CHIZAP: Community- and Health Facility-Based Intervention With Zinc as Adjuvant Therapy for Childhood Pneumonia

• Risk of treatment failure and the duration of illness. For those with severe pneumonia: length of hospital stay. [ Time Frame: Within 2 weeks after enrollment ] [ Designated as safety issue: No ]
  Enrolled children will be followed and given zinc or placebo for 14 days.
  
  
• Non-injury clinic visits and hospital admissions after treatment has been initiated [ Time Frame: Within 2 weeks after enrollment ] [ Designated as safety issue: No ]
  
• Active and passive morbidity surveillance for six months after the 14-day supplementation period is completed [ Time Frame: six months ] [ Designated as safety issue: No ]
  
• Difference in growth and thymic size between the treatment groups measured at three and six months after the zinc supplementation [ Time Frame: six months ] [ Designated as safety issue: No ]
  
• Adverse effects [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
  Vomiting, regurgitation, pain in abdomen for 15 minutes after zinc or placebo administration.
  
  

• Whether the following are modifiers for the above-mentioned effect of zinc given during pneumonia: i. severe inflammation, reflected in: high fever and/or elevated plasma C-reactive protein (CRP) concentration [ Time Frame: Within 2 weeks after enrollment ] [ Designated as safety issue: No ]
  
• The efficacy of zinc according to breast feeding status and in different age categories [ Time Frame: Within 2 weeks after enrollment ] [ Designated as safety issue: No ]
  
• The efficacy of zinc in malnourished and non-malnourished children [ Time Frame: Within 2 weeks after enrollment ] [ Designated as safety issue: No ]
  We will compare the efficacy of zinc in those that are stunted, wasted or underweight with those who are not.
  
  
• Will presence of a RNA virus modify the effect of zinc [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  We will compare the efficacy of zinc according to virus detected in nasopharyngeal secretions
  
  
• Folate, cobalamin and vitamin D status of the enrolled children [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  And whether or not these vitamins predict treatment failure and duration of illness.
  
  

Hypothesis: Zinc deficiency is a major public health problem in developing counties. Poor zinc status is associated with stunted growth and reduced resistance to infections. Several in vitro experiments and in vivo studies in animals and humans have demonstrated detrimental effects of zinc depletion on almost all facets of the immune system. The epithelial linings in the gut and in the respiratory tract are important for the resistance to infections and continuous cell division is required for proper function of these barriers. Zinc is crucial for cellular division and for the maintenance of organs with cells with a rapid turnover, including epithelial cells. Clinical trials in children in developing countries have demonstrated improved growth and reduced prevalence of diarrhea and respiratory tract infections following zinc supplementation. Furthermore, zinc has a well-documented therapeutic effect when given during acute or persistent diarrhea. The effect of zinc may be explained by correction of a deficiency state and/or by a pharmacological, as yet poorly described, action.

Due to the promising results from previous studies, WHO are now supporting large clinical trials in Nepal, India and Tanzania to assess whether routine zinc supplementation reduces mortality in early childhood. If the results of these trials show a mortality reduction, routine zinc supplementation or zinc dense foods may be promoted. However, while the first approach is logistically difficult and expensive, the second approach is difficult because zinc dense foods and foods with low phytic acid content are expensive and not readily available. Moreover, both approaches may be perceived to be incompatible with the current breast-feeding recommendations for the youngest children in most developing countries.

There is limited information on zinc as adjunct therapy for pneumonia. A recent hospital-based study in young children with severe pneumonia, showed that the zinc group had a faster recovery, resulting in a shortening of stay in hospital of one day. However, this study was small and no community based study has been conducted so far. Whether zinc has an effect during respiratory infections has to be assessed in studies with larger sample sizes in children with less severe disease and should be repeated in children with more severe disease. Short-term zinc administration during infections may become an alternative or an addition to long-term supplementation or promotion of zinc dense foods. Furthermore, therapeutic administration of zinc will not interfere with the current breast-feeding recommendations.

Hypothesis: Zinc as adjunct therapy for pneumonia may lead to faster recovery. Furthermore, long-term beneficial effects may include improved immuno-nutritional status measured by thymus size, less morbidity and improved growth.

Comparison: Duration of illness, risk of treatment failure, for those with severe pneumonia: length of hospital stay. Number of non-injury clinic visits and hospitalizations during the intervention with Zinc and an in a 6 month period after enrolment. Growth assessed by anthropometry and thymus size assessed by ultrasonography. Explore the efficacy of zinc in etiology-sub groups including those defined by nutritional status, inflammation, fever, gender, breastfeeding status and viral etiology.