Sepsis Clinical Trial
Official title:
Zinc as an Immunomodulator in the Treatment of Possible Serious Bacterial Infections in Infants 7 Days and up to 4 Months of Age
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.
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.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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