Amoxicillin for 3 or 5 Days for Chest-Indrawing Pneumonia in Malawian Children.

BACKGROUND: Evidence regarding the appropriate duration of treatment with antibiotic agents in children with pneumonia in low-resource settings in Africa is lacking. METHODS: We conducted a double-blind, randomized, controlled, noninferiority trial in Lilongwe, Malawi, to determine whether treatment with amoxicillin for 3 days is less effective than treatment for 5 days in children with chest-indrawing pneumonia (cough lasting <14 days or difficulty breathing, along with visible indrawing of the chest wall with or without fast breathing for age). Children not infected with human immunodeficiency virus (HIV) who were 2 to 59 months of age and had chest-indrawing pneumonia were randomly assigned to receive amoxicillin twice daily for either 3 days or 5 days. Children were followed for 14 days. The primary outcome was treatment failure by day 6; noninferiority of the 3-day regimen to the 5-day regimen would be shown if the percentage of children with treatment failure in the 3-day group was no more than 1.5 times that in the 5-day group. Prespecified secondary analyses included assessment of treatment failure or relapse by day 14. RESULTS: From March 29, 2016, to April 1, 2019, a total of 3000 children underwent randomization: 1497 children were assigned to the 3-day group, and 1503 to the 5-day group. Among children with day 6 data available, treatment failure had occurred in 5.9% in the 3-day group (85 of 1442 children) and in 5.2% (75 of 1456) in the 5-day group (adjusted difference, 0.7 percentage points; 95% confidence interval [CI], -0.9 to 2.4) - a result that satisfied the criterion for noninferiority of the 3-day regimen to the 5-day regimen. Among children with day 14 data available, 176 of 1411 children (12.5%) in the 3-day group and 154 of 1429 (10.8%) in the 5-day group had had treatment failure by day 6 or relapse by day 14 (between-group difference, 1.7 percentage points; 95% CI, -0.7 to 4.1). The percentage of children with serious adverse events was similar in the two groups (9.8% in the 3-day group and 8.8% in the 5-day group). CONCLUSIONS: In HIV-uninfected Malawian children, treatment with amoxicillin for chest-indrawing pneumonia for 3 days was noninferior to treatment for 5 days. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT02678195.).

Financing child rights in Malawi.

BACKGROUND: Nearly all countries have ratified the United Nations Convention on the Rights of the Child and, therefore, support children having access to their rights. However, only a small minority of children worldwide have access to their environmental, economic, and social rights. The most recent global effort to address these deficits came in 2015, when the United Nations General Assembly agreed to a plan for a fairer and more sustainable future by 2030 and outlined the Sustainable Development Goals (SDGs). One remediable cause is the lack of revenue in many countries, which affects all SDGs. However, illicit financial flows from low-income to high-income countries, including international tax abuse, continue unabated. METHODS: Using the most recent estimates of tax abuse perpetuated by multinational companies and tax evasion through offshore wealth, and precise econometric modelling, we illustrate the potential regarding child rights (or progress towards the SDGs) if there was an increase in revenue equivalent to tax abuse in Malawi, a low-income country particularly vulnerable to climate change. The Government Revenue and Development Estimations model provides realistic estimates of government revenue changes in developmental outcomes. Using panel data on government revenue per capita, it models the impact of increased revenue on governance and SDG progress. RESULTS: If cross-border tax abuse and tax evasion were curtailed, the equivalent increase in government revenue in one country, Malawi, would be associated with 12,000 and 20,000 people having access to basic water and sanitation respectively each year. Each year, an additional 5000 children would attend school, 150 additional children would survive, and 10 mothers would survive childbirth. CONCLUSIONS: More children would access their economic and social rights if actions were taken to close the gap in global governance regarding taxation. We discuss the responsibility of duty bearers, the need for a global body to arbitrate and monitor international tax matters, and how the Government of Malawi could take further domestic action to mitigate the gaps in global governance and protect itself against illicit financial flows, including tax abuse.

Chest radiography in children aged 2-59 months enrolled in the Innovative Treatments in Pneumonia (ITIP) project in Lilongwe Malawi: a secondary analysis.

BACKGROUND: Pneumonia is the leading infectious cause of death in children aged under 5 years in low- and middle-income countries (LMICs). World Health Organization (WHO) pneumonia diagnosis guidelines rely on non-specific clinical features. We explore chest radiography (CXR) findings among select children in the Innovative Treatments in Pneumonia (ITIP) project in Malawi in relation to clinical outcomes. METHODS: When clinically indicated, CXRs were obtained from ITIP-enrolled children aged 2 to 59 months with community-acquired pneumonia hospitalized with treatment failure or relapse. ITIP1 (fast-breathing pneumonia) and ITIP2 (chest-indrawing pneumonia) trials enrolled children with non-severe pneumonia while ITIP3 enrolled children excluded from ITIP1 and ITIP2 with severe pneumonia and/or selected comorbidities. A panel of trained pediatricians classified the CXRs using the standardized WHO CXR research methodology. We analyzed the relationship between CXR classifications, enrollee characteristics, and outcomes. RESULTS: Between March 2016 and June 2018, of 114 CXRs obtained, 83 met analysis criteria with 62.7% (52/83) classified as having significant pathology per WHO standardized interpretation. ITIP3 (92.3%; 12/13) children had a higher proportion of CXRs with significant pathology compared to ITIP1 (57.1%, 12/21) and ITIP2 (57.1%, 28/49) (p-value = 0.008). The predominant pathological CXR reading was "other infiltrates only" in ITIP1 (83.3%, 10/12) and ITIP2 (71.4%, 20/28), while in ITIP3 it was "primary endpoint pneumonia"(66.7%, 8/12,; p-value = 0.008). The percent of CXRs with significant pathology among children clinically cured (60.6%, 40/66) vs those not clinically cured (70.6%, 12/17) at Day 14 was not significantly different (p-value = 0.58). CONCLUSIONS: In this secondary analysis we observed that ITIP3 children with severe pneumonia and/or selected comorbidities had a higher frequency of CXRs with significant pathology, although these radiographic findings had limited relationship to Day 14 outcomes. The proportion of CXRs with "primary endpoint pneumonia" was low. These findings add to existing data that additional diagnostics and prognostics are important for improving the care of children with pneumonia in LMICs. TRIAL REGISTRATION: ITIP1, ITIP2, and ITIP3 were registered with ClinicalTrials.gov ( NCT02760420 , NCT02678195 , and NCT02960919 , respectively).

Methods for conducting a double-blind randomized controlled clinical trial of three days versus five days of amoxicillin dispersible tablets for chest indrawing childhood pneumonia among children two to 59 months of age in Lilongwe, Malawi: a study protocol.

BACKGROUND: Pneumonia is the leading infectious cause of death in children under 5 years of age around the globe. In addition to preventing pneumonia, there is a critical need to provide greater access to appropriate and effective treatment. Studies in Asia have evaluated the effectiveness of 3 days of oral amoxicillin for the treatment of fast-breathing pneumonia; however, further evidence is needed to determine if 3 days of oral amoxicillin is also effective for the treatment of chest indrawing pneumonia. METHODS: This is a double-blind, randomized, non-inferiority trial with the objective to assess the effectiveness of shorter duration amoxicillin dispersible tablet (DT) treatment of chest indrawing childhood pneumonia in a malaria-endemic region of Malawi. The primary objective of this study is to determine whether 3 days of treatment with oral amoxicillin DT in HIV-uninfected Malawian children two to 59 months of age with chest indrawing pneumonia is as effective as 5 days of treatment. The study will enroll 2000 children presenting to Kamuzu Central or Bwaila District Hospitals in Lilongwe, Malawi. Each child will be randomized to either 3 days of amoxicillin DT followed by 2 days of placebo DT or 5 days of amoxicillin DT. Children in the study will be hospitalized for 48 h after enrollment and will have scheduled study visits at Days 2, 4, 6 and 14. Treatment failure by Day 6 is the primary outcome. We hypothesize that the rates of treatment failure will be similar in both arms and that 3 days of treatment will be non-inferior to 5 days of amoxicillin DT for chest indrawing pneumonia using a relative non-inferiority margin of 1.5. This trial was approved by the Western Institutional Review Board and Malawi College of Medicine Research and Ethics Committee. DISCUSSION: Given the paucity of data from Africa, African-based research is necessary to establish appropriate duration of treatment with amoxicillin DT for chest indrawing childhood pneumonia in malaria-endemic settings in the region. An expanded evidence base will contribute to future iterations of World Health Organization Integrated Management of Childhood Illness guidelines. TRIAL REGISTRATION: NCT02678195 : Pre-results. Date registered February 9, 2016.

Effectiveness of three commonly used transition phase diets in the inpatient management of children with severe acute malnutrition: a pilot randomized controlled trial in Malawi.

BACKGROUND: The case fatality rate of severely malnourished children during inpatient treatment is high and mortality is often associated with diarrhea. As intestinal carbohydrate absorption is impaired in severe acute malnutrition (SAM), differences in dietary formulations during nutritional rehabilitation could lead to the development of osmotic diarrhea and subsequently hypovolemia and death. We compared three dietary strategies commonly used during the transition of severely malnourished children to higher caloric feeds, i.e., F100 milk (F100), Ready-to-Use Therapeutic Food (RUTF) and RUTF supplemented with F75 milk (RUTF + F75). METHODS: In this open-label pilot randomized controlled trial, 74 Malawian children with SAM aged 6-60 months, were assigned to either F100, RUTF or RUTF + F75. Our primary endpoint was the presence of low fecal pH (pH ≤ 5.5) measured in stool collected 3 days after the transition phase diets were introduced. Secondary outcomes were duration of hospital stay, diarrhea and other clinical outcomes. Chi-square test, two-way analysis of variance and logistic regression were conducted and, when appropriate, age, sex and initial weight for height Z-scores were included as covariates. RESULTS: The proportion of children with acidic stool (pH ≤5.5) did not significantly differ between groups before discharge with 30, 33 and 23% for F100, RUTF and RUTF + F75, respectively. Mean duration of stay after transitioning was 7.0 days (SD 3.4) with no differences between the three feeding strategies. Diarrhea was present upon admission in 33% of patients and was significantly higher (48%) during the transition phase (p < 0.05). There was no significant difference in mortality (n = 6) between diets during the transition phase nor were there any differences in other secondary outcomes. CONCLUSIONS: This pilot trial does not demonstrate that a particular transition phase diet is significantly better or worse since biochemical and clinical outcomes in children with SAM did not differ. However, larger and more tightly controlled efficacy studies are needed to confirm these findings. TRIAL REGISTRATION: ISRCTN13916953 Registered: 14 January 2013.

Task sharing within a managed clinical network to improve child health in Malawi.

BACKGROUND: Eighty per cent of Malawi's 8 million children live in rural areas, and there is an extensive tiered health system infrastructure from village health clinics to district hospitals which refers patients to one of the four central hospitals. The clinics and district hospitals are staffed by nurses, non-physician clinicians and recently qualified doctors. There are 16 paediatric specialists working in two of the four central hospitals which serve the urban population as well as accepting referrals from district hospitals. In order to provide expert paediatric care as close to home as possible, we describe our plan to task share within a managed clinical network and our hypothesis that this will improve paediatric care and child health. PRESENTATION OF THE HYPOTHESIS: Managed clinical networks have been found to improve equity of care in rural districts and to ensure that the correct care is provided as close to home as possible. A network for paediatric care in Malawi with mentoring of non-physician clinicians based in a district hospital by paediatricians based at the central hospitals will establish and sustain clinical referral pathways in both directions. Ultimately, the plan envisages four managed paediatric clinical networks, each radiating from one of Malawi's four central hospitals and covering the entire country. This model of task sharing within four hub-and-spoke networks may facilitate wider dissemination of scarce expertise and improve child healthcare in Malawi close to the child's home. TESTING THE HYPOTHESIS: Funding has been secured to train sufficient personnel to staff all central and district hospitals in Malawi with teams of paediatric specialists in the central hospitals and specialist non-physician clinicians in each government district hospital. The hypothesis will be tested using a natural experiment model. Data routinely collected by the Ministry of Health will be corroborated at the district. This will include case fatality rates for common childhood illness, perinatal mortality and process indicators. Data from different districts will be compared at baseline and annually until 2020 as the specialists of both cadres take up posts. IMPLICATIONS OF THE HYPOTHESIS: If a managed clinical network improves child healthcare in Malawi, it may be a potential model for the other countries in sub-Saharan Africa with similar cadres in their healthcare system and face similar challenges in terms of scarcity of specialists.

Improvement of temperature surveillance of neonates in low-resource settings by a simple low-cost device: a descriptive study.

INTRODUCTION: Neonatal hypothermia in low-resource settings is prevalent and closely associated with high morbidity and mortality. We examined if an easy-to-read temperature detector device improves health outcomes. METHODS: In a descriptive study, 1009 admissions to a neonatal ward in a tertiary care hospital in Lilongwe, Malawi, were analysed and divided into a baseline and a trial group. The data of 531 newborns with standard care (SC) before the trial were compared with 478 newborns during the implementation of the device (device care=DC). Staff and caregivers were trained on using the device and how to react in case of hypothermia. Data were collected from patient files, device documentation sheets, interviews and focus group discussions. Hypothermia was defined as a body temperature <36.5°C. RESULTS: During the trial, body temperatures throughout the hospital stay were significantly more often obtained (p<0.0001). The median temperature measurements per newborn per day were 1.3 times with SC and 1.6 times with DC, and mild hypothermia was more frequently detected. Moderate hypothermia was avoided in the lightest weight group possibly contributing to significantly shorter hospital stays of surviving newborns (p=0.007). Many caregivers had difficulties using and interpreting the device correctly, and 47% of the reported colours did not match the registered temperatures. Contrary to the above, a questionnaire and focus group discussions with caregivers and health workers showed a high acceptance and the overall opinion that the device was beneficial. CONCLUSION: With more frequent temperature checks, infants with lower birth weight possibly benefited from implementing an easy-to-read continuous temperature indicator, but hypothermia rates remained high. Our data and experiences reveal structural, communicational and consistency/interpretation deficits. Although specifically designed for low-resource settings, the implementation of the device needs a well-working and structured environment, especially regarding staff and caregiver communication.

"I Need to Be the First One with a Different Approach and to Make a Difference to the People": A Mixed Methods Pilot Study on Non-Physician Clinicians Training in Malawi.

Purpose: To improve child health care depends on the availability of sufficient numbers of skilled healthcare workers. To achieve this, the German Society of Tropical Paediatrics & International Child Health supported the existing three-year Bachelor of Science in Paediatrics and Child Health training for Clinical Officers, a non-physician clinician cadre, from 09/2017 to 08/2019. This study aims to evaluate the project to inform forthcoming training. Methods: All 17 students who were in training took part in this study. Quantitative data collection took place between 01/2018 to 06/2019 using the post-self-assessment bloc course survey, Research Self-Efficacy Scale (RSES), and Stages of Change (SOC) model. Students and key informants participated in three focus group discussions and five in-depth interviews during April 1-10, 2019. Results: Students mostly perceived bloc course contents "At their level" (92%) and "Very important/relevant" (61%) with "Good quality" teaching (70.5%). The mean (SD) score for RSES (10-point scale) was 9.10 (0.91). The SOC (4-point scale) scores were higher for "Attitude" and "Intention" statements than "Action". Students found the program well-paced, felt that their clinical knowledge and skills had improved, and valued the acquired holistic disease management approach. They reported increased confidence and being more prepared for leadership roles in their future work. The involvement of international teachers and supervisors enriched their global perspectives. Conclusion: Students improved their clinical and non-clinical skills, developed self-efficacy and attitudes toward research, and were confident to build and utilize their networks. These transformative experiences could facilitate the development of change agents among current and future trainees.

Severe anemia in Malawian children.

BACKGROUND: Severe anemia is a major cause of sickness and death in African children, yet the causes of anemia in this population have been inadequately studied. METHODS: We conducted a case-control study of 381 preschool children with severe anemia (hemoglobin concentration, <5.0 g per deciliter) and 757 preschool children without severe anemia in urban and rural settings in Malawi. Causal factors previously associated with severe anemia were studied. The data were examined by multivariate analysis and structural equation modeling. RESULTS: Bacteremia (adjusted odds ratio, 5.3; 95% confidence interval [CI], 2.6 to 10.9), malaria (adjusted odds ratio, 2.3; 95% CI, 1.6 to 3.3), hookworm (adjusted odds ratio, 4.8; 95% CI, 2.0 to 11.8), human immunodeficiency virus infection (adjusted odds ratio, 2.0; 95% CI, 1.0 to 3.8), the G6PD(-202/-376) genetic disorder (adjusted odds ratio, 2.4; 95% CI, 1.3 to 4.4), vitamin A deficiency (adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.8), and vitamin B12 deficiency (adjusted odds ratio, 2.2; 95% CI, 1.4 to 3.6) were associated with severe anemia. Folate deficiency, sickle cell disease, and laboratory signs of an abnormal inflammatory response were uncommon. Iron deficiency was not prevalent in case patients (adjusted odds ratio, 0.37; 95% CI, 0.22 to 0.60) and was negatively associated with bacteremia. Malaria was associated with severe anemia in the urban site (with seasonal transmission) but not in the rural site (where malaria was holoendemic). Seventy-six percent of hookworm infections were found in children under 2 years of age. CONCLUSIONS: There are multiple causes of severe anemia in Malawian preschool children, but folate and iron deficiencies are not prominent among them. Even in the presence of malaria parasites, additional or alternative causes of severe anemia should be considered.

