The following types of studies were excluded; i) studies reported diagnostic accuracy of only us-RDT or co-RDT, but not both, ii) relevant full-text studies with inadequate data for 2X2 tables after two email contact of corresponding authors, iii) non-original studies, such as reviews, conference papers, and letters.
Records obtained using literature searches were kept in EndNote X 8 and the selection of eligible studies was conducted independently by two authors (YY and MJA) based on pre-determined eligibility criteria. First, we removed duplicate studies and then we reviewed titles and abstracts of the remaining studies. Secondly, titles and abstracts not pertinent to the objectives of this study were removed. Following the removal of duplicate records and titles and abstracts screening, full-text of the remaining studies were thoroughly reviewed and ineligible studies were further removed. Fourthly, data were extracted from full-text studies that met eligible criteria. Disagreements between two authors were resolved through discussion.
Data extraction and quality assessment
Data extraction format was prepared to compile data from eligible studies. For each study, we extracted information such as study author/s and year, country where the study conducted, level of malaria endemicity, (low or/and medium or/and high transmission settings), study population(asymptomatic or/and symptomatic), reference and index tests, and complete data for 2X2 table (TP, TN, FP, FN). Each country classified a territory or geographic area based on confirmed malaria cases in a particular year, characterized as low, medium, or high malaria intensity transmission per 1,000 people under surveillance [ 22 ]. Consequently, we recorded low, medium, or high malaria transmission based on the reported stratification/classification of malaria endemicity in the included studies. When the data were insufficient to complete the 2X2 table, corresponding authors were contacted through email to acquire masked data. Data extraction was carried out independently by two authors (YY and MJA) and the discrepancy was resolved by consensus.
Quality assessment
For quality assessment, we used the revised tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) [ 23 ]. The QUADAS‐2 tool includes four key domains; (1) patient selection, (2) index test, (3) reference standard, and (4) flow and timing. Review Manager 5(RevMan 5.4.1) was used to generate the risk of bias summary and graph. Two authors (YY and MJA) independently assessed the quality of included studies using the QUADAS‐2 tool and any disagreement was resolved through consensus.
Data analysis
We constructed 2X2 contingency tables consisting of TP, TN, FP, and FN. We calculated pooled diagnostic measures, including sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio by STATA version 15 software using midas commands. Between studies heterogeneity was examined using Cochrane’s Q test and quantified with the inconsistency (I 2 ) test, using a random-effects model. Summary receiver operating characteristic (SROC) was drawn and the area under the summary receiver operating characteristic curve (AUC) was calculated to estimate overall test performance. We also performed subgroup analysis based on the level of malaria endemicity. Publication bias was evaluated using Deeks funnel plot asymmetry test [ 24 ].
Search results and basic characteristics of included studies
A total of 1687 records were retrieved from database searches, of which 633 were duplicate records. After the exclusion of duplicate records, the remaining records (1055) were screened for titles and abstracts and 13 of these were removed due to the unavailability of their abstracts. 1042 studies were left for full-text evaluation, and 1027 of these were removed with reasons. The most prominent reasons for exclusion are as follow: no report of RDT in studies (531), studies not evaluated diagnostic test accuracy (235), studies are not related to malaria (110), and studies assessed the performance of only co-RDT or only us-RDT rather than both tests (65) ( Fig 1 ). As a result, 15 studies were selected for the present study. Additional searches of reference lists of selected studies and relevant reviews resulted in the inclusion of one additional study [ 25 ]. Overall, a total of 16 studies (conducted in 17 malaria transmission settings) were included in the final quantitative synthesis.
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https://doi.org/10.1371/journal.pone.0263770.g001
The basic characteristics of the included studies are presented in S1 Table . All included studies were conducted from 2017 to 2021. In total, 20,236 paired co-RDT and us-RDT tests were compared with standard methods. Seven, five, and two included studies, respectively, were based on asymptomatic populations only, both symptomatic and asymptomatic populations, and symptomatic populations only, whereas two studies did not report the clinical status of the study populations. All included studies are from 11 countries: Myanmar (3 studies) [ 10 , 25 , 26 ], Tanzania (2 studies) [ 14 , 27 ], Colombia (2 studies) [ 12 , 28 ], Uganda (2 studies) [ 10 , 19 ] and one each in Mozambique [ 29 ], Haiti [ 30 ], Indonesia [ 31 ], Cambodia [ 16 ], Ethiopia [ 15 ], Benin [ 32 ], and Papua New Guinea [ 13 ]. Seven studies were carried out in each of high and low endemicity region, two studies in medium endemicity region and one in moderate and high endemicity. All included studies used the same brand of us-RDT (Alere™ Malaria Ag P.f Ultra-Sensitive rapid diagnostic test). Standard methods used for comparison with conventional and ultrasensitive tests were quantitative Polymerase Chain Reaction (PCR) (9 studies), nested PCR (6 studies), and HRP2 bead-based immunoassay (one study). Gene targets for molecular methods were 18s ribosomal RNA, var gene sequences, 18s ribosomal DNA and genomic DNA in, eight, two, one, and one studies, respectively, while gene targets for molecular methods were not reported in four included studies.
Methodological quality of included studies
As pointed out in the risk of bias and applicability concerns graph ( Fig 2A ) and summary ( Fig 2B ), the overall quality of included studies was adequate. Low risk of bias for participants’ selection was observed in 93.75% of included studies, while the reaming 6.25% of studies showed an unclear risk of bias. The quality of confirmation of reference methods and the use of index testes were considered sufficient in 97% of studies. None of the included is case-control. Seven out of fifteen included studies did not provide information about the selection of study participants.
A. Risk of bias and applicability concerns graph of included studies that compared diagnostic performance of co-RDT and us-RDT in the same populations, between 2017 and 2021. B. Risk of bias and applicability concerns summary of included studies that compared diagnostic performance of co-RDT and us-RDT in the same populations, from 2017 to 2021.
https://doi.org/10.1371/journal.pone.0263770.g002
Meta-analysis
Diagnostic accuracy of co-rdt and us-rdt for the detection of malaria..
co-RDT sensitivity ranged from 15% (95%CI: 3–38%) to 94% (95%CI: 91–96%), while us-RDT sensitivity ranged from 20% (95%CI: 14–27%) to 95% (95%CI: 92–97%), with specificity ranged from 71% (95%CI: 29–96%) to 100% (95%CI: 99.9–100%) and from 29% (95%CI: 4–71%) to 100% (95%CI: 99–100%) for co-RDT and us-RDT, respectively. The pooled sensitivity were 42% (95%CI: 25–62%) for co-RDT, 61% (95%CI: 47–73%) for us-RDT and specificity were 99% (95%CI: 98–100%) for co-RDT, 99% (95%CI: 96–99%) for us-RDT ( Figs 3 and 4 ). The pooled estimates for the positive likelihood ratio (PLR), negative likelihood ratio(NLR), and diagnostic odds ratio(DOR) for co-RDT were 61.8 (95%CI: 21.5–177.5), 0.58 (95%CI: 0.41–0.82) and 106 (95%CI: 36–328), respectively, and the overall PLR, NLR, and DOR for us-RDT were 42.3 (95%CI: 17.9–99.7), 0.40 (95%CI: 0.28–0.55) and 107 (95%CI: 45–253), respectively. The AUC for co-RDT and us-RDT were 0.94 (95%CI: 0.92–0.96) and 0.93 (95%CI: 0.90–0.95), respectively.
https://doi.org/10.1371/journal.pone.0263770.g003
https://doi.org/10.1371/journal.pone.0263770.g004
High heterogeneity of sensitivity and specificity were observed in co-RDT (Q = 742.42, I 2 = 97.98, P<0.001 and Q = 351.94, I 2 = 95.71, P<0.001, respectively) and us-RDT (Q = 554.79, I 2 = 97.3, P<0.001 sensitivity and Q = 652.13, I 2 = 97.70, P<0.001 for specificity, respectively) tests. Sub-group analysis were carried out based on reference tests used and level of malaria endemicity. In low transmission settings, pooled sensitivity for co-RDT was 36% (95%CI: 9–76%) and 62% (95%CI: 44–77%) for us-RDT, while in high transmission areas, pooled sensitivity for co-RDT and us-RDT were 62% (95%CI: 39–80%) and 75% (95%CI: 57–87%), respectively ( Table 1 ). When nested-PCR and quantitative-PCR used as reference tests, the sensitivity and specificity of co-RDT were 51% (95%CI: 10.37–65%) and 99% (95%CI: 96–100%) and 28% (95%CI: 11–57%) and 100% (95%CI: 97–100%), respectively. The sensitivity and specificity of us-RDT when nested-PCR and quantitative-PCR used as a reference tests was 56% (95%CI: 37–74%) and 99% (95%CI: 97–100%) and 58% (95%CI: 42–72%) and 99% (95%CI: 94–100%), respectively. The Deeks’ funnel plot asymmetry test of DOR did not show substantial asymmetry (P = 0.17 for co-RDT and P = 0.18 for us-RDT), pinpointing that there could be no detectable publication bias ( Figs 5 and 6 ).
ESS; effective sample size. P value <0.005 were considered significant.
https://doi.org/10.1371/journal.pone.0263770.g005
https://doi.org/10.1371/journal.pone.0263770.g006
https://doi.org/10.1371/journal.pone.0263770.t001
Diagnostic accuracy of co-RDT and us-RDT for the detection of asymptomatic and symptomatic malaria.
A total of eight studies assessed the diagnostic accuracy of co-RDT and us-RDT in the same asymptomatic study population. The pooled sensitivity and specificity of co-RDT was 27% (95%CI: 8–58%) and 100% (95%CI: 97–100%) ( Fig 7 ), respectively, while us-RDT had a sensitivity 98% (95%CI: 94–100%) and specificity of 50% (95%CI: 33–68%) ( Fig 8 ), respectively. The AUC was 90% (95%CI: 87–92%) in co-RDT test and 86% (95%CI: 83–89%) in us-RDT test. In symptomatic populations, co-RDT sensitivity and specificity was 69% (95%CI: 65–72%) and 99% (95%CI: 99–100%), respectively, while us-RDT sensitivity and specificity was 73% (95%CI: 69–76%) and 99% (95%CI: 99–100%), respectively ( Table 1 ).
https://doi.org/10.1371/journal.pone.0263770.g007
https://doi.org/10.1371/journal.pone.0263770.g008
As many countries progress from malaria control to elimination, ultrasensitive and field-deployable diagnostic tests that are capable of detecting both symptomatic and asymptomatic plasmodium infections are of paramount importance to guide and measure the success of elimination strategies [ 3 , 33 ]. In light of this, efforts have been made to develop highly sensitive diagnostic tests, including recently developed highly sensitive RDT (Alere™ Malaria Ag Pf ultra-sensitive RDT) [ 34 ]. Various studies have assessed diagnostic accuracy of the newly developed highly sensitive RDT and conventional RDT testes. This review, therefore, was undertaken to estimate pooled diagnostic test accuracy of co-RDT and us-RDT in the same study populations. In this review, us-RDT (61% (95%CI: 47-73%) showed better pooled sensitivity than co-RDT (42% (95%CI: 25-62%)), while similar pooled specificity were observed between co-RDT and us-RDT (99% (95%CI: 98–100%) for co-RDT vs. 99% (95%CI: 96–99%) for us-RDT). It was found that the pooled sensitivity of us-RDT test was better than co-RDT in low malaria transmission settings (62% (95%CI: 44–77%) for us-RDT vs. 36% (95%CI: 9–76%) for co-RDT) and asymptomatic study population (50% (95%CI: 33–68%) for us-RDT vs. 27% (95%CI; 8–58%) for co-RDT).
Our systematic review and meta-analysis revealed improved sensitivity of us-RDT compared to co-RDT; however, high heterogenity in sensitivity across included studies was observed, which could be related to variations in clinical status of study populations, age of study participants, parasite density and endemicity of malaria in study areas. In a study conducted among pregnant women in Benin, the sensitivity of co-RDT(44.2%) and us-RDT(60.5%) were shown to be similar [ 32 ]. Primary studies carried out in Ethiopia (7.3% for co-RDT vs.50% for us-RDT) [ 15 ], and Papua New Guinea (15% for co-RDT vs. 27% for us-RDT) [ 13 ] demonstrated lower sensitivity compared to this meta-analysis. Conversely, the pooled sensitivity of this review was lower than the sensitivity of studies conducted in Indonesia (62% for co-RDT vs. 84% for us-RDT) [ 31 ] and Colombia (64.3% for co-RDT vs.71.4%uRDT) [ 12 ]. The discrepancy in the sensitivity may be related to the difference in the endemicity of malaria in studies, study population, sample size and reference methods.
Malaria transmission intensity is stratified for a given country, territory, or geographic area based on confirmed malaria cases in a specific year, expressed per 1,000 population under surveillance. According to WHO indicative metrics of malaria transmission intensity, areas of high transmission are characterized by an annual parasite incidence of about 450 or more cases per 1000 population and P . falciparum prevalence rate of ≥35%, while low transmission have an annual parasite incidence of 100–250 cases per 1000 population and a prevalence of P . falciparum/P . vivax of 1–10% [ 22 ] Nonetheless, each country can conduct a stratification to classify geographical units according to local malaria transmission [ 22 ]. For detecting low density infection and monitoring malaria transmission in low-transmission areas, more sensitive diagnostic tests are required [ 36 ]. Currently available commercial co-RDTs are not capable of detecting malaria in endemic areas with a parasite density of 100,000 parasites/ml, however us-RDT is.
In malaria elimination campaign, asymptomatic individuals harbor Plasmodium parasites with no overt clinical signs and low level of parasite density, making difficult to detect using co-RDTs [ 35 ]. To bridge this gap, us-RDT test was introduced to be able to able to detect more asymptomatic infection below 200 p/μl parasite density [ 34 ]. The pooled sensitivity of us-RDT in asymptomatic individuals in this study was 1.85 fold higher than co-RDT test. The specificities of the two tests were similar (100% for co-RDT and 98% for us-RDT). A study conducted among asymptomatic individuals from Myanmar revealed that us-RDT detected 2- fold more Plasmodium infections than co-RDT [ 25 ]. A significant proportion of asymptomatic individuals harbor the lowest parasite density, as low as 1000 parasites per ml, which is below the limit of detection threshold of commonly used RDTs(with low a lower detection limit of 100,000 parasites per ml) [ 36 , 37 ]. As a result, studies using conventional RDTs, which are capable of detecting parasite density exceeding 100,000 parasites/ml may fail to detect some proportions of Plasmodium infection, thus the diagnostic performance of co-RDT reduce [ 34 ]. The possible superior performance of us-RDT to co-RDT for detecting asymptomatic malaria infection may result from the improved performance of us-RDT, with a capacity to detect 100–10,000 p/ml [ 34 ].
This study had some limitations. First, considerable heterogenity among included studies was observed. To explore the existing source of heterogeneity, we performed sub-group analysis based on reference standards and level of malaria endemicity; nevertheless, we failed to find the factor responsible for heterogeneity. Second, all included studies are from a limited number of countries (11 countries). Third, literature searches were performed only in English, which may introduce language bias. Fourth, due to the lack of adequate information, subgroup analysis based on other factors such as age, sex, and parasite density were not explored. Fifth, this review protocol was not registered in PROSPERO since we have initiated literature searches prior to protocol registration.
In conclusion, this review confirmed higher overall performance of us-RDT, compared to co-RDT, to detect Plasmodium infections. Considerably higher pooled sensitivity of us-RDT observed particularly for detection of malaria in areas of low transmission settings and asymptomatic individuals, suggesting the superior performance of us-RDT to co-RDT for surveillance of asymptomatic malaria asymptomatic individuals that are key for malaria elimination. Taking into account substantial heterogenity across included studies, further large-scale, well-designed, and multi-center studies including various study participants symptoms, age, sex, parasite density, and malaria transmission settings of the study areas are needed to reliably understand the true performance of us-RDT test for malaria surveillance.
Supporting information
S1 table. the basic characteristics of the included studies that compared diagnostic performance of co-rdt and us-rdt in the same populations, 2017 to 2021..
https://doi.org/10.1371/journal.pone.0263770.s001
S1 Checklist. PRISMA diagnostic test accuracy checklist.
PRISMA-DTA guideline.
https://doi.org/10.1371/journal.pone.0263770.s002
S1 File. Search strategies to retrieve as many studies as possible that compared diagnostic performance of co-RDT and us-RDT in the same populations, 2021.
https://doi.org/10.1371/journal.pone.0263770.s003
- 1. WHO. Global technical strategy for malaria 2016–2030: World Health Organization; 2015. Available from: https://www.who.int/docs/default-source/documents/global-technical-strategy-for-malaria-2016-2030.pdf .
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