When Is “Malaria” Malaria? The Different Burdens of Malaria Infection, Malaria Disease, and Malaria-Like Illnesses

K. A. Koram 0 1 M. E. Molyneux 0 1 0 Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi 1 Department of Epidemiology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Lego; Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi; School of Tropical Medicine, University of Liverpool , United Kingdom In this review we discuss the different meanings of the term 'malaria' and urge writers and readers to distinguish accurately between them. The distinction is important in clinical practice, clinical trials, epidemiology, and the evaluation of control programs. Both over- and under-diagnosis of malaria as the cause of a disease episode are inevitable; over-diagnosis is common in high-transmission areas and underdiagnosis is common in areas with little or no transmission. Parasite density thresholds, attributable fractions, and clinical algorithms have played important but only partial roles in strengthening diagnosis. Methods by which malaria infection could be confidently identified as the cause, rather than an irrelevant accompaniment, of an illness, are important targets for research. One such 'signature' is a distinctive retinopathy that occurs in severe malaria and not in clinically similar diseases. Other indicators of a malarial etiology of clinical disease are needed to strengthen clinical and scientific approaches to the control of malaria. - The word malaria has varieties of meaning that can be misleading if not carefully distinguished: 1. Malaria in an individual is an illness or disease that is due to parasites of the genus Plasmodium in the blood or tissues 2. Malaria is a generic term often used for protozoa of the genus Plasmodium, usually as part of the compound term malaria parasites. Malaria transmission is a phrase utilizing this definition (malaria parasites are transmitted, malaria disease is not). The presence of parasites of any stage, in any part of the human body indicates the presence of malarial infection, which may or may not be causing disease. 3. Malaria is a public health problem afflicting a community, and consisting of the combined effects of the infection on the population as a whole. Each of these can be measured or counted in various situations, when it is essential to be aware of what is being reported. The statement > 50% of children in primary schools had malaria on the day of the survey probably refers to definition 2 rather than definition 1, whereas malaria diminishes productivity refers to definition 3 and is a statement that cannot be quantified simply by measuring the sum of 1 and 2. The measurement of each of these varieties of malaria is susceptible to error: 1. None of the many forms of illness that can result from plasmodial infection is distinctive: all can be accurately mimicked by other microbial or non-infectious diseases. The presence of parasites in the blood provides no proof of causality because people in high-transmission areas learn to tolerate parasitemia, many without illness are parasitemic, and parasites accompanying an illness may be passengers, not agents of the disease. 2. The sensitivity of common methods of detecting para sitemia is such that low but important densities of parasitemia can be missed, even by a competent microscopist, especially in the non-immune and in young children (who are at greatest risk of severe disease if infected). 3. Several studies suggest that public health consequences of plasmodial infections are greater than can be predicted by counting recognizable illnesses or parasitemias (i.e., that there are indirect consequences for health [anemia, malnutrition and the risk of other infections being fatal] that can be recognized only by the improvements that follow when the parasite life-cycle has been interrupted).1,2 WHEN ACCURATE MEASUREMENT IS IMPORTANT An erroneous identification of malaria illness or infection can have costly or dangerous consequences. Accurate recognition is particularly important: 1. In the management of an individual patient, when incorrect diagnosis can result either in failure to treat a potentially dangerous malarial illness, or failure to seek and treat an alternative cause of the illness 2. In enrolling cases to a study of pathogenesis or therapy, when false diagnoses may mask important results or bring up spurious ones 3. In identifying endpoints in preventive or therapeutic intervention trials 4. In documenting the extent of the public health problem (the burden of malaria) and how this changes over time, when properly identified trends may indicate the need for new efforts or the success of existing ones. Misdiagnosis of malaria is common both in the identification of uncomplicated disease (the febrile illness) and in the diagnosis of severe or complicated malaria. Both underdiagnosis and over-diagnosis may occur. The implications of this inaccuracy depend upon whether diagnosis is being used for clinical or for research purposes. THE OVERDIAGNOSIS OF MALARIAL ILLNESS Malaria as an illness may be overdiagnosed (a) when a disease episode is presumed to be due to plasmodial infection without any attempt to identify parasites in the individuals blood, (b) when parasites are looked for but not found, yet because of the possibility of an undetectable but dangerous infection being present, treatment is deemed to be advisable, and (c) when parasitemia is correctly identified but wrongly assumed to be the cause of the illness (Figure 1). Each of these may be unavoidable or even necessary strategies in many circumstances; however, when they are used, it is important for the implications to be recognized. Presumptive diagnosis of uncomplicated malaria. The World Health Organization (WHO) advises presumptive diagnosis as the basis for first-line treatment of uncomplicated malaria in places where a parasitological test is not possible. This policy allows uncomplicated malarial illnesses to be treated by village health workers, shopkeepers, or relatives in the home, and thus minimizes delays in treatment, especially for those living a long way from formal health facilities. Several investigators have measured the extent to which this policy leads to overdiagnosis of malaria as the cause of illness. Amexo and colleagues collected 24 such studies; among subjects with clinically diagnosed malarial illness, the percentage with a negative blood film ranged from 3293%. The mean in 24 studies was 61%.3 To conclude that the film-negative patients with febrile illness in these studies were misdiagnosed as malaria involves several assumptions: (1) that a negative blood film excludes malaria as a cause of illnessin populations living in areas of intense transmission, this assumption will nearly always be correct; (2) that the blood film has been competently made, stained and interpreted27% of negative malaria fil (...truncated)