Antigen avoidance and outcome of nonfibrotic and fibrotic hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is classified into nonfibrotic and fibrotic phenotypes. Patients with nonfibrotic HP often experience recurrence and develop fibrosis, whereas those with fibrotic HP have a poor prognosis. Although antigen avoidance has long been the first line of treatment for HP, its impact on prognosis has been poorly reported.
METHODS: Medical records of 121 patients with HP diagnosed by new diagnostic criteria of American Thoracic Society/Japanese Respiratory Society/Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) guidelines and treated at our institution in Saitama, Japan, were retrospectively analysed. HP was classified into nonfibrotic and fibrotic phenotypes and six HP subtypes: summer-type, bird-related, home-related and occupational HP, humidifier lung, and hot tub lung. Achievement of reduced exposure to inciting agents was divided into complete antigen avoidance (CAA) and incomplete antigen avoidance (IAA) by HP subtype.
RESULTS: Of the 74 patients with nonfibrotic HP, 30 achieved CAA and experienced no recurrence or development of fibrosis. In the remaining 44 patients with IAA, 24 (54.5%) experienced recurrence and/or development of fibrosis. The all-cause 5-year mortality rate in the 47 patients with fibrotic HP was 47.8%. Negative prognostic factors of HP-related mortality in these patients were <50% lymphocytes in bronchoalveolar lavage (BAL) and honeycombing. Multivariate analysis showed a tendency for IAA to be related to poorer survival (hazard ratio 3.452, 95% CI 0.964-12.359, p=0.057).
CONCLUSIONS: In the patients with nonfibrotic HP, CAA resulted in no recurrence or development of fibrosis and longer survival. In the patients with fibrotic HP, <50% lymphocytes in BAL and honeycombing were negative prognostic factors for mortality.

Introduction

Hypersensitivity pneumonitis (HP) is an inflammatory and/or fibrotic disease affecting the lung parenchyma and small airways. It typically results from an immune-mediated reaction provoked by an overt or occult inhaled antigen in susceptible individuals [1]. Although various alternative definitions of HP have been proposed [2-5], clinical practice guidelines were developed by the American Thoracic Society (ATS), the Japanese Respiratory Society (JRS) and the Asociación Latinoamericana del Tórax (ALAT) [6] for the accurate diagnosis of HP. Accurate and timely diagnosis can help patients avoid culpable environmental factors known to induce HP and potentially change the disease course [7-9].

HP was historically categorised as acute, subacute or chronic [5]. However, these categories are not easily demarcated, and their delineation has been variable and arbitrary in many studies [10-12]. Because the presence of radiographic or histopathological fibrosis is the primary determinant of prognosis [7–9, 13–19], the ATS/JRS/ALAT guideline categorises HP as either nonfibrotic or fibrotic. Patients with nonfibrotic HP often experience recurrence and develop fibrosis, whereas those with fibrotic HP have a poor prognosis. Whether complete antigen avoidance (CAA) improves the outcome of patients with nonfibrotic or fibrotic HP requires further study. We hypothesised that CAA would reduce the incidences of recurrence and fibrosis development in nonfibrotic HP patients and would prolong survival in patients with fibrotic HP.

Thus, the present study aimed to retrospectively review the medical records of 121 patients with HP diagnosed according to the new diagnostic criteria of the ATS/JRS/ALAT guideline to assess both the relationship of CAA with recurrence or fibrosis development in patients with nonfibrotic HP and prognostic factors including CAA in patients with fibrotic HP.

Study design and methods

Study design

We performed a retrospective cohort study in Saitama Cardiovascular and Respiratory Center, Saitama, Japan. We studied 121 HP patients aged >18 years who fulfilled the 2020 ATS/JRS/ALAT diagnostic criteria of definite, high confidence and moderate confidence, and were newly diagnosed from 1991 through 2016 (table 1). Following publication of the ATS/JRS/ALAT clinical practice guideline in 2020, we reviewed all clinical, radiographic, bronchoalveolar lavage (BAL) and pathological data, treatments, CAA and outcomes from medical records of all patients who had been diagnosed as having HP. Patients with a diagnosis of HP of low confidence or not excluded were not included. Standard high-resolution computed tomography (HRCT) protocols were used to obtain images for evaluation. The scans were reviewed independently in a blinded fashion by two observers (N.T. and T.K.). Scans consistent with fibrotic HP contained irregular fine or coarse reticulation with architectural lung distortion and traction bronchiectasis and were divided into two groups: those with and without honeycombing. In cases of disagreement, consensus was obtained following further review. All patients were classified as having fibrotic or nonfibrotic HP based on the presence or absence, respectively, of radiological fibrosis. HRCT scan features and histopathological criteria for the diagnosis of HP were classified according to the following three patterns: typical HP, compatible HP or indeterminate HP and HP, probable HP or indeterminate for HP, respectively (table 1). Based on exposure history and/or serum antibody testing, HP was classified into six categories: summer-type HP, bird-related HP, home-related HP, occupational HP (including mushroom worker's lung, isocyanate alveolitis, farmer's lung and workplace-associated HP due to Aspergillus fumigatus), humidifier lung and hot tub lung (table 2).

