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Short-Term Variation of Lung Function and Airway Inflammation in Children and Adolescents with Bronchiolitis Obliterans

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Abstract

Purpose

Bronchiolitis obliterans (BO) is an inadequately researched disease in terms of lung function as well as inflammatory profile. The short-term variation of these parameters has not been investigated. Therefore, the objective of this study was the investigation of lung function, sputum cells and cytokine profiles in BO at two visits within of four to six weeks.

Methods

Twenty patients with BO (median age = 14.6, range 8.3–24.3) performed lung function tests, airway reversibility testing and induction of sputum within four to six weeks. The cell composition in the sputum was analysed and cytokine levels of IL-1ß, IL-6 and IL-8 were determined by cytometric bead array analysis. The short-term variation was then statistically quantified and compared to that of twenty-two healthy controls. Furthermore, we compared data on short-term variation of lung function and airway inflammation with a previous investigation in these patients 10–15 months earlier.

Results

Patients with BO showed minimal variation of lung function (VCmax, FVC, FEV1, FEV1/VC, MEF25 and RV/TLC) and the inflammatory cell profile. The lung function data were significantly lower for FVC, FEV1, the Tiffeneau index and MEF25 compared to the control group, whereas RV/TLC was significantly increased. Analysis of the BO sputum cells showed a consistent neutrophil inflammation. The levels of inflammatory cytokines IL-1ß, IL-6 and IL-8 had a great variability.

Conclusions

The short-term variability of sputum neutrophilia and lung function is low in BO patients. This finding should be considered to identify successful treatment in the individual patient and could be used as endpoints for future BO-related studies.

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Abbreviations

BO:

Bronchiolitis obliterans

CBA:

Cytometric bead array

VC:

Vital capacity

FVC:

Forced vital capacity

FEV1:

Forced expiratory volume in 1 second

FEV1/VC:

Tiffeneau index

MEF25:

25 % of the maximal expiratory flow

RV:

Residual volume

RV/TLC:

Residual volume expressed as percent of TLC

IL-1ß:

Interleukin-1 beta

IL-6:

Interleukin-6

IL-8:

Interleukin-8

HR-CT:

High-resolution Computer tomogram

BAL:

Bronchoalveolar lavage

hPIVs:

Human Parainfluenza Viruses

NaCl:

Sodium Chloride

DTT:

Dithiothreitol

PBS:

Phosphate-buffered saline

MAP:

Mitogen-activated protein

mAb:

Anti-CD132

PCR:

Polymerase chain reaction

V1:

Visit 1

V2:

Visit 2

References

  1. Verleden SE, Vasilescu DM, Willems S, Ruttens D, Vos R, Vandermeulen E, Hostens J, McDonough JE, Verbeken EK, Verschakelen J, Van Raemdonck DE, Rondelet B, Knoop C, Decramer M, Cooper J, Hogg JC, Verleden GM, Vanaudenaerde BM (2014) The site and nature of airway obstruction after lung transplantation. Am J Respir Crit care Med 189(3):292–300. doi:10.1164/rccm.201310-1894OC

    Article  PubMed  Google Scholar 

  2. Hardy KA, Schidlow DV, Zaeri N (1988) Obliterative bronchiolitis in children. Chest 93(3):460–466

    Article  CAS  PubMed  Google Scholar 

  3. Aguerre V, Castanos C, Pena HG, Grenoville M, Murtagh P (2010) Postinfectious bronchiolitis obliterans in children: clinical and pulmonary function findings. Pediatric Pulm 45(12):1180–1185. doi:10.1002/ppul.21304

    Article  CAS  Google Scholar 

  4. Bergeron A, Godet C, Chevret S, Lorillon G, Peffault de Latour R, de Revel T, Robin M, Ribaud P, Socie G, Tazi A (2013) Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis. Bone Marrow Transplant 48(6):819–824. doi:10.1038/bmt.2012.241

    Article  CAS  PubMed  Google Scholar 

  5. Solomon M, Grasemann H, Keshavjee S (2010) Pediatric lung transplantation. Pediatric Clin N Am 57(2):375–391. doi:10.1016/j.pcl.2010.01.017

    Article  CAS  Google Scholar 

  6. Castro-Rodriguez JA, Daszenies C, Garcia M, Meyer R, Gonzales R (2006) Adenovirus pneumonia in infants and factors for developing bronchiolitis obliterans: a 5-year follow-up. Pediatric Pulmonol 41(10):947–953. doi:10.1002/ppul.20472

    Article  Google Scholar 

  7. Colom AJ, Teper AM, Vollmer WM, Diette GB (2006) Risk factors for the development of bronchiolitis obliterans in children with bronchiolitis. Thorax 61(6):503–506. doi:10.1136/thx.2005.044909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kim CK, Kim SW, Kim JS, Koh YY, Cohen AH, Deterding RR, White CW (2001) Bronchiolitis obliterans in the 1990s in Korea and the United States. Chest 120(4):1101–1106

