Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Exposure to antibiotics with anaerobic activity before respiratory viral infection is associated with respiratory disease progression after hematopoietic cell transplant

Abstract

We examined associations between specific antibiotic exposures and progression to lower respiratory tract disease (LRTD) following individual respiratory viral infections (RVIs) after hematopoietic cell transplantation (HCT). We analyzed allogeneic HCT recipients of all ages with their first RVI during the first 100 days post-HCT. For the 21 days before RVI onset, we recorded any receipt of specific groups of antibiotics, and the cumulative sum of the number of antibiotics received for each day (antibiotic-days). We used Cox proportional hazards models to assess the relationship between antibiotic exposure and progression to LRTD. Among 469 patients with RVI, 124 progressed to LRTD. Compared to no antibiotics, use of antibiotics with broad anaerobic activity in the prior 21 days was associated with progression to LRTD after adjusting for age, virus type, hypoalbuminemia, neutropenia, steroid use, and monocytopenia (HR 2.2, 95% CI 1.1–4.1). Greater use of those antibiotics (≥7 antibiotic days) was also associated with LRTD in adjusted models (HR 2.2, 95% CI 1.1–4.3). Results were similar after adjusting for lymphopenia instead of monocytopenia. Antibiotic use is associated with LRTD after RVI across different viruses in HCT recipients. Prospective studies using anaerobe-sparing antibiotics should be explored to assess impact on LRTD in patients undergoing HCT.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Cumulative incidence of proven/probable/possible LRTD by tertiles of number of antibiotic-days in the 21 days before RVI, overall and by virus.
Fig. 2: Cumulative incidence of proven/probable/possible LRTD by categories of antibiotic-days for antibiotic-days of antibiotics with broad anaerobic activity in the 21 days before RVI, overall and by virus.
Fig. 3: Model estimates for unadjusted and adjusted associations of antibiotic exposures in the 21 days prior to 1 day before RVI onset with progression to proven/probable/possible LRTD.

Data availability

Data supporting the findings from this study are available from the corresponding author upon reasonable request.

References

  1. Pinana JL, Gomez MD, Perez A, Madrid S, Balaguer-Rosello A, Gimenez E, et al. Community-acquired respiratory virus lower respiratory tract disease in allogeneic stem cell transplantation recipient: Risk factors and mortality from pulmonary virus-bacterial mixed infections. Transpl Infect Dis. 2018;20:e12926.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Khanna N, Steffen I, Studt JD, Schreiber A, Lehmann T, Weisser M, et al. Outcome of influenza infections in outpatients after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2009;11:100–5.

    Article  CAS  PubMed  Google Scholar 

  3. Khanna N, Widmer AF, Decker M, Steffen I, Halter J, Heim D, et al. Respiratory syncytial virus infection in patients with hematological diseases: single-center study and review of the literature. Clin Infect Dis. 2008;46:402–12.

    Article  CAS  PubMed  Google Scholar 

  4. Spahr Y, Tschudin-Sutter S, Baettig V, Compagno F, Tamm M, Halter J, et al. Community-Acquired Respiratory Paramyxovirus Infection After Allogeneic Hematopoietic Cell Transplantation: A Single-Center Experience. Open Forum Infect Dis. 2018;5:ofy077.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vakil E, Sheshadri A, Faiz SA, Shah DP, Zhu Y, Li L, et al. Risk factors for mortality after respiratory syncytial virus lower respiratory tract infection in adults with hematologic malignancies. Transpl Infect Dis. 2018;20:e12994.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ogimi C, Krantz EM, Golob JL, Waghmare A, Liu C, Leisenring WM, et al. Antibiotic Exposure Prior to Respiratory Viral Infection Is Associated with Progression to Lower Respiratory Tract Disease in Allogeneic Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transpl. 2018;24:2293–301.

    Article  CAS  Google Scholar 

  7. Bergeron A, Chevret S, Granata A, Chevallier P, Vincent L, Huynh A, et al. Effect of Azithromycin on Airflow Decline-Free Survival After Allogeneic Hematopoietic Stem Cell Transplant: The ALLOZITHRO Randomized Clinical Trial. JAMA. 2017;318:557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bradley KC, Finsterbusch K, Schnepf D, Crotta S, Llorian M, Davidson S, et al. Microbiota-Driven Tonic Interferon Signals in Lung Stromal Cells Protect from Influenza Virus Infection. Cell Rep. 2019;28:245–56.e244.

    Article  CAS  PubMed  Google Scholar 

  9. Steed AL, Christophi GP, Kaiko GE, Sun L, Goodwin VM, Jain U, et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science. 2017;357:498–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci USA 2011;108:5354–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vissers M, de Groot R, Ferwerda G. Severe viral respiratory infections: are bugs bugging? Mucosal Immunol. 2014;7(Mar):227–38.

    Article  CAS  PubMed  Google Scholar 

  12. Wu S, Jiang ZY, Sun YF, Yu B, Chen J, Dai CQ, et al. Microbiota regulates the TLR7 signaling pathway against respiratory tract influenza A virus infection. Curr Microbiol. 2013;67:414–22.

