EUROPEAN RESPIRATORY JOURNAL
ORIGINAL RESEARCH ARTICLE
D. ZHANG ET AL.

Telomere length and immunosuppression in non-idiopathic
pulmonary fibrosis interstitial lung disease
David Zhang 1,9, Ayodeji Adegunsoye2,9, Justin M. Oldham3, Julia Kozlitina 4, Nicole Garcia2,
Maria Poonawalla2, Rachel Strykowski2, Angela L. Linderholm5, Brett Ley6, Shwu-Fan Ma7, Imre Noth7,
Mary E. Strek2, Paul J. Wolters6, Christine Kim Garcia 1 and Chad A. Newton 8
1

Division of Pulmonary and Critical Care Medicine, Columbia University, New York, NY, USA. 2Section of Pulmonary and Critical Care,
Department of Medicine, University of Chicago, Chicago, IL, USA. 3Division of Pulmonary and Critical Care Medicine, University ofMichigan, Ann Arbor, MI, USA. 4Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern
Medical Center, Dallas, TX, USA. 5Division of Pulmonary, Critical Care, and Sleep Medicine, University of California Davis, Sacramento,
CA, USA. 6Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA,
USA. 7Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA. 8Division of Pulmonary andCritical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. 9These two authors contributed equally tothis work.
Corresponding author: Chad A. Newton (chad.newton@utsouthwestern.edu)

Shareable abstract (@ERSpublications)Fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients who have age-adjusted
leukocyte telomere length <10th percentile may experience reduced survival when exposed toimmunosuppression, similar to IPF patients https://bit.ly/3DJDLYg
Cite this article as: Zhang D, Adegunsoye A, Oldham JM, et al. Telomere length andimmunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease. Eur Respir J 2023;
62: 2300441 [DOI: 10.1183/13993003.00441-2023].

Copyright ©The authors 2023.
This version is distributed under
the terms of the Creative
Commons Attribution NonCommercial Licence 4.0. Forcommercial reproduction rights
and permissions contact
permissions@ersnet.org
This article has an editorialcommentary:https://doi.org/10.1183/
13993003.01852-2023
Received: 13 March 2023
Accepted: 26 July 2023

Abstract
Background Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte
telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains
unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD).
Methods A retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity
pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five
centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed asage-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores
were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL
on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating timedependent immunosuppressant exposure.
Results The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of
patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. fHP and uILD
patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or
azathioprine in the discovery cohort (mortality hazard ratio (HR) 4.97, 95% CI 2.26–10.92; p<0.001) andreplication cohort (mortality HR 4.90, 95% CI 1.74–13.77; p=0.003). Immunosuppressant exposure was
not associated with differential survival in patients with LTL ⩾10th percentile. There was a significant
interaction between LTL <10th percentile and immunosuppressant exposure (discovery pinteraction=0.013;
replication pinteraction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup
analyses for CTD-ILD.
Conclusion Similar to IPF, fHP and uILD patients with age-adjusted LTL <10th percentile may experience
reduced survival when exposed to immunosuppression.

Introduction
The interstitial lung diseases (ILDs) are a diverse group of inflammatory and fibrotic disorders that often
require pharmacological therapy to mitigate progressive loss of lung function. The initial treatment choice
is primarily dictated by the ILD subtype. Antifibrotics are the preferred treatment for idiopathic pulmonary
https://doi.org/10.1183/13993003.00441-2023

Eur Respir J 2023; 62: 2300441

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

fibrosis (IPF) [1, 2], while immunosuppressants have been the mainstay for non-IPF ILDs, including
fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease(CTD)-ILD. Inaccurate ILD classification can result in suboptimal management for some patients;
therefore, biomarkers that inform treatment selection irrespective of ILD subtype are needed.
Telomeres are 6-nucleotide repeats at ends of chromosomes that normally shorten with cellular replication
and ageing. Telomere dysfunction has been inexorably linked with ILD development and disease trajectory[3–12]. Short leukocyte telomere length (LTL) has been found in 13–62% of patients with various ILDs
and is consistently associated with reduced survival and rapid progression [13–21]. For certain ILDs, there
may also exist a pharmacogenomic relationship between short LTL and immunosuppressive therapies. We
previously reported that historical use of immunosuppression was associated with worse survival for IPF
patients with short age-adjusted LTL [21]. We also described differential survival for fHP patients treatedwith mycophenolate when stratified by telomere quartiles [17]. This current study seeks to expand thesefindings by examining a generalisable age-adjusted LTL percentile measurement across multiple cohorts,
additional ILD subtypes and other immunosuppressive therapies while accounting for potential immortal
time bias in previous analyses [22].
In this observational study, we examined fHP, uILD and CTD-ILD patients from five US academic ILD
centres split into discovery and replication cohorts. Within each cohort, we explored the association
between time-dependent exposure to mycophenolate or azathioprine and transplant-free survival in non-IPF
ILD patients stratified by age-adjusted LTL in percentiles. We also assessed the longitudinal forced vital
capacity (FVC) trajectory across immunosuppressant exposure and LTL groups.
Methods
Study populations
Patients with fHP, uILD and CTD-ILD were identified from the University of Texas Southwestern (UTSW;
2003–2019), University of California San Francisco (UCSF; 2004–2017), University of California Davis(UCD; 2013–2017), University of Chicago (Chicago; 2001–2015) and Columbia University Medical
Center (CUMC; 2019–2020). The institutional review boards for each centre approved this study. All
patients provided written inform consent and a blood sample for research LTL measurement. LTL was
independently assessed at UTSW/CUMC or UCSF, which comprised the discovery and replication cohorts.
A portion of this cohort with fHP has been previously described [17].
Eligible patients had non-IPF ILD diagnoses conferred through multidisciplinary discussion at each centre.
Patients were excluded if baseline FVC and diffusing capacity of the lung for carbon monoxide (DLCO)
measurements were unavailable, chest high-resolution computed tomography did not demonstrate fibrosis
per centre radiologist, were exposed to immunosuppressants (mycophenolate, azathioprine,
cyclophosphamide or rituximab) or antifibrotics ( pirfenidone or nintedanib) before blood collection for
LTL measurement, or were exposed to antifibrotics before immunosuppressants. Patients were grouped into
immunosuppressant exposed (initiated on mycophenolate or azathioprine within 2 years of bloodcollection) or unexposed. Prednisone exposure was variable and largely coincided with otherimmunosuppressant exposure; therefore, patients were not excluded based on prednisone therapy topreserve sample size. Patients subsequently exposed to pirfenidone or nintedanib were censored atinitiation of antifibrotic therapy.
Leukocyte telomere length
Genomic DNA was collected from leukocytes using Autopure LS (Qiagen, Germantown, MD, USA;UTSW and CUMC), Gentra Puregene (Qiagen; UCSF and UCD) and FlexiGene DNA kit (Qiagen;
Chicago). All LTLs were measured using a similar quantitative PCR (qPCR) methodology at either
UTSW/CUMC (discovery cohort) or UCSF (replication cohort) as previously reported [19, 21, 23, 24].
The UTSW and CUMC protocol was identical and performed by the same laboratory, so the data werecombined. Age-adjusted LTL was calculated by comparing observed to expected telomere length(supplementary methods) and dichotomised for comparative analyses: <10th and ⩾10th percentile of thereference population. Patients who underwent LTL measurement at both sites were included in thereplication cohort only.
Statistical analysis
Groups were compared using Chi-squared, Fisher’s exact test, t-test, Mann–Whitney–Wilcoxon test or
one-way ANOVA, where appropriate. Relationships between continuous variables were examined using
Pearson’s correlation.
https://doi.org/10.1183/13993003.00441-2023