TABLE 1

Hypersensitivity pneumonitis diagnosis based on incorporation of imaging, exposure assessment, BAL lymphocytosis and histopathological findings according to the official ATS/JRS/ALAT Clinical Practice Guideline

Demographics	All patients	Nonfibrotic	Fibrotic
Number of patients	121 (100)	74 (100)	47 (100)
HRCT
Typical	110 (90.9)	73 (98.6)	37 (78.7)
Compatible	11 (9.1)	1 (1.4)	10 (21.3)
Indeterminate	0 (0)	0 (0)	0 (0)
Exposure assessment
Improved with antigen avoidance test	97 (78.5)	73 (98.6)	24 (51.1)
Challenge test positive	83 (68.6)	57 (77.0)	26 (55.3)
Specific antibodies positive	99 (81.8)	59 (79.7)	40 (85.1)
BAL lymphocytosis (>30%)	92 (76.0)	65 (87.8)	27 (57.4)
Histopathology
SLB	10 (8.3)	1 (1.4)	9 (19.1)
TBLB	97 (80.2)	68 (91.9)	29 (61.7)
Typical	31 (25.6)	24 (32.4)	7 (14.9)
Probable	7 (5.7)	2 (4.3)	5 (10.6)
Indeterminate	40 (54.1)	29 (39.2)	11 (23.4)
Diagnosis
Definite	70 (57.9)	55 (74.3)	15 (31.9)
High confidence	19 (15.7)	12 (16.2)	7 (14.9)
Moderate confidence	32 (26.4)	7 (9.50)	25 (53.2)
Low confidence	0	0	0

Data are given as n (%). BAL: bronchoalveolar lavage; ATS: American Thoracic Society; JRS: Japanese Respiratory Society; ALAT: Asociación Latinoamericana del Tórax; HRCT: high-resolution computed tomography; SLB: surgical lung biopsy; TBLB: transbronchial lung biopsy.

TABLE 2

Diagnosis of hypersensitivity pneumonitis (HP) subtype according to exposure assessment and serum antibody and definition of antigen avoidance

Subtype of HP	Exposure assessment (number of positive patients/number of total patients)	Serum antibody (number of positive patients/number of total patients)	Definition of complete antigen avoidance
Summer-type HP	Occurred in summer (52/52). Positive inhalation challenge at home or relapse in summer (47/52). The other 5 patients moved to another house and did not have a challenge test.	Trichosporon: 52/52	Changing homes
Bird-related HP	History of avian contact (32/32). Positive inhalation challenge at home with bird (19/32).	Avian antigens: 28/32	Changing homes and removal of birds
Home-related HP	Occurred in home (17/17). Positive inhalation challenge at home (12/17). The other 5 patients had relapse at home the following year.	Trichosporon: 0/17 Fungus#: 12/17	Changing homes
Occupational HP	Positive inhalation challenge with mushrooms (6/6), isocyanate (3/3), mouldy hay (1/1) and at workplace (1/1).	Mushrooms: 2/6, isocyanate 1/3, Aspergillus niger 1/1 (Farmer's lung), A. fumigatus 1/1 (HP at workplace)	Job change, relocation
Humidifier lung	Used ultrasonic humidifier (8/8). Positive inhalation challenge using humidifier at hospital (8/8).	Fungus: 2/8	Do not use a humidifier
Hot tub lung	Positive inhalation challenge using hot tub at home and culture of Mycobacterium avium complex from both patient and hot tub (1/1).	Not done	Do not use hot tub

#: antibodies to fungi included Cephalosporium acremonium (n=5), Penicillium digitatum (n=5), Candida albicans (n=5), Aspergillus niger (n=4), A. versicolor (n=4), A. fumigatus (n=4), A. flavus (n=3), A. nidulans (n=3), A. restrictus (n=2) and Aureobasidium pullulans (n=1). Many patients had multiple antibodies.

All patients are advised to reduce or avoid offending environmental factors, and reduction in the intensity of exposure to inciting antigens was classified into the categories of CAA and incomplete antigen avoidance (IAA). In patients with summer-type, bird-related and home-related HP, changing homes was considered to be CAA, whereas renovation, clean-up or stopping breeding of birds but continuing to live in the same house was considered IAA. In patients with occupational HP, humidifier lung and hot tub lung, job change or job relocation, not using the humidifier and not using the hot tub, respectively, were considered CAA (table 2). Patients were followed through December 2018 or until death before then. Survival status was obtained from medical records and/or telephone interviews. In patients with nonfibrotic HP, we examined whether IAA was associated with recurrence (re-exacerbation of respiratory symptoms and ground-glass opacities on HRCT) and/or fibrosis development and searched for predictors of recurrence and/or fibrosis development in the patients with nonfibrotic HP who did not do CAA. In the patients with fibrotic HP, prognosis and prognostic markers were investigated.

Data analysis

Categorical baseