Antibiotic treatment failure in children aged 1 to 59 months with World Health Organization-defined severe pneumonia in Malawi: A CPAP IMPACT trial secondary analysis.

BACKGROUND: Pneumonia is a leading cause of mortality in children <5 years globally. Early identification of hospitalized children with pneumonia who may fail antibiotics could improve outcomes. We conducted a secondary analysis from the Malawi CPAP IMPACT trial evaluating risk factors for antibiotic failure among children hospitalized with pneumonia. METHODS: Participants were 1-59 months old with World Health Organization-defined severe pneumonia and hypoxemia, severe malnutrition, and/or HIV exposure/infection. All participants received intravenous antibiotics per standard care. First-line antibiotics were benzylpenicillin and gentamicin for five days. Study staff assessed patients for first-line antibiotic failure daily between days 3-6. When identified, patients failing antibiotics were switched to second-line ceftriaxone. Analyses excluded children receiving ceftriaxone and/or deceased by hospital day two. We compared characteristics between patients with and without treatment failure and fit multivariable logistic regression models to evaluate associations between treatment failure and admission characteristics. RESULTS: From June 2015-March 2018, 644 children were enrolled and 538 analyzed. Antibiotic failure was identified in 251 (46.7%) participants, and 19/251 (7.6%) died. Treatment failure occurred more frequently with severe malnutrition (50.2% (126/251) vs 28.2% (81/287), p<0.001) and amongst those dwelling ≥10km from a health facility (22.3% (56/251) vs 15.3% (44/287), p = 0.026). Severe malnutrition occurred more frequently among children living ≥10km from a health facility than those living <10km (49.0% (49/100) vs 35.7% (275/428), p = 0.014). Children with severe malnutrition (adjusted odds ratio (aOR) 2.2 (95% CI 1.52, 3.24), p<0.001) and pre-hospital antibiotics ((aOR 1.47, 95% CI 1.01, 2.14), p = 0.043) had an elevated aOR for antibiotic treatment failure. CONCLUSION: Severe malnutrition and pre-hospital antibiotic use predicted antibiotic treatment failure in this high-risk severe pneumonia pediatric population in Malawi. Our findings suggest addressing complex sociomedical conditions like severe malnutrition and improving pneumonia etiology diagnostics will be key for better targeting interventions to improve childhood pneumonia outcomes.

Identifying modifiable risk factors for mortality in children aged 1-59 months admitted with WHO-defined severe pneumonia: a single-centre observational cohort study from rural Malawi.

OBJECTIVE: Although HIV infection, severe malnutrition and hypoxaemia are associated with high mortality in children with WHO-defined severe pneumonia in sub-Saharan Africa, many do not have these conditions and yet mortality remains elevated compared with high-resource settings. Further stratifying mortality risk for children without these conditions could permit more strategic resource utilisation and improved outcomes. We therefore evaluated associations between mortality and clinical characteristics not currently recognised by the WHO as high risk among children in Malawi with severe pneumonia but without HIV (including exposure), severe malnutrition and hypoxaemia. METHODS: Between May 2016 and March 2018, we conducted a prospective observational study alongside a randomised controlled trial (CPAP IMPACT) at Salima District Hospital in Malawi. Children aged 1-59 months hospitalised with WHO-defined severe pneumonia without severe malnutrition, HIV and hypoxaemia were enrolled. Study staff assessed children at admission and ascertained hospital outcomes. We compared group characteristics using Student's t-test, rank-sum test, χ2 test or Fisher's exact test as appropriate. RESULTS: Among 884 participants, grunting (10/112 (8.9%) vs 11/771 (1.4%)), stridor (2/14 (14.2%) vs 19/870 (2.1%)), haemoglobin <50 g/L (3/27 (11.1%) vs 18/857 (2.1%)) and malaria (11/204 (5.3%) vs 10/673 (1.4%)) were associated with mortality compared with children without these characteristics. Children who survived had a 22 g/L higher mean haemoglobin and 0.7 cm higher mean mid-upper arm circumference (MUAC) than those who died. CONCLUSION: In this single-centre study, our analysis identifies potentially modifiable risk factors for mortality among hospitalised Malawian children with severe pneumonia: specific signs of respiratory distress (grunting, stridor), haemoglobin <50 g/L and malaria infection. Significant differences in mean haemoglobin and MUAC were observed between those who survived and those who died. These factors could further stratify mortality risk among hospitalised Malawian children with severe pneumonia lacking recognised high-risk conditions.

Focus group discussions on low-flow oxygen and bubble CPAP treatments among mothers of young children in Malawi: a CPAP IMPACT substudy.

