The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.

Background Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. Methods and findings A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severePlasmodium falciparummalaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring >= 7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus <= 24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to <= 4 days versus <= 24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. Conclusions Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment. Author summaryWhy was this study done? In 2018, severe malaria was responsible for an estimated 405,000 deaths worldwide. Patient access to first-line antimalarials in health facilities remains suboptimal in many endemic areas. The contribution of delay to treatment of uncomplicated malaria is often believed to be a risk factor for developing severe malaria, but this relationship has not been systematically quantified, and findings are not consistent across all studies. Understanding this relationship is critical to determine how quickly patients need to receive treatment and to quantify the impact of treatment interventions. What did the researchers do and find? We conducted a pooled individual-participant meta-analysis to estimate the association between delay from onset of symptoms to seeking treatment and risk of presenting with different types of severe malaria rather than uncomplicated malaria. The risk of severe disease was significantly higher in children and adults who had longer delays from symptom onset to treatment-seeking, and this relationship was the strongest for progression to severe malarial anaemia. We estimate that almost half of the severe anaemia cases in both children and adults could be prevented if they presented within the first 24 hours of symptom onset. What do these findings mean? The findings of this individual-participant data (IPD) meta-analysis highlight the importance of improving access to prompt first-line treatment in preventing severe malarial anaemia cases and reducing the need for potentially harmful blood transfusions. Our findings highlight that provision of timely treatment is essential in preventing severe disease and death. Providing quantitative setting-specific estimates of the benefits of timely treatment through programs such as community health workers or strengthened health systems is essential in guiding their implementation and in determining the best allocation of resources amongst all malaria interventions.