Therapeutic Zinc in Infant Bacterial Illness
Condition: Sepsis; Bacterial Infections; Pneumonia
MeSH terms: Infections; Bacterial Infections
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Infections are the important cause of high mortality in young infants in developing
      countries. Zinc is a crucial micronutrient as it influences various immune mechanisms and
      modulates host resistance to several pathogens. It has shown benefits as an adjunct therapy
      in infections like diarrhea and pneumonia in older children Given the predisposition of young
      infants in developing countries to zinc deficiency and infections, addition of zinc to
      standard treatment of serious bacterial infections may lead to significant improvements in
      the outcomes.

      Several hypotheses will be examined in this clinical trial. The primary objective is to
      measure, in a double blind randomized controlled trial, the efficacy of giving 2 RDA
      (Required Daily Allowance 10 mg) of zinc orally in addition to routine antibiotics, for
      treatment of possible serious bacterial infection in infants >= 7 days and up to 4 months of
      age in reducing the proportion of treatment failures and time to discharge from the hospital.
      This will evaluate the clinical consequences of the possible immunomodulation by zinc
      supplementation. This is critical to demonstrate because nearly 80% of infant mortality
      occurs in first months of life.

      Young infants with possible serious bacterial infections fulfilling the inclusion criteria
      will be enrolled in the study and stratified into 4 groups on basis of weight for age 'z'
      scores < -2 z and >=- 2 z and whether he/she has diarrhea or not. Within each stratum the
      subjects will be randomized to receive zinc or placebo. Treatment failures will be defined by
      the need for a change of initial antibiotic therapy. The minimum duration of monitoring will
      be till clinical recovery (using predetermined criteria). Serum copper, serum ferritin and
      serum transferrin receptors will be determined at enrollment, 72 hours after enrollment and
      at discharge from the hospital. Concentrations of CRP and procalcitonin will be measured at
      baseline, 72 hours after enrolment and at clinical recovery.

      Documentation of efficacy of addition of zinc to standard therapy may provide a simple and
      low-cost strategy to improve survival in serious infections in young infants. This is likely
      to have a significant impact on infant morbidity and mortality. It will be good example of
      using a simple immunomodulator beneficially in improving child health.
    

Detailed description: 
      Infant mortality rate continues to be high in most developing countries despite advances in
      child health care. Infections are the most important cause of deaths in infants. There is
      increasing recognition that nutritional deficiencies including micronutrients are important
      determinants of infection and their outcomes. Zinc is a crucial micronutrient as it
      influences various immune mechanisms and modulates host resistance to several pathogens.
      Supplementation with zinc has been documented to provide protection against common childhood
      infections. It has also shown benefits as an adjunct therapy in infections like diarrhea and
      pneumonia in older children. Given the predisposition of young infants in developing
      countries to zinc deficiency and infections, addition of zinc to standard treatment of
      serious bacterial infections may lead to significant improvements in the outcomes. This is
      critical to demonstrate because nearly 80% of infant mortality occurs in first 2 months of
      life.

      The infant mortality rates in India continue to be in excess of 60 per 1000 live births.
      Neonatal mortality contributes to over 64% of the infant deaths particularly in those who are
      born low birth weight. Most of the other deaths occur in the second and third months. Serious
      systemic infections like sepsis and pneumonia constitute 30-40% of the causes of mortality.
      Any health programme that aims at reducing infant mortality rate needs to address mortality
      in the first two months of life.

      Almost 90% of all low birth weight (LBW) babies are born in developing countries,
      particularly in the Indian subcontinent. Nearly 70% of these are small for gestational age
      unlike in the developed world where the bulk of low birth weight babies are preterms. Zinc
      deficiency during fetal development is documented to cause intra-uterine growth retardation
      and also impaired postnatal immune functions making these babies more susceptible to severe
      infections. Studies have shown good correlation between cord blood zinc, maternal zinc
      concentration and birth weights.

      The zinc content of the breast milk decreases rapidly after birth. In addition, the
      requirements are likely to be high as young infants in developing countries live in high
      microbial load environment and are exposed to recurrent infections. Further, malnourished
      infants need more zinc for catch up growth. All these predispose them to develop zinc
      deficiency and infections. In a population based study by our group last year, nearly 40% of
      young infants had low plasma zinc despite being breast-fed, probably a reflection of
      inadequate tissue stores (unpublished data).

      Zinc influences many aspects of the immune system starting with its effects on the barrier
      and various components of innate and acquired immunity. There is sufficient data from animal
      and human studies of increased host susceptibility to infections with zinc deficiency. A
      vicious cycle of infection and zinc deficiency exists. Infection reduces the plasma zinc
      concentration, which reflects the severity of the infection and inflammation. This may be
      observed early during the illness. Organs such as the skin, thymus, bones and the epithelium
      also become depleted during this process. Severe bacterial illnesses also lead to zinc
      redistribution. It is plausible that this redistribution increases the infection severity.

      There is limited data on therapeutic effect of zinc supplementation on severe infections in
      young infants less than 4 months of age. A short inexpensive course of zinc for patients with
      serious bacterial infections can become a simple but potent intervention to reduce young
      infant mortality and morbidity. While the effects of zinc deficiency and of supplementation
      are reasonably well documented eventually the benefits on clinical outcome alone can result
      in its application.
    

Intervention name(s): Drug: Zinc (zinc sulphate); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Dissolvable tablet 10 mg. Once daily during the illness; Placebo tablet, once daily
Other intervention name(s): Produced by Nutriset; Malaunay, France; Produced by Nutriset; Malaunay, France
Intervention MeSH terms: Zinc Sulfate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Infants; India; Zinc; Bacterial illness; Treatment