While age, haemoglobin level and presence of respiratory symptoms provide some guide to diagnostic probability, clinical predictors of malaria are still insufficient to guide treatment. The advent of RDTs provides the potential to target anti-malarial treatment on a scale that has hitherto been impossible. However, doubts remain in the minds of many clinicians about the safety of not treating parasite-negative patients for malaria, and these have probably contributed to the observation from a number of studies in Africa that up to half of those with a negative rapid test or blood slide result for malaria are treated with anti-malarials anyway. Additionally the question 'if it is not malaria what is it?' is important for framing a rational diagnostic and treatment strategy. Appropriate use of anti-microbial drugs is a key issue given the high mortality of children admitted to hospital with invasive bacterial disease but whose treatment is restricted by high levels of resistance to commonly used agents .
This study adds to other evidence that anti-malarial treatment based on parasitological testing misses few true cases of malaria. Njama-Meyer et al used expert microscopy to guide the treatment of 2,359 illness episodes in children under the age of 10 years in a malaria-endemic area of Uganda; fewer than 1% of initial blood slide readings were false-negatives, and only 13 (0.8%) of 1,602 slide-negative illness episodes became positive over the following even days, and none of these was severely ill . D'Acremont et al followed up 603 RDT-negative children who had not been treated for malaria and only three children developed a positive result in the following week, all of whom were successfully treated .
Although the study results are reassuring, the policy of RDT-directed treatment for suspected malaria represents a substantial change in the delivery of routine care in Africa and some questions still remain. Firstly, it is impossible to distinguish between 'new' or 'missed' diagnoses of malaria during routine follow-up of RDT-negative patients. As observed in the current study, a significant minority of children will be admitted for malaria within days of being seen with a non-severe febrile illness and a negative RDT result. Although the PCR primers used in this study were not the most sensitive, the results suggest that the malaria diagnoses following enrolment into the study were 'new' infections and that it is rational and safe to treat RDT-negative children for a non-malarial illness. However, the perception of clinicians and parents may be that a child with malaria has been denied the best treatment as a result of application of new guidelines with RDTs. Given evidence of a strong preference for a diagnosis of malaria among parents and clinicians , such an interpretation is quite likely and may undermine efforts to implement the policy of RDT-directed anti-malarial treatment. To guard against this, clinicians should be reminded that 'no test is perfect' and to advise parents to bring their child back if they remain unwell. Secondly, there is still a possibility that presumptive treatment for malaria in all children with fever might provide a benefit due to intermittent prophylaxis that might protect against malaria and/or anaemia. Recent results of trials of intermittent treatment for malaria in children suggest that this is possible, and a cluster randomized trial of presumptive compared to RDT-directed anti-malarial treatment is in progress .
The commonest indication for anti-microbial treatment in our study was the IMCI diagnosis of non-severe pneumonia. While the overlap between malaria and pneumonia has been previously described both in severe and non-severe illness, the proportion of children meeting WHO criteria for non-severe pneumonia was higher than expected from previous studies [15, 19–21]]. Preferential recording by study clinicians in order to justify prescribing an anti-microbial drug seems unlikely as the number of children meeting the WHO definition was slightly higher than the number actually diagnosed. In addition, there was no evidence of a change in the proportion diagnosed with pneumonia as the study progressed, nor was there evidence of clustering of respiratory counts near the cut-off values that define raised levels. It's possible that 'cough or difficulty breathing' was over-interpreted or there may be local variations in the perception or reporting of respiratory problems in children . In addition, the finger-prick undertaken approximately 15 minutes before examination may have resulted in transiently increased respiratory rates.
As new guidelines and RDTs are introduced across Africa it is possible that there will be a compensatory over-use of the IMCI diagnosis of non-severe pneumonia but this will be difficult to assess since there is no gold standard definition of the diagnosis of pneumonia. Even of the true pneumonias some will be viral, including the vaccine-preventable RSV pneumonias, where antibiotics will make little positive impact on outcome [23, 24]. In addition, studies of the quality of care suggest that IMCI procedures to diagnose pneumonia, in particular examining the chest and recording respiratory rate, are not well undertaken outside research settings [25, 26].
Consistent with at least one other study, we found that bacteraemia was uncommon in children with non-severe illness, especially in children who were RDT-positive . However, blood culture lacks sensitivity and early recognition and treatment of blood stream infections has the potential to avert progression to severe disease with high associated mortality [14, 28]. While RDTs can improve targeting of anti-malarial drugs there is no comparable test for bacterial disease. The POC measure of blood lactate was increased in children who were RDT-positive compared to RDT-negative, but was unhelpful in distinguishing between children with and without invasive bacterial infection. While the small numbers of children with bacteraemia in our study reduced the likelihood of finding a statistically significant association with clinical and laboratory features, our findings are consistent with other studies that bacteraemia occurs predominantly in young children, up to three-quarters of whom present with a 'current fever'. However, these indicators lack both sensitivity and specificity and there is still a need for more accurate measures of bacterial infection; devices measuring acute phase proteins such as C-reactive protein or procalcitonin merit further research .
This study has a number of inevitable limitations. The study was conducted in hospital outpatients where the patient population may differ in a number of ways from those attending primary health facilities generally. The accuracy of RDT interpretation may have been higher than under routine practice, and certainly higher than routine microscopy in some clinics in the region. Clinicians were aware that they were being observed (in the sense that their findings and prescriptions were being recorded) and may have been more likely to follow IMCI guidelines and to prescribe antibiotics, thus over-estimating antibiotic usage that would occur under similar conditions in routine practice. The clinical care provided in the study followed IMCI guidelines and did not have access to an otoscope or urine examination resulting in possible neglect of otitis media or urinary tract infections. The lack of validating investigations for the IMCI diagnosis of pneumonia has already been discussed.
In conclusion, this study demonstrates that use of RDT's to direct the use of anti-malarial drugs in young children is a safe strategy and did not result in any missed diagnoses of malaria. However, new episodes of malaria do occur within a short period of an initial consultation in malaria endemic areas and these may undermine confidence in parasitological testing for malaria. Invasive bacterial disease is relatively uncommon in children with non-severe illness; while most cases occurred in infants with a current fever there is a need for more specific diagnostic tests to detect these infections at the point of care.