AJTCCM VOL. 28 NO. 4 2022 163
RESEARCH
Background. Hypersensitivity pneumonitis (HP) is a syndrome caused by sensitisation to inhaled antigens that leads to an abnormal
immune response in the airways and lung parenchyma. Some patients previously diagnosed with certain types of brotic interstitial lung
diseases (f-ILDs), including brotic HP (f-HP), are susceptible to develop a progressive brosing phenotype (PF-ILD), despite initial state-
of-the-art management.
Objectives. To characterise a cohort of patients with a multidisciplinary diagnosis (MTD) of chronic f-HP, who were followed up in an ILD
outpatient clinic of a hospital in Portugal, and to assess the prevalence of PF-ILD criteria in these patients.
Methods. Data were collected from all patients with a denite or provisional diagnosis of f-HP aer a multidisciplinary team discussion.
Patients were followed up between December 2014 and July 2019. Data included clinical characteristics, high-resolution chest
tomography (HRCT) disease patterns, lung function tests, bronchoalveolar lavage and further immunological work-up, biopsy reports
(conventional transbronchial lung biopsy, transbronchial lung cryobiopsy or surgical video-assisted thoracoscopic lung biopsy), all ILD
multidisciplinary team records and diagnostic condence levels. Patients were assessed according to PF-ILD criteria as dened in the
INBUILD trial.
Results. We identied 83 patients with an MTD of HP, who had been followed up for at least 12months. Of these, 63 (75.9%) were diagnosed
with f-HP. Of the 63 f-HP patients, 33.3% (n=21) fullled the predened criteria for PF-HP: 66.7% had a relative decline of ≥10% forced vital
capacity (FVC); 5% a relative decline of 5-9% FVC, with worsening symptoms or increased brosis on HRCT; and 23.8% had worsening
respiratory symptoms with radiological progression.
Conclusion. is single-centre cohort study demonstrated that a third of f-HP patients presented with PF-ILD, as determined by progression
during initial standard-of-care treatment. A usual interstitial pneumonia (UIP)/UIP-like pattern was present in >70% of patients with f-HP,
and two-thirds of these patients had an FVC decline of ≥10%. PF-HP patients were also more exacerbation prone. According to recent trial
data, this segment of patients can be considered possible candidates for antibrotic treatment, with a reasonable prospect of eectiveness.
Further eorts should focus on rening knowledge of longitudinal behaviour of large multicentric cohorts of f-HP patients, establishing
a consensual and uniform denition of progression for use in clinical practice, as well as developing prognostic prediction tools to better
(and early) inform the disease course.
Keywords: hypersensitivity pneumonitis, pulmonary brosis, progressive
Afr J Thoracic Crit Care Med 2022;28(4):163-166. https://doi.org/10.7196/AJTCCM.2022.v28i4.250
Hypersensitivity pneumonitis (HP) is a syndrome caused by
sensitisation to inhaled antigens that leads to an abnormal immune
response in the airways and lung parenchyma. Disease susceptibility
is regulated by host-related factors (genetic variations of immune
response), antigen properties and exposure-related factors.[1]
A fraction of the patients previously diagnosed with certain types
of brotic interstitial lung diseases (f-ILDs), including brotic HP
(f-HP), are susceptible to develop a progressive brosing phenotype
(PF-ILD), despite initial state-of-the-art management.[2-6] It is
estimated that 18-32% of patients diagnosed with non-idiopathic
pulmonary brosis (non-IPF) f-ILDs develop this type of disease
behaviour.[7] is subgroup amalgamates dierent types of diseases,
showing striking similarities to the clinical course seen in IPF. is
is the result of similar pathogenic mechanisms, ultimately leading
to ongoing collagen deposition and subsequent progressive lung
function decline, worsening symptoms and health-related quality of
life, treatment refractoriness and early mortality.[8-15]
There are several risk factors for progression and mortality
regarding PF-ILD, such as older age, male sex, lower forced vital
capacity (FVC) and diffusing capacity of the lungs for carbon
monoxide (DLCO) at baseline, a pathological or radiological pattern
of usual interstitial pneumonia (UIP), honeycombing and traction
bronchiectasis in high-resolution chest tomography (HRCT) and
acute exacerbations.[15-24]
Some patients with HP may partially recover from the disease,
especially those with the inflammatory/non-fibrotic form.
Criteria for progressive brotic hypersensitivity pneumonitis
inaPortuguese patient cohort
E Seixas,1 MD ; M Ferreira,2 MD; P Serra,3 MD; R Aguiar,4 MD; I Cunha,4 MD; P G Ferreira,5 MD
1 Department of Pulmonology, Centro Hospitalar Baixo Vouga, Aveiro, Portugal
2 Department of Radiology, Centro Hospitalar Baixo Vouga, Aveiro, Portugal
3 Department of Pathology, Centro Hospitalar Baixo Vouga, Aveiro, Portugal
4 Department of Rheumatology, Centro Hospitalar Baixo Vouga, Aveiro, Portugal
5 Department of Pulmonology, Centro Hospitalar e Universitário de Coimbra, Portugal
Corresponding author: E Seixas (eduarda.seixas1@gmail.com)
164 AJTCCM VOL. 28 NO. 4 2022
RESEARCH
Nonetheless, in several previous studies, the radiological and/or
histopathological evidence of f-HP has been strongly correlated with
poor survival.[25,26] is subset of patients frequently experiences
disease progression, particularly if the inciting antigen cannot be
identied and removed.[3,27] It is estimated that only 58% of patients
with f-HP are alive 7 years after diagnosis.[28] Besides antigen
avoidance, the immune dysregulation component of this disease
has traditionally been targeted by the use of corticosteroids and
immunosuppressants, even though there are no controlled clinical
trials to support their ecacy in this setting. However, there is some
low-quality retrospective evidence suggesting that drugs such as
mycophenolate mofetil and azathioprine can potentially reduce the
need for corticosteroids and may improve the trajectory of lung
function decline in some patients.[3,4,29]
The INBUILD trial included a miscellaneous group of several
non-IPF f-ILD patients (26% were f-HP patients), showing previous
progression with standard-of-care treatment. e study also found
that antibrotic treatment with nintedanib can signicantly impact
subsequent lung function decline in this population.[30]
Pirfenidone, a medication with antibrotic properties approved for
IPF, may also be useful in the management of f-HP and PF-HP,[31-33] and
is currently being investigated further in clinical trials (NCT02496182;
NCT02958917).
Objectives and methods
This retrospective cross-sectional study aimed to characterise a
cohort of patients with a multidisciplinary diagnosis (MTD) of
f-HP, followed up in an ILD outpatient clinic of a Portuguese district
hospital (CentroHospitalar do Baixo Vouga, with 450 beds, serving
a population of ~300 000), and to assess the prevalence of PF-ILD
criteria in the same cohort.
Data were collected from all patients with a denite or provisional
diagnosis of f-HP after a multidisciplinary team discussion,
including an ILD specialist, a thoracic radiologist, rheumatologist
and pathologist. e patients were followed up at the designated
centre between December 2014 and July 2019. e dataset included
clinical characteristics, HRCT disease patterns, lung function tests,
bronchoalveolar lavage and further immunological work-up, biopsy
reports (relating to conventional transbronchial lung biopsy (TBLB),
transbronchial lung cryobiopsy (TBLCB) or surgical video-assisted
thoracoscopic lung biopsy (VATS)) and all ILD multidisciplinary
team records and diagnostic condence levels.
Patients were assessed for the presence of PF-ILD criteria, as dened
in the INBUILD trial. Accordingly, a brosing progressive behaviour
in this cohort of HP patients (PF-HP) was acknowledged if ≥1 of the
following criteria were present in the previous 24months: a relative
decline in FVC of at least 10% of the predicted value; a relative FVC
decline of 5-9% predicted, with worsening respiratory symptoms,
or increased extent of brosis on HRCT. Patients receiving o-label
antibrotic drugs were excluded from the analysis.
Statistical analysis
Qualitative variables are expressed as absolute values and
percentages, while quantitative variables are expressed as means
and standard deviations (SDs) for normally distributed data, and
median and interquartile range (IQR) for non-normally distributed
data. e descriptive analysis was performed using SPSS version 25
(IBM Corp., USA).