OBJECTIVE: To determine the acceptability of bubble continuous positive airway pressure (bCPAP) and low-flow oxygen among mothers of children who had received either therapy. SETTING: A district hospital in Salima, Malawi. PARTICIPANTS: We conducted eight focus group discussions (FGDs) with a total of 54 participants. Eligible participants were mothers of children 1 to 59 months of age with severe pneumonia and a comorbidity (HIV-infection, HIV-exposure, malnutrition or hypoxaemia) who, with informed consent, had been enrolled in a randomised clinical trial, CPAP IMPACT (Improving Mortality for Pneumonia in African Children Trial), comparing low-flow oxygen and bCPAP treatments (ClinicalTrials.gov, NCT02484183). PRIMARY AND SECONDARY OUTCOME MEASURES: FGDs assessed mothers' attitudes and feelings towards oxygen and bCPAP before and after therapy along with general community perceptions of respiratory therapies. Data was analysed using inductive thematic analysis to assess themes and subthemes of the transcripts. RESULTS: Community perceptions of oxygen and bCPAP were widely negative. Mothers recounted that they are told that 'oxygen kills babies'. They are often fearful of allowing their child to receive oxygen therapy and will delay treatment or seek alternative therapies. Mothers report limiting oxygen and bCPAP by intermittently removing the nasal cannulas or mask. After oxygen or bCPAP treatment, regardless of patient outcome, mothers were supportive of the treatment their child received and would recommend it to other mothers. CONCLUSION: There are significant community misconceptions around oxygen and bCPAP causing mothers to be fearful of either treatment. In order for low-flow oxygen treatment and bCPAP implementation to be effective, widespread community education is necessary.

Bubble continuous positive airway pressure for children with high-risk conditions and severe pneumonia in Malawi: an open label, randomised, controlled trial.

BACKGROUND: Pneumonia is the leading cause of death among children globally. Most pneumonia deaths in low-income and middle-income countries (LMICs) occur among children with HIV infection or exposure, severe malnutrition, or hypoxaemia despite antibiotics and oxygen. Non-invasive bubble continuous positive airway pressure (bCPAP) is considered a safe ventilation modality that might improve child pneumonia survival. bCPAP outcomes for high-risk African children with severe pneumonia are unknown. Since most child pneumonia hospitalisations in Africa occur in non-tertiary district hospitals without daily physician oversight, we aimed to examine whether bCPAP improves severe pneumonia mortality in such settings. METHODS: This open-label, randomised, controlled trial was done in the general paediatric ward of Salima District Hospital, Malawi. We enrolled children aged 1-59 months old with WHO-defined severe pneumonia and either HIV infection or exposure, severe malnutrition, or an oxygen saturation of less than 90%. Children were randomly assigned 1:1 to low-flow nasal cannula oxygen or nasal bCPAP. Non-physicians administered care; the primary outcome was hospital survival. Primary analyses were by intention-to-treat and interim and adverse events analyses per protocol. This trial is registered with ClinicalTrials.gov, number NCT02484183, and is closed. FINDINGS: We screened 1712 children for eligibility between June 23, 2015, and March 21, 2018. The data safety and monitoring board stopped the trial for futility after 644 of the intended 900 participants were enrolled. 323 children were randomly assigned to oxygen and 321 to bCPAP. 35 (11%) of 323 children who received oxygen died in hospital, as did 53 (17%) of 321 who received bCPAP (relative risk 1·52; 95% CI 1·02-2·27; p=0·036). 13 oxygen and 17 bCPAP patients lacked hospital outcomes and were considered lost to follow-up. Suspected adverse events related to treatment occurred in 11 (3%) of 321 children receiving bCPAP and 1 (<1%) of 323 children receiving oxygen. Four bCPAP and one oxygen group deaths were classified as probable aspiration episodes, one bCPAP death as probable pneumothorax, and six non-death bCPAP events included skin breakdown around the nares. INTERPRETATION: bCPAP treatment in a paediatric ward without daily physician supervision did not reduce hospital mortality among high-risk Malawian children with severe pneumonia, compared with oxygen. The use of bCPAP within certain patient populations and non-intensive care settings might carry risk that was not previously recognised. bCPAP in LMICs needs further evaluation before wider implementation for child pneumonia care. FUNDING: Bill & Melinda Gates Foundation, International AIDS Society, Health Empowering Humanity.

Bubble CPAP and oxygen for child pneumonia care in Malawi: a CPAP IMPACT time motion study.

BACKGROUND: In some low-resource settings bubble continuous positive airway pressure (bCPAP) is increasingly used to treat children with pneumonia. However, the time required for healthcare workers (HCWs) to administer bCPAP is unknown and may have implementation implications. This study aims to compare HCW time spent administering bCPAP and low-flow nasal oxygen care at a district hospital in Malawi during CPAP IMPACT (Improving Mortality for Pneumonia in African Children Trial). METHODS: Eligible participants were 1-59 months old with WHO-defined severe pneumonia and HIV-infection, HIV-exposure, severe malnutrition, or hypoxemia and were randomized to either bCPAP or oxygen. We used time motion techniques to observe hospital care in four hour blocks during treatment initiation or follow up (maintenance). HCW mean time per patient at the bedside over the observation period was calculated by study arm. RESULTS: Overall, bCPAP required an average of 34.71 min per patient more than low-flow nasal oxygen to initiate (bCPAP, 118.18 min (standard deviation (SD) 42.73 min); oxygen, 83.47 min (SD, 20.18 min), p < 0.01). During initiation, HCWs spent, on average, 12.45 min longer per patient setting up bCPAP equipment (p < 0.01) and 11.13 min longer per patient setting up the bCPAP nasal interface (p < 0.01), compared to oxygen equipment and nasal cannula set-up. During maintenance care, HCWs spent longer on average per patient adjusting bCPAP, compared to oxygen equipment (bCPAP 4.57 min (SD, 4.78 min); oxygen, 1.52 min (SD, 2.50 min), p = 0.03). CONCLUSION: Effective bCPAP implementation in low-resource settings will likely create additional HCW burden relative to usual pneumonia care with oxygen. TRIAL REGISTRATION: Clinicaltrials.gov NCT02484183 , June 29, 2015.