2

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

Given the observational nature of the study, inverse probability of treatment weighting (IPTW) using
propensity scores was used to minimise indication bias and estimate the average treatment effect of
immunosuppression across the entire cohort (supplementary methods). Propensity scores were generatedusing multivariable logistic regression to estimate the conditional probability of either mycophenolate or
azathioprine exposure, adjusted for age, sex, race/ethnicity, family history of ILD, smoking status, baseline
FVC and DLCO % pred, radiographic usual interstitial pneumonia (UIP), prednisone exposure, ILD
diagnosis, and centre. Weights were calculated by taking the inverse of the propensity score for
immunosuppressant-exposed patients and one minus the inverse of the propensity score for the unexposed
patients; the weights were used to determine each patient’s contribution to a pseudo-population withbalanced covariate distributions across treatment groups [25]. Variables with standardised mean difference(SMD) >0.15 after weighting were considered unbalanced and included as covariates in outcome models.
Given that prednisone exposure may similarly impact outcomes and is commonly used for non-IPF ILDs, aseparate IPTW procedure was conducted for prednisone monotherapy using similar methods.
The primary aim was to determine if immunosuppression was associated with differential 2-year
transplant-free survival, defined as time from blood collection for LTL measurement to death or transplant,in patients stratified by the age-adjusted LTL 10th percentile. We constructed weighted multivariable Cox
proportional hazards regression models with robust variance estimation (supplementary methods).
Immunosuppressant exposure was treated as a time-dependent covariate to address immortal time bias,
whereby patients initiated on mycophenolate or azathioprine during follow-up were considered unexposed
until drug start date. Models were adjusted for centre, radiographic honeycombing and ILD diagnosis given
residual imbalances after weighting and survival differences across diagnoses and presence ofhoneycombing [26, 27]. We assessed the pharmacogenomic interaction using an interaction term for LTL
group and immunosuppressant exposure. The discovery and replication cohorts were analysed separately,
then a meta-analysis across cohorts was performed using a random effects model. There was no evidenceof non-proportional hazards which were examined by plotting Schoenfeld residuals versus time.
Multiple secondary survival analyses were performed. First, survival was assessed for each non-IPF ILD
diagnosis using within-diagnoses meta-analysis of the discovery and replication cohorts. Second, we
examined survival associations between immunosuppressant exposure and LTL percentile as a continuous
variable. Third, we restricted the exposed cohort to patients initiated on immunosuppressants within 1 yearof blood collection and who had >3 months of exposure. Lastly, survival associations were individuallyassessed for mycophenolate and azathioprine. For this analysis, the propensity scores and IPTWs were
calculated for each medication separately. For patients exposed to both medications sequentially, the first
immunosuppressant drug was considered primary.
Longitudinal FVC trajectory was analysed using joint models incorporating survival and linear mixed
effects submodels (supplementary methods) [28, 29]. Both submodels were constructed similar to theprimary survival model, including terms for immunosuppressant exposure, LTL group, centre, radiographic
honeycombing and diagnosis. The linear mixed effects submodel also included terms for FVC, time andan interaction term for FVC, time and immunosuppressant exposure. Immunosuppressant-exposed patientswere included if they had at least two FVC measurements during exposure within 2 years of bloodcollection, while unexposed patients were included if they had at least two FVC measurements within
2 years of blood collection. p-values <0.05 were considered significant. All analyses were performed using
R version 4.2.0 (www.r-project.org).
Results
Study cohorts
Of the 1332 non-IPF ILD patients identified across five centres, 938 met eligibility criteria, including 613
and 325 in the discovery and replication cohorts, respectively (figure 1 and supplementary figure E1).
CTD-ILD was the most common ILD subtype in the discovery cohort followed by uILD and fHP, while
uILD was more common in the replication cohort followed by fHP and CTD-ILD (tables 1 and 2). Among
the CTD-ILDs, rheumatoid arthritis ILD and scleroderma-related ILD were the most common diagnoses inboth cohorts. The distribution of radiographic patterns and honeycombing differed by ILD subtype(supplementary figure E2).
In the discovery cohort, 45% of patients were exposed to either mycophenolate or azathioprine within
2 years of blood collection (table 1), while only 32% were exposed in the replication cohort ( p<0.001)(table 2). Exposure rates were similar between the discovery and replication cohorts for CTD-ILD (49%versus 50%; p=1.0) and fHP (48% versus 39%; p=0.15), but not uILD (40% versus 23%; p<0.001). Over
80% of patients from both cohorts were initiated on immunosuppressants within 1 year of blood collection
https://doi.org/10.1183/13993003.00441-2023

3

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

Discovery cohort(n=613)

Replication cohort(n=325)fHP (n=156)
uILD (n=224)
CTD-ILD (n=233)

fHP (n=126)
uILD (n=163)
CTD-ILD (n=36)

IS exposure
Mycophenolate (n=179)
Azathioprine (n=99)

No IS exposure(n=335)

No IS exposure(n=220)IS exposure
Mycophenolate (n=91)
Azathioprine (n=14)

LTL interaction with immunosupression
FIGURE 1 STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) diagram. fHP:
fibrotic hypersensitivity pneumonitis; uILD: unclassifiable interstitial lung disease; CTD-ILD: connective tissue
disease-associated interstitial lung disease; IS: immunosuppressant; LTL: leukocyte telomere length.

