Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Shivanthan Shanthikumar¹, William A Gower², Kenneth R Cooke³, Anne Bergeron⁴, Kirk R Schultz⁵, Amisha Barochia⁶, Maximiliano Tamae-Kakazu⁷, Edward Charbek⁸, Erin E Reardon⁹, Charlotte Calvo¹⁰, Alicia Casey¹¹, Pi Chun Cheng¹², Theresa S Cole¹³, Stella M Davies¹⁴, Shailendra Das¹⁵, Alive De¹⁶, Robin R Deterding¹⁷, Deborah R Liptzin¹⁸, Francoise Mechinaud¹⁹, Jonathan H Rayment²⁰, Paul D Robinson²¹, Roopa Siddaiah²², Anne Stone²³, Saumini Srinivasin²⁴, Christopher T Towe²⁵, Gregory A Yanik²⁶, Narayan P Iyer²⁷, Samuel B Goldfarb²⁸

Affiliations

¹ Respiratory and Sleep Medicine, Royal Children's Hospital, Melbourne, Australia; Respiratory Diseases, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address: shivanthan.shanthikumar@rch.org.au.
² Division of Pulmonology, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
³ Department of Oncology, Pediatric Blood and Marrow Transplantation Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
⁴ Pneumology Department, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
⁵ Pediatric Hematology/Oncology/BMT, BC Children's Research Institute/UBC, Vancouver, British Columbia, Canada.
⁶ Laboratory of Asthma and Lung Inflammation, Critical Care Medicine and Pulmonary Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
⁷ Division of Pulmonary and Critical Care, Corewell Health, Grand Rapids, Michigan; Department of Medicine, Michigan State University College of Human Medicine, Michigan.
⁸ Department of Internal Medicine, Saint Louis University, St Louis, Missouri.
⁹ Woodruff Health Sciences Center Library, Emory University, Atlanta, Georgia.
¹⁰ Pediatric Hematology and Immunology Department, Robert Debré Hospital, Paris Cité University, Paris, France; Human Immunology, Pathophysiology and Immunotherapy, INSERM UMR-976, Institut de Recherche Saint-Louis, Paris, France.
¹¹ Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
¹² Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
¹³ Department of Paediatrics, University of Melbourne, Melbourne, Australia; Children's Cancer Centre, Royal Children's Hospital, Melbourne, Australia; Infection & immunity, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁴ Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
¹⁵ Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
¹⁶ Division of Pediatric Pulmonology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.
¹⁷ Chief Pediatric Pulmonary and Sleep Medicine, University of Colorado and Children's Hospital Colorado, Aurora, Colorado.
¹⁸ Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.
¹⁹ Pediatric Hematology and Immunology Department, Robert Debré Hospital, Paris Cité University, Paris, France.
²⁰ Division of Respiratory Medicine, BC Children's Hospital, Vancouver, Canada; Department of Pediatrics, University of British Columbia, Vancouver, Canada.
²¹ Department of Respiratory Medicine, Queensland Children's Hospital, Queensland, Australia; Children's Health and Environment Program, Child Health Research Centre, University of Queensland, Queensland, Australia; Airway Physiology and Imaging Group, Woolcock Institute of Medical Research, New South Wales, Australia.
²² Division of Pulmonology, Department of Pediatrics, Penn State Health Children's Hospital, Hershey, Pennsylvania.
²³ Division of Pediatric Pulmonology, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon.
²⁴ Department of Pediatrics, University of Tennessee College of Medicine, Le Bonheur Children's Hospital, Memphis, Tennessee.
²⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Pulmonary Medicine, Cincinnati Children's Hospital, Cincinnati, Ohio.
²⁶ Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
²⁷ Division of Neonatology, Fetal and Neonatal Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
²⁸ Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; Division of Pulmonary Medicine, Masonic Children's Hospital, Minneapolis, Minnesota.

PMID: 38897861
PMCID: PMC11393806
DOI: 10.1016/j.jtct.2024.05.012

Review

Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Shivanthan Shanthikumar et al. Transplant Cell Ther. 2024 Aug.

. 2024 Aug;30(8):760-769.

doi: 10.1016/j.jtct.2024.05.012. Epub 2024 Jun 18.