    Article  CAS  PubMed  Google Scholar 

  13. Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012;37:158–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee JR, Huang J, Magruder M, Zhang LT, Gong C, Sholi AN, et al. Butyrate-producing gut bacteria and viral infections in kidney transplant recipients: A pilot study. Transpl Infect Dis. 2019;21:e13180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Haak BW, Littmann ER, Chaubard JL, Pickard AJ, Fontana E, Adhi F, et al. Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood. 2018;131:2978–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transpl. 2014;20:640–5.

    Article  Google Scholar 

  17. Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8:339ra371.

    Article  Google Scholar 

  18. Taur Y, Pamer EG. The intestinal microbiota and susceptibility to infection in immunocompromised patients. Curr Opin Infect Dis. 2013;26:332–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shono Y. Gut microbiota and graft-versus-host disease: broad-spectrum antibiotic use increases post-allogeneic hematopoietic stem cell transplant graft-versus-host disease-related mortality. Rinsho Ketsueki. 2017;58:835–42.

    PubMed  Google Scholar 

  20. Routy B, Letendre C, Enot D, Chenard-Poirier M, Mehraj V, Seguin NC, et al. The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation. Oncoimmunology. 2017;6:e1258506.

    Article  PubMed  Google Scholar 

  21. Golob JL, Pergam SA, Srinivasan S, Fiedler TL, Liu C, Garcia K, et al. Stool Microbiota at Neutrophil Recovery Is Predictive for Severe Acute Graft vs Host Disease After Hematopoietic Cell Transplantation. Clin Infect Dis. 2017;65:1984–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Romick-Rosendale LE, Haslam DB, Lane A, Denson L, Lake K, Wilkey A, et al. Antibiotic Exposure and Reduced Short Chain Fatty Acid Production after Hematopoietic Stem Cell Transplant. Biol Blood Marrow Transpl. 2018;24:2418–24.

    Article  CAS  Google Scholar 

  23. Brook I. Treatment of anaerobic infection. Expert Rev Anti-Infective Ther. 2007;5:991–1006.

    Article  CAS  Google Scholar 

  24. Zimmermann P, Curtis N. The effect of antibiotics on the composition of the intestinal microbiota - a systematic review. J Infect. 2019;79:471–89.

    Article  PubMed  Google Scholar 

  25. Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, et al. Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transpl. 2017;23:845–52.

    Article  CAS  Google Scholar 

  26. Hirsch HH, Martino R, Ward KN, Boeckh M, Einsele H, Ljungman P. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. Clin Infect Dis. 2013;56:258–66.

    Article  PubMed  Google Scholar 

  27. Seo S, Waghmare A, Scott EM, Xie H, Kuypers JM, Hackman RC, et al. Human rhinovirus detection in the lower respiratory tract of hematopoietic cell transplant recipients: association with mortality. Haematologica. 2017;102:1120–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Campbell AP, Guthrie KA, Englund JA, Farney RM, Minerich EL, Kuypers J, et al. Clinical outcomes associated with respiratory virus detection before allogeneic hematopoietic stem cell transplant. Clin Infect Dis. 2015;61:192–202.

    Article  CAS  PubMed  Google Scholar 

  29. Kuypers J, Wright N, Corey L, Morrow R. Detection and quantification of human metapneumovirus in pediatric specimens by real-time RT-PCR. J Clin Virol. 2005;33:299–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kuypers J, Wright N, Morrow R. Evaluation of quantitative and type-specific real-time RT-PCR assays for detection of respiratory syncytial virus in respiratory specimens from children. J Clin Virol. 2004;31:123–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim Y, Waghmare A, Xie H, Holmberg LA, Pergam SA, Jerome KR, et al. Respiratory viruses in hematopoietic cell transplant candidates: impact of preexisting lower tract disease on outcomes. Blood Adv. 2022. https://doi.org/10.1182/bloodadvances.2021004915.

  32. Weber D, Oefner PJ, Hiergeist A, Koestler J, Gessner A, Weber M, et al. Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood. 2015;126:1723–8.

    Article  CAS  PubMed  Google Scholar 

  33. Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55:905–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Koh AY. The microbiome in hematopoietic stem cell transplant recipients and cancer patients: Opportunities for clinical advances that reduce infection. PLoS Pathog. 2017;13:e1006342.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Whangbo J, Ritz J, Bhatt A. Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transpl. 2017;52:183–90.

    Article  CAS  Google Scholar 

  36. Chemaly RF, Shah DP, Boeckh MJ. Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies. Clin Infect Dis. 2014;59:S344–351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shahani L, Ariza-Heredia EJ, Chemaly RF. Antiviral therapy for respiratory viral infections in immunocompromised patients. Expert Rev Anti-Infective Ther. 2017;15:401–15.

    Article  CAS  Google Scholar 

  38. Seo S, Xie H, Campbell AP, Kuypers JM, Leisenring WM, Englund JA, et al. Parainfluenza virus lower respiratory tract disease after hematopoietic cell transplant: viral detection in the lung predicts outcome. Clin Infect Dis. 2014;58:1357–68.