(supplementary figure E3); median (interquartile range (IQR)) time to immunosuppressant initiation was
0.1 (0.0–0.5) years and 0.2 (0.0–0.7) years and median (IQR) exposure time was 1.7 (0.7–2.0) years and1.5 (0.5–2.0) years in the discovery and replication cohorts, respectively. Baseline differences between
immunosuppressant-exposed and unexposed patients, including age, severity of lung function impairment
and radiographic features, were balanced (SMD <0.15) with propensity score weighting to account forindication bias; however, centre remained imbalanced in the replication cohort (supplementary figure E4).
Leukocyte telomere length
Continuous age-adjusted LTL (median (IQR)) was shorter in the discovery cohort (−0.09 (−0.26–0.09))
than the replication cohort (0.09 (−0.34–0.55); p<0.001) (supplementary figure E5). When dichotomising
LTL, more patients in the replication cohort had LTL <10th percentile (26% versus 20%; p=0.04). The
prevalence of LTL <10th percentile was highest in uILD (33%) followed by fHP (28%) and CTD-ILD(12%) (supplementary figure E6). In contrast, >80% of CTD-ILD patients had LTL >50th percentile
compared with 41% of fHP and 45% of uILD patients. The presence of radiographic UIP or
honeycombing was more prevalent in patients with LTL <10th percentile (supplementary table E1). Of thepatients with LTL <10th percentile, 47% and 25% were exposed to immunosuppression in the discovery
and replication cohorts, respectively. The correlation of 40 individual LTL measurements performed atboth UTSW/CUMC and UCSF was found to be in high agreement across sites (r=0.86, p<0.001)(supplementary figure E7).
Transplant-free survival
The 2-year transplant-free survival was similar for the discovery and replication cohorts ( p=0.19) andacross centres ( p=0.95) (supplementary figure E8). Patients with CTD-ILD had better survival than fHP( p<0.001) or uILD ( p<0.001). Radiographic honeycombing, but not radiographic UIP, was associated with
reduced 2-year transplant-free survival in adjusted analyses (supplementary table E2). Compared with
unexposed patients, neither mycophenolate (hazard ratio (HR) 1.47, 95% CI 0.88–2.46; p=0.14) nor
azathioprine (HR 1.67, 95% CI 0.83–3.36; p=0.15) exposure was associated with differential 2-year
transplant-free survival. There was also no survival difference between mycophenolate and azathioprine
exposure ( p=0.22).
Immunosuppressant exposure was associated with worse 2-year transplant-free survival for both fHP anduILD patients with LTL <10th percentile, but not those with LTL ⩾10th percentile (figure 2). In CTD-ILD
patients, the low 2-year event rate (6%) and prevalence of LTL <10th percentile (12%) precluded
meaningful subgroup survival analyses. In the combined analysis of fHP and uILD patients withage-adjusted LTL <10th percentile, immunosuppressant exposure was associated with worse transplant-freesurvival in both discovery (HR 4.97, 95% CI 2.26–10.92; p<0.001) and replication cohorts (HR 4.90, 95%
CI 1.74–13.77; p=0.003; meta-analysis HR 4.94, 95% CI 2.64–9.25; p<0.001) (figure 3).
Immunosuppression was not associated with survival in fHP and uILD patients with LTL ⩾10th percentile( pooled meta-analysis HR 1.08, 95% CI 0.59–1.98). There was a significant interaction between
https://doi.org/10.1183/13993003.00441-2023

4

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

TABLE 1 Unweighted and weighted discovery cohort patient characteristics stratified by immunosuppressant (IS) exposure
Discovery cohort

CentreUTSW
UCSF
Chicago
UCD
CUMC
ILD diagnosis
fHP
CTD-ILD#uILD
Age, years
Male
Ethnicity/raceWhite
African American
Hispanic
Asian
Other¶
Ever-smoker
Family history of ILD
Lung function
FVC % pred
DLCO % predRadiographic features
UIP+
Honeycombing
IS therapy
Mycophenolate
Azathioprine
IS exposure, years
Prednisone
LTL
LTL <10th percentile
Age-adjusted LTL
Follow-up, years
OutcomeDeath within 2 years
Transplant within 2 years

IS exposed(n=278)IS unexposed(n=335)171 (62)34 (12)69 (25)157 (47)
51 (15)119 (36)

4 (1)

8 (2)

Weighted discovery cohort
p-value

IS exposed(n=286)

IS unexposed(n=332)p-valueSMD

138 (48)
56 (19)88 (31)171 (51)50 (15)105 (32)

0.62

0.13

4 (2)

6 (2)

73 (25)107 (37)106 (37)62±10
109 (38)

83 (25)131 (39)
118 (36)62±12128 (39)

0.91

0.04

0.93
0.93
0.76

0.01
0.01
0.03

232 (70)
59 (18)32 (10)9 (3)1 (0)172 (52)
31 (9)

0.81
0.94

0.02
0.01

<0.01

0.10
75 (27)114 (41)
89 (32)60±11113 (41)

81 (24)119 (36)135 (40)63±12129 (39)204 (73)37 (13)27 (10)9 (3)1 (0)130 (47)
32 (12)226 (68)59 (18)37 (11)
12 (4)1 (0)178 (53)
31 (9)

