Prospective cohort study of referred Malawian children and their survival by hypoxaemia and hypoglycaemia status.

Objective: To investigate survival in children referred from primary care in Malawi, with a focus on hypoglycaemia and hypoxaemia progression. Methods: The study involved a prospective cohort of children aged 12 years or under referred from primary health-care facilities in Mchinji district, Malawi in 2019 and 2020. Peripheral blood oxygen saturation (SpO2) and blood glucose were measured at recruitment and on arrival at a subsequent health-care facility (i.e. four hospitals and 14 primary health-care facilities). Children were followed up 2 weeks after discharge or their last clinical visit. The primary study outcome was the case fatality ratio at 2 weeks. Associations between SpO2 and blood glucose levels and death were evaluated using Cox proportional hazards models and the treatment effect of hospitalization was assessed using propensity score matching. Findings: Of 826 children recruited, 784 (94.9%) completed follow-up. At presentation, hypoxaemia was moderate (SpO2: 90-93%) in 13.1% (108/826) and severe (SpO2: < 90%) in 8.6% (71/826) and hypoglycaemia was moderate (blood glucose: 2.5-4.0 mmol/L) in 9.0% (74/826) and severe (blood glucose: < 2.5 mmol/L) in 2.3% (19/826). The case fatality ratio was 3.7% (29/784) overall but 26.3% (5/19) in severely hypoglycaemic children and 12.7% (9/71) in severely hypoxaemic children. Neither moderate hypoglycaemia nor moderate hypoxaemia was associated with mortality. Conclusion: Presumptive pre-referral glucose treatment and better management of hypoglycaemia could reduce the high case fatality ratio observed in children with severe hypoglycaemia. The morbidity and mortality burden of severe hypoxaemia was high; ways of improving hypoxaemia identification and management are needed.

Hypoxemia, hypoglycemia and IMCI danger signs in pediatric outpatients in Malawi.

Hypoxemia and hypoglycemia are known risks for mortality in children in low-income settings. Routine screening with pulse oximetry and blood glucose assessments for outpatients could assist in early identification of high-risk children. We assessed the prevalence of hypoglycemia and hypoxemia, and the overlap with Integrated Management of Childhood Illness (IMCI) general danger signs, among children seeking outpatient care in Malawi. A cross-sectional study was conducted at 14 government primary care facilities, four rural hospitals and one district referral hospital in Mchinji district, Malawi from August 2019-April 2020. All children aged 0-12 years seeking care with an acute illness were assessed on one day per month in each facility. Study research assistants measured oxygen saturation using Lifebox LB-01 pulse oximeter and blood glucose was assessed with AccuCheck Aviva glucometers. World Health Organization definitions were used for severe hypoglycemia (<2.5mmol/l) and hypoxemia (SpO2 <90%). Moderate hypoglycemia (2.5-4.0mmol/l) and hypoxemia (SpO2 90-93%) were also calculated and prevalence levels compared between those with and without IMCI danger signs using chi2 tests. In total 2,943 children were enrolled, with a median age of 41 (range: 0-144) months. The prevalence of severe hypoxemia was 0.6% and moderate hypoxemia 5.4%. Severe hypoglycemia was present in 0.1% of children and moderate hypoglycemia in 11.1%. IMCI general danger signs were present in 29.3% of children. All severely hypoglycemic children presented with an IMCI danger sign (p <0.001), but only 23.5% of the severely hypoxemic and 31.7% of the moderately hypoxemic children. We conclude that while the prevalence of severe hypoxemia and hypoglycemia were low, moderate levels were not uncommon and could potentially be useful as an objective tool to determine referral needs. IMCI danger signs identified hypoglycemic children, but results highlight the challenge to detect hypoxemia. Future studies should explore case management strategies for moderate hypoxemia and hypoglycemia.

Prospective cohort study of referred Malawian children and their survival by hypoxaemia and hypoglycaemia status