    Article  PubMed  Google Scholar 

  39. Kim YJ, Guthrie KA, Waghmare A, Walsh EE, Falsey AR, Kuypers J, et al. Respiratory syncytial virus in hematopoietic cell transplant recipients: factors determining progression to lower respiratory tract disease. J Infect Dis. 2014;209:1195–204.

    Article  CAS  PubMed  Google Scholar 

  40. Seo S, Gooley TA, Kuypers JM, Stednick Z, Jerome KR, Englund JA, et al. Human Metapneumovirus Infections Following Hematopoietic Cell Transplantation: Factors Associated With Disease Progression. Clin Infect Dis. 2016;63:178–85.

    Article  CAS  PubMed  Google Scholar 

  41. Shah DP, Shah PK, Azzi JM, Chemaly RF. Parainfluenza virus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review. Cancer Lett. 2016;370:358–64.

    Article  CAS  PubMed  Google Scholar 

  42. Waghmare A, Xie H, Kuypers J, Sorror ML, Jerome KR, Englund JA, et al. Human Rhinovirus Infections in Hematopoietic Cell Transplant Recipients: Risk Score for Progression to Lower Respiratory Tract Infection. Biol Blood Marrow Transplant. 2019;25:1011–21.

    Article  PubMed  Google Scholar 

  43. Ogimi C, Xie H, Waghmare A, Jerome KR, Leisenring WM, Milano F, et al. Correlation of initial upper respiratory tract viral burden with progression to lower tract disease in adult allogeneic hematopoietic cell transplant recipients. J Clin Virol. 2022;150–1:105152.

    Article  Google Scholar 

  44. Eichenberger EM, Soave R, Zappetti D, Small CB, Shore T, van Besien K, et al. Incidence, significance, and persistence of human coronavirus infection in hematopoietic stem cell transplant recipients. Bone Marrow Transpl. 2019;54:1058–66.

    Article  CAS  Google Scholar 

  45. Thackray LB, Handley SA, Gorman MJ, Poddar S, Bagadia P, Briseno CG, et al. Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections. Cell Rep. 2018;22:3440–53.e3446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Doan T, Arzika AM, Ray KJ, Cotter SY, Kim J, Maliki R, et al. Gut Microbial Diversity in Antibiotic-Naive Children After Systemic Antibiotic Exposure: A Randomized Controlled Trial. Clin Infect Dis. 2017;64:1147–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Parker EPK, Praharaj I, John J, Kaliappan SP, Kampmann B, Kang G, et al. Changes in the intestinal microbiota following the administration of azithromycin in a randomised placebo-controlled trial among infants in south India. Sci Rep. 2017;7:9168.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Waghmare A, Xie H, Kimball L, Yi J, Ozkok S, Leisenring W, et al. Supplemental Oxygen-Free Days in Hematopoietic Cell Transplant Recipients With Respiratory Syncytial Virus. J Infect Dis. 2017;216:1235–44.

    Article  CAS  PubMed  Google Scholar 

  49. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sorror ML, Logan BR, Zhu X, Rizzo JD, Cooke KR, McCarthy PL, et al. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transpl. 2015;21:1479–87.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Chris Davis, Madeline Kesten and Ryan Basom for database services.

Funding

This work was supported by the National Institutes of Health (grant numbers K23AI139385 to CO, R01HL081595 and K24HL093294 to MB, CA18029 to WML [clinical database]); the Fred Hutchinson Cancer Center Vaccine and Infectious Disease Division (biorepository); Seattle Children’s Research Institute Clinical Research Scholars Program Award to CO.

Author information

Authors and Affiliations

Authors

Contributions

Authorship contribution: CO designed this study, assisted in analysis, interpreted results, and wrote the manuscript; EMK and WML performed the statistical analysis and wrote the manuscript; JLG, CL, AW, SAP and DNF provided clinical input, interpretation of results, and reviewed the manuscript; KRJ provided technical oversight for laboratory, and reviewed the manuscript; JAE and MB provided oversight, designed this study, interpreted results, and reviewed the manuscript.

Corresponding authors

Correspondence to Chikara Ogimi or Michael Boeckh.

Ethics declarations

Competing interests

AW reports grant support from Ansun Biopharma, Allovir, VB Tech, Amazon, Inc, GlaxoSmithKline and Pfizer, and is an Advisory Board Member for Kyorin Pharmaceutical. JAE reports grant support from AstraZeneca, Merck, Pfizer, GlaxoSmithKline and Novavax, an Advisory Board Member and consultant for Sanofi Pasteur, Meissa Vaccines, Teva Pharmaceuticals and Astra Zeneca. MB reports grant support from Amazon, GSK, Janssen, Gilead and VirBio, and a consultant for Allovir, Merck, Janssen, Gilead, Kyorin Pharmaceuticals, and VirBio, and an Advisory Board Member for Evrys Bio. All other authors report no potential conflicts. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ogimi, C., Krantz, E.M., Golob, J.L. et al. Exposure to antibiotics with anaerobic activity before respiratory viral infection is associated with respiratory disease progression after hematopoietic cell transplant. Bone Marrow Transplant 57, 1765–1773 (2022). https://doi.org/10.1038/s41409-022-01790-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-022-01790-8

Search

Quick links