0.14
0.43

196 (68)43 (15)30 (10)17 (6)1 (0)151 (53)
26 (9)

62±17
42±19

69±20
48±20

<0.01
<0.01

66±18
45±19

66±19
45±20

0.97
0.77

<0.01
0.03

54 (19)75 (27)78 (23)121 (36)

0.29
0.02

61 (21)78 (27)72 (22)112 (33)

0.92
0.15

0.01
0.11

201 (61)

0.77

0.03

0.01
0.65
0.58

179 (64)
99 (36)
1.7 (0.7–2.0)
231 (83)

143 (43)<0.01

184 (64)102 (36)
1.9 (0.6–2.0)
169 (60)

57 (21)−0.1 (−0.3–0.1)
2.0 (1.4–2.0)

65 (19)−0.1 (−0.3–0.1)
2.0 (1.3–2.0)

0.81
0.39
0.73

51 (17)−0.1 (−0.2–0.1)
2.0 (1.3–2.0)

65 (20)−0.1 (0.3–0.1)
2.0 (1.8–2.0)

0.52
0.55
0.32

0.06
0.06
<0.01

42 (15)15 (5)

31 (9)
5 (2)

0.04
0.01

41 (14)11 (4)

29 (9)
4 (1)

0.06
0.02

0.18
0.17

Data are presented as n (%), mean±SD or median (interquartile range). SMD: standardised mean difference; UTSW: University of Texas Southwestern;
UCSF: University of California San Francisco; Chicago: University of Chicago; UCD: University of California Davis; CUMC: Columbia University Medical
Center; ILD: interstitial lung disease; fHP: fibrotic hypersensitivity pneumonitis; CTD: connective tissue disease; uILD: unclassifiable ILD; FVC: forced
vital capacity: DLCO: diffusing capacity of the lung for carbon monoxide; UIP: usual interstitial pneumonia; LTL: leukocyte telomere length. #: CTD-ILD
diagnoses: scleroderma n=63, rheumatoid arthritis n=69, inflammatory myositis n=36, mixed CTD n=32, Sjögren’s syndrome n=24, systemic lupus
erythematosus n=10; ¶: other ethnicity/race: unknown n=2; +: radiographic UIP incudes definite UIP.

immunosuppressant exposure and LTL 10th percentile (discovery pinteraction=0.013; replication
pinteraction=0.011; meta-analysis pinteraction<0.001) for patients with fHP and uILD.
Sensitivity analyses using age-adjusted LTL percentile as a continuous variable confirmed that shorter LTL
was associated with worse survival overall regardless of exposure, but this detrimental association was
magnified by immunosuppression treatment ( pinteraction=0.01) for fHP and uILD patients (figure 4). In a
subset of fHP and uILD patients initiated on immunosuppression within 1 year of blood collection andwho had >3 months of exposure, immunosuppression was similarly associated with reduced survival inthose with LTL <10th percentile (supplementary figure E9). Both mycophenolate and azathioprine
individually were associated with reduced transplant-free survival in fHP and uILD patients with LTL<10th percentile; however, the interaction between LTL and azathioprine exposure was inconsistenthttps://doi.org/10.1183/13993003.00441-2023

5

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

TABLE 2 Unweighted and weighted replication cohort patient characteristics stratified by immunosuppressant (IS) exposure and leukocyte
telomere length (LTL) group
Replication cohort
IS exposed(n=105)
CohortUTSW
UCSF
Chicago
UCD
CUMC
ILD diagnosis
fHP
CTD-ILD#uILD
Age, years
Male
Ethnicity/raceWhite
African American
Hispanic
Asian
Other¶
Ever-smoker
Family history of ILD
Lung function
FVC % pred
DLCO % predRadiographic UIP
UIP+
Honeycombing
IS therapy
Mycophenolate
Azathioprine
IS exposure, years
Prednisone
LTL
LTL <10th percentile
Age-adjusted LTL
Follow-up, years
OutcomeDeath within 2 years
Transplant within 2 years

IS unexposed(n=220)Weighted replication cohort
p-value

IS exposed(n=112)

IS unexposed(n=217)<0.01
50 (48)14 (13)41 (39)120 (55)
56 (26)44 (20)49 (47)18 (17)38 (36)63±1249 (47)77 (35)18 (8)
125 (57)69±10110 (50)59 (56)20 (19)16 (15)6 (6)4 (4)46 (44)13 (12)143 (65)
41 (19)19 (9)
14 (6)3 (2)134 (61)
15 (7)

65±16
50±19
8 (8)
22 (21)p-value

SMD

0.24

0.28

0.70

0.13

0.58
0.98
0.86

0.11
0.01
0.03

74 (66)14 (13)24 (21)117 (54)47 (22)53 (24)36 (32)14 (13)62 (56)68±11
54 (48)84 (39)22 (10)111 (51)67±11
105 (49)

0.01
0.14

73 (65)17 (15)12 (11)8 (7)3 (3)73 (65)
11 (10)137 (63)
37 (17)24 (11)16 (8)3 (1)
125 (57)
20 (9)

0.51
0.84

0.11
0.04

71±21
51±21

<0.01
0.62

72±16
50±17

70±20
50±21

0.50
0.85

0.11
0.03

38 (17)56 (25)0.03
0.45

10 (9)
21 (19)30 (14)45 (21)

0.41
0.77

0.12
0.05

103 (48)

0.72

0.07

<0.01

<0.01
0.66
0.08

91 (87)14 (13)
1.5 (0.5–2.0)
87 (83)70 (32)<0.01

99 (89)13 (11)
1.7 (0.8–2.0)
50 (44)21 (20)0.2 (−0.3–0.6)
2.0 (2.0–2.0)

63 (29)0.1 (−0.4–0.5)
2.0 (1.1–2.0)

0.13
0.12
0.03

26 (24)0.1 (−0.3–0.4)
2.0 (2.0–2.0)

62 (29)0.1 (−0.4–0.5)
2.0 (1.4–2.0)

0.61
0.75
0.34

0.12
0.03
0.23

17 (16)1 (1)42 (19)
3 (1)

0.63
1.0

21 (19)1 (1)39 (18)
2 (1)

