SEPSIS Observational Cohort Study in Young Infants in Bangladesh
Condition: Severe Infection and Non-injury Death
MeSH terms: Infections
Study type: Observational

Summary: 
      Globally, infectious diseases such as sepsis, meningitis and pneumonia are among the leading
      causes of neonatal deaths. A recent observational study in South Asia highlighted the
      contribution of both bacterial and viral infections to the burden of illness in infants <60
      days of age; however, there remains a need to quantify the risk of severe infection (SI)
      among newborns in a Bangladeshi population. In collaboration with researchers in Bangladesh,
      investigators aim to generate knowledge regarding the incidence and risk factors of SI,
      including the composition of the intestinal microbiome, in young infants (birth to 60 days of
      age) in Dhaka, Bangladesh. Data will support the design and implementation of future trials
      to test the efficacy of novel interventions for the prevention of SI in young infants, to
      promote optimal growth and development, and to determine effects on other health outcomes in
      early infancy.
    

Detailed description: 
      Globally, infectious diseases including sepsis, meningitis, and pneumonia are among the
      leading causes of neonatal deaths. In 2017, these three conditions were estimated to account
      for 540,000 newborn deaths worldwide, approximately 21% of all neonatal deaths globally.
      Previous studies have suggested that South Asia has a relatively high incidence of possible
      serious bacterial infection (pSBI) in young infants, particularly in areas where neonatal and
      under-five mortality rates are highest.

      A large body of evidence from inpatient neonatal populations, and the recent evidence from
      the Panigrahi et al. community trial in India, support an important role of intestinal
      dysbiosis in the pathogenesis of sepsis/SI in young infants. This mechanism may be
      particularly important in low- and middle-income countries in Africa and South Asia, where
      low-cost routine interventions to reduce the burden of SI (e.g., probiotics or synbiotics)
      could have an important impact on the burden of morbidity and mortality in young infants.
      However, there are limited data regarding the composition of the early postnatal microbiome
      in the general population of infants (rather than selected groups of preterm or hospitalized
      newborns) in South Asia and the role of the microbiome in modulating the risk of SI.

      This observational study will generate new knowledge about the incidence and risk factors of
      SI, including the composition of the intestinal microbiome, in young infants (birth to 60
      days of age) in Dhaka, Bangladesh. The aims of this study are to:

        1. Estimate the incidence of SI in a facility-recruited cohort of Bangladeshi newborns
           during the first 60 days of life, and examine the sensitivity of the estimates to
           variations in SI case definitions;

        2. Explore the associations between maternal-infant characteristics (e.g., mode of
           delivery, feeding practices, gestational age, antibiotic exposure) and the risk of SI in
           the first 60 days of life;

        3. Estimate the absolute and relative stool abundances and age at initial colonization of
           Bifidobacterium longum subspecies (ssp.) infantis (B. infantis), Bifidobacterium longum
           ssp. longum (B. longum longum), Bifidobacterium breve (B. breve) and all bifidobacteria
           species combined during the first 60 days of life in Bangladeshi newborns, overall and
           within sub-groups defined by: mode of delivery, feeding practices, prior or current
           infant exposure to antibiotics, and whether there is colonization with the specific
           bacterial species or subspecies;

        4. Explore the associations between maternal-infant characteristics (e.g., mode of
           delivery, feeding practices, gestational age, antibiotic use) and stool abundance (or
           age at initial colonization) of B. infantis, B. longum longum, and B. breve;

        5. Estimate the association between stool abundance of B. infantis and SI in Bangladeshi
           newborns during the first 60 days of life;

        6. Describe the composition, diversity, and stability of the microbiome in Bangladeshi
           newborns at multiple time-points during the first 60-days of life, and examine how the
           composition, diversity, and stability varies by mode of delivery and other
           maternal-infant and household characteristics;

        7. In a facility-recruited cohort of Bangladeshi newborns, estimate the incidence
           proportions and/or incidence rates and/or prevalence of the following clinical outcomes
           up to 7 days, 28 days, 60 days of life, 3 months, and 6 months of age:

             1. Hospitalization for any reason other than for routine postnatal care

             2. Upper respiratory tract infections (URTI);

             3. Lower respiratory tract infections (LRTI);

             4. Acute or persistent diarrhea;

             5. Significant neurological impairment or disability diagnosed by 6 months of age;
                and,

             6. All-cause and non-injury-related mortality

        8. Describe child anthropometry (length, weight, and head circumference) and standardized
           anthropometric indices (length-for-age, weight-for age, and weight-for-height, and head
           circumference-for-age z-scores) up to 60 days of age in a facility-recruited cohort of
           Bangladeshi newborns;

        9. Estimate the cohort accrual rates of eligible newborns at two public maternal-child
           health care facilities in Dhaka, Bangladesh

      Study personnel will conduct active and passive clinical surveillance and routine specimen
      collection (e.g. stool, nasal, skin and oral swabs etc.). Additional specimen collection may
      also be triggered in the event of physician-confirmed clinical severe infection, or if
      infants meet the case definition of LRTI (fast breathing with at least one of the following:
      cough, nasal congestion, or runny nose) or are hospitalized with diarrhea and/or vomiting.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy Bangladeshi newborns, delivered at two public hospitals (Maternal and Child Health
        Training Institute and Mohammadpur Fertility Services and Training Centre), and their
        mothers in Dhaka, Bangladesh. Newborns will be enrolled between 0 and 4 days postnatal age
        (n=3,000).
      
Biospecimen description: 
      Routine specimen collection:

        1. Infant: stool; nasal, skin, oral swabs; blood. Skin swabs, oral swabs and blood will
           only be collected in a sub-set of participants.

        2. Maternal: stool, vaginal swabs, breast milk. Stool and vaginal swabs will only be
           collected in a sub-set of mothers.

        3. Stool sample from a sibling closest in age to the participant will be collected from a
           subset of participants (excluding twin).

      Specimen collection triggered by presence of clinical severe infection (CSI): infant stool,
      nasal swab, blood, urine; and, skin swabs and cerebrospinal fluid (CSF) at treating
      physician's discretion.

      Nasal swabs will also be collected from infants with LRTI (fast breathing with at least one
      of cough, nasal congestion, or runny nose) or in hospitalized infants with diarrhea and/or
      vomiting.
    
Keywords: Severe infection; Sepsis; Microbiome; Bangladesh; Young infants