Objective To investigate survival in children referred from primary care in Malawi, with a focus on hypoglycaemia and hypoxaemia progression. Methods The study involved a prospective cohort of children aged 12 years or under referred from primary health-care facilities in Mchinji district, Malawi in 2019 and 2020. Peripheral blood oxygen saturation (SpO2) and blood glucose were measured at recruitment and on arrival at a subsequent health-care facility (i.e. four hospitals and 14 primary health-care facilities). Children were followed up 2 weeks after discharge or their last clinical visit. The primary study outcome was the case fatality ratio at 2 weeks. Associations between SpO2 and blood glucose levels and death were evaluated using Cox proportional hazards models and the treatment effect of hospitalization was assessed using propensity score matching. Findings Of 826 children recruited, 784 (94.9%) completed follow-up. At presentation, hypoxaemia was moderate (SpO2: 90­93%) in 13.1% (108/826) and severe (SpO2: < 90%) in 8.6% (71/826) and hypoglycaemia was moderate (blood glucose: 2.5­4.0 mmol/L) in 9.0% (74/826) and severe (blood glucose: < 2.5 mmol/L) in 2.3% (19/826). The case fatality ratio was 3.7% (29/784) overall but 26.3% (5/19) in severely hypoglycaemic children and 12.7% (9/71) in severely hypoxaemic children. Neither moderate hypoglycaemia nor moderate hypoxaemia was associated with mortality. Conclusion Presumptive pre-referral glucose treatment and better management of hypoglycaemia could reduce the high case fatality ratio observed in children with severe hypoglycaemia. The morbidity and mortality burden of severe hypoxaemia was high; ways of improving hypoxaemia identification and management are needed.

Paediatric Emergency Triage, Assessment and Treatment (ETAT) - preparedness for implementation at primary care facilities in Malawi.

BACKGROUND: The majority of deaths amongst children under 5 years are still due to preventable infectious causes. Emergency care has been identified as a key health system weakness, and referrals are often challenging. OBJECTIVE: We aimed to establish how prepared frontline facilities in Malawi are to implement WHO Emergency Triage Assessment and Treatment (ETAT) guidelines, to support policy and planning decisions. METHODS: We conducted a concurrent mixed-methods study, including facility audit; healthcare provider survey; focus group discussions (FGD) and semi-structured interviews with facility staff. The study was conducted in two districts in Malawi, Zomba and Mchinji, between January and May 2019. We included all frontline facilities, including dispensaries, primary health centres, rural and community hospitals. Quantitative data were described using proportions, means and linear regression. Qualitative data was analysed using a framework approach. Data were analysed separately and then triangulated into common themes. RESULTS: Forty-seven facilities and 531 healthcare providers were included in the audit and survey; 6 FGDs and 5 interviews were completed. Four common themes emerged: (1) current emergency case management; (2) referral practices; (3) trained staff capacity; (4) opportunities and barriers for ETAT. Triage was conducted in most facilities with various methods described, and 53% reporting all staff are responsible. Referrals were common, but challenging due to issues in transportation. Twelve percent of survey respondents had ETAT training, with clinical officers (41%) reporting this more frequently than other cadres. Training was associated with increased knowledge, independent of cadre. The main barriers to ETAT implementation were the lack of resources, but opportunities to improve quality of care were reported. CONCLUSIONS: Malawian frontline facilities are already providing a level of emergency paediatric care, but issues in training, drug supplies and equipment were present. To effectively scale-up ETAT, policies need to include supply chain management, maintenance and strengthening referral communication.

Integrated Management of Childhood Illnesses (IMCI): a mixed-methods study on implementation, knowledge and resource availability in Malawi.

Background: The introduction of the WHO's Integrated Management of Childhood Illnesses (IMCI) guidelines in the mid-1990s contributed to global reductions in under-five mortality. However, issues in quality of care have been reported. We aimed to determine resource availability and healthcare worker knowledge of IMCI guidelines in two districts in Malawi. Methods: We conducted a mixed-methods study, including health facility audits to record availability and functionality of essential IMCI equipment and availability of IMCI drugs, healthcare provider survey and focus group discussions (FGDs) with facility staff. The study was conducted between January and April 2019 in Mchinji (central region) and Zomba (southern region) districts. Quantitative data were described using proportions and χ2 tests; linear regression was conducted to explore factors associated with IMCI knowledge. Qualitative data were analysed using a pragmatic framework approach. Qualitative and quantitative data were analysed and presented separately. Results: Forty-seven health facilities and 531 healthcare workers were included. Lumefantrine-Artemether and cotrimoxazole were the most available drugs (98% and 96%); while amoxicillin tablets and salbutamol nebuliser solution were the least available (28% and 36%). Respiratory rate timers were the least available piece of equipment, with only 8 (17%) facilities having a functional device. The mean IMCI knowledge score was 3.96 out of 10, and there was a statistically significant association between knowledge and having received refresher training (coeff: 0.42; 95% CI 0.01 to 0.82). Four themes were identified in the FGDs: IMCI implementation and practice, barriers to IMCI, benefits of IMCI and sustainability. Conclusion: We found key gaps in IMCI implementation; however, these were not homogenous across facilities, suggesting opportunities to learn from locally adapted IMCI best practices. Improving on-going mentorship, training and supervision should be explored to improve quality of care, and programming which moves away from vertical financing with short-term support, to a more holistic approach with embedded sustainability may address the balance of resources for different conditions.

Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study.

BACKGROUND: The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi. METHODS AND FINDINGS: We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0-59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation (SpO2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted (for age, sex, respiratory rate, and, in analyses of HC data only, Weight for Age Z-score [WAZ]) regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 (95% CI: 2.17-40.4, p = 0.003); CHW RR, 6.85 (1.15-40.9, p = 0.035). SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 (1.52-29.4, p = 0.012). Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data. CONCLUSIONS: Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone. Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.

The Epidemiology of Hypoxemic Pneumonia among Young Infants in Malawi.

We describe hypoxemic pneumonia prevalence in outpatient and inpatient settings, in-hospital mortality, and clinical guideline performance for identifying hypoxemia in young infants in Malawi. In this retrospective analysis of a prospective cohort study, we investigate infants younger than 2 months participating in pneumonia surveillance at seven hospitals and 18 outpatient health centers in Malawi between 2011 and 2014. Logistic regression, multiple imputation with chained equations, and pattern mixture modeling were used to determine the association between peripheral capillary oxyhemoglobin saturation (SpO2) levels and hospital mortality. We describe outpatient clinician hospital referral recommendations based on clinical characteristics and SpO2 distributions. Among 1,879 analyzed cases, SpO2 < 90% was more prevalent among outpatient health center cases compared with hospitalized cases (22.6% versus 13.5%, 95% CI: 17.6-28.4% and 12.0-15.3%, respectively). A larger proportion of hospitalized infants had signs of respiratory distress compared with infants at health centers (67.7% versus 56.6%, P < 0.001) and most hospitalized infants were boys (56.7% versus 40.6%, P < 0.001). An SpO2 of 90-92% and < 90% was associated with similarly increased odds of in-hospital mortality (adjusted odds ratio [aOR]: 4.3 and 4.4, 95% CI: 1.7-11.1 and 1.8-10.5, respectively). Unrecorded, or unobtainable, SpO2 was highly associated with mortality (n = 127, aOR: 18.1; 95% CI: 7.6-42.8). Four of 22 (18%) infants at health centers who did not meet clinical referral criteria had an SpO2 ≤ 92%. Clinicians should consider hospital referral in young infants with a SpO2 ≤ 92%. Infants with unobtainable SpO2 readings should be considered a high-risk group, and hospital referral of these cases may be appropriate.

Performance of a novel reusable pediatric pulse oximeter probe.

OBJECTIVE: To assess the performance of reusable pulse oximeter probe and microprocessor box combinations, of varying price-points, in the context of a low-income pediatric setting. METHODS: A prospective, randomized cross-over study comparing time to biologically plausible oxygen saturation (SpO2 ) between: (1) Lifebox LB-01 probe with Masimo Rad-87 box (L + M) and (2) a weight-appropriate reusable Masimo probe with Masimo Rad-87 box (M + M). A post hoc secondary analysis comparison with historical usability testing data with the Lifebox LB-01 probe and Lifebox V1.5 box (L + L) was also conducted. Participants, children aged 0 to 35 months, were recruited from pediatric wards and outpatient clinics in the central region of Malawi. The primary outcome was time taken to achieve a biologically plausible SpO 2 measurement, compared using t tests for equivalence. RESULTS: We recruited 572 children. Plausible SpO2 measurements were obtained in less than 1 minute, 71%, 70%, and 63% for the M + M, L + M, and L + L combinations, respectively. A similar pattern was seen for less than 2 minutes, however, this effect disappeared at less than 5 minutes with 96%, 96%, and 95% plausible measurements. Using a ±10 second threshold for equivalence, we found L + M and M + M to be equivalent, but were under-powered to assess equivalence for L + L. CONCLUSIONS: The novel reusable pediatric Lifebox probe can achieve a quality SpO2 measurement within a pragmatic time range of weight-appropriate Masimo equivalent probes. Further research, which considers the cost of the devices, is needed to assess the added value of sophisticated motion tolerance software.

Non-adherence to oral antibiotics for community paediatric pneumonia treatment in Malawi - A qualitative investigation.

