Severe pneumonia in hospitalized young Nepalese children. Studies on the efficacy of oral zinc, respiratory viruses and prognostic determinants

Abstract

Pneumonia is a leading cause of death in children less than five years of age in low and middle income countries and contributes importantly to their disease burden. Zinc, essential for normal function of the immune system, is an important micronutrient for children. While routine zinc supplementation has been shown to reduce the risk of pneumonia in children, results from studies on the therapeutic effect of zinc for pneumonia are inconsistent. We conducted a randomized double blind placebo controlled clinical trial, which formed the basis for the work described in this thesis. The aim of the trial was to estimate the extent to which administration of oral zinc reduces time till recovery and risk of treatment failure in children hospitalized with severe pneumonia defined as community acquired pneumonia with chest indrawing. We later performed a secondary analysis to identify clinical, radiological and laboratory prognostic factors for illness duration and risk of treatment failure. We also collected nasopharyngeal aspirates from the included children, to identify seven common respiratory viruses using a multiplex reverse transcription polymerase chain reaction assay. In the trial we followed up 598 children that were 2 - 35 months of age and enrolled with severe pneumonia shortly after they were admitted to a centrally located general children's hospital in Kathmandu, Nepal. Trial participants were randomized to receive zinc sulphate (10 mg in children less than 12 months and 20 mg in older children) or placebo daily until discharge or up to a maximum of 14 days. The children were monitored by study physicians until they were discharged. In this large cohort of children with severe pneumonia, the median time till recovery was 2 days and treatment failure was detected in one third. We found a non-significant and clinically unimportant 10% reduction of illness duration in the children receiving zinc. Similarly, the proportion of children who had recovered within 72, 96 and 120 hours after enrolment or at risk of treatment failure was not significantly different between the zinc and placebo arms. Vomiting was more frequently observed in the children who received zinc. Younger age, radiographic consolidation and hypoxia on admission were independent predictors of both delayed recovery and increased risk of treatment failure. At least one of the seven respiratory viruses was detected in 30% of the children. Respiratory syncytial virus, detected in 14%, was by far the most common. During the study period of 30 months, the observed pneumonia epidemics occurred in 2 main annual peaks, but the timing of the epidemics varied. The findings from this randomized controlled clinical trial contribute to the evidence that zinc is not an effective adjunct to standard treatment of hospitalized children with severe pneumonia in low and middle income countries. Younger age, hypoxia and radiographic consolidation on admission predicted delayed recovery and treatment failure, and can be useful tools to guide the management of severe pneumonia in hospitalized children in resource poor settings. Our work on molecular based detection of seven respiratory viruses in nasopharyngeal aspirates identified respiratory syncytial virus as an important pathogen in children hospitalized with pneumonia, which is relevant for a country where the epidemiology of pneumonia is changing and viral pneumonia is still unrecognized as a cause of hospital admissions. Our findings contribute to the understanding of childhood pneumonia and provide arguments for not using zinc as adjunct therapy in children hospitalized for severe pneumonia.