0.95
0.40

0.01
0.07

Data are presented as n (%), mean±SD or median (interquartile range). SMD: standardised mean difference; UTSW: University of Texas Southwestern;
UCSF: University of California San Francisco; Chicago: University of Chicago; UCD: University of California Davis; CUMC: Columbia University Medical
Center; ILD: interstitial lung disease; fHP: fibrotic hypersensitivity pneumonitis; CTD: connective tissue disease; uILD: unclassifiable ILD; FVC: forced
vital capacity: DLCO: diffusing capacity of the lung for carbon monoxide; UIP: usual interstitial pneumonia. #: CTD-ILD diagnoses: scleroderma n=19,
rheumatoid arthritis n=5, inflammatory myositis n=6, mixed CTD n=1, Sjögren’s syndrome n=2, systemic lupus erythematosus n=3; ¶: other ethnicity/
race: Middle Eastern n=2, Native American n=2, Pacific Islander n=3; +: radiographic UIP incudes definite UIP.

(supplementary figure E10). Prednisone monotherapy was not associated with differential 2-year transplantfree survival for non-IPF ILD patients with LTL <10th or ⩾10th percentile (supplementary table E3).
Longitudinal FVC trajectory
There were 286 immunosuppressant-exposed patients (201 mycophenolate, 85 azathioprine) and 251
unexposed patients from both cohorts included in this analysis. The median (IQR) FVC measurement
timespan was similar between exposed (1.17 (0.55–1.71) years) and unexposed patients (1.27 (0.68–1.65) years;
p=0.75). The annualised rate of FVC change over 2 years did not differ by study cohort or ILD
subtype (supplementary table E4). Immunosuppressant exposure was not associated with differential FVC
change (exposed: −60 (95% CI −91– −30) mL per year versus unexposed: −83 (95% CI −116– −50) mL
https://doi.org/10.1183/13993003.00441-2023

6

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

Diagnosis

Hazard ratio for IS exposure

HR (95% CI)

p-value pinteractionvalue

LTL

IS
No IS
n (events) n (events)≥10th

91 (13)122 (15)

1.23 (0.51–2.97)<10th

33 (17)36 (6)

6.45 (2.38–17.43) <0.001≥10th

100 (18)188 (33)

1.12 (0.48–2.60)

0.79

<10th

27 (11)72 (24)

3.97 (1.74–9.06)

0.001

0.65

fHP

0.017

uILD

0.024

0 1 2

8
4
6
10
Hazard ratio (95% CI)

12

FIGURE 2 Association between immunosuppressant (IS) exposure (mycophenolate or azathioprine) comparedwith no exposure and 2-year transplant-free survival in fibrotic hypersensitivity pneumonitis (fHP) andunclassifiable interstitial lung disease (uILD) patients stratified by age-adjusted leukocyte telomere length (LTL)<10th and ⩾10th percentile of normal. Weighted Cox proportional hazards regression model with robust
variance estimation and adjustment for radiographic honeycombing and centre.

per year; p=0.32). Patients with LTL <10th percentile experienced faster FVC decline (−125 (95% CI−178– −72) mL per year) than those with LTL ⩾10th percentile (−59 (95% CI −84– −35) mL per year;
p=0.027). However, neither the composite (table 3) nor the individual immunosuppressant medications(supplementary table E5) were associated with differential FVC trajectory in patients stratified by theage-adjusted LTL 10th percentile threshold.
Discussion
This study evaluated the impact of commonly used immunosuppressants on 2-year transplant-free survival
in non-IPF ILD patients stratified by age-adjusted LTL percentiles. We found that immunosuppressant
exposure was associated with reduced survival for fHP and uILD patients with age-adjusted LTL <10thpercentile. However, the study was underpowered to examine the survival associations between
immunosuppressant exposure and age-adjusted LTL for CTD-ILD patients. In addition, LTL <10thpercentile was associated with faster FVC decline independent of immunosuppressant exposure. These datasuggest that commonly used immunosuppressants may be associated with higher mortality risk, but notprogressive lung function decline, in a subset of fHP and uILD patients.

CohortHazard ratio for IS exposure

HR (95% CI)

p-value pinteractionvalue

LTL

IS
No IS
n (events) n (events)≥10th

122 (23)170 (23)

1.31 (0.61–2.83)<10th

42 (20)46 (11)4.97 (2.26–10.92) <0.001≥10th

69 (8)

140 (25)

0.78 (0.29–2.10)

0.63

<10th

18 (8)

62 (19)4.90 (1.74–13.77)

0.003

≥10th

191 (31)310 (48)1.08 (0.59–1.98)

0.80

<10th

60 (28)108 (30)

4.94 (2.64–9.25)<0.0010.49

Discovery

0.013

Replication

0.011

Meta-analysis<0.001

0 1 2

4
6
8
10
Hazard ratio (95% CI)

12

FIGURE 3 Association between immunosuppressant (IS) exposure (mycophenolate or azathioprine) and 2-year
transplant-free survival in combined fibrotic hypersensitivity pneumonitis and unclassifiable interstitial lungdisease (uILD) patients stratified by age-adjusted leukocyte telomere length (LTL) <10th and ⩾10th percentile
of normal. Weighted Cox proportional hazards regression model with robust variance estimation andadjustment for non-idiopathic pulmonary fibrosis ILD diagnosis, radiographic honeycombing and centre.

https://doi.org/10.1183/13993003.00441-2023

7

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

8
IS: HR 0.97 (95% CI 0.95–0.98); p<0.001
No IS: HR 0.99 (95% CI 0.98–0.998); p=0.009
pinteraction=0.01

Hazard ratio (95% CI)

6

4

2

0
1

10

20

30

40
50
60
Age-adjusted LTL percentile

70

80

90

100

FIGURE 4 Association between immunosuppressant (IS) exposure and age-adjusted leukocyte telomere length(LTL) percentile as a continuous variable for fibrotic hypersensitivity pneumonitis and unclassifiable interstitiallung disease (uILD) patients. Weighted Cox proportional hazards regression model with robust varianceestimation and adjustment for non-idiopathic pulmonary fibrosis ILD diagnosis, radiographic honeycombing
and centre.

