Mark D Perkins; David R Bell

“ Malaria control has recently seen a long-overdue resurgence in interest and funding, a belated recognition that malaria is still dominating the lives and health of millions, and holding whole populations in poverty. In places where these renewed efforts have been systematically applied, insecticide-treated bed nets, indoor residual spraying, and artemisinin-based combination therapy (ACT) have demonstrated their capacity to reduce both incidence and mortality from malaria. ”

“ Sustained malaria control will depend on the global capacity to accurately detect malaria and map its distribution. The specific detection of malaria parasites is now possible even at the village level with high quality rapid diagnostic tests. Driven by the extent of over-diagnosis and misdiagnosis of malaria when syndromic approaches are used, global efforts are underway to increase the utilization of parasite-based diagnosis, and to ensure the quality of tests that are used. ”

“ While standards vary and microscopy remains invaluable for diagnosis, parasite quantitation and treatment monitoring where good standards can be maintained, ensuring the quality of microscopy as a system-wide approach has proved beyond the capability of most malaria control programmes.
For these reasons the development, in the early 1990s, of lateral flow immunochromatographic tests that could detect malaria parasite antigens in a fingerprick blood sample was a major advance [20] , [21] . ”

“ A drive towards malaria elimination will increase the need for broad use of quality assured diagnostics for malaria, and possibly the development of novel assays to address specific needs such as the sensitivity at low parasite densities and minimal invasiveness required for population-based surveys for parasite reservoirs. The imperative for parasitologic diagnosis will be dramatically increased where malaria incidence falls, and where reflex treatment of fever with antimalarial drugs would be ineffective and even harmful in the vast majority of cases. ”

“ Overdiagnosis of malaria and fever mismanagement
Unfortunately, the clinical presentation of malaria is highly variable and overlaps with that of a number of other common illnesses, including pneumonia, which are associated with significant morbidity and mortality [3] , [4] . Attempts to develop clinical scoring systems with high predictive values have largely been unsuccessful [ [5] - [6] , and health workers without access to tools for parasite-based diagnosis often manage most or all fevers as malaria. ”

“ Without clear and detailed evidence of the impact of donor spending on malaria case rates and geographic distribution, donors cannot be expected to continue to fund control campaigns. The Global Polio Eradication Initiative, spearheaded by WHO, Rotary International, the US CDC and UNICEF, has spent more money since it missed its goal of eradicating polio by the year 2000 than in the years leading up to that milestone. ”

“ At a societal level, mismanagement of fever erodes patient's faith in the health system, wastes drug resources, augments drug pressure toward resistance [ [14] , and contributes to ignorance of the true causes of illness in these populations. In the face of this, it should be disturbing that less than 20% of suspected malaria cases receive a confirmatory diagnosis in 75% of African countries [ [10] .
High mortality at 10 Tanzanian hospitals among patients admitted with severe disease and treated for malaria. ”

“ This momentum has been captured by a new call for malaria elimination. Without wide implementation of accurate and discriminating diagnostic testing, and reporting of results, most fever will be inappropriately managed, millions of doses of ACT will be wasted, and malaria control programmes will be blindfolded to the impact of their efforts. ”

“ Global sales of malaria RDTs are thought to surpass 70 million tests a year. From a single manufacturer in 1993, there are now dozens of diagnostics companies manufacturing or re-branding malaria RDTs. There are several sources of monoclonal antibodies against the common antigen targets, and companies making lateral flow tests for other indications such as pregnancy testing, screening for illicit drugs or diagnosis of infectious diseases can, without much difficulty or expense, add malaria to their test portfolio. ”

“ Malaria misdiagnosis and subsequent mis-management has individual as well as societal repercussions. At the individual level, misdiagnosis results in wasted resources on drug purchase, especially in the private sector, exposure to drug side effects, and most importantly morbidity due to improper management of the true cause of fever. ”

“ More expensive artemisinin combination therapy (ACT) has been widely introduced, simple immunochromatographic tests for malaria have been developed that can be used as an alternative to microscopy by village health workers, and recognition of the health cost of mismanaging non-malarial fever is growing. In most of the world a small fraction of fever is due to malaria, and reflex treatment with ACT does not make medical or economic sense. ”

“ The sensitivity of tests for malaria may need to higher in areas where good malaria control is being effected than current testing allows. Microscopy and RDTs both become relatively insensitive at parasite densities below 100 parasites/μl. PCR studies have shown that low-level parasitaemia missed by RDTs and conventional microscopy can be uncovered with sensitive molecular methods. As individuals with low-level parasitaemia may act as reservoirs for transmission, their detection may be necessary to accelerate elimination. ”

“ As ACTs are increasingly used, however, it is likely that non-falciparum malaria will form an ever-greater fraction of cases. This is already true in parts of Ethiopia, where the conventional ratio of 70/30 falciparum/non-falciparum recently reversed in some areas of the country. Public sector deployment of RDTs in Africa may increasingly shift away from falciparum-only tests. Ongoing research aims to develop more stable tests that allow species differentiation, against either the current targets or novel target antigens. ”

“ It is likely that if success in malaria control is obtained, it will lead to the need for, and development of, new diagnostic tests. Much of the large public sector market for malaria RDTs is served by tests that detect only P. falciparum, especially in Africa. ”

“ At the recent 2008 Millennium Development Goals Malaria Summit, an ambitious new Global Malaria Action Plan was endorsed and nearly $3 billion committed towards reducing the number of malaria deaths to near zero by 2015. ”

“ Scaled-up use of ACT and RDTs in India, in millions. The profusion of malaria test manufacturers, many of them small, combined with their difficulty obtaining reference clinical materials from well-characterized malaria patients and the lack of biologic reference standards, has resulted in significant variability in the quality of tests being manufactured. ”

“ HRP2 is present in Plasmodium falciparum only, whereas pLDH and aldolase, with some conserved and some variable epitopes, are present in all four major species causing human malaria. RDTs have the obvious advantage of requiring less training, being easily performed in remote or village settings, and putting most of the quality control responsibility in the hands of the manufacturer instead of the user. ”

“ Currently, very few RDT results are recorded and transmitted back to centralized levels of the health system in a way that could serve surveillance needs. For both HIV and tuberculosis, relatively robust systems are in place that capture the results of testing in peripheral settings and establish the basis for national reporting. ”

“ Yuen, KY; et al. (2006) , Sensitive and inexpensive molecular test for falciparum malaria: detecting Plasmodium falciparum dna directly from heat-treated blood by loop-mediated isothermal amplification, vol. ”