BACKGROUND: Pneumonia remains the leading cause of paediatric infectious mortality globally. Treatment failure, which can result from non-adherence to oral antibiotics, can lead to poor outcomes and therefore improving adherence could be a strategy to reduce pneumonia related morbidity and mortality. However, there is little published evidence from low-resource settings for the drivers of non-adherence to oral antibiotics in children. OBJECTIVE: We aimed to investigate reasons for adherence and non-adherence in children diagnosed and treated in the community with fast-breathing pneumonia in rural Malawi. METHODS: We conducted focus group discussions (FGDs) with caregivers of children known to have been diagnosed and treated with oral antibiotics for fast-breathing pneumonia in the community and key informant interviews with community healthcare workers (CHW). FGDs and interviews were conducted within communities in Chichewa, the local language. We used a framework approach to analyze the transcripts. RESULTS: We conducted 4 FGDs with caregivers and 10 interviews with CHWs. We identified four themes, which were common across caregivers and CHWs: knowledge and understanding, effort, medication perceptions and community influences. Caregivers and CHWs demonstrated good knowledge of pneumonia and types of treatment, but caregivers showed confusion around dosing and treatment durations. Effort was needed to seek care, prepare medication and understand regimens, acting as a barrier to adherence. Perceptions of how well the treatment was working influenced adherence, with both quick recovery and slow recovery leading to non-adherence. Community influences were both supportive, with transport assistance for referrals and home visits to improve adherence, and detrimental, with pressure to share treatments. CONCLUSION: Adherence to oral antibiotic treatment for fast-breathing pneumonia was understood to be important, however considerable barriers we described within this rural low-resource setting, such as the effort preparing and administering medication, community pressures to share drugs and potential complexity of regimens.

Usability Testing of a Reusable Pulse Oximeter Probe Developed for Health-Care Workers Caring for Children < 5 Years Old in Low-Resource Settings.

Hypoxemia measured by pulse oximetry predicts child pneumonia mortality in low-resource settings (LRS). Existing pediatric oximeter probes are prohibitively expensive and/or difficult to use, limiting LRS implementation. Using a human-centered design, we developed a low-cost, reusable pediatric oximeter probe for LRS health-care workers (HCWs). Here, we report probe usability testing. Fifty-one HCWs from Malawi, Bangladesh, and the United Kingdom participated, and seven experts provided reference measurements. Health-care workers and experts measured the peripheral arterial oxyhemoglobin saturation (SpO2) independently in < 5 year olds. Health-care worker measurements were classed as successful if recorded in 5 minutes (or shorter) and physiologically appropriate for the child, using expert measurements as the reference. All expert measurements were considered successful if obtained in < 5 minutes. We analyzed the proportion of successful SpO2 measurements obtained in < 1, < 2, and < 5 minutes and used multivariable logistic regression to predict < 1 minute successful measurements. We conducted four testing rounds with probe modifications between rounds, and obtained 1,307 SpO2 readings. Overall, 67% (876) of measurements were successful and achieved in < 1 minute, 81% (1,059) < 2 minutes, and 90% (1,181) < 5 minutes. Compared with neonates, increasing age (infant adjusted odds ratio [aOR]; 1.87, 95% confidence interval [CI]: 1.16, 3.02; toddler aOR: 4.33, 95% CI: 2.36, 7.97; child aOR; 3.90, 95% CI: 1.73, 8.81) and being asleep versus being calm (aOR; 3.53, 95% CI: 1.89, 6.58), were associated with < 1 minute successful measurements. In conclusion, we designed a novel, reusable pediatric oximetry probe that was effectively used by LRS HCWs on children. This probe may be suitable for LRS implementation.

Opportunities and barriers in paediatric pulse oximetry for pneumonia in low-resource clinical settings: a qualitative evaluation from Malawi and Bangladesh.

OBJECTIVE: To gain an understanding of what challenges pulse oximetry for paediatric pneumonia management poses, how it has changed service provision and what would improve this device for use across paediatric clinical settings in low-income countries. DESIGN: Focus group discussions (FGDs), with purposive sampling and thematic analysis using a framework approach. SETTING: Community, front-line outpatient, and hospital outpatient and inpatient settings in Malawi and Bangladesh, which provide paediatric pneumonia care. PARTICIPANTS: Healthcare providers (HCPs) from Malawi and Bangladesh who had received training in pulse oximetry and had been using oximeters in routine paediatric care, including community healthcare workers, non-physician clinicians or medical assistants, and hospital-based nurses and doctors. RESULTS: We conducted six FGDs, with 23 participants from Bangladesh and 26 from Malawi. We identified five emergent themes: trust, value, user-related experience, sustainability and design. HCPs discussed the confidence gained through the use of oximeters, resulting in improved trust from caregivers and valuing the device, although there were conflicts between the weight given to clinical judgement versus oximeter results. HCPs reported the ease of using oximeters, but identified movement and physically smaller children as measurement challenges. Challenges in sustainability related to battery durability and replacement parts, however many HCPs had used the same device longer than 4 years, demonstrating robustness within these settings. Desirable features included back-up power banks and integrated respiratory rate and thermometer capability. CONCLUSIONS: Pulse oximetry was generally deemed valuable by HCPs for use as a spot-check device in a range of paediatric low-income clinical settings. Areas highlighted as challenges by HCPs, and therefore opportunities for redesign, included battery charging and durability, probe fit and sensitivity in paediatric populations. TRIAL REGISTRATION NUMBER: NCT02941237.

Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Clinical and Hypoxemic Childhood Pneumonia over Three Years in Central Malawi: An Observational Study.

BACKGROUND: The pneumococcal conjugate vaccine's (PCV) impact on childhood pneumonia during programmatic conditions in Africa is poorly understood. Following PCV13 introduction in Malawi in November 2011, we evaluated the case burden and rates of childhood pneumonia. METHODS AND FINDINGS: Between January 1, 2012-June 30, 2014 we conducted active pneumonia surveillance in children <5 years at seven hospitals, 18 health centres, and with 38 community health workers in two districts, central Malawi. Eligible children had clinical pneumonia per Malawi guidelines, defined as fast breathing only, chest indrawing +/- fast breathing, or, ≥1 clinical danger sign. Since pulse oximetry was not in the Malawi guidelines, oxygenation <90% defined hypoxemic pneumonia, a distinct category from clinical pneumonia. We quantified the pneumonia case burden and rates in two ways. We compared the period immediately following vaccine introduction (early) to the period with >75% three-dose PCV13 coverage (post). We also used multivariable time-series regression, adjusting for autocorrelation and exploring seasonal variation and alternative model specifications in sensitivity analyses. The early versus post analysis showed an increase in cases and rates of total, fast breathing, and indrawing pneumonia and a decrease in danger sign and hypoxemic pneumonia, and pneumonia mortality. At 76% three-dose PCV13 coverage, versus 0%, the time-series model showed a non-significant increase in total cases (+47%, 95% CI: -13%, +149%, p = 0.154); fast breathing cases increased 135% (+39%, +297%, p = 0.001), however, hypoxemia fell 47% (-5%, -70%, p = 0.031) and hospital deaths decreased 36% (-1%, -58%, p = 0.047) in children <5 years. We observed a shift towards disease without danger signs, as the proportion of cases with danger signs decreased by 65% (-46%, -77%, p<0.0001). These results were generally robust to plausible alternative model specifications. CONCLUSIONS: Thirty months after PCV13 introduction in Malawi, the health system burden and rates of the severest forms of childhood pneumonia, including hypoxemia and death, have markedly decreased.

Pulse oximetry for children with pneumonia treated as outpatients in rural Malawi.

OBJECTIVE: To investigate implementation of outpatient pulse oximetry among children with pneumonia, in Malawi. METHODS: In 2011, 72 health-care providers at 18 rural health centres and 38 community health workers received training in the use of pulse oximetry to measure haemoglobin oxygen saturations. Data collected, between 1 January 2012 and 30 June 2014 by the trained individuals, on children aged 2-59 months with clinically diagnosed pneumonia were analysed. FINDINGS: Of the 14 092 children included in the analysis, 13 266 (94.1%) were successfully checked by oximetry. Among the children with chest indrawing and/or danger signs, those with a measured oxygen saturation below 90% were more than twice as likely to have been referred as those with higher saturations (84.3% [385/457] vs 41.5% [871/2099]; P < 0.001). The availability of oximetry appeared to have increased the referral rate for severely hypoxaemic children without chest indrawing or danger signs from 0% to 27.2% (P < 0.001). In the absence of oximetry, if the relevant World Health Organization (WHO) guidelines published in 2014 had been applied, 390/568 (68.7%) severely hypoxaemic children at study health centres and 52/84 (61.9%) severely hypoxaemic children seen by community health workers would have been considered ineligible for referral. CONCLUSION: Implementation of pulse oximetry by our trainees substantially increased the referrals of Malawian children with severe hypoxaemic pneumonia. When data from oximetry were excluded, retrospective application of the guidelines published by WHO in 2014 failed to identify a considerable proportion of severely hypoxaemic children eligible only via oximetry.