Background
Chronic lung allograft dysfunction (CLAD) increases morbidity and mortality for lung
transplant recipients. Club cell secretory protein (CCSP), produced by airway club
cells, is reduced in the bronchoalveolar lavage fluid (BALF) of lung recipients with
CLAD. We sought to understand the relationship between BALF CCSP and early posttransplant
allograft injury and determine if early posttransplant BALF CCSP reductions indicate
later CLAD risk.
Methods
We quantified CCSP and total protein in 1606 BALF samples collected over the first
posttransplant year from 392 adult lung recipients at 5 centers. Generalized estimating
equation models were used to examine the correlation of allograft histology or infection
events with protein-normalized BALF CCSP. We performed multivariable Cox regression
to determine the association between a time-dependent binary indicator of normalized
BALF CCSP level below the median in the first posttransplant year and development
of probable CLAD.
Results
Normalized BALF CCSP concentrations were 19% to 48% lower among samples corresponding
to histological allograft injury as compared with healthy samples. Patients who experienced
any occurrence of a normalized BALF CCSP level below the median over the first posttransplant
year had a significant increase in probable CLAD risk independent of other factors
previously linked to CLAD (adjusted hazard ratio 1.95; p = 0.035).
Conclusions
We discovered a threshold for reduced BALF CCSP to discriminate future CLAD risk;
supporting the utility of BALF CCSP as a tool for early posttransplant risk stratification.
Additionally, our finding that low CCSP associates with future CLAD underscores a
role for club cell injury in CLAD pathobiology.
KEYWORDS
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of Heart and Lung TransplantationAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
REFERENCES
- The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult lung transplantation report - 2020; focus on deceased donor characteristics.J Heart Lung Transplant. 2020; 39: 1016-1027
- Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis.Mod Pathol. 2013; 26: 350-356
- The histomorphological spectrum of restrictive chronic lung allograft dysfunction and implications for prognosis.Mod Pathol. 2018; 31: 780-790
- Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-a consensus report from the Pulmonary Council of the ISHLT.J Heart Lung Transplant. 2019; 38: 493-503
- Epithelial clara cell injury occurs in bronchiolitis obliterans syndrome after human lung transplantation.Am J Transplant. 2012; 12: 3076-3084
- An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants.JCI Insight. 2019; 5e124732
- Clara cell secretory protein modulates lung inflammatory and immune responses to respiratory syncytial virus infection.J Immunol. 2003; 171: 1051-1060
- Regulation and function of CCSP during pulmonary Pseudomonas aeruginosa infection in vivo.Am J Physiol Lung Cell Mol Physiol. 2000; 279: L452-L459
- Clara cell secretory protein deficiency increases oxidant stress response in conducting airways.Am J Physiol. 1998; 275: L348-L356
- Depletion of bone marrow CCSP-expressing cells delays airway regeneration.Mol Ther. 2015; 23: 561-569
- Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion.Am J Respir Cell Mol Biol. 2001; 24: 671-681
- Highlights from the clinical trials in organ transplantation (CTOT)-20 and CTOT-22 Consortium studies in lung transplant.Am J Transplant. 2020; 20: 1489-1494
- International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation.J Heart Lung Transplant. 2020; 39: 1171-1190
- Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection.J Heart Lung Transplant. 2007; 26: 1229-1242
- Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: data from a multicenter prospective cohort study.Am J Transplant. 2022; 22: 3002-3011
- Illustrating the impact of a time-varying covariate with an extended kaplan-meier estimator.Am Stat. 2005; 59: 301-307
- Decreased serum and bronchoalveolar lavage levels of Clara cell secretory protein (CC16) is associated with bronchiolitis obliterans syndrome and airway neutrophilia in lung transplant recipients.Transplantation. 2002; 73: 1264-1269
- Elevated plasma clara cell secretory protein concentration is associated with high-grade primary graft dysfunction.Am J Transplant. 2011; 11: 561-567
- Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation.Am J Transplant. 2014; 14: 446-452
- Donor clara cell secretory protein polymorphism is a risk factor for bronchiolitis obliterans syndrome after lung transplantation.Transplantation. 2012; 94: 652-658
- CCSP modulates airway dysfunction and host responses in an Ova-challenged mouse model.Am J Physiol Lung Cell Mol Physiol. 2001; 281: L1303-L1311
- CC16 Binding to alpha4beta1 Integrin Protects against Mycoplasma pneumoniae Infection.Am J Respir Crit Care Med. 2021; 203: 1410-1418
- VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses.Proc Natl Acad Sci U S A. 2004; 101: 11058-11063
- The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome.Pediatr Res. 2005; 58: 15-21
Article info
Publication history
Published online: February 27, 2023
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 International Society for Heart and Lung Transplantation. All rights reserved.