Over the last decade, ILD treatment strategy has shifted from near-universal use of immunosuppressants tothoughtful medication selection guided by ILD subtype. Based on high-quality studies, an IPF diagnosis
mandates avoidance of immunosuppressants in favour of antifibrotics [1, 2, 30]. In contrast, treatment
selection and timing in non-IPF ILDs is highly variable. Immunosuppressants have been a common
therapeutic option for non-IPF ILD patients requiring therapy based on limited clinical trials andobservational studies [31–35]. However, monitoring for progression without therapy may be appropriate
for some non-IPF ILD patients [36]. In this study, 60% of patients were not initiated on therapy during the
2-year follow-up. Therefore, there is an urgent need for biomarkers that can identify high-risk patients andinform their treatment strategy. Given the current data, we propose that LTL may serve both functions.
We confirm prior studies demonstrating that non-IPF ILD patients with short LTL are at high risk ofprogression, experience worse mortality and may benefit from earlier treatment [13–20]. While LTL testingfor IPF patients may similarly aid in prognostication, it is unlikely to inform treatment selection since
antifibrotics appear safe and effective in patients with telomere dysfunction [10, 37]. However, we find that
LTL may allow personalised management for some non-IPF ILDs. Our study found that

TABLE 3 Annualised change in forced vital capacity (FVC) for non-idiopathic pulmonary fibrosis interstitial lungdisease (ILD) patients stratified by immunosuppressant (IS) exposure and age-adjusted leukocyte telomere
length (LTL) <10th and ⩾10th percentile of normal
IS exposed

LTL <10th percentile
LTL ⩾10th percentile

IS unexposedn (n FVC)

ΔFVC, mL per year
(95% CI)#n (n FVC)

ΔFVC, mL per year
(95% CI)#

55 (209)
231 (978)−141 (−218– −65)
−46 (−79– −12)56 (177)
195 (673)−111 (−184– −39)
−76 (−113– −39)

p-value

0.58
0.23

#

: joint model incorporating time-to-event and linear mixed effects submodels, adjusted for ILD diagnosis,
radiographic honeycombing and ILD centre. Restricted to patients with at least two FVC measurements whileon immunosuppression within 2 years of blood collection for exposed patients and at least two FVC
measurements within 2 years of blood collection for unexposed patients.

https://doi.org/10.1183/13993003.00441-2023

8

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

immunosuppressant exposure was associated with higher mortality risk in fHP and uILD patients withage-adjusted LTL <10th percentile. While prospective studies are needed, our findings suggest that LTL
testing may inform treatment selection whereby immunosuppressants should be considered with caution in
fHP and uILD patients with LTL <10th percentile.
The current study differs from our prior report [17] examining the differential impact of mycophenolate for
fHP patients stratified by LTL quartiles in multiple ways. First, we applied age-adjusted LTL percentiles
that are generalisable outside of our study cohort. Second, we dichotomised by age-adjusted LTL <10thpercentile as a biologically relevant threshold; prior studies demonstrated this threshold to be sensitive todetecting carriers with pathogenic telomere gene mutations [5]. However, immunosuppressant exposure
was associated with higher mortality risk across the continuum of LTL percentiles, driven by the shortest
LTLs. Third, we mitigated immortal time bias [22] by enrolling at time of LTL measurement and modelledimmunosuppressant exposure as a time-dependent covariate [38]. Using this approach, we found that
mycophenolate was not associated with favourable survival in any subpopulation and was associated withworse outcomes in those with LTL <10th percentile. Lastly, the current study expanded the size and scopeof the analysis to include additional ILD subtypes and immunosuppressants in additional cohorts. These
efforts uncovered a significant interaction between short LTL and immunosuppressant exposure for fHP
and uILD patients, whereby immunosuppressant exposure was associated with higher mortality risk for
those with age-adjusted LTL <10th percentile.
We also found important differences across the non-IPF ILD subtypes included in this study. While thephenotypic heterogeneity within the CTDs may have limited this subgroup analysis, there were also fewer
events and lower prevalence of short telomeres that limited the assessment of an immunosuppression and
LTL interaction. In contrast to CTD-ILD, the fHP and uILD cohorts had a higher prevalence of LTL <10thpercentile, which approached the level seen in IPF cohorts [20]. In addition, the current study found thatradiographic UIP and honeycombing were present in a higher proportion of non-IPF ILD patients with
LTL <10th percentile, similar to a prior study in fHP patients [15]. However, the effect of these “UIP-like”
features on survival was smaller than the effect of LTL and neither UIP nor honeycombing modified theimpact of immunosuppression on survival. Therefore, the current data suggest that short LTL may
predispose to a “UIP-like” phenotype, but the short LTL confers a greater impact on survival that may befurther magnified by immunosuppressive therapies.
Immunosuppressant exposure was not associated with differential FVC decline in non-IPF ILD patientswith LTL <10th percentile, suggesting a harmful effect unrelated to progressive lung fibrosis.
Immunosuppressants are associated with non-pulmonary complications in lung transplant recipients withshort LTL or telomere gene mutations [39–42]. These medications may unmask extrapulmonary short
telomere syndrome manifestations, including bone marrow suppression and impaired adaptive immunity[43, 44], tipping the balance toward harmful inhibition of protective immunity without causing progressive
lung function decline. Prospective studies with systematic evaluation of pulmonary and non-pulmonary
effects of immunosuppressants are needed.
The current study has limitations. First, this retrospective study demonstrates associations but not causal
links. Future clinical trials are needed to validate these findings and inform clinical practice. Second, we
accounted for indication bias by using measured variables that influence immunosuppressant exposure to
generate weighted propensity scores. Using this approach, we were able to balance the distribution ofimportant covariates such as age, sex, severity of disease and radiographic patterns across exposure groups,
thus limiting their influence on effect estimates. However, given the non-randomised nature of this study,
we cannot exclude the possibility of unmeasured effects impacting our results. Third, subsetting therelatively large total cohort reduced the effective sample size and may have led to imprecision. However,similar direction and magnitude of effects were seen across secondary analysis, increasing confidence thatthe associations may approach reality. Fourth, we used banked genomic DNA to measure LTL by qPCR at
two sites, which may have introduced variability in the LTL measurement, although the correlation
between site measurements was high. Given the potential for LTL variability across sites, we chose toperform meta-analysis of the two cohorts, instead of combining. Next, only fibrotic ILDs were included so
it remains unknown if a similar interaction exists in non-fibrotic ILDs. Lastly, we were unable tosystematically assess immunosuppressant-related adverse effects due to the non-standardised follow-up or
the impact of other ILD treatments due to lower usage in the cohorts.
Conclusions
By identifying a harmful pharmacogenomic interaction between LTL <10th percentile of normal andmycophenolate or azathioprine exposure, we demonstrate that LTL may be a clinically viable genomic
https://doi.org/10.1183/13993003.00441-2023