Ethical approval
The study and all procedures were performed according to the
ethical standards in the 1964 Declaration of Helsinki and its later
amendments, or comparable ethical standards. As this was a
retrospective study, formal consent was not required. All data were
collected anonymously.
Results
We identied 83 patients with an MTD of HP aer having been followed
up for at least 12months. Of these, 63 (75.9%) were diagnosed with
f-HP. is subgroup of patients had a mean age of 69.3 (SD11.8)years
and a slight female predominance (55.6%). Avian proteins (57.1%)
and moulds (25.4%) were the most common recognisable inducing
antigens (Table1).
At diagnosis, 79.4% of patients had never smoked and 20.6% were
previous smokers (mean of 53.0 pack-years). Regarding lung function,
mean FVC at baseline was 77.6% predicted and the last mean FVC was
73.3%. e mean DLCO at baseline was 51.0% and the last DLCO was
50.5%. e 6-min walk distance at diagnosis was 351.8 m.
At baseline, 68.3% of patients presented with grade 1 or 2 mMRC
(modied Medical Research Council) dyspnoea, 23.8% with grade 3
and 7.9% with grade 4 (Table2).
Approximately 68.3% of the patients with f-HP complained of
chronic cough and 14.3% presented with weight loss. A UIP/UIP-like
pattern was present on HRCT and/or biopsy in 46.0% of patients.
Regarding bronchoalveolar lavage (BAL), at diagnosis the mean total
cell count was 357 000 cells/mL, with a mean lymphocyte count of
122094 cells/µL. About two-thirds (66.7%) of f-HP patients showed
elevated IgG titres for context-relevant suspicious antigens.
In 42.9% of patients a lung biopsy procedure was undertaken during
the diagnostic work-up: VATS (70.4%), conventional TBLB (25.9%)
and TBLCB (3.7%).
Table1. Chronic brotic hypersensitivity pneumonitis and
inducing antigen
Causal antigen n (%)
Avian induced 36 (57.1)
Mould induced 16 (25.4)
Avian and mould induced 5 (7.9)
Isocyanate induced 3 (4.8)
Other antigens 2 (3.2)
No identiable antigen 1 (1.6)
Table2. Baseline dyspnoea in brotic hypersensitivity
pneumonitis patients
Baseline dyspnoea (mMRC), grade n (%)
1 8 (12.7)
2 35 (55.6)
3 15 (23.8)
4 5 (7.9)
mMRC = modied Medical Research Council.
AJTCCM VOL. 28 NO. 4 2022 165
RESEARCH
The diagnosis of HP in these patients was
based on imaging, exposure assessment, BAL
lymphocytosis and histopathological ndings
(when available or deemed necessary), and
for all patients there was a multidisciplinary
discussion and a condence level assessment.
Approximately 58.7% received a denite or
high-condence provisional diagnosis, 31.7%
a moderate-condence provisional diagnosis
and 9.5% a low-confidence provisional
diagnosis.
Of the 63 f-HP patients, 33.3% (n=21)
fullled the predened criteria for PF-HP:
66.7% by a relative decline of ≥10% FVC;
9.5% by a relative decline of 5-9% FVC and
worsening symptoms or increased extent
of fibrosis on HRCT; and 23.8% through
worsening respiratory symptoms with
radiological progression (Fig.1).
Compared with the non-progressive
subgroup, the PF-HP patients were of a
similar age at diagnosis (69.6 years and
68.8 years, respectively), with lower BAL
lymphocytes (128520 cells/µL and 109 242
cells/µL, respectively), although with a non-
statistically signicant dierence (p=0.19).
e prevalence of a UIP/UIP-like pattern on
HRCT was 61.9% in the PF-HP subgroup, but
only 38.1% in patients with a non-progressive
phenotype (p=0.05).
