We performed systematic reviews to quantify estimates of PE for the following interventions for preventing mortality due directly to malaria in children in sub-Saharan Africa: prompt effective case management with ACTs for uncomplicated malaria, and effective case management with intravenous quinine of children hospitalized with malaria. The lack of controlled trials and the need to use numerous lower quality data sources make this exercise challenging.
Given the lack of placebo-controlled trials of treatment for malaria due to ethical reasons, we were unable to directly determine PE for prompt effective treatment of uncomplicated malaria for preventing malaria child mortality, as compared to no treatment. A meta-analysis was used to quantify the CFR for children with uncomplicated malaria that received prompt effective treatment. Results showed that death following uncomplicated malaria treated promptly with an effective antimalarial is very rare (0.068%, 95% CI 0.024 – 0.112). Because of a paucity of available data, we based the estimate of the natural mortality history of uncomplicated P. falciparum malaria on a previously published Delphi method, which found that experts estimated the risk of death among untreated children with uncomplicated P. falciparum malaria to be 5% for <2 year olds and 2% for 2-5 year olds. Combining these estimates, we estimated a very high PE of prompt ACT treatment of uncomplicated malaria compared to no treatment [99% (94-100%) for children younger than 2 years old, and 97% (86-99%) for children 2-5 years old].
For programmatic utility, we estimated a PE of effective case management of all children hospitalized with malaria. The CFR of 3.4% (95% CI 1.6-5.2) for all hospitalized children estimated by this method is very similar to that found by other authors [71
], and the CFR of 13.6% for strictly defined malaria is slightly higher than the AQUAMAT trial [9
], not surprising for observational studies compared to clinical trial conditions. As a proxy for mortality of untreated hospitalized malaria (natural history), we used mortality data from observational studies in the setting of chloroquine failure, during the era when chloroquine resistance was being established and chloroquine was still in widespread use. This resulted in the estimated CFR of untreated hospitalized malaria ranging from 13-21%. The higher bound (21%) is problematic, as the majority of the children in this sample who died had received chloroquine, and died despite respite receiving intravenous quinine after being admitted in critical condition, thus it may be a major underestimation. A qualitative study in Mali found that mortality for severe malaria (by maternal definition during interview) was 17.0% regardless of treatment-seeking [83
], which falls in the middle of this range and lends some credence to its accuracy. Thus we believe that a PE of 82% for protective efficacy of effective case management with intravenous quinine is reasonable. Given that these studies all used intravenous quinine, the PE of intravenous artesunate for preventing mortality would be expected to be even higher.
There are numerous limitations to using the LiST model to predict the number of child deaths that could be prevented by scaling-up case management of uncomplicated and severe malaria. First, no placebo-controlled data exists and the historical literature is of insufficient quality to establish a CFR for children who go untreated for uncomplicated and severe P. falciparum malaria (natural history). For uncomplicated P. falciparum malaria, we relied on expert opinion from a Delphi survey to obtain an estimate of the probability of a child dying following uncomplicated P. falciparum malaria when left untreated, within the context of stable transmission. Such an estimate from a Delphi study is clearly subject to bias, although the direction and magnitude are unknown. For estimating the probability of a child dying from severe P. falciparum malaria when left untreated, we relied on a proxy estimated as the probability of a child dying from severe malaria after treatment with chloroquine, in the context of high chloroquine resistance, which ranged from 13.1-21.1%. While this was a helpful proxy, it likely underestimates the true untreated CFR and therefore underestimates the true PE of case management of children hospitalized with P. falciparum malaria. Second, while the majority of children with uncomplicated malaria are still not treated with an ACT, and many hospitalized children receive inadequate care, often with sub-optimal medication as well as ancillary treatment, many do receive some form of treatment. Thus hospitalized children who had received chloroquine likely had somewhat better outcomes than children who received no treatment. Third, our approach takes into account only a given episode of malaria, and does not take into account longitudinal impact of adequate or inadequate treatment, or the post-prophylactic effect of some antimalarials. If more reliable estimates of untreated mortality of uncomplicated and severe disease become available, it will be important to update the estimates. Finally, while it would be optimal to generate these estimates for children with stringently defined severe malaria, as CFR for severe malaria after treatment with intravenous artesunate has been well documented, no proxy for untreated mortality in severe disease currently exists. If these data become available, the protective efficacy of case management with intravenous artesunate in this subset of children should be estimated.
Case management coverage indicators in most sub-Saharan African countries lag far behind coverage indicators for malaria prevention, in part because the delivery of effective case management of both uncomplicated and severe disease is quite complex and involves not only procurement of the drugs, but supply chain management, health worker training and supervision, revision of payment schemes to remove financial barriers, extending this care to more peripheral levels of the health care system, and working to encourage use of these services by the population.
The currently recommended coverage indicator for prompt effective treatment is the proportion of children <5 years old with fever in the past two weeks who received an ACT within 24 hours from the onset of fever [84
]. While an attempt has been made to standardize this indicator to be measured by most nationally-representative household surveys (e.g. Demographic and Health Survey, UNICEF’s Multiple Indicator Cluster Survey and Malaria Indicator Surveys), it is problematic for measuring trends in coverage over time for several reasons. First, as scale-up of prevention interventions such as ITNs increases, the proportion of fevers due to malaria is likely to decrease. Second, most countries have now adopted the policy of laboratory diagnosis [5
], with either microscopy or rapid diagnostic tests, for all suspected malaria cases seeking treatment through the health system. For this reason when assessing trends in coverage for prompt effective treatment of malaria fevers, the proportion receiving treatment has actually gone down in most countries since 2005 as countries have switched from clinical diagnosis to laboratory diagnosis. Finally, most countries switched their first-line antimalarial from a monotherapy to an often less available ACT within the last 5-8 years [5
], decreasing treatment with a recommended first line antimalarial in some countries over the past decade.
There is currently no established indicator for measuring the proportion of children hospitalized with P. falciparum malaria that receive effective case management. Establishing such an indicator will be difficult. Mortality of hospitalized patients depends not only on the quality of care received once hospitalized, but the delay in reaching such care, which depends on multiple factors including the distance to referral level care, availability of transportation, and cost of treatment, each of which may increase the delay and decrease the likelihood that the child will reach referral level care. However, programs are much more likely to be able to collect and report data on the management and outcomes of all children hospitalized with malaria than of a subset of children with stringently defined severe malaria.