9

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

marker to aid treatment decisions for fHP and uILD patients. The findings should form the basis forprospective validation studies to determine if LTL-informed personalised treatment selection improves
outcomes.
Acknowledgements: We are grateful to all participating patients and research staff that assisted with patient
recruitment, data collection and technical analyses (Leslie Vickers at Columbia University Medical Center,
New York, NY, USA; Jane Berkeley at University of California San Francisco, San Francisco, CA, USA).
Author contributions: Study design: D. Zhang, A. Adegunsoye, C.K. Garcia and C.A. Newton. Patient recruitment ordata collection: D. Zhang, A. Adegunsoye, J.M. Oldham, N. Garcia, M. Poonawalla, R. Strykowski, S-F. Ma, I. Noth,
M.E. Strek, P.J. Wolters, C.K. Garcia and C.A. Newton. Data analysis: J. Kozlitina and C.A. Newton. Interpretation of
the results: D. Zhang, A. Adegunsoye, J.M. Oldham, J. Kozlitina, P.J. Wolters, C.K. Garcia and C.A. Newton.
Manuscript preparation: D. Zhang, A. Adegunsoye and C.A. Newton. All authors reviewed and approved the final
manuscript.
Conflict of interest: D. Zhang reports consulting fees from Boehringer Ingelheim, and grant support from the Stony
Wold-Herbert Fund and Parker B. Francis Foundation. A. Adegunsoye reports consulting fees from Genentech,
Inogen, Medscape, PatientMpower and Boehringer Ingelheim, lecture honoraria from Boehringer Ingelheim, andgrant support from the NHLBI. J.M. Oldham reports consulting fees from Boehringer Ingelheim, Lupin
Pharmaceuticals, AmMax Bio, Roche and Veracyte, advisory board participation with Endeavor Biomedicines, andgrant support from the NHLBI; J.M. Oldham also has a patent “TOLLIP TT genotype for NAC use in IPF” issued,
and is an associate editor of CHEST, as well as a member of the programme committee for the American Thoracic
Society. I. Noth reports consulting fees from Boehringer Ingelheim and Sanofi, data safety monitoring board
participation with Yale, and grant support from Veracyte and the NIH. M.E. Strek reports honoraria from
Boehringer Ingelheim, Fibrogen and the American College of Chest Physicians, advisory board participation with
Fibrogen, and grant support from Boehringer Ingelheim and the Pulmonary Fibrosis Foundation; M.E. Strek also
reports being a member of the scientific review committee of the Pulmonary Fibrosis Foundation. P.J. Wolters
reports grant support from Boehringer Ingelheim, Roche, Sanofi, Pliant and the NIH, and consulting fees from
Blade Therapeutics. C.K. Garcia reports grant support from the NIH, DOD and Boehringer Ingelheim, lecturehonoraria from Three Lakes Foundation, Stanford, UPenn, UCSF and Cedar-Sinai. C.A. Newton reports consulting
fees from Boehringer Ingelheim and grant support from the NHLBI; C.A. Newton is also a member of the scientificreview committee for the Pulmonary Fibrosis Foundation, member of the editorial board for CHEST and memberof the planning committee for the American Thoracic Society. J. Kozlitina, N. Garcia, M. Poonawalla, R. Strykowski,
A.L. Linderholm, B. Ley and S-F. Ma have nothing to disclose.
Support statement: Support from the National Institutes of Health includes K23HL146942 (A. Adegunsoye),
K23HL138190 and R56HL158935 ( J.M. Oldham), UG3HL145266 (I. Noth), R01HL093096 (C.K. Garcia), K23HL148498
and UL1TR001105 (C.A. Newton); Stony Wold-Herbert Fund and Parker B. Francis Foundation (D. Zhang), Nina
Ireland Program for Lung Health (P.J. Wolters). Funding information for this article has been deposited with the
Crossref Funder Registry.

References
1
2
3
4
5
6
7
8
9

King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic
pulmonary fibrosis. N Engl J Med 2014; 370: 2083–2092.
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.
N Engl J Med 2014; 370: 2071–2082.
Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase.
Proc Natl Acad Sci USA 2007; 104: 7552–7557.
Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis.
N Engl J Med 2007; 356: 1317–1326.
Stuart BD, Choi J, Zaidi S, et al. Exome sequencing links mutations in PARN and RTEL1 with familial
pulmonary fibrosis and telomere shortening. Nat Genet 2015; 47: 512–517.
Kannengiesser C, Borie R, Menard C, et al. Heterozygous RTEL1 mutations are associated with familial
pulmonary fibrosis. Eur Respir J 2015; 46: 474–485.
Cogan JD, Kropski JA, Zhao M, et al. Rare variants in RTEL1 are associated with familial interstitial
pneumonia. Am J Respir Crit Care Med 2015; 191: 646–655.
Petrovski S, Todd JL, Durheim MT, et al. An exome sequencing study to assess the role of rare genetic
variation in pulmonary fibrosis. Am J Respir Crit Care Med 2017; 196: 82–93.
Ley B, Torgerson DG, Oldham JM, et al. Rare protein-altering telomere-related gene variants in patients withchronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2019; 200: 1154–1163.