During follow-up, we found that acute
exacerbations occurred in 14 (22.2%)
patients (26.2% of PF-HP patients and 14.3%
of non-PF-HP patients), with a 30-day
mortality rate of 42.9%. e global all-cause
mortality rate was 31.7% and respiratory-
related mortality was 60.0% (30.8% in
PF-HP patients and 69.2% in non-PF-HP
patients).
f-HP patients (~95.2%) were being treated
with immunomodulation: 95.2% with low-
dose prednisolone, 55% with mycophenolate
mofetil, 20% with azathioprine and 33%
with add-on hydroxychloroquine (Fig.2).
Globally, the majority of patients (71.4%)
showed a relatively satisfactory antigen
avoidance, with slightly higher compliance
in the PF-HP subgroup (76.2%) than in the
non-PF-HP subgroup (69.0%), even though
a non-exposure to moulds is considered
impracticable, given their ubiquitous
nature. Around 38.1% of f-HP patients
were started on ambulation oxygen support
and 15.9% on continuous oxygen support.
Globally, 27.0%were referred for respiratory
rehabilitation.
Conclusion
A relevant subgroup of f-HP patients does
not respond to antigen avoidance and
immunosuppressive therapy, potentially
assuming a progressive brosing phenotype.
There are hardly any credible evidence-
based therapies; however, this phenotypical
behaviour of HP has recently gained attention
in clinical trials (completed or ongoing) with
antibrotic therapy. is single-centre cohort
study demonstrates that a third of f-HP
patients present with a PF-ILD behaviour,
as determined by eective progression with
initial standard-of-care treatment. A UIP/
UIP-like pattern was present in >70% of
patients with PF-HP, and two-thirds of these
patients progressed with an FVC decline
of ≥10%. PF-HP patients were also more
exacerbation prone.
According to recent trial data, this segment
of patients can be considered possible
candidates for antifibrotic treatment, with
reasonable eectiveness. Further eorts should
focus on refining knowledge regarding the
longitudinal behaviour of large multicentric
cohorts of patients with f-HP, establishing
a consensual and uniform definition of
progression for use in clinical practice, as well
as developing prognostic prediction tools to
better (and early) inform on disease course.
Declaration. None.
Acknowledgements. None.
Author contributions. EA was involved in
the design of the study, analysis of the data,
interpretation of the results, and drafting and
writing of themanuscript; MF contributed to
the design of the study and analysis of the data;
PS, RA and IC contributed to the design of the
study and analysis of the data; PGF was the senior
investigator and was involved in all aspects of the
study: design, analysis, interpretation of the results
and supervising the writing of the manuscript.
Funding. None.
Conicts of interest. ES has received speaking
fees from Boehringer-Ingelheim and travel
expenses from Menarini, Boehringer-Ingelheim,
HP, n=82
f-HP, n=63
5 - 9% relative FVC decline
and worsening symptoms
or progression of brosis
on HRCT,
9.5%
Worsening symptoms
and increased
radiological
extent of brosis,
23.8%
≥10% relative
FVC decline,
66.7%
Criteria for PF-HP,
n=21 (33.3%)
Fig.1. Progression criteria met in the f-HP cohort. (HP = hypersensitivity pneumonitis; f-HP
= brotic HP; PF-HP = progressive brotic HP; FVC = forced vital capacity; HRCT = high-
resolution chest tomography.)
Immunomodulation
treatment,
95.2%
Mycophenolate
mofetil,
55%
Low-dose
prednisolone,
95.2%
Add-on
hydroxychloroquine,
33
Azathioprine,
20%
Criteria for PF-HP,
n=21 (33.3%)
Fig.2. Pharmacological drug regimen in the brotic hypersensitivity pneumonitis cohort.
166 AJTCCM VOL. 28 NO. 4 2022
RESEARCH
Novartis and Mundipharma, outside the submitted work. PGF has
received speaking fees and travel expenses from Boehringer-Ingelheim,
Roche, Menarini, Novartis, Medinfar, Mundipharma and GSK, outside the
submitted work. PGF has also participated on the advisory boards of Roche
and Boehringer-Ingelheim.
1. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: Insights in diagnosis
and pathobiology. Am J Respir Crit Care Med 2012;186(4):314-324. https://doi.
org/10.1164/rccm.201203-0513CI
2. Fernández Pérez ER, Swigris JJ, Forssén AV, etal. Identifying an inciting antigen
is associated with improved survival in patients with chronic hypersensitivity
pneumonitis. Chest 2013;144(5):1644-1651. https://doi.org/10.1378/chest.12-2685
3. Vašáková M, Morell F, Walsh S, etal. Hypersensitivity pneumonitis: Perspectives in
diagnosis and management. Am J Respir Crit Care Med 2017;196(6):680-689. https://
doi.org/10.1164/rccm.201611-2201PP
4. Salisbury ML, Myers JL, Belloli EA, etal. Diagnosis and treatment of fibrotic
hypersensitivity pneumonia. Where we stand and where we need to go. Am J Respir
Crit Care Med 2017;196(6):690-699. https://doi.org/10.1164/rccm.201608-1675PP
5. Raghu G, Collard HR, Egan JJ, etal. An Ocial ATS/ERS/JRS/ALAT statement.
Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and
management. Am J Respir Crit Care Med 2011;183(6):788-824. https://doi.
org/10.1164/rccm.2009-040GL
6. Cottin V, Hirani NA, Hotchkin DL, etal. Presentation, diagnosis and clinical course
of the spectrum of progressive-brosing interstitial lung diseases. Eur Respir Rev
2018;27(150):180076. https://doi.org/10.1183/16000617.0076-2018
7. Wijsenbeek M, Kreuter M, Olson A, etal. Progressive brosing interstitial lung
diseases: Current practice in diagnosis and management. Curr Med Res Opin
2019;35(11):2015-2024. https://doi.org/10.1080/03007995.2019.1647040
8. Kolb M, Vašáková M. e natural history of progressive brosing interstitial lung
diseases. Respir Res 2019;20(1):57. https://doi.org/10.1186/s12931-019-1022-1
9. Baron M, Sutton E, Hudson M, etal. e relationship of dyspnoea to function and
quality of life in systemic sclerosis. Ann Rheum Dis 2008;67(5):644-650. https://doi.
org/10.1136/ard.2007.075721
10. Kreuter M, Swigris J, Pittrow D, etal. Health related quality of life in patients with
idiopathic pulmonary brosis in clinical practice: INSIGHTS-IPF registry. Respir Res
2017;18(1):139. https://doi.org/1186/s12931-017-0621-y
11. Kreuter M, Stansen W, Stowasser S, etal. Impact of lung function decline on health-
related quality of life in patients with idiopathic pulmonary brosis (IPF). Am J Respir
Crit Care Med 2018;197:A1604.
12. Tashkin DP, Elashoff R, Clements PJ, etal. Cyclophosphamide versus placebo
in scleroderma lung disease. N Engl J Med 2006;354(25):2655-2666. https://doi.
org/10.1056/NEJMoa055120
13. Flaherty KR, Brown KK, Wells AU, etal. Design of the PF-ILD trial: A double-
blind, randomised, placebo-controlled phase III trial of nintedanib in patients with
progressive brosing interstitial lung disease. BMJ Open Respir Res 2017;4(1):e000212.
https://doi.org/10.1136/bmjresp-2017-000212
14. Wells AU, Brown KK, Flaherty KR, etal. What’s in a name? at which we call IPF,
by any other name would act the same. Eur Respir J 2018;51(5):1800692. https://doi.
org/10.1183/13993003.00692-2018
15. Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases:
Knowns and unknowns. Eur Respir Rev 2019;28(151):180100. https://doi.
org/10.1183/16000617.0100-2018
16. Mooney JJ, Elicker BM, Urbania TH, etal. Radiographic brosis score predicts
survival in hypersensitivity pneumonitis. Chest 2013;144(2):586-592. https://doi.
org/10.1378/chest.12-2623
17. Gimenez A, Storrer K, Kuranishi L, etal. Change in FVC and survival in chronic
fibrotic hypersensitivity pneumonitis. Thorax 2017;73(4):391-392. https://doi.
