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.

  • Article
  • Published:

Late-onset pulmonary complications following allogeneic hematopoietic cell transplantation in pediatric patients: a prospective multicenter study

Bone Marrow Transplantation (2024)Cite this article

Subjects

Abstract

The primary objective of our multicenter prospective study was to describe the incidence of late-onset non-infectious pulmonary complications (LONIPCs) in children undergoing hematopoietic cell transplantation (HCT) using sensitive criteria for pulmonary function test (PFT) abnormalities including the non-specific pattern of airflow obstruction. Secondary objectives were to assess the factors associated with LONIPC occurrence and the sensitivity of the 2014 NIH-Consensus Criteria of bronchiolitis obliterans syndrome (BOS). PFT and clinical assessment were performed prior to HCT and at 6, 12, 24, and 36 months post-HCT. LONIPC diagnosis was validated by an Adjudication Committee. The study comprised 292 children from 12 centers. Thirty-two individuals (11%, 95% CI: 8–15%) experienced 35 LONIPCs: 25 BOS, 4 interstitial lung diseases, 4 organizing pneumonia and 2 pulmonary veno-occlusive diseases. PFT abnormalities were obstructive defects (FEV1/FVC z-score < −1.645; n = 12), restrictive defects (TLC < 80% predicted, FEV1 and FVC z-scores < −1.645; n = 7) and non-specific pattern (FEV1 and FVC z-score< −1.645, FEV1/FVC z-score > −1.645, and TLC > 80% predicted; n = 8). HCT for malignant disease was the only factor associated with LONIPC (P = 0.04). The 2014 NIH-Consensus Criteria would only diagnose 8/25 participants (32%) as having BOS. In conclusion, 11% of children experienced a LONIPC in a prospective design. Clinical Trials.gov identifier (NCT number): NCT02032381.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Flow chart.
Fig. 2: PFT abnormalities in the whole population.
Fig. 3: PFT course of the 32 children with LONIPC, centred on the time of LONIPC diagnosis.
Fig. 4: Cumulative incidence of LONIPCs, BOS and extrapulmonary GVHD in the 32 children with LONIPCs.

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Nishio N, Yagasaki H, Takahashi Y, Muramatsu H, Hama A, Tanaka M, et al. Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children. Bone Marrow Transplant. 2009;44:303–8.

    Article  CAS  PubMed  Google Scholar 

  2. Park M, Koh KN, Kim BE, Im HJ, Seo JJ. Clinical features of late onset non-infectious pulmonary complications following pediatric allogeneic hematopoietic stem cell transplantation. Clin Transplant. 2011;25:E168–176.

    Article  PubMed  Google Scholar 

  3. Walther S, Rettinger E, Maurer HM, Pommerening H, Jarisch A, Sörensen J, et al. Long-term pulmonary function testing in pediatric bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Pediatr Pulmonol. 2020;55:1725–35.

    Article  PubMed  Google Scholar 

  4. Bergeron A, Chevret S, Peffault de Latour R, Chagnon K, de Margerie-Mellon C, Rivière F, et al. Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation. Eur Respir J. 2018;51:1702617.

    Article  PubMed  Google Scholar 

  5. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21:389–401.e1.

    Article  PubMed  Google Scholar 

  6. Bergeron A, Godet C, Chevret S, Lorillon G, Peffault de Latour R, de Revel T, et al. Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis. Bone Marrow Transplant. 2013;48:819–24.

    Article  CAS  PubMed  Google Scholar 

  7. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948–68.

    Article  CAS  PubMed  Google Scholar 

  8. Stanojevic S, Kaminsky DA, Miller M, Thompson B, Aliverti A, Barjaktarevic I, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J. 2021;60:2101499.

    Article  Google Scholar 

  9. Hyatt RE, Cowl CT, Bjoraker JA, Scanlon PD. Conditions associated with an abnormal nonspecific pattern of pulmonary function tests. Chest. 2009;135:419–24.

    Article  PubMed  Google Scholar 

  10. Chevalier-Bidaud B, Gillet-Juvin K, Callens E, Chenu R, Graba S, Essalhi M, et al. Non specific pattern of lung function in a respiratory physiology unit: causes and prevalence: results of an observational cross-sectional and longitudinal study. BMC Pulm Med. 2014;14:148.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cuvelier GDE, Nemecek ER, Wahlstrom JT, Kitko CL, Lewis VA, Schechter T, et al. Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria. Blood. 2019;134:304–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Merkus PJFM, Stocks J, Beydon N, Lombardi E, Jones M, McKenzie SA, et al. Reference ranges for interrupter resistance technique: the Asthma UK Initiative. Eur Respir J. 2010;36:157–63.

    Article  CAS  PubMed  Google Scholar 

  13. Kirkby J, Stanojevic S, Welsh L, Lum S, Badier M, Beardsmore C, et al. Reference equations for specific airway resistance in children: the Asthma UK initiative. Eur Respir J. 2010;36:622–9.

    Article  CAS  PubMed  Google Scholar 

  14. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–38.

    Article  CAS  PubMed  Google Scholar 

  15. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26:511–22.

    Article  CAS  PubMed  Google Scholar 

  16. Beydon N, Davis SD, Lombardi E, Allen JL, Arets HGM, Aurora P, et al. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit Care Med. 2007;175:1304–45.

    Article  PubMed  Google Scholar 

  17. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40:1324–43.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zapletal A, Paul T, Samánek M. [Normal values of static pulmonary volumes and ventilation in children and adolescents]. Cesk Pediatr. 1976;31:532–9.

    CAS  PubMed  Google Scholar 

  19. Global Initiative for Asthma. Global Initiative for Asthma - GINA. https://ginasthma.org/ (accessed 19 Jul2021).

  20. Versluys AB, Rossen JWA, van Ewijk B, Schuurman R, Bierings MB, Boelens JJ. Strong association between respiratory viral infection early after hematopoietic stem cell transplantation and the development of life-threatening acute and chronic alloimmune lung syndromes. Biol Blood Marrow Transplant. 2010;16:782–91.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bergeron A, Cheng G-S. Bronchiolitis Obliterans Syndrome and Other Late Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation. Clin Chest Med. 2017;38:607–21.

    Article  PubMed  Google Scholar 

  22. Uhlving HH, Bang CL, Christensen IJ, Buchvald F, Nielsen KG, Heilmann CJ, et al. Lung function after allogeneic hematopoietic stem cell transplantation in children: a longitudinal study in a population-based cohort. Biol Blood Marrow Transplant. 2013;19:1348–54.

    Article  PubMed  Google Scholar 

  23. Bergeron A, Chevret S, Chagnon K, Godet C, Bergot E, Peffault de Latour R, et al. Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2015;191:1242–9.

    Article  CAS  PubMed  Google Scholar 

  24. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–56.

    Article  PubMed  Google Scholar 

  25. Chien JW, Duncan S, Williams KM, Pavletic SZ. Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16:S106–114.

    Article  PubMed  Google Scholar 

  26. Jacobsohn DA. Optimal management of chronic graft-versus-host disease in children. Br J Haematol. 2010;150:278–92.

    Article  CAS  PubMed  Google Scholar 

  27. Dufetelle E, Mulier G, Taytard J, Boizeau P, Le Roux E, Beydon N. Peripheral obstruction without airflow limitation is rare and not specific to asthma in children. Pediatr Pulmonol. 2021;56:858–65.

    Article  PubMed  Google Scholar 

  28. Iyer VN, Schroeder DR, Parker KO, Hyatt RE, Scanlon PD. The nonspecific pulmonary function test: longitudinal follow-up and outcomes. Chest. 2011;139:878–86.

    Article  PubMed  Google Scholar 

  29. Pastre J, Plantier L, Planes C, Borie R, Nunes H, Delclaux C, et al. Different KCO and VA combinations exist for the same DLCO value in patients with diffuse parenchymal lung diseases. BMC Pulm Med. 2015;15:100.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Nagasawa M, Mitsuiki N, Aoki Y, Ono T, Isoda T, Imai K, et al. Effect of reduced-intensity conditioning and the risk of late-onset non-infectious pulmonary complications in pediatric patients. Eur J Haematol. 2017;99:525–31.

    Article  CAS  PubMed  Google Scholar 

  31. Wolff D, Radojcic V, Lafyatis R, Cinar R, Rosenstein RK, Cowen EW, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2020 highly morbid forms report. Transpl Cell Ther. 2021;27:817–35.

    Article  Google Scholar 

  32. Jamani K, He Q, Liu Y, Davis C, Hubbard J, Schoch G, et al. Early post-transplantation spirometry is associated with the development of bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2020;26:943–8.

    Article  PubMed  Google Scholar 

  33. Epstein DJ, Liang EC, Sharifi H, Lai YK, Arai S, Graber-Naidich A, et al. Epidemiology of lower respiratory tract infections and community-acquired respiratory viruses in patients with bronchiolitis obliterans syndrome after hematopoietic cell transplantation: a retrospective cohort study. Transpl Cell Ther. 2022;28:705.e1–705.e10.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank the Pulmonology and Hematology’s children group: Karima Yakouben; Mohny Fahd; Laurence Le Clainche; Arthur Sterin; Caroline Thumerelle; Laurence Weiss; Tiphaine Bihouee; Hala Caron-Feghali; Sophie L’excellent; Cécile Renard; Emmanuelle Bosdure; Martin Castelle; Marine Michelet; Christophe Marguet; Nimrod Buchbinder. The authors also thank the children and parents for their contribution to the research, and Pierre Coste, Sandra Argues, Sophie Caillat Zucman and Stephane Bonacorsi for their help to this study.

Funding

The RESPPEDHEM study was supported by a research grant from the French Health Ministry (PHRC National) and sponsored by the Direction de la Recherche et de l'Innovation, APHP [AOM 12035]. The sponsor had no role in data analysis and decision to submit the manuscript.

Author information

Authors and Affiliations

  1. Université de Paris Cité, AP-HP, Hôpital Robert Debré, Service de Pneumopédiatrie, RESPIRARE, INSERM U976, Paris, France

    Véronique Houdouin

  2. Université Aix-Marseille, AP-HM, Hôpital universitaire Timone-Enfants, Service de Pneumopédiatrie, MEPHI, Méditerranée-Infection, Marseille, France

    Jean Christophe Dubus

  3. AP-HP, Hôpital Robert Debré, Unité d’Epidémiologie Clinique, Inserm, CIC-EC 1426, Paris, France

    Sophie Guilmin Crepon, Justine Pages & Adyla Yacoubi

  4. Hôpital de la mère et l’enfant, Service d’hématologie pédiatrique, Nantes, France

    Fanny Rialland

  5. Hôpital Jeanne de Flandre, Service d’hématologie pédiatrique, Lille, France

    Bénedicte Bruno

  6. Centre hospitalo-universitaire de Bordeaux, Service d’hématologie pédiatrique, Bordeaux, France

    Charlotte Jubert

  7. Université Lyon 1, Hôpital Femme Mère Enfant, Service de pneumologie, allergologie, mucoviscidose, CNRS, Laboratoire de Biométrie et biologie Evolutive UMR, 5558, Villeurbanne, France

    Philippe Reix

  8. Centre hospitalo-universitaire de Toulouse Purpan, Hôpital des enfants, Service d’immuno-hémato-oncologie pédiatrique, INSERM U1037, Toulouse, France

    Marlène Pasquet

  9. Centre hospitalo-universitaire de Strasbourg, Service d’hématologie pédiatrique, Strasbourg, France

    Catherine Paillard

  10. Centre hospitalo-universitaire de Grenoble, Service d’hématologie pédiatrique, Grenoble, France

    Dalila Adjaoud

  11. Centre hospitalo-universitaire de Nancy, Service de Physiologie respiratoire Pédiatrique, Nancy, France

    Cyril Schweitzer

  12. AP-HP, Hôpital Necker Enfants Malades, Service de pneumologie pédiatrique, Paris, France

    Muriel Le Bourgeois

  13. Université de Paris Cité, AP-HP, Hôpital Robert Debré, Service d’hématologie pédiatrique, Paris, France

    Jean Hugues Dalle

  14. Université de Genève, Hôpitaux Universitaires de Genève, Genève, Suisse

    Anne Bergeron

  15. Université de Paris Cité, AP-HP, Hôpital Robert Debré, Service de Physiologie Pédiatrique -Centre du Sommeil, INSERM NeuroDiderot, Paris, France

    Christophe Delclaux

Authors
  1. Véronique Houdouin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jean Christophe Dubus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sophie Guilmin Crepon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fanny Rialland
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bénedicte Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charlotte Jubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Philippe Reix
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marlène Pasquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Catherine Paillard
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dalila Adjaoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cyril Schweitzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Muriel Le Bourgeois
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Justine Pages
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Adyla Yacoubi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jean Hugues Dalle
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Anne Bergeron
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Christophe Delclaux
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Véronique Houdouin and Christophe Delclaux: substantial contributions to the conception and design of the work, acquisition and analysis, and interpretation of data for the work; Drafting the work and revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Fanny Rialland, Bénedicte Bruno, Charlotte Jubert, Philippe Reix, Marlène Pasquet, Catherine Paillard, Dalila Adjaoud, Cyril Schweitzer, Muriel. Le Bourgeois: they made substantial contributions to the acquisition of data for the work; revising it critically for important intellectual content; final approval of the version to be published, and agreement to be accountable for all aspects of the work Jean Christophe Dubus, Jean Hugues Dalle, Anne Bergeron: substantial contributions to the conception and design of the work, acquisition and analysis, and interpretation of data for the work; Drafting the work and revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Sophie Guilmin-Crepon, Justine Pages, Adyla Yacoubi: substantial contributions to the conception of the work, analysis and interpretation of data for the work; Drafting the work and revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Guarantor statement: Véronique Houdouin takes responsibility for the content of the manuscript, including the data and analysis.

Corresponding author

Correspondence to Véronique Houdouin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

41409_2024_2258_MOESM1_ESM.docx

Late-onset pulmonary complications following allogeneic hematopoietic cell transplantation in pediatric patients: a prospective multicenter study

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) 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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Houdouin, V., Dubus, J.C., Crepon, S.G. et al. Late-onset pulmonary complications following allogeneic hematopoietic cell transplantation in pediatric patients: a prospective multicenter study. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02258-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41409-024-02258-7

Search

Advanced search

Quick links