    Article  CAS  PubMed  Google Scholar 

  9. Alvarez AE, Marson FA, Bertuzzo CS, Arns CW, Ribeiro JD (2013) Epidemiological and genetic characteristics associated with the severity of acute viral bronchiolitis by respiratory syncytial virus. J Pediatr 89(6):531–543. doi:10.1016/j.jped.2013.02.022

    Article  Google Scholar 

  10. Meyer KC, Raghu G, Verleden GM, Corris PA, Aurora P, Wilson KC, Brozek J, Glanville AR, Committee IAEBTF, Committee IAEBTF (2014) An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur respir J 44(6):1479–1503. doi:10.1183/09031936.00107514

    Article  PubMed  Google Scholar 

  11. Rosewich M, Zissler UM, Kheiri T, Voss S, Eickmeier O, Schulze J, Herrmann E, Ducker RP, Schubert R, Zielen S (2015) Airway inflammation in children and adolescents with bronchiolitis obliterans. Cytokine 73(1):156–162. doi:10.1016/j.cyto.2014.10.026

    Article  CAS  PubMed  Google Scholar 

  12. Colom AJ, Maffey A, Garcia Bournissen F, Teper A (2015) Pulmonary function of a paediatric cohort of patients with postinfectious bronchiolitis obliterans. A long term follow-up. Thorax 70(2):169–174. doi:10.1136/thoraxjnl-2014-205328

    Article  PubMed  Google Scholar 

  13. Rosewich M, Eckrich J, Zielen S (2015) Long-term lung function in postinfectious bronchiolitis obliterans. Thorax 70(8):792. doi:10.1136/thoraxjnl-2015-206998

    Article  PubMed  Google Scholar 

  14. Teixeira MF, Rodrigues JC, Leone C, Adde FV (2013) Acute bronchodilator responsiveness to tiotropium in postinfectious bronchiolitis obliterans in children. Chest 144(3):974–980. doi:10.1378/chest.12-2280

    Article  CAS  PubMed  Google Scholar 

  15. Tomikawa SO, Adde FV, da Silva Filho LV, Leone C, Rodrigues JC (2014) Follow-up on pediatric patients with bronchiolitis obliterans treated with corticosteroid pulse therapy. Orphanet J Rare Dis 9:128. doi:10.1186/s13023-014-0128-2

    Article  PubMed  PubMed Central  Google Scholar 

  16. Suresh Babu K, Kastelik J, Morjaria JB (2013) Role of long term antibiotics in chronic respiratory diseases. Respir Med 107(6):800–815. doi:10.1016/j.rmed.2013.02.009

    Article  CAS  PubMed  Google Scholar 

  17. Schulze J, Voss S, Zissler U, Rose MA, Zielen S, Schubert R (2012) Airway responses and inflammation in subjects with asthma after four days of repeated high-single-dose allergen challenge. Respir Res 13:78. doi:10.1186/1465-9921-13-78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eickmeier O, Huebner M, Herrmann E, Zissler U, Rosewich M, Baer PC, Buhl R, Schmitt-Grohe S, Zielen S, Schubert R (2010) Sputum biomarker profiles in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) and association between pulmonary function. Cytokine 50(2):152–157. doi:10.1016/j.cyto.2010.02.004

    Article  CAS  PubMed  Google Scholar 

  19. Soubani AO, Uberti JP (2007) Bronchiolitis obliterans following haematopoietic stem cell transplantation. Eur Respir J 29(5):1007–1019. doi:10.1183/09031936.00052806

    Article  CAS  PubMed  Google Scholar 

  20. Todd JL, Palmer SM (2011) Bronchiolitis obliterans syndrome: the final frontier for lung transplantation. Chest 140(2):502–508. doi:10.1378/chest.10-2838

    Article  PubMed  Google Scholar 

  21. Gibson PG, Simpson JL (2009) The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax 64(8):728–735. doi:10.1136/thx.2008.108027

    Article  CAS  PubMed  Google Scholar 

  22. Barisione G, Bacigalupo A, Crimi E, Brusasco V (2011) Acute bronchodilator responsiveness in bronchiolitis obliterans syndrome following hematopoietic stem cell transplantation. Chest 139(3):633–639. doi:10.1378/chest.10-1442

    Article  PubMed  Google Scholar 

  23. De Baets F (2011) Bronchiolitis obliterans in children: a ghostly journey to the origin. Allergol Immunopathol 39(5):251–252. doi:10.1016/j.aller.2011.05.003

    Article  Google Scholar 

  24. Madill J, Aghdassi E, Arendt BM, Gutierrez C, Singer L, Chow CW, Keshavjee S, Allard JP (2009) Oxidative stress and nutritional intakes in lung patients with bronchiolitis obliterans syndrome. Transplant Proc 41(9):3838–3844. doi:10.1016/j.transproceed.2009.04.012

    Article  CAS  PubMed  Google Scholar 

  25. Regamey N, Jeffery PK, Alton EW, Bush A, Davies JC (2011) Airway remodelling and its relationship to inflammation in cystic fibrosis. Thorax 66(7):624–629. doi:10.1136/thx.2009.134106

