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

Abstract

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 severe Plasmodium falciparum malaria 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.

Fig 1. Prevalence of SM phenotypes amongst severe cases by age group.

Proportions were calculated for severe cases with no missing values for a given measure. Information for all phenotypes was not available in all studies (Table 1, S2 and S4 Tables). Each case can present with more than 1 phenotype. SM, severe malaria.

Fig 2. Illness duration (in days) prior to arrival at the health facility by SM phenotype and age group.

Box-and-whisker plots showing median and IQR of duration of illness/fever in children and adults stratified by severity group (ages <15 years: N_UM = 3,277, N_SM = 3,708; ages ≥15 years: N_UM = 300, N_SM = 226). Outliers (observations that are 1.5 × IQR from the lower or upper quartiles) are denoted. Extreme outliers, defined as duration of illness of over 3 weeks, are omitted from these plots (0.6% of cases [20 UM and 25 SM] were omitted). SM, severe malaria; UM, uncomplicated malaria.

Fig 3

Treatment delay and odds of presenting with any SM (A), SMA (B), and receiving blood transfusion (C) in children under 15. ORs (and 95% CIs) for presentation with severe disease rather than UM (A & B) with each additional reported day of delay after initial symptoms, compared with patients receiving treatment within 1 day of symptom onset (N_UM = 3,277, N_SM = 3,708, N_SMA = 1,774). Amongst 5 studies with information on blood transfusions during hospital admission, 27.7% (1,520/5,496) of children aged under 15 with available data had received a blood transfusion. ORs (and 95% CIs) for receiving a blood transfusion was estimated for each additional day of illness duration amongst all uncomplicated and severe cases. All ORs shown were obtained from a mixed-effects logistic regression adjusted for age as a linear predictor and allowed for random study effects. Statistically significant ORs are denoted in red (dashed purple line: OR = 1). OR, odds ratio; SM, severe malaria; SMA, severe malarial anaemia; UM, uncomplicated malaria.

Fig 4

Treatment delay and change in Hb levels for (A) children aged under 15 and (B) adults aged 15 years and over. The change in Hb in g/dl for each extra day of delay compared with Hb in those treated within 24 hours. An increase in delay was associated with decrease in Hb levels (children: likelihood ratio χ²₍₇₎ = 361.16, p < 0.001; adults: likelihood ratio χ²₍₇₎ = 41.62, p < 0.001). Hb was recorded for 5,908 individuals in 10 of the studies, and its concentration was normally distributed. A mixed-effects general linear model was used to examine the relationship between delay and Hb levels, irrespective of severity group. On average, children who were admitted to the hospital more than 3 days after symptom onset had a reduction in Hb of at least 2 g/dl compared with those receiving treatment in the first day after illness onset. Hb, haemoglobin.

Fig 5

Treatment delay and odds of presenting with CM (A–B) and respiratory distress (C–D) in children <15 years. ORs (and 95% CIs) for presentation with severe disease with each additional reported day of illness before attending the health facility compared with patients attending within 1 day of reported illness onset (A and C; N_UM = 3,277, N_CM = 737, N_RDS = 945) or fever onset (B and D; N_UM = 492, N_CM = 441, N_RDS = 251). ORs were obtained from a mixed-effects logistic regression adjusted for age as a linear predictor and allowed for random study effects. Statistically significant ORs are denoted in red (dashed purple line: OR = 1). The same plots for other SM phenotypes are shown in S9 Fig. CM, cerebral malaria; OR, odds ratio; RDS, respiratory distress syndrome; SM, severe malaria UM, uncomplicated malaria.

Fig 6. Association between delay to treatment and SMA for different levels of transmission intensity in children <15 years.

ORs for the association between duration of illness and SMA from 2 age-adjusted mixed-effects models: one adjusting for transmission intensity level and one accounting for an interaction between transmission intensity and delay. Transmission intensity was categorised into low (PfPR_2–10 < 10%), moderate (PfPR_2–10 10% to <35%), and high (PfPR_2–10 ≥ 35%). CIs around the OR estimates are shown in S10 Table. OR, odds ratio; SMA, severe malarial anaemia.