Dataset Information

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.

SUBMITTER: Mousa A

PROVIDER: S-EPMC7571702 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Mousa Andria A Al-Taiar Abdullah A Anstey Nicholas M NM Badaut Cyril C Barber Bridget E BE Bassat Quique Q Challenger Joseph D JD Cunnington Aubrey J AJ Datta Dibyadyuti D Drakeley Chris C Ghani Azra C AC Gordeuk Victor R VR Grigg Matthew J MJ Hugo Pierre P John Chandy C CC Mayor Alfredo A Migot-Nabias Florence F Opoka Robert O RO Pasvol Geoffrey G Rees Claire C Reyburn Hugh H Riley Eleanor M EM Shah Binal N BN Sitoe Antonio A Sutherland Colin J CJ Thuma Philip E PE Unger Stefan A SA Viwami Firmine F Walther Michael M Whitty Christopher J M CJM William Timothy T Okell Lucy C LC

PLoS medicine 20201019 10

<h4>Background</h4>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 commu ...[more]

PMID: 33075101

Similar Datasets

Project description:BACKGROUND:Gaps remain in understanding the role of caregiver responses on time to seek appropriate care. The objective of this study was to describe caregiver responses to illness and the impact of these responses on time to seek appropriate care among children with malaria. METHODS:A case-control study of 325 children with severe (cases) and 325 children with uncomplicated (controls) malaria was conducted in Jinja, Uganda. Caregivers' responses to their children's illnesses and time to seek appropriate care were documented. Responses included staying at home, seeking care at drug shops, and seeking care at public health facilities classified into two types: (1) health facilities where caregiver initially sought care before enrollment, and (2) health facilities where children were provided appropriate care and enrolled in the study. Weighted Cox regression was used to determine risk factors for delays in time to seek appropriate care within 24 h of illness onset. RESULTS:Children staying home on self-medication was the most common initial response to illness among caregivers of controls (57.5%) and cases (42.4%, p?<?0.001), followed by staying at home without medication (25.2%) and seeking care at drug shops (32.0%) for caregivers of controls and cases, respectively. Seeking care at drug shops was more common among caregivers of cases than of controls (32.0% vs. 12.3%; p?<?0.001). However, compared to public health facilities, drug shops offered sub-optimal services with children less likely to have been examined (50.0% vs. 82.9%; p?<?0.001) or referred to another facility (12.5% vs. 61.4%; p?<?0.001). Upon adjustment for known risk factors for delay, initially seeking care at a drug shop (HR 0.37, p?=?0.036) was associated with delay in seeking care at a health facility where appropriate care was provided. In contrast, those initially seeking care at public health facility before enrollment were more likely to subsequently seek care at another public health facility where appropriate care was provided (HR 5.55, p?<?0.001). CONCLUSION:Caregivers should be educated on the importance of promptly seeking care at a health facility where appropriate care can be provided. The role of drug shops in providing appropriate care to children with malaria needs to be reviewed.

Project description:BACKGROUND:Severe falciparum malaria is a medical emergency characterised by potentially lethal vital organ dysfunction. Patient fatality rates even with parenteral artesunate treatment remain high. Despite considerable research into adjuvant therapies targeting organ and tissue dysfunction, none have shown efficacy apart from renal replacement therapy. Understanding the causal contributions of clinical and laboratory abnormalities to mortality is essential for the design and evaluation of novel therapeutic interventions. METHODS AND FINDINGS:We used a structural model causal inference approach to investigate causal relationships between epidemiological, laboratory, and clinical variables in patients with severe falciparum malaria enrolled in clinical trials and their in-hospital mortality. Under this causal model, we analysed records from 9,040 hospitalised children (0-12 years, n = 5,635) and adults (n = 3,405, 12-87 years) with severe falciparum malaria from 15 countries in Africa and Asia who were studied prospectively over the past 35 years. On admission, patient covariates associated with increased in-hospital mortality were severity of acidosis (odds ratio [OR] 2.10 for a 7-mEq/L increase in base deficit [95% CI 1.93-2.28]), renal impairment (OR 1.71 for a 2-fold increase in blood urea nitrogen [95% CI 1.58, 1.86]), coma (OR 3.59 [95% CI 3.07-4.21]), seizures (OR 1.40 [95% CI 1.16-1.68]), shock (OR 1.51 [95% CI 1.14-1.99]), and presumed pulmonary oedema (OR 1.58 [95% CI 1.04-2.39]). Lower in-hospital mortality was associated with moderate anaemia (OR 0.87 for a decrease of 10 percentage points in haematocrit [95% CI 0.80-0.95]). Circulating parasite density was not associated with mortality (OR 1.02 for a 6-fold increase [95% CI 0.94-1.11]), so the pathological effects of parasitaemia appear to be mediated entirely by the downstream effects of sequestration. Treatment with an artemisinin derivative decreased mortality compared with quinine (OR 0.64 [95% CI 0.56-0.74]). These estimates were consistent across children and adults (mainly representing African and Asian patients, respectively). Using inverse probability weighting, transfusion was not estimated to be beneficial in children with admission haematocrit values between 15% and 25% (OR 0.99 [95% CI 0.97-1.02]). Except for the effects of artemisinin treatment and transfusion, causal interpretations of these estimates could be biased by unmeasured confounding from severe bacterial sepsis, immunity, and duration of illness. CONCLUSION:These data suggest that moderate anaemia is associated with a reduced risk of death in severe falciparum malaria. This is possibly a direct causal association. The severe anaemia threshold criteria for a definition of severe falciparum malaria should be reconsidered.

Project description:BackgroundMalaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women.MethodsWe did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013.FindingsOf the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57-14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14-0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34-0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18-0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29-23·82).InterpretationEfficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.FundingThe Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.

Dataset Information

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.

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets