Randomised Trials in Child and Adolescent Health in Developing Countries

BACKGROUND: Pneumonia is the leading cause of child mortality under five years of age worldwide. For pneumonia with chest indrawing in children aged 3-59 months, injectable penicillin and hospitalization was the recommended treatment. This increased the health care cost and exposure to nosocomial infections. We compared the clinical and cost outcomes of a seven day treatment with oral amoxicillin with the first 48 h of treatment given in the hospital (hospital group) or at home (home group). METHODS: We conducted an open-label, multi-center, two-arm randomized clinical trial at six tertiary hospitals in India. Children aged 3 to 59 months with chest indrawing pneumonia were randomized to home or hospital group. Clinical outcomes, treatment adherence, and patient safety were monitored through home visits on day 3, 5, 8, and 14 with an additional visit for the home group at 24 h. Clinical outcomes included treatment failure rates up to 7 days (primary outcome) and between 8-14 days (secondary outcome) using the intention to treat and per protocol analyses. Cost outcomes included direct medical, direct non-medical and indirect costs for a random 17% subsample using the micro-costing technique. RESULTS: 1118 children were enrolled and randomized to home (n = 554) or hospital group (n = 564). Both groups had similar baseline characteristics. Overall treatment failure rate was 11.5% (per protocol analysis). The hospital group was significantly more likely to fail treatment than the home group in the intention to treat analysis. Predictors with increased risk of treatment failure at any time were age 3-11 months, receiving antibiotics within 48 h prior to enrolment and use of high polluting fuel. Death rates at 7 or 14 days did not differ significantly. (Difference -0.0%; 95% CI -0.5 to 0.5). The median total treatment cost was Rs. 399 for the home group versus Rs. 602 for the hospital group (p < 0.001), for the same effect of 5% failure rate at the end of 7 days of treatment in the random subsample. CONCLUSIONS: Home based oral amoxicillin treatment was equivalent to hospital treatment for first 48 h in selected children of chest indrawing pneumonia and was cheaper. Consistent with the recent WHO simplified guidelines, management with home based oral amoxicillin for select children with only fast breathing and chest-indrawing can be a cost effective intervention. http://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-015-0510-9 Randomised trials in child health in developing countries 2015-16 12 Comment There were over 6000 children screened for the above study of “chest indrawing” pneumonia, and over 3000 were excluded for clinical reasons, including likely asthma or bronchodilator responsive wheeze (1010), chronic cough or other chronic condition (419), severe malnutrition (163), presence of danger signs (412). 308 could not be a part of the study because they lived too far away to be followed up. So this gives some idea of the overall case mix and epidemiology of the populations presenting with respiratory disease. In translating the evidence from these community-based antibiotic trials into practice, the message should not be that “severe pneumonia can be managed at home”, but that if comorbidities and risk factors for severity and poor outcomes can be identified and excluded, then for very low risk children, home management of ARI with chest indrawing is safe. There were only 2 deaths in this study, one on each hospital and home care group. J Med Assoc Thai. 2015 Sep;98(9):858-63. Comparison between the Efficacy of Switch Therapy and Conventional Therapy in Pediatric Community-Acquired Pneumonia. In-iw S, Winijkul G, Sonjaipanich S, Manaboriboon B. Abstract OBJECTIVE: Compare the treatment outcomes ofswitch therapy and conventional therapy inpediatricpatients aged one month to five years old, diagnosed with community-acquired pneumonia who required hospitalization.OBJECTIVE: Compare the treatment outcomes ofswitch therapy and conventional therapy inpediatricpatients aged one month to five years old, diagnosed with community-acquired pneumonia who required hospitalization. MATERIAL AND METHOD: The present study was performed and approved by the Siriraj Research Ethics Committee. With informed consent, 57 patients who fitted the inclusion criteria were randomized into two groups, 1) the switch therapy group (SWT), who switched their method of receiving antibiotics from IV to oral within 24 hours after clinical improvement and body temperature under 37.8 °C at least eight hours, and 2) the control group, the group treated as routine general practice. Chisquare tests, Fisher's exact tests, unpaired t-tests, and Mann-Whitney U tests were used in analysis. A non-inferiority analysis to estimate 1-sided 95% CIs was performed to determine the greatest difference (worst case) between groups. RESULTS: There were no significant differences in age, sex, clinical presentations, and antibiotics provided between the two groups. A statistically significant reduction in length of hospital stay was found in the SWT group (P = 0.019), whereas the readmission rate for both groups was not significantly different (p = 0.66). Morbidity and mortality were not found in either groups. The SWT group demonstrated non-inferior efficacy comparing to control group (difference 20%; p<0. 001). CONCLUSION: In pediatric community-acquired pneumonia, early switching from administer IV antimicrobial agents to oral form when clinical signs improved were safe and effective. Switch therapy showed non-inferiority outcomes compared to conventional therapy, and had advantages in shortening the length of stay and indirectly lowering the cost of hospitalization. Randomised trials in child health in developing countries 2015-16 13 Lancet. 2015 Sep 12;386(9998):1057-65. doi: 10.1016/S0140-6736(15)60249-5. Epub 2015 Aug 19. Bubble continuous positive airway pressure for children with severe pneumonia and hypoxaemia in Bangladesh: an open, randomised controlled trial. Chisti MJ, Salam MA, Smith JH, Ahmed T, Pietroni MA, Shahunja KM, Shahid AS, Faruque AS, Ashraf H,Bardhan PK, Sharifuzzaman, Graham SM, Duke T. Abstract BACKGROUND: In developing countries, mortality in children with very severe pneumonia is high, even with the provision of appropriate antibiotics, standard oxygen therapy, and other supportive care. We assessed whether oxygen therapy delivered by bubble continuous positive airway pressure (CPAP) improved outcomes compared with standard low-flow and high-flow oxygen therapies.BACKGROUND: In developing countries, mortality in children with very severe pneumonia is high, even with the provision of appropriate antibiotics, standard oxygen therapy, and other supportive care. We assessed whether oxygen therapy delivered by bubble continuous positive airway pressure (CPAP) improved outcomes compared with standard low-flow and high-flow oxygen therapies. METHODS: This open, randomised, controlled trial took place in Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh. We randomly assigned children younger than 5 years with severe pneumonia and hypoxaemia to receive oxygen therapy by either bubble CPAP (5 L/min starting at a CPAP level of 5 cm H2O), standard low-flow nasal cannula (2 L/min), or high-flow nasal cannula (2 L/kg per min up to the maximum of 12 L/min). Randomisation was done with use of the permuted block methods (block size of 15 patients) and Fisher and Yates tables of random permutations. The primary outcome was treatment failure (ie, clinical failure, intubation and mechanical ventilation, death, or termination of hospital stay against medical advice) after more than 1 h of treatment. Primary and safety analyses were by intention to treat. We did two interim analyses and stopped the trial after the second interim analysis on Aug 3, 2013, as directed by the data safety and monitoring board. FINDINGS: Between Aug 4, 2011, and July 17, 2013, 225 eligible children were recruited. We randomly allocated 79 (35%) children to receive oxygen therapy by bubble CPAP, 67 (30%) to lowflow oxygen therapy, and 79 (35%) to high-flow oxygen therapy. Treatment failed for 31 (14%) children, of whom five (6%) had received bubble CPAP, 16 (24%) had received low-flow oxygen therapy, and ten (13%) had received high-flow oxygen therapy. Significantly fewer children in the bubble CPAP group had treatment failure than in the low-flow oxygen therapy group (relative risk [RR] 0·27, 99·7% CI 0·07-0·99; p=0·0026). No difference in treatment failure was noted between patients in the bubble CPAP and those in the high-flow oxygen therapy group (RR 0·50, 99·7% 0·11-2·29; p=0·175). 23 (10%) children died. Three (4%) children died in the bubble CPAP group, ten (15%) children died in the low-flow oxygen therapy group, and ten (13%)children died in the high-flow oxygen therapy group. Children who received oxygen by bubble CPAP had significantly lower rates of death than the children who received oxygen by low-flow oxygen therapy (RR 0·25, 95% CI 0·070·89; p=0·022). INTERPRETATION: Oxygen therapy delivered by bubble CPAP improved outcomes in Bangladeshi children with very severe pneumonia and hypoxaemia compared with standard low-flow oxygen therapy. Use of bubble CPAP oxygen therapy could have a large effect in hospitals in developing countries where the only respiratory support for severe childhood pneumonia and hypoxaemia is low-flow oxygen therapy. The trial was stopped early because of higher mortality in the low-flow oxygen group than in the bubble CPAP group, and we acknowledge that the early cessation of the trial reduces the certainty of the findings. Further research is needed to test Randomised trials in child health in developing countries 2015-16 14 the feasibility of scaling up bubble CPAP in district hospitals and to improve bubble CPAP delivery technology. Comment WHO has recently published a manual of Oxygen Therapy for Children, which describes how to make low-cost CPAP (http://apps.who.int/iris/handle/10665/204584). Other descriptions are in CPAP: a guide for clinicians in developing countries http://www.tandfonline.com/doi/pdf/10.1179/2046905513Y.0000000102 Trop Med Int Health. 2015 Oct;20(10):1320-8. doi: 10.1111/tmi.12557. Epub 2015 Jul 15. Stunting is associated with poor outcomes in childhood pneumonia. Moschovis PP, Addo-Yobo EO, Banajeh S, Chisaka N, Christiani DC, Hayden D, Jeena P, MacLeod WB, Mino G, Patel A, Qazi S, Santosham M, Thea DM, Hibberd PL. Abstract OBJECTIVE: Stunting affects 26.7% of children worldwide, and little is known about its effects on the outcomes of childhood pneumonia. We evaluated the effect of stunting on the outcomes of pneumonia among children enrolled in two large clinical trials.OBJECTIVE: Stunting affects 26.7% of children worldwide, and little is known about its effects on the outcomes of childhood pneumonia. We evaluated the effect of stunting on the outcomes of pneumonia among children enrolled in two large clinical trials. METHODS: We analysed data from two WHO and USAID-sponsored inpatient treatment trials, the Severe Pneumonia Evaluation Antimicrobial Research study (n = 958) and the Amoxicillin Penicillin Pneumonia International Study (n = 1702), which enrolled children aged 2-59 months across 16 sites in LMICs. We assessed the effect of stunting (height-for-age Z score < -2) on treatment outcome and time to resolution of hypoxaemic pneumonia. RESULTS: Among 2542 (96%) children with valid data for height, 28% were stunted and 12.8% failed treatment by 5 days. The failure rate among stunted patients was 16.0% vs. 11.5% among non-stunted patients [unadjusted RR = 1.24 (95% CI 1.08, 1.41); adjusted RR = 1.28 (95% CI 1.10, 1.48)]. An inverse relationship was observed between height and failure rates, even among non-stunted children. Among 845 patients with hypoxaemic pneumonia, stunting was associated with a lower probability of normalisation of respiratory rate [HR = 0.63 (95% CI 0.52, 0.75)] and oxygen saturation [HR = 0.74 (95% CI 0.61, 0.89)]. CONCLUSIONS: Stunting increases the risk of treatment failure and is associated with a longer course of recovery in children with pneumonia. Strategies to decrease stunting may decrease the burden of adverse outcomes in childhood pneumonia in low-resource settings.