https://doi.org/10.1183/13993003.00441-2023

10

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

10

11
12
13

14
15

16
17
18
19
20
21
22
23
24
25

26
27
28
29
30
31
32

33
34
35
36

37

Dressen A, Abbas AR, Cabanski C, et al. Analysis of protein-altering variants in telomerase genes and theirassociation with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate
gene sequencing study. Lancet Respir Med 2018; 6: 603–614.
Alder JK, Chen JJ, Lancaster L, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc
Natl Acad Sci USA 2008; 105: 13051–13056.
Duckworth A, Gibbons MA, Allen RJ, et al. Telomere length and risk of idiopathic pulmonary fibrosis andchronic obstructive pulmonary disease: a Mendelian randomisation study. Lancet Respir Med 2021; 9: 285–294.
Stuart BD, Lee JS, Kozlitina J, et al. Effect of telomere length on survival in patients with idiopathic
pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med 2014; 2:
557–565.
Dai J, Cai H, Li H, et al. Association between telomere length and survival in patients with idiopathic
pulmonary fibrosis. Respirology 2015; 20: 947–952.
Ley B, Newton CA, Arnould I, et al. The MUC5B promoter polymorphism and telomere length in patients withchronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir Med 2017; 5:
639–647.
Wang H, Zhuang Y, Peng H, et al. The relationship between MUC5B promoter, TERT polymorphisms andtelomere lengths with radiographic extent and survival in a Chinese IPF cohort. Sci Rep 2019; 9: 15307.
Adegunsoye A, Morisset J, Newton CA, et al. Leukocyte telomere length and mycophenolate therapy inchronic hypersensitivity pneumonitis. Eur Respir J 2021; 57: 2002872.
Ley B, Liu S, Elicker BM, et al. Telomere length in patients with unclassifiable interstitial lung disease: acohort study. Eur Respir J 2020; 56: 2000268.
Liu S, Chung MP, Ley B, et al. Peripheral blood leucocyte telomere length is associated with progression ofinterstitial lung disease in systemic sclerosis. Thorax 2021; 76: 1186–1192.
Newton CA, Oldham JM, Ley B, et al. Telomere length and genetic variant associations with interstitial lungdisease progression and survival. Eur Respir J 2019; 53: 1801641.
Newton CA, Zhang D, Oldham JM, et al. Telomere length and use of immunosuppressive medications in
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2019; 200: 336–347.
Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 2008; 167: 492–499.
de Leon AD, Cronkhite JT, Katzenstein AL, et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT)
mutations. PLoS One 2010; 5: e10680.
Faust HE, Golden JA, Rajalingam R, et al. Short lung transplant donor telomere length is associated withdecreased CLAD-free survival. Thorax 2017; 72: 1052–1054.
Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting(IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med
2015; 34: 3661–3679.
Adegunsoye A, Oldham JM, Bellam SK, et al. CT honeycombing identifies a progressive fibrotic phenotype
with increased mortality across diverse interstitial lung diseases. Ann Am Thorac Soc 2019; 16: 580–588.
Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable interstitial lung disease.
Eur Respir J 2013; 42: 750–757.
Crowther MJ, Abrams KR, Lambert PC. Flexible parametric joint modelling of longitudinal and survival data.
Stat Med 2012; 31: 4456–4471.
Hogan JW, Laird NM. Model-based approaches to analysing incomplete longitudinal and failure time data.
Stat Med 1997; 16: 259–272.
The Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteinefor pulmonary fibrosis. N Engl J Med 2012; 366: 1968–1977.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease.
N Engl J Med 2006; 354: 2655–2666.
Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide inscleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group
trial. Lancet Respir Med 2016; 4: 708–719.
Morisset J, Johannson KA, Vittinghoff E, et al. Use of mycophenolate mofetil or azathioprine for the
management of chronic hypersensitivity pneumonitis. Chest 2017; 151: 619–625.
Adegunsoye A, Oldham JM, Fernandez Perez ER, et al. Outcomes of immunosuppressive therapy in chronic
hypersensitivity pneumonitis. ERJ Open Res 2017; 3: 00016-2017.
Oldham JM, Lee C, Valenzi E, et al. Azathioprine response in patients with fibrotic connective tissue
disease-associated interstitial lung disease. Respir Med 2016; 121: 117–122.
Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive
pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care
Med 2022; 205: e18–e47.
Justet A, Klay D, Porcher R, et al. Safety and efficacy of pirfenidone and nintedanib in patients with
idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation. Eur Respir J 2021; 57: 2003198.

https://doi.org/10.1183/13993003.00441-2023

11

EUROPEAN RESPIRATORY JOURNAL

ORIGINAL RESEARCH ARTICLE | D. ZHANG ET AL.

38
39
40

41

42
43
44

Suissa S, Suissa K. Antifibrotics and reduced mortality in idiopathic pulmonary fibrosis: immortal time bias.
Am J Respir Crit Care Med 2023; 207: 105–109.
Borie R, Kannengiesser C, Hirschi S, et al. Severe hematologic complications after lung transplantation inpatients with telomerase complex mutations. J Heart Lung Transplant 2015; 34: 538–546.
Courtwright AM, Lamattina AM, Takahashi M, et al. Shorter telomere length following lung transplantation isassociated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-freesurvival. ERJ Open Res 2020; 6: 00003-2020.
Newton CA, Kozlitina J, Lines JR, et al. Telomere length in patients with pulmonary fibrosis associated withchronic lung allograft dysfunction and post-lung transplantation survival. J Heart Lung Transplant 2017; 36:
845–853.
Tokman S, Singer JP, Devine MS, et al. Clinical outcomes of lung transplant recipients with telomerase
mutations. J Heart Lung Transplant 2015; 34: 1318–1324.
Popescu I, Mannem H, Winters SA, et al. Impaired cytomegalovirus immunity in idiopathic pulmonary fibrosis
lung transplant recipients with short telomeres. Am J Respir Crit Care Med 2019; 199: 362–376.
Wang P, Leung J, Lam A, et al. Lung transplant recipients with idiopathic pulmonary fibrosis have impaired
alloreactive immune responses. J Heart Lung Transplant 2022; 41: 641–653.

https://doi.org/10.1183/13993003.00441-2023

12