org/10.1136/thoraxjnl-2017-210035
18. Zamora-Lego JA, Krause ML, Crowson CS, etal. Progressive decline of lung function
in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol
2017;69(3):542-549. https://doi.org/10.1002/art.39971
19. Guler SA, Winstone TA, Murphy D, etal. Does systemic sclerosis-associated interstitial
lung disease burn out? Specic phenotypes of disease progression. Ann Am orac
Soc 2018;15(12):1427-1433. https://doi.org/10.1513/AnnalsATS.201806-362OC
20. Reiseter S, Gunnarsson R, Mogens Aalokken T, etal. Progression and mortality of
interstitial lung disease in mixed connective tissue disease: A long-term observational
nationwide cohort study. Rheumatology (Oxford) 2018;57(2):255-262. https://doi.
org/10.1093/rheumatology/kex077
21. Flaherty KR, Thwaite EL, Kazerooni EA, etal. Radiological versus histological
diagnosis in UIP and NSIP: Survival implications. orax 2003;58(2):143-148. https://
doi.org/10.1136/thorax.58.2.143
22. Kim EJ, Elicker BM, Maldonado F, etal. Usual interstitial pneumonia in rheumatoid
arthritis-associated interstitial lung disease. Eur Respir J 2010;35(6):1322-1328.
https://doi.org/10.1183/09031936.00092309
23. Oldham JM, Adegunsoye A, Valenzi E, et al. Characterisation of patients with
interstitial pneumonia with autoimmune features. Eur Respir J 2016;47(6):1767-1775.
https://doi.org/10.1183/13993003.01565-2015
24. Collard HR, Ryerson CJ, Corte TJ, etal. Acute exacerbation of idiopathic pulmonary
fibrosis. An international working group report. Am J Respir Crit Care Med
2016;194(3):265-275. https://doi.org/10.1164/rccm.201604-0801CI
25. VourlekisJS,SchwarzMI,CherniackRM,etal. e eect of pulmonary brosis on
survival in patients with hypersensitivity pneumonitis.Am J Med2004;116(10):662-
668. https://doi.org/10.1016/j.amjmed.2003.12.030
26. WangP, JonesKD,UrismanA,etal. Pathologic ndings and prognosis in a large
prospective cohort of chronic hypersensitivity pneumonitis.Chest 2017;152(3):502-
509. https://doi.org/10.1016/j.chest.2017.02.011
27. Salisbury ML, Gu T, Murray S, etal. Hypersensitivity pneumonitis: Radiologic
phenotypes are associated with distinct survival time and pulmonary function
trajectory. Chest. 2019;155(4):699-711. https://doi.org/10.1016/j.chest.2018.08.1076
28. Fernández Pérez ER, Kong AM, Raimundo K, etal. Epidemiology of hypersensitivity
pneumonitis among an insured population in the United States: A claims-based
cohort analysis. Ann Am orac Soc 2018;15(4):460-469. https://doi.org/10.1513/
AnnalsATS.201704-288OC
29. Morisset J, Johannson KA, Vittingho E, etal. Use of mycophenolate mofetil or
azathioprine for the management of chronic hypersensitivity pneumonitis. Chest
2017;151(3):619-625. https://doi.org/10.1016/j.chest.2016.10.029
30. Flaherty KR, Wells AU, Cottin V, etal. Nintedanib in progressive brosing interstitial
lung diseases. N Engl J Med 2019;381(18):1718-1727. https://doi.org/10.1056/
NEJMoa1908681
31. Guenther A,Prasse A,Kreuter M, etal. Exploring ecacy and safety of oral pirfenidone
for progressive, non-IPF lung brosis (RELIEF). BMC Pulm Med 2017;17(1):122.
https://doi.org/10.1186/s12890-017-0462-y
32. Shibata S, Furusawa H, Inase N. Pirfenidone in chronic hypersensitivity pneumonitis:
A real-life experience. Sarcoidosis Vasc Diuse Lung Dis 2018;35(2):139-142. https://
doi.org/10.36141/svdld.v35i2.6170
33. Shebl E, Hamdy T. Evaluation of the ecacy of pirfenidone in progressive chronic
hypersensitivity pneumonitis. Egypt J Bronchol 2021;15:18. https://doi.org/10.1186/
s43168-021-00065-y
Accepted 27 September 2022.