Malawian children with fast-breathing pneumonia with and without comorbidities.

BACKGROUND: Due to high risk of mortality, children with comorbidities are typically excluded from trials evaluating pneumonia treatment. Understanding heterogeneity of outcomes among children with pneumonia and comorbidities is critical to ensuring appropriate treatment. METHODS: We explored whether the percentage of children with fast-breathing pneumonia cured at Day 14 was lower among those with selected comorbidities enrolled in a prospective observational study than among those enrolled in a concurrent randomized controlled trial evaluating treatment with amoxicillin in Lilongwe, Malawi. RESULTS: Among 79 children with fast-breathing pneumonia in the prospective observational cohort, 57 (72.2%) had HIV infection/exposure, 20 (25.3%) had malaria, 2 (2.5%) had severe acute malnutrition, and 17 (21.5%) had anemia. Treatment failure rate was slightly (not significantly) lower in children with comorbidities (4.1%, 3/73) compared to those without comorbidities (4.5%, 25/552) similarly treated. There was no significant difference in clinical cure rates by Day 14 (95.8% with vs 96.7% without comorbidity). CONCLUSIONS: Children with fast-breathing pneumonia excluded from a concurrent clinical trial due to comorbidities did not fare worse. Children at higher risk whose caregivers seek care early and who receive appropriate risk assessment (e.g., pulse oximetry, hemoglobin, HIV/malaria testing) and treatment, can achieve clinical cure by Day 14. TRIAL REGISTRATION: ClinicalTrials.gov NCT02960919 ; registered November 8, 2016.

Outcomes of in-hospital paediatric cardiac arrest from a tertiary hospital in a low-income African country.

Background: There are scarce data on outcomes of in-hospital paediatric cardiac arrest (CA) in resource-poor settings and none for World Bank-defined low-income countries.Aim: To report the outcomes of in-hospital paediatric CA from a university-affiliated referral hospital in Malawi.Methods: Data were collected prospectively on patients aged 30 days to 13 years who experienced CA and underwent cardiopulmonary resuscitation (CPR) at Kamuzu Central Hospital in Lilongwe, Malawi from January through June 2017. Utstein-style reporting guidelines for CAs were used to define outcomes; the primary outcome was survival to hospital discharge. A data collection form was used to record patient, arrest and resuscitation characteristics.Results: A total of 135 patients fulfilled the criteria for inclusion in the study. Resuscitation outcomes are presented in Figure 1 using a modified Utstein template. In-hospital CA was associated with 100% mortality. Return of spontaneous circulation (ROSC) was obtained in 6% of patients and sustained ROSC in 4%; 24-h survival was zero. The most common admission diagnosis was malaria (51%). Most arrests occurred on the paediatric ward (90%) rather than critical care units. Most resuscitations were led by trainees and mid-level providers (58%) rather than paediatricians (23%).Conclusion: Survival following in-hospital paediatric CA was zero, suggesting that CPR may have no benefit in this tertiary hospital. Future efforts to improve outcomes should focus on advocating better pre-arrest care and research interventions aimed to identify and treat children at risk of CA within the resource constraints of this setting.

The outcome of non-typhoidal salmonella meningitis in Malawian children, 1997-2006.

INTRODUCTION: The clinical course and outcome of non-typhoidal salmonella (NTS) meningitis in Malawian children over a 10-year period (1997-2006) is described. METHODS: Demographic, clinical and laboratory data were collected for all children over 2 months of age admitted with salmonella meningitis to Queen Elizabeth Central Hospital from 1997 to 2006. In the 1st year, salmonellae were susceptible to chloramphenicol, and children received 2 weeks of chloramphenicol treatment. When NTS resistance to chloramphenicol started to appear in 1998, treatment was changed to ceftriaxone. From 2002, the duration of antibiotic therapy was extended to 4-weeks which included 2 weeks of intravenous ceftriaxone and a further 2 weeks of oral ciprofloxacin. RESULTS: The in-hospital case fatality rate (CFR) was 52.3% (48.2% until 2002 and 53.9% after prolonged antibiotic therapy was introduced). Of the survivors, one in 12 (8.3%) became completely well (sequelae-free) in the period 1997-2001 while 18 of 31 survivors (58.1%) made a complete recovery during 2002-2006 (p<0.01). After the 4-week course of antimicrobial therapy was introduced, the number of relapses or recurrences fell from nine in 15 (60%) survivors treated with chloramphenicol or ceftriaxone to three in 35 (8.7%) survivors who received 4 weeks of antibiotics (p<0.0001). CONCLUSION: In Malawi, salmonella meningitis has a CFR of approximately 50%, which has remained constant over many years. Residual morbidity, however, has decreased over 10 years, despite rising numbers of multi-drug-resistant cases of NTS. This improvement might be owing to better treatment and management and/or reduced pathogenicity of the multi-drug-resistant bacteria.

