A randomized synbiotic trial to prevent sepsis among infants in rural India (original) (raw)

Change history

Please see accompanying Corrigendum (http://doi.org/10.1038/nature25006). In this Article, the statement ‘There were 88 culture-positive and 94 culture-negative cases’ has been corrected to ‘Apart from 88 cases of suspect sepsis that included both culture-negative and culture-positive infants, there were an additional 94 culture-negative cases’.

References

  1. Thaver, D. & Zaidi, A. K. Burden of neonatal infections in developing countries: a review of evidence from community-based studies. Pediatr. Infect. Dis. J. 28 (suppl. 1), S3–S9 (2009)
    Article PubMed Google Scholar
  2. Liu, L. et al. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 385, 430–440 (2015)
    Article PubMed Google Scholar
  3. United Nations Inter-agency Group for Child Mortality Estimation. Levels and Trends in Child Mortality ; https://www.unicef.org/media/files/Levels_and_Trends_in_Child_Mortality_2014.pdf (UNICEF, WHO, The World Bank, UNDP, 2014)
  4. Seale, A. C. et al. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect. Dis. 14, 731–741 (2014)
    Article PubMed PubMed Central Google Scholar
  5. Blencowe, H. et al. Estimates of neonatal morbidities and disabilities at regional and global levels for 2010: introduction, methods overview, and relevant findings from the Global Burden of Disease study. Pediatr. Res. 74 (suppl. 1), 4–16 (2013)
    Article PubMed PubMed Central Google Scholar
  6. Lawn, J. E. et al. Every Newborn: progress, priorities, and potential beyond survival. Lancet 384, 189–205 (2014)
    Article PubMed Google Scholar
  7. Oza, S., Lawn, J. E., Hogan, D. R., Mathers, C. & Cousens, S. N. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000–2013. Bull. World Health Organ. 93, 19–28 (2015)
    Article PubMed Google Scholar
  8. Boghossian, N. S. et al. Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J. Pediatr. 162, 1120–1124.e1 (2013)
    Article PubMed PubMed Central Google Scholar
  9. Marshall, J. C. Why have clinical trials in sepsis failed? Trends Mol. Med. 20, 195–203 (2014)
    Article PubMed Google Scholar
  10. The INIS Collaborative Group. Treatment of neonatal sepsis with intravenous immune globulin. N. Engl. J. Med. 365, 1201–1211 (2011)
  11. Mullany, L. C., Darmstadt, G. L. & Tielsch, J. M. Safety and impact of chlorhexidine antisepsis interventions for improving neonatal health in developing countries. Pediatr. Infect. Dis. J. 25, 665–675 (2006)
    Article PubMed PubMed Central Google Scholar
  12. Gewolb, I. H., Schwalbe, R. S., Taciak, V. L., Harrison, T. S. & Panigrahi, P. Stool microflora in extremely low birthweight infants. Arch. Dis. Child. Fetal Neonatal Ed. 80, F167–F173 (1999)
    Article CAS PubMed PubMed Central Google Scholar
  13. AlFaleh, K. & Anabrees, J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst. Rev. http://dx.doi.org/10.1002/14651858.CD005496.pub4 (2014)
  14. Dilli, D. et al. Treatment outcomes of infants with cyanotic congenital heart disease treated with synbiotics. Pediatrics 132, e932–e938 (2013)
    Article PubMed Google Scholar
  15. Dilli, D. et al. The ProPre-Save study: effects of probiotics and prebiotics alone or combined on necrotizing enterocolitis in very low birth weight infants. J. Pediatr. 166, 545–51.e1 (2015)
    Article PubMed Google Scholar
  16. Nandhini, L. et al. Synbiotics for decreasing incidence of necrotizing enterocolitis among preterm neonates—a randomized controlled trial. J. Matern. Fetal Neonatal Med. 29, 821–825 (2016)