    Article  PubMed  Google Scholar 

  26. Cazzato S, Poletti V, Bernardi F, Loroni L, Bertelli L, Colonna S, Zappulla F, Timoncini G, Cicognani A (2008) Airway inflammation and lung function decline in childhood post-infectious bronchiolitis obliterans. Pediatric Pulm 43(4):381–390. doi:10.1002/ppul.20784

    Article  Google Scholar 

  27. DeNicola MM, Weigt SS, Belperio JA, Reed EF, Ross DJ, Wallace WD (2013) Pathologic findings in lung allografts with anti-HLA antibodies. J Heart Lung Transplant 32(3):326–332. doi:10.1016/j.healun.2012.11.018

    Article  PubMed  Google Scholar 

  28. Moermans C, Poulet C, Henket M, Bonnet C, Willems E, Baron F, Beguin Y, Louis R (2013) Lung function and airway inflammation monitoring after hematopoietic stem cell transplantation. Respir Med 107(12):2071–2080. doi:10.1016/j.rmed.2013.10.013

    Article  CAS  PubMed  Google Scholar 

  29. Corris PA, Ryan VA, Small T, Lordan J, Fisher AJ, Meachery G, Johnson G, Ward C (2015) A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation. Thorax. doi:10.1136/thoraxjnl-2014-205998

    Google Scholar 

  30. Vanaudenaerde BM, Meyts I, Vos R, Geudens N, De Wever W, Verbeken EK, Van Raemdonck DE, Dupont LJ, Verleden GM (2008) A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy. Eur Respir J 32(4):832–843. doi:10.1183/09031936.00134307

    Article  CAS  PubMed  Google Scholar 

  31. Verleden GM, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE (2006) Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 174(5):566–570. doi:10.1164/rccm.200601-071OC

    Article  CAS  PubMed  Google Scholar 

  32. Vos R, Vanaudenaerde BM, Verleden SE, De Vleeschauwer SI, Willems-Widyastuti A, Van Raemdonck DE, Schoonis A, Nawrot TS, Dupont LJ, Verleden GM (2011) A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J 37(1):164–172. doi:10.1183/09031936.00068310

    Article  CAS  PubMed  Google Scholar 

  33. Leaker BR, Barnes PJ, O’Connor B (2013) Inhibition of LPS-induced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist. Respir Res 14:137. doi:10.1186/1465-9921-14-137

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hechinger AK, Smith BA, Flynn R, Hanke K, McDonald-Hyman C, Taylor PA, Pfeifer D, Hackanson B, Leonhardt F, Prinz G, Dierbach H, Schmitt-Graeff A, Kovarik J, Blazar BR, Zeiser R (2015) Therapeutic activity of multiple common gamma-chain cytokine inhibition in acute and chronic GVHD. Blood 125(3):570–580. doi:10.1182/blood-2014-06-581793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eickmeier O, Seki H, Haworth O, Hilberath JN, Gao F, Uddin M, Croze RH, Carlo T, Pfeffer MA, Levy BD (2013) Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol 6(2):256–266. doi:10.1038/mi.2012.66

    Article  CAS  PubMed  Google Scholar 

  36. Pedersen F, Holz O, Lauer G, Quintini G, Kiwull-Schone H, Kirsten AM, Magnussen H, Rabe KF, Goldmann T, Watz H (2015) Multi-analyte profiling of inflammatory mediators in COPD sputum–the effects of processing. Cytokine 71(2):401–404. doi:10.1016/j.cyto.2014.10.008

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

A grant from the Starke Lunge Foundation supported this study.

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Authors and Affiliations

  1. Department of Paediatric Pulmonology, Allergy and Cystic Fibrosis, Children’s Hospital, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Jonas Eckrich, Sandra Voss, Ralf Schubert, Stefan Zielen & Martin Rosewich

  2. Institute of Biostatistics and Mathematical Modelling, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Eva Herrmann

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  1. Jonas Eckrich
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Correspondence to Jonas Eckrich.

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Conflict of Interest

The authors declare that they have no conflict of interest. No author has a financial relationship with a commercial entity with an interest in the subject of this manuscript.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed Consent

Human guidelines of good clinical practice and the declaration of Helsinki (1964) and Edinburgh (2000) were followed in the conduct of the trial. The study was approved by the Ethics Committee of University Hospital Frankfurt am Main and registered at www.clinicaltrials.gov (NCT01633385). Informed consent was obtained from all individual participants included in the study. All the parents and all patients older than sixteen years of age provided written informed consent.

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Eckrich, J., Herrmann, E., Voss, S. et al. Short-Term Variation of Lung Function and Airway Inflammation in Children and Adolescents with Bronchiolitis Obliterans. Lung 194, 571–579 (2016). https://doi.org/10.1007/s00408-016-9907-y

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  • DOI: https://doi.org/10.1007/s00408-016-9907-y

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