Clinical Outcomes of Pneumonia and Other Comorbidities in Children Aged 2-59 Months in Lilongwe, Malawi: Protocol for the Prospective Observational Study "Innovative Treatments in Pneumonia".

BACKGROUND: Pneumonia is the leading infectious cause of death worldwide among children below 5 years of age. Clinical trials are conducted to determine optimal treatment; however, these trials often exclude children with comorbidities and severe illness. CONCLUSIONS: Given the paucity of data from Africa, African-based research is necessary to establish optimal management of childhood pneumonia in malaria-endemic settings in the region. An expanded evidence base that includes children with pneumonia and other comorbidities, who are at high risk for mortality or have other complications and are therefore typically excluded from childhood pneumonia clinical trials, can contribute to future iterations of the World Health Organization Integrated Management of Childhood Illness guidelines. METHODS: The study enrolled 1000 children with pneumonia presenting to the outpatient departments of Kamuzu Central or Bwaila District Hospitals in Lilongwe, Malawi, who were excluded from concurrent randomized controlled clinical trials investigating fast breathing and chest indrawing pneumonia and who met the inclusion criteria for this prospective observational study. Each child received standard care for their illnesses per Malawian guidelines and hospital protocol and was prospectively followed up with scheduled study visits on days 1, 2 (if hospitalized), 6, 14 (in person), and 30 (by phone). Our primary objectives are to describe the clinical outcomes of children who meet the inclusion criteria for this study and to investigate whether the percentages of children cured at day 14 among those with either fast breathing or chest indrawing pneumonia and comorbidities such as severe malaria, anemia, severe acute malnutrition, or HIV are lower than those in children without these comorbidities in the standard care groups in concurrent clinical trials. This study was approved by the Western Institutional Review Board, Malawi College of Medicine Research and Ethics Committee, and the Malawi Pharmacy, Medicines and Poisons Board. OBJECTIVE: This prospective observational study aimed to assess the clinical outcomes of children aged 2-59 months with both pneumonia and other comorbidities in a malaria-endemic region of Malawi. RESULTS: The Innovative Treatments in Pneumonia project was funded by the Bill and Melinda Gates Foundation (OPP1105080) in April 2014. Enrollment in this study began in 2016, and the primary results are expected in 2019. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13377.

Title Correction: Clinical Outcomes of Pneumonia and Other Comorbidities in Children Aged 2-59 Months in Lilongwe, Malawi: Protocol for the Prospective Observational Study "Innovative Treatments in Pneumonia".

[This corrects the article DOI: 10.2196/13377.].

Analysis of serious adverse events in a paediatric fast breathing pneumonia clinical trial in Malawi.

Introduction: Pneumonia is the leading infectious killer of children. We conducted a double-blind, randomised controlled non-inferiority trial comparing placebo to amoxicillin treatment for fast breathing pneumonia in HIV-negative children aged 2-59 months in Malawi. Occurrence of serious adverse events (SAEs) during the trial were examined to assess disease progression, co-morbidities, recurrence of pneumonia and side effects of amoxicillin. Methods: Enrolled children with fast breathing for age and a history of cough <14 days or difficult breathing were randomised to either placebo or amoxicillin for 3 days, and followed for 14 days to track clinical characteristics and outcomes. Medical history, physical exam, laboratory results and any chest radiographs collected at screening, enrolment and during hospitalisation were evaluated. All SAE reports were reviewed for additional information regarding hospitalisation, course of treatment and outcome. Results: In total, 102/1126 (9.0%) enrolled children with fast breathing pneumonia were reported to have a SAE. Seventy-five per cent (n=77) of SAEs were pneumonia-related (p<0.01). Children<2 years of age represented the greatest proportion (61/77, 79.2%) of those with a pneumonia-related SAE. In the amoxicillin group, there were 46 SAEs and 5 (10.9%) cases were identified as possibly related to study drug (4 gastroenteritis and 1 fever). There were no life-threatening pneumonia SAEs or deaths in either group, and by the time of exit from the study, all children recovered without sequelae. Discussion: In this fast breathing pneumonia clinical trial, SAEs occurred infrequently in both the amoxicillin and placebo groups, and amoxicillin was well tolerated. Trial registration number: NCT02760420. https://clinicaltrials.gov/ct2/show/NCT02760420?term=ginsburg&rank=9.

Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children Aged 2 to 59 Months: A Double-blind, Randomized Clinical Noninferiority Trial.

Importance: Pneumonia is the leading infectious killer of children. Rigorous evidence supporting antibiotic treatment of children with nonsevere fast-breathing pneumonia in low-resource African settings is lacking. Objective: To assess whether treatment with placebo for nonsevere fast-breathing pneumonia is substantively less effective than 3 days of treatment with amoxicillin. Design, Setting, and Participants: This double-blind, 2-arm, randomized clinical noninferiority trial with follow-up of 14 days screened 1343 HIV-uninfected children aged 2 to 59 months with nonsevere fast-breathing pneumonia at outpatient departments of hospitals in Lilongwe, Malawi, Africa, between June 2016 and June 2017. Interventions: Placebo or amoxicillin dispersible tablets administered twice daily for 3 days. Main Outcomes and Measures: The primary end point was the proportion of children failing treatment by day 4 with a relative noninferiority margin of 1.5 times the failure rate in the amoxicillin group. Primary analyses were performed based on the intention-to-treat principle. Planned secondary analyses included treatment failure or relapse by day 14. Results: In total, 1126 children were randomized to 3 days of amoxicillin (n = 564) or placebo (n = 562) therapy. Baseline demographic and clinical characteristics were similar between the groups. For the entire study population, the mean (SD) age was 21.3 (15.1) months, and 601 (53.4%) were female. After an interim analysis, the data safety monitoring board stopped the study because children receiving amoxicillin had a 4.0% (22 of 552 with outcome data) treatment failure rate by day 4, whereas children receiving placebo had a 7.0% (38 of 543) treatment failure rate (adjusted relative risk, 1.78; 95% CI, 1.07%-2.97%; adjusted absolute difference, 3.0%; 95% CI, 0.4%-5.7%). Among children with known day 14 outcomes, 56 of 552 (10.1%) receiving amoxicillin and 64 of 543 (11.8%) receiving placebo had either treatment failure by day 4 or relapse by day 14 (relative risk, 1.16; 95% CI, 0.83%-1.63%; absolute difference, 1.6%; 95% CI, -2.1% to 5.4%). There were no deaths. Conclusions and Relevance: In HIV-uninfected children aged 2 to 59 months in a malaria-endemic region of Malawi, placebo treatment of nonsevere fast-breathing pneumonia was significantly inferior to treatment with amoxicillin. However, by day 4, approximately 93% of children receiving placebo were without treatment failure, and there was no significant difference between groups in treatment failure or relapse by day 14. The number of children with nonsevere fast-breathing pneumonia that needed amoxicillin treatment for 1 child to benefit was 33. Trial Registration: ClinicalTrials.gov Identifier: NCT02760420.

Use of bubble continuous positive airway pressure (bCPAP) in the management of critically ill children in a Malawian paediatric unit: an observational study.

Introduction: In low-resource countries, respiratory failure is associated with a high mortality risk among critically ill children. We evaluated the role of bubble continuous positive airway pressure (bCPAP) in the routine care of critically ill children in Lilongwe, Malawi. Methods: We conducted an observational study between 26 February and 15 April 2014, in an urban paediatric unit with approximately 20 000 admissions/year (in-hospital mortality <5% approximately during this time period). Modified oxygen concentrators or oxygen cylinders provided humidified bCPAP air/oxygen flow. Children up to the age of 59 months with signs of severe respiratory dysfunction were recruited. Survival was defined as survival during the bCPAP-treatment and during a period of 48 hours following the end of the bCPAP-weaning process. Results: 117 children with signs of respiratory failure were included in this study and treated with bCPAP. Median age: 7 months. Malaria rapid diagnostic tests were positive in 25 (21%) cases, 15 (13%) had severe anaemia (Hb < 7.0 g/dL); 55 (47%) children had multiorgan failure (MOF); 22 (19%) children were HIV-infected/exposed. 28 (24%) were severely malnourished. Overall survival was 79/117 (68%); survival was 54/62 (87%) in children with very severe pneumonia (VSPNA) but without MOF. Among the 19 children with VSPNA (single-organ failure (SOF)) and negative HIV tests, all children survived. Survival rates were lower in children with MOF (including shock) (45%) as well as in children with severe malnutrition (36%) and proven HIV infection or exposure (45%). Conclusion: Despite the limitations of this study, the good outcome of children with signs of severe respiratory dysfunction (SOF) suggests that it is feasible to use bCPAP in the hospital management of critically ill children in resource-limited settings. The role of bCPAP and other forms of non-invasive ventilatory support as a part of an improved care package for critically ill children with MOF at tertiary and district hospital level in low-resource countries needs further evaluation. Critically ill children with nutritional deficiencies and/or HIV infection/exposure need further study to determine bCPAP efficacy.