    Article CAS PubMed Google Scholar
  17. Jacobs, S. E. et al. Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics 132, 1055–1062 (2013)
    Article PubMed Google Scholar
  18. Costeloe, K. et al. Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial. Lancet 387, 649–660 (2016)
    Article PubMed Google Scholar
  19. Agarwal, R. et al. Effects of oral Lactobacillus GG on enteric microflora in low-birth-weight neonates. J. Pediatr. Gastroenterol. Nutr. 36, 397–402 (2003)
    Article PubMed Google Scholar
  20. Panigrahi, P. et al. Long-term colonization of a Lactobacillus plantarum synbiotic preparation in the neonatal gut. J. Pediatr. Gastroenterol. Nutr. 47, 45–53 (2008)
    Article PubMed Google Scholar
  21. National Health Mission. Health Statistics; http://www.nrhmorissa.gov.in/frmhealthstatistics.aspx (2011)
  22. Sinha, A. et al. Role of probiotics VSL#3 in prevention of suspected sepsis in low birthweight infants in India: a randomised controlled trial. BMJ Open 5, e006564 (2015)
    Article PubMed PubMed Central Google Scholar
  23. Waters, D. et al. Aetiology of community-acquired neonatal sepsis in low and middle income countries. J. Glob. Health 1, 154–170 (2011)
    PubMed PubMed Central Google Scholar
  24. Panigrahi, P., Gupta, S., Gewolb, I. H. & Morris, J. G. Jr. Occurrence of necrotizing enterocolitis may be dependent on patterns of bacterial adherence and intestinal colonization: studies in Caco-2 tissue culture and weanling rabbit models. Pediatr. Res. 36, 115–121 (1994)
    Article CAS PubMed PubMed Central Google Scholar
  25. Panigrahi, P., Bamford, P., Horvath, K., Morris, J. G. Jr & Gewolb, I. H. Escherichia coli transcytosis in a Caco-2 cell model: implications in neonatal necrotizing enterocolitis. Pediatr. Res. 40, 415–421 (1996)
    Article CAS PubMed Google Scholar
  26. Khailova, L., Baird, C. H., Rush, A. A., McNamee, E. N. & Wischmeyer, P. E. Lactobacillus rhamnosus GG improves outcome in experimental pseudomonas aeruginosa pneumonia: potential role of regulatory T cells. Shock 40, 496–503 (2013)
    Article CAS PubMed PubMed Central Google Scholar
  27. Chu, H. & Mazmanian, S. K. Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat. Immunol. 14, 668–675 (2013)
    Article CAS PubMed PubMed Central Google Scholar
  28. Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat. Rev. Immunol. 12, 9–23 (2011)
    Article PubMed CAS Google Scholar
  29. Arrieta, M. C., Stiemsma, L. T., Amenyogbe, N., Brown, E. M. & Finlay, B. The intestinal microbiome in early life: health and disease. Front. Immunol. 5, 427 (2014)
    Article PubMed PubMed Central CAS Google Scholar
  30. Deshmukh, H. S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–530 (2014)
    Article CAS PubMed PubMed Central Google Scholar
  31. Kiso, M. et al. Protective efficacy of orally administered, heat-killed Lactobacillus pentosus b240 against influenza A virus. Sci. Rep. 3, 1563 (2013)
    Article PubMed PubMed Central CAS Google Scholar
  32. Tanaka, A. et al. Lactobacillus pentosus strain b240 suppresses pneumonia induced by Streptococcus pneumoniae in mice. Lett. Appl. Microbiol. 53, 35–43 (2011)
    Article CAS PubMed Google Scholar
  33. Moles, L. et al. Bacterial diversity in meconium of preterm neonates and evolution of their fecal microbiota during the first month of life. PLoS One 8, e66986 (2013)
    Article ADS CAS PubMed PubMed Central Google Scholar