Authors

Affiliations

¹ Respiratory and Sleep Medicine, Royal Children's Hospital, Melbourne, Australia; Respiratory Diseases, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address: shivanthan.shanthikumar@rch.org.au.
² Division of Pulmonology, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
³ Department of Oncology, Pediatric Blood and Marrow Transplantation Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
⁴ Pneumology Department, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
⁵ Pediatric Hematology/Oncology/BMT, BC Children's Research Institute/UBC, Vancouver, British Columbia, Canada.
⁶ Laboratory of Asthma and Lung Inflammation, Critical Care Medicine and Pulmonary Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
⁷ Division of Pulmonary and Critical Care, Corewell Health, Grand Rapids, Michigan; Department of Medicine, Michigan State University College of Human Medicine, Michigan.
⁸ Department of Internal Medicine, Saint Louis University, St Louis, Missouri.
⁹ Woodruff Health Sciences Center Library, Emory University, Atlanta, Georgia.
¹⁰ Pediatric Hematology and Immunology Department, Robert Debré Hospital, Paris Cité University, Paris, France; Human Immunology, Pathophysiology and Immunotherapy, INSERM UMR-976, Institut de Recherche Saint-Louis, Paris, France.
¹¹ Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
¹² Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
¹³ Department of Paediatrics, University of Melbourne, Melbourne, Australia; Children's Cancer Centre, Royal Children's Hospital, Melbourne, Australia; Infection & immunity, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁴ Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
¹⁵ Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
¹⁶ Division of Pediatric Pulmonology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.
¹⁷ Chief Pediatric Pulmonary and Sleep Medicine, University of Colorado and Children's Hospital Colorado, Aurora, Colorado.
¹⁸ Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.
¹⁹ Pediatric Hematology and Immunology Department, Robert Debré Hospital, Paris Cité University, Paris, France.
²⁰ Division of Respiratory Medicine, BC Children's Hospital, Vancouver, Canada; Department of Pediatrics, University of British Columbia, Vancouver, Canada.
²¹ Department of Respiratory Medicine, Queensland Children's Hospital, Queensland, Australia; Children's Health and Environment Program, Child Health Research Centre, University of Queensland, Queensland, Australia; Airway Physiology and Imaging Group, Woolcock Institute of Medical Research, New South Wales, Australia.
²² Division of Pulmonology, Department of Pediatrics, Penn State Health Children's Hospital, Hershey, Pennsylvania.
²³ Division of Pediatric Pulmonology, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon.
²⁴ Department of Pediatrics, University of Tennessee College of Medicine, Le Bonheur Children's Hospital, Memphis, Tennessee.
²⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Pulmonary Medicine, Cincinnati Children's Hospital, Cincinnati, Ohio.
²⁶ Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
²⁷ Division of Neonatology, Fetal and Neonatal Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
²⁸ Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; Division of Pulmonary Medicine, Masonic Children's Hospital, Minneapolis, Minnesota.

PMID: 38897861
PMCID: PMC11393806
DOI: 10.1016/j.jtct.2024.05.012

Erratum in

Corrigendum to Diagnosis of post-hematopoietic stem cell transplant bronchiolitis obliterans syndrome in children: time for a rethink? Transplantation and Cellular Therapy. 2024 Aug;30(8):760-769.
Shanthikumar S, Gower WA, Cooke KR, Bergeron A, Schultz KR, Barochia A, Tamae-Kakazu M, Charbek E, Reardon EE, Calvo C, Casey A, Cheng PC, Cole TS, Davies SM, Das S, De A, Deterding RR, Liptzin DR, Mechinaud F, Rayment JH, Robinson PD, Siddiah R, Stone A, Srinivasin S, Towe CT, Yanik GA, Iyer NP, Goldfarb SB. Shanthikumar S, et al. Transplant Cell Ther. 2025 Jun 16:S2666-6367(25)01172-8. doi: 10.1016/j.jtct.2025.05.009. Online ahead of print. Transplant Cell Ther. 2025. PMID: 40518130 Free PMC article. No abstract available.

Abstract

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV₁) threshold, focus on obstructive defects defined by FEV₁/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.

Keywords: bronchiolitis obliterans; bronchiolitis obliterans syndrome; pediatrics; stem cell transplantation.

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References

1. Fitch T, Myers KC, Dewan M, Towe C, Dandoy C. Pulmonary Complications After Pediatric Stem Cell Transplant. Front Oncol. 2021;11:755878. - PMC - PubMed
1. Williams KM. Williams KM. Noninfectious complications of hematopoietic cell transplantation. Hematology Am Soc Hematol Educ Program. 2021;2021:578–586. Hematology Am Soc Hematol Educ Program. 2022;2022(1):724. - PMC - PubMed
1. Tamburro RF, Cooke KR, Davies SM, Goldfarb S, Hagood JS, Srinivasan A, et al. Pulmonary Complications of Pediatric Hematopoietic Cell Transplantation. A National Institutes of Health Workshop Summary. Ann Am Thorac Soc. 2021;18(3):381–94. - PMC - PubMed
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Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Affiliations

Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Authors

Affiliations

Erratum in

Abstract

References

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Grants and funding

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