Building Sustainable Partnerships to Strengthen Pediatric Capacity at a Government Hospital in Malawi.

INTRODUCTION: To achieve sustained reductions in child mortality in low- and middle-income countries, increased local capacity is necessary. One approach to capacity building is support offered via partnerships with institutions in high-income countries. However, lack of cooperation between institutions can create barriers to successful implementation of programs and may inadvertently weaken the health system they are striving to improve. A coordinated approach is necessary. BACKGROUND: Three U.S.-based institutions have separately supported various aspects of pediatric care at Kamuzu Central Hospital (KCH), the main government referral hospital in the central region of Malawi, for several years. Within each institution's experience, common themes were recognized, which required attention in order to sustain improvements in care. Each recognized that support of clinical care is a necessary cornerstone before initiating educational or training efforts. In particular, the support of emergency and acute care is paramount in order to decrease in-hospital mortality. Through the combined efforts of Malawian partners and the US-based institutions, the pediatric mortality rate has decreased from >10 to <4% since 2011, yet critical gaps remain. To achieve further improvements, representatives with expertise in pediatric emergency medicine (PEM) from each US-based institution hypothesized that coordinated efforts would be most effective, decrease duplication, improve communication, and ensure that investments in education and training are aligned with local priorities. CALL TO ACTION: Together with local stakeholders, the three US-based partners created a multi-institutional partnership, Pediatric Alliance for Child Health Improvement in Malawi at Kamuzu Central Hospital and Environs (PACHIMAKE). Representatives from each institution gathered in Malawi late 2016 and sought input and support from local partners at all levels to prioritize interventions, which could be collectively undertaken by this consortium. Long- and short-term goals were identified and approved by local partners and will be implemented through a phased approach. CONCLUSION: The development of a novel partnership between relevant stakeholders in Malawi and US-based partners with expertise in PEM should help to further decrease pediatric mortality through the coordinated provision of acute care expertise and training as well as investment in the development of educational, research, and clinical efforts in PEM at KCH.

Severe anemia in Malawian children.

BACKGROUND: Severe anemia is a major cause of sickness and death in African children, yet the causes of anemia in this population have been inadequately studied. METHODS: We conducted a case-control study of 381 preschool children with severe anemia (hemoglobin concentration, <5.0 g per deciliter) and 757 preschool children without severe anemia in urban and rural settings in Malawi. Causal factors previously associated with severe anemia were studied. The data were examined by multivariate analysis and structural equation modeling. RESULTS: Bacteremia (adjusted odds ratio, 5.3; 95% confidence interval [CI], 2.6 to 10.9), malaria (adjusted odds ratio, 2.3; 95% CI, 1.6 to 3.3), hookworm (adjusted odds ratio, 4.8; 95% CI, 2.0 to 11.8), human immunodeficiency virus infection (adjusted odds ratio, 2.0; 95% CI, 1.0 to 3.8), the G6PD-202/-376 genetic disorder (adjusted odds ratio, 2.4; 95% CI, 1.3 to 4.4), vitamin A deficiency (adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.8), and vitamin B12 deficiency (adjusted odds ratio, 2.2; 95% CI, 1.4 to 3.6) were associated with severe anemia. Folate deficiency, sickle cell disease, and laboratory signs of an abnormal inflammatory response were uncommon. Iron deficiency was not prevalent in case patients (adjusted odds ratio, 0.37; 95% CI, 0.22 to 0.60) and was negatively associated with bacteremia. Malaria was associated with severe anemia in the urban site (with seasonal transmission) but not in the rural site (where malaria was holoendemic). Seventy-six percent of hookworm infections were found in children under 2 years of age. CONCLUSIONS: There are multiple causes of severe anemia in Malawian preschool children, but folate and iron deficiencies are not prominent among them. Even in the presence of malaria parasites, additional or alternative causes of severe anemia should be considered.