  34. Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra65 (2014)
    PubMed PubMed Central Google Scholar
  35. Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152 (2015)
    Article PubMed CAS Google Scholar
  36. Khosravi, A. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15, 374–381 (2014)
    Article CAS PubMed PubMed Central Google Scholar
  37. Hensey, O. J., Hart, C. A. & Cooke, R. W. Serious infection in a neonatal intensive care unit: a two-year survey. J. Hyg. (Lond.) 95, 289–297 (1985)
    Article CAS Google Scholar
  38. Spigelblatt, L., Saintonge, J., Chicoine, R. & Laverdière, M. Changing pattern of neonatal streptococcal septicemia. Pediatr. Infect. Dis. 4, 56–58 (1985)
    Article CAS PubMed Google Scholar
  39. West, P. W. et al. Speciation of presumptive viridans streptococci from early onset neonatal sepsis. J. Med. Microbiol. 47, 923–928 (1998)
    Article CAS PubMed Google Scholar
  40. Schrag, S. J. et al. Epidemiology of invasive early-onset neonatal sepsis, 2005 to 2014. Pediatrics 138, e20162013 (2016)
    Article PubMed Google Scholar
  41. Jalilsood, T. et al. Characterization of pR18, a novel rolling-circle replication plasmid from Lactobacillus plantarum. Plasmid 73, 1–9 (2014)
    Article CAS PubMed Google Scholar
  42. Jacobsen, L. et al. Horizontal transfer of tet(M) and erm(B) resistance plasmids from food strains of Lactobacillus plantarum to Enterococcus faecalis JH2-2 in the gastrointestinal tract of gnotobiotic rats. FEMS Microbiol. Ecol. 59, 158–166 (2007)
    Article CAS PubMed Google Scholar
  43. Feld, L. et al. Selective pressure affects transfer and establishment of a Lactobacillus plantarum resistance plasmid in the gastrointestinal environment. J. Antimicrob. Chemother. 61, 845–852 (2008)
    Article CAS PubMed Google Scholar
  44. Toomey, N., Bolton, D. & Fanning, S. Characterisation and transferability of antibiotic resistance genes from lactic acid bacteria isolated from Irish pork and beef abattoirs. Res. Microbiol. 161, 127–135 (2010)
    Article CAS PubMed Google Scholar
  45. Bujalance, C., Jiménez-Valera, M., Moreno, E. & Ruiz-Bravo, A. A selective differential medium for Lactobacillus plantarum. J. Microbiol. Methods 66, 572–575 (2006)
    Article CAS PubMed Google Scholar
  46. Lai, E. M., Nathan, A. M., de Bruyne, J. A. & Chan, L. L. Should all children admitted with community acquired pneumonia have blood cultures taken? Indian J. Pediatr. 82, 439–444 (2015)
    Article PubMed Google Scholar
  47. McCulloh, R. J. et al. Evaluating the use of blood cultures in the management of children hospitalized for community-acquired pneumonia. PLoS One 10, e0117462 (2015)
    Article PubMed PubMed Central CAS Google Scholar
  48. Das, A., Patgiri, S. J., Saikia, L., Dowerah, P. & Nath, R. Bacterial pathogens associated with community-acquired pneumonia in children aged below five years. Indian Pediatr. 53, 225–227 (2016)
    Article PubMed Google Scholar
  49. Young Infants Clinical Signs Study Group. Clinical signs that predict severe illness in children under age 2 months: a multicentre study. Lancet 371, 135–142 (2008)
  50. Carlo, W. A. et al. Newborn-care training and perinatal mortality in developing countries. N. Engl. J. Med. 362, 614–623 (2010)
    Article CAS PubMed PubMed Central Google Scholar
  51. Panigrahi, P. et al. Neonatal sepsis in rural India: timing, microbiology and antibiotic resistance in a population-based prospective study in the community setting. J. Perinatal. http://dx.doi.org/10.1038/jp.2017.67 (2017)

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Acknowledgements

We are thankful to the Indian Council of Medical Research and the Ministry of Health and Family Welfare Government of India for their review and timely clearance. The Government of Odisha, Department of Health and Family Welfare provided necessary approvals and directives at the block level for implementation of the project in the hospitals and the community setting. We are grateful to the Director of Capital Hospital, Bhubaneswar, and Ispat General Hospital for providing dedicated clinical research space and laboratory space to set up the Bactec blood culture, microbiology, and data management facilities. Our gratitude to Dayananda Das (now deceased) of Jana Sikshan Sansthan for his management skills and each of the >200 members in the three-tier community intervention team. K. Pradhan and K. Mishra deserve thanks for managing the study in the two districts. Our thanks to the DSMB members for reviewing all serious adverse events and convening yearly in person for further review of compiled data and providing valuable insights. This study could not have been possible without the unconditional support of the parents of the newborns born in the study districts and the physicians, nurse-midwives, and Anganwadi workers of the government system who provided assistance throughout the conduct of the study. This study was funded by grants U01 HD 40574 and R01 HD 53719 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, USA.

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Authors and Affiliations

  1. Department of Epidemiology, Center for Global Health and Development, College of Public Health, University of Nebraska Medical Center, Nebraska, USA
    Pinaki Panigrahi & Lorena Baccaglini
  2. Department of Pediatrics, Center for Global Health and Development, College of Public Health, University of Nebraska Medical Center, Nebraska, USA
    Pinaki Panigrahi
  3. Department of Pediatrics, SCB Medical College, Cuttack, Odisha, India
    Sailajanandan Parida
  4. Department of Pediatrics, Ispat General Hospital, Rourkela, Odisha, India
    Nimai C. Nanda
  5. Asian Institute of Public Health, Bhubaneswar, Odisha, India
    Radhanath Satpathy, Arjit Mohapatra, Subhranshu S. Mohapatra & Pravas R. Misra
  6. Department of Pediatrics, Capital Hospital, Bhubaneswar, Odisha, India
    Lingaraj Pradhan
  7. Department of Environmental, Agricultural & Occupational Health, Center for Global Health and Development, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, USA
    Dinesh S. Chandel
  8. Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India
    Rama Chaudhry
  9. Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
    Hegang H. Chen
  10. Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA
    Judith A. Johnson & J. Glenn Morris
  11. Departments of Epidemiology, Pediatrics & Human Development, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
    Nigel Paneth
  12. Division of Neonatology, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
    Ira H. Gewolb

Authors

  1. Pinaki Panigrahi
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  2. Sailajanandan Parida
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  3. Nimai C. Nanda
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  4. Radhanath Satpathy
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  5. Lingaraj Pradhan
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  6. Dinesh S. Chandel
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  7. Lorena Baccaglini
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  8. Arjit Mohapatra
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  9. Subhranshu S. Mohapatra
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  10. Pravas R. Misra
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  11. Rama Chaudhry
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  12. Hegang H. Chen
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  13. Judith A. Johnson
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  14. J. Glenn Morris
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  15. Nigel Paneth
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  16. Ira H. Gewolb
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Contributions

P.P. and I.G. conceived the study and P.P. wrote the first draft. P.P., S.N.P., I.G., N.P. and J.G.M. designed the study with help from the other authors. N.N., R.S., L.P. and A.M. were responsible for clinical operations. S.S.M. managed the field activities. J.J. and R.C. were in charge of developing microbiology protocols and standard operating procedures. R.C. was in charge of the reference laboratory and supervised the final strain designation of blood isolates. H.C. and L.B. conducted the data management and statistical analyses. D.C. managed the protocol from the principal investigator’s laboratory and handled data acquisition, microbiology quality assurance, and institutional review board matters. All authors contributed in writing different sections of the manuscripts.

Corresponding author

Correspondence toPinaki Panigrahi.

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Competing interests

Following institutional procedures for federally funded grants, a new invention disclosure on the use of a combination of L. plantarum and fructooligosaccharides against infection and inflammation was made to the UNMC office of technology transfer (UNeMed). UNeMed, upon its decision not to pursue the invention, has released the rights to the inventor (P.P.). A PCT patent application has been filed (pending examination) and assigned to the Asian Institute of Public Health. None of the authors, including P.P., has any financial or management interest with any commercial entity.

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Reviewer Information Nature thanks R. Feng, T. Kollmann, D. J. Tancredi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Site maps.

Location of study sites in Odisha, India. Source: India and Odisha state maps, redrawn to show the geographic location of study sites. Reproduced with permission from ref. [51](/articles/nature23480#ref-CR51 "Panigrahi, P. et al. Neonatal sepsis in rural India: timing, microbiology and antibiotic resistance in a population-based prospective study in the community setting. J. Perinatal. http://dx.doi.org/10.1038/jp.2017.67

             (2017)").

Extended Data Figure 2 Site structure.

Three-tier structure for field operations and implementation of the clinical trial in the community. Reproduced with permission from ref. [51](/articles/nature23480#ref-CR51 "Panigrahi, P. et al. Neonatal sepsis in rural India: timing, microbiology and antibiotic resistance in a population-based prospective study in the community setting. J. Perinatal. http://dx.doi.org/10.1038/jp.2017.67

             (2017)").

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Panigrahi, P., Parida, S., Nanda, N. et al. A randomized synbiotic trial to prevent sepsis among infants in rural India.Nature 548, 407–412 (2017). https://doi.org/10.1038/nature23480

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