Great strides have been made in tackling malaria as a result of the millennium development goal 6c that aimed to halt or reverse the incidence of malaria by 2015. Consequently, malaria incidence has fallen by 37% worldwide and death rates by 60%. The Global technical strategy for malaria aims for a further 90% reduction in the malaria incidence by 2030 (). Ultimately this strategy will underpin the decline in prevalence of HMS through prevention. However, until malaria incidence is sufficiently ameliorated a reasonable and affordable treatment strategy is required for HMS, given the significant mortality. Both established evidence based treatments Chloroquine and Proguanil are not available in the area, and the latter is too expensive for long term treatment in these patients comprised mainly of subsistence farmers. It is clear that a pragmatic and effective treatment is required.
Doxycycline is highly effective in providing malaria prophylaxis with efficacy between 84–96% in p.falciparum, higher in p.vivax (). It is highly effective as a blood schizontacidal agent, with partial activity as a causal prophylactic (against the liver stage). It is generally well tolerated with few side effects, few drug interactions and can be taken long term. A treatment for 6 months is not uncommon in dermatological conditions such as acne vulgaris and lymphatic filariasis (). The hospital had selected a course of 6 months in the absence of national or international guidelines on the subject, and the understanding that patients would likely be quickly re-exposed following treatment. It was felt that 6 months would give sufficient time for immune and splenic recovery, although alternative courses could be considered in the absence of reliable data.
Doxycycline use previously in HMS is limited and in non-endemic populations. One European case report used Malarone for malaria treatment followed by doxycycline for 30 days, resulting in resolution of splenomegaly (). However recent developments suggest prophylaxis in a non-endemic area is unnecessary if standard curative treatment is administered in the absence of re-exposure (16). In a retrospective case series of HMS ex-patriots and immigrants in Italy, patients were treated with a standard short course for acute malaria, and doxycycline was prescribed only in those visiting their countries of origin for the duration of their stay. Of those who took regular prophylaxis, 8/9 were “improved or cured”, whereas 10/13 who took “intermittent treatment instead” were similarly “improved or cured”; presumably this was in terms of spleen size, blood results are not specified (16). Although this is a different population, returning to different risk areas, this suggests some efficacy. The group taking intermittent treatment are hard to characterise as this would depend on malaria endemicity, and the frequency and nature of their treatment. It is clearly practically and financially impossible to advocate lifelong prophylaxis in Kagando. A 6-month course provides a reasonable clearance time to allow recovery and could be re-instated, as a pulsed treatment, depending on refractory splenomegaly or recurrence following withdrawal. It is interesting that improvement persisted in our cohort even in the patients who re-presented late.
Consideration needs to be given to the antibiotic and anti-inflammatory effect of doxycycline. It has broad spectrum bacteriostatic activity and with efficacy against numerous tropical infections including rickettsia and leptospirosis. In theory this could afford these patients additional protection given that overwhelming sepsis is the major component of the significant associated mortality in HMS. Clearly this is unique to antibiotic prophylaxis. Furthermore, doxycycline has an anti-inflammatory effect, even in sub-antimicrobial levels. A decrease in inflammatory mediated cytokines as a result could create synergy in mediating the aberrant immune response in HMS (,). This mirrors the immune-regulatory effect of chloroquine in HMS where efficacy has been noted even in resistant p. falciparum infections ().
The logistics of follow up in rural western Uganda are a significant issue. The population primarily consists of farmers working in subsistence agriculture, who would struggle to afford travel to hospital and tests unless acutely unwell. This is the likely cause for those lost to follow up, coupled with a lack of infrastructure to facilitate this from the institution. A minority returned at their agreed follow up date, others returned opportunistically at a later date. This results in variability, in terms of time off prophylaxis and re-exposure to malaria, in a presumed high-risk environment. Despite this the spleen size and blood parameters demonstrated marked improvement even after a significant number of months from when the prophylaxis finished.
Another point of consideration is lack of diagnosis for the initial presentation to hospital. Patients are likely to have received a 3 day course of ACT for acute malaria in view of their clinical condition, positive rapid diagnostic test or blood film, yet this is not recorded. Whilst, a co-infection or another febrile tropical illness could have resulted in the presentation and affected the blood results. For instance Kagando is unable to locally test for arboviruses. Furthermore, although the majority of patients were treated by an experienced Medical Officer, due to staff turnover, later patients were not. There will be an element of subjectivity to spleen measurement and a margin of error, possibly more so in later returns. However the majority of returnees were found to have an impalpable spleen.
Although patients continue to be treated in Kagando in this manner, without funding and close oversight patient follow up will remain sporadic. Ideally patients would be recruited in an outpatient setting with no acute illness, yet patient identification would be limiting. Therefore, an attractive strategy would be to call the patients near their agreed 6-month appointment and subsidise travel and investigations. Alternatively, assessment could take place at local clinics and the results phoned through to Kagando, yet this would still require funding for phone credit charges and investigation costs. Certainly, formalisation and facilitation of follow up with a resultant expansion of returns would allow more accurate analysis and firmer conclusions. It would be desirable to know if these benefits were then lasting, how long for and the impact on mortality.