Improved patient care with better malaria diagnosis

The vast majority of diagnoses in Sub-Saharan Africa are based on clinical findings. In effect, this means that a patient presenting with fever or a history of fever will be assumed to have malaria, and treated accordingly. Whilst this strategy was appropriate in an era when malaria transmission was intense, and the treatment, chloroquine, was known to be safe, efficacious, readily available and inexpensive, the situation has now changed. Reports from several countries suggest that the intensity of transmission is declining and, as a result, malaria may not always be the predominant, or exclusive cause of fever [1–4]. Furthermore, the first-line treatment of malaria is increasingly artemisinincombination therapy (ACT), which is relatively expensive and only fully cost-effective if targeted at patients who have confirmed Plasmodium falciparum infection [5]. The need to maximize the cost–effectiveness of malaria treatment and the changing epidemiology of the disease are compelling reasons to improve diagnostics. In addition, robust diagnostic strategies are necessary in order to monitor disease burden, and to evaluate the impact of malaria control strategies [101]. There are therefore many good, malaria-based reasons to improve the diagnosis of plasmodial infections. In addition, the observation of a higher inpatient case-fatality rate in admitted patients treated for malaria, but found to have a negative malaria test [6], suggests that the confident exclusion of malaria as a diagnosis, by stimulating the search for nonmalaria diagnoses, will improve the case-management of nonmalaria febrile illness [7]. The 2009 WHO malaria case-management guidelines recommend the confirmation of malaria through parasite-based diagnosis in all patients prior to the start of treatment. This is standard practice in five of the six WHO regions, but not in Africa where over 75% of diagnoses are presumptive [102]. Prompt parasitological confirmation by microscopy or rapid diagnostic tests (RDT) is recommended in all patients suspected of having malaria before treatment is started. Treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible. This push towards universal parasitological diagnosis will require major re-orientation of malaria control programs, and consideration of funding mechanisms to facilitate adequate malaria diagnosis prior to treatment. This has implications for training, supervision, logistics, monitoring and quality control.


Improved patient care with better malaria diagnosis
The vast majority of diagnoses in Sub-Saharan Africa are based on clinical findings. In effect, this means that a patient presenting with fever or a history of fever will be assumed to have malaria, and treated accordingly. Whilst this strategy was appropriate in an era when malaria transmission was intense, and the treatment, chloroquine, was known to be safe, efficacious, readily available and inexpensive, the situation has now changed. Reports from several countries suggest that the intensity of transmission is declining and, as a result, malaria may not always be the predominant, or exclusive cause of fever [1][2][3][4]. Furthermore, the first-line treatment of malaria is increasingly artemisinincombination therapy (ACT), which is relatively expensive and only fully cost-effective if targeted at patients who have confirmed Plasmodium falciparum infection [5]. The need to maximize the cost-effectiveness of malaria treatment and the changing epidemiology of the disease are compelling reasons to improve diagnostics. In addition, robust diagnostic strategies are necessary in order to monitor disease burden, and to evaluate the impact of malaria control strategies [101]. There are therefore many good, malaria-based reasons to improve the diagnosis of plasmodial infections. In addition, the observation of a higher inpatient case-fatality rate in admitted patients treated for malaria, but found to have a negative malaria test [6], suggests that the confident exclusion of malaria as a diagnosis, by stimulating the search for nonmalaria diagnoses, will improve the case-management of nonmalaria febrile illness [7].
The 2009 WHO malaria case-management guidelines recommend the confirmation of malaria through parasite-based diagnosis in all patients prior to the start of treatment. This is standard practice in five of the six WHO regions, but not in Africa where over 75% of diagnoses are presumptive [102]. Prompt parasitological confirmation by microscopy or rapid diagnostic tests (RDT) is recommended in all patients suspected of having malaria before treatment is started. Treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible. This push towards universal parasitological diagnosis will require major re-orientation of malaria control programs, and consideration of funding mechanisms to facilitate adequate malaria diagnosis prior to treatment. This has implications for training, supervision, logistics, monitoring and quality control.
"…confident exclusion of malaria as a diagnosis, by stimulating the search for nonmalaria diagnoses, will improve the case-management of nonmalaria febrile illness."

Diagnostic approaches for malaria
The classical approach to malaria diagnosis is by means of a blood smear stained with Giemsa or Fields stains. Thick films are used for routine diagnosis in many settings, though carefully prepared thin films are needed for speciation. There is some discussion over the optimal approach to determining parasite densities in research settings, where multiple readings of a slide are usually performed, and agreement-based criteria are applied to determine whether a third reading should be performed, as well as how the results should be manipulated to generate a definitive parasite density. Microscopy has the potential to afford additional benefits, compared with other diagnostic methods, when optimally performed. Hemozoin quantitation in neutrophils and monocytes is a prognostic marker, particularly in young children in endemic areas [8], as is the detection of circulating P. falciparum schizonts, which warn of progression to severe disease. Microscopy can also be used to diagnose infections with blood-dwelling helminths, and the use of differential white cell counts can help identify viral and bacterial infections. However, the reading of blood slides requires a functioning microscope and skilled microscopist which, for health facilities that are often located in remote and rural settings, may be challenging in terms of availability, affordability, quality control and maintenance. Realistically, it may only be feasible to retain expert malaria microscopy in major hospitals and reference centers in much of the malaria endemic and nonendemic world. The challenge of making molecular technology available in remote settings precludes its widespread adoption for routine diagnosis in most settings. The Foundation for Innovative New Diagnostics (FIND) [104] is working with the WHO and many in-country partners in Africa, Southeast Asia and South America to support research into malaria RDTs, as well as novel diagnostic products, including heat-stable point-of-care tests, and highly sensitive tests for malaria endemic countries.

Rapid diagnostic tests
The development of RDTs in recent years has created the potential to revolutionize malaria diagnosis. Inexpensive, self-contained, singleuse, disposable tests have been developed that detect, with reasonable sensitivity and specificity [105], the presence of P. falciparum and, depending on the test, P. vivax and other plasmodia, in the blood. The tests generally require a drop of blood to be placed on a disposable cassette, a few drops of buffer to be added, and the test then read after a defined period of time (e.g., 15 min). A control line appears to confirm that the test has worked, and the test is positive if a second line appears. Two broad groups of tests exist: those detecting species-specific parasite lactate dehydrogenase (pLDH) and those detecting the P. falciparum-specific histidinerich-protein (HRP)-2, often combined with pan-specific plasmodial aldolase ('panmalarial antigen'). pLDH-based tests have the advantage of becoming negative once the infection has been successfully treated, enabling an assessment to be made of the efficacy of the treatment. In contrast, HRP-2 may remain detectable in the circulation for more than a month after an active infection has been cured, resulting in reduced specificity of HRP-2-based tests, especially in high-transmission settings. Currently available RDTs are not able to indicate parasite density. RDTs are relatively quick and simple to use, but their cost, at US$0.6-1.5 per test [10,106], is an important consideration, as are issues of quality control, including lot testing and the development of positive control wells, the safe disposal of used tests and related paraphernalia, appropriate storage and delivery of tests, staff training and capacity of the health staff and health system to appropriately manage positive and negative results [11].
Recent years have seen progress with improved intra-and inter-batch quality and shelf life under tropical conditions, but there is still a need to identify further suitable antigens to improve on Plasmodium ovale, Plasmodium vivax and, possibly, Plasmodium knowlesi diagnosis. The performance of RDTs has been evaluated in a number of reviews, although only recently has a comprehensive assessment been completed [105], and some of the public health issues and possible impact on malaria management as a whole been taken into account [12,13]. Despite existing technical limitations, RDTs have the potential to reduce overtreatment of malaria and improve the management of nonmalaria febrile illness.

Compliance with malaria diagnostic test results
Reyburn and colleagues [6] drew attention to the major overtreatment of malaria in Northern Tanzania, a phenomenon documented in several other settings [14,15]. Working in an environment where blood-slide microscopy was available, Reyburn found that approximately half of the patients with a negative blood slide were nevertheless treated with antimalarial drugs. future science group Such prescribing practice has been attributed to concerns over the quality of blood-slide results, recognizing the absence of external quality assurance mechanisms and the possibility of 'slide-negative' malaria. A subsequent controlled trial randomized individuals to receive a diagnostic test with either microscopy or an RDT and monitored prescribers' practice [16]. The prescribers and patients were aware that a single line on the RDT cassette indicated a negative result and a double line reflected a positive result. Surprisingly, even with these relatively clear diagnostic test results, approximately half of those with a negative malaria test result were still prescribed an antimalarial drug. Subsequent work has suggested that the poor compliance to test results may be due to perceived patient pressure [17][18][19]. Traditionally, antimalarials have been inexpensive and safe, and it has been common practice to make presumptive diagnoses and provide antimalarial treatment. It is likely to take a concerted behavior change communication program directed at prescribers and communities to change these common practices. It is important to be realistic about the likely timeframe involved: campaigns have been running for decades in Europe and North America to reduce unnecessary prescribing of antibiotics to patients presenting with viral conditions.

Access to antimalarial treatment & diagnosis
A large proportion, sometimes the majority, of antimalarial treatments are obtained through the private sector. In many settings, a local shop will be a more immediately available source of antimalarial treatment than the local health facility. In order to improve access to ACTs, a global subsidy -The Affordable Medicines Facility for Malaria (AMFm) [107] -will facilitate the availability of inexpensive, quality anti malarial treatments in both the public and private sectors. Studies are underway to explore the feasibility of also introducing RDTs into the private sector, for example at licensed drug shops, and at the community level, in settings where home-based management of fever is being deployed [108]. It will be necessary to address financing issues of the diagnostic tests in these settings in order to ensure an incentive exists to perform a test before dispensing malaria treatment.

Conclusion
Universal parasitological diagnosis prior to treatment will need RDT deployment in a sustainable, quality-assured and safe manner, accompanied by adequate behavior-change communication programs that target prescribers' behavior and communities' acceptance of a negative malaria test result. Trials are underway to explore the feasibility of, and to generate operational experience on, these critical issues.  Improved patient care with better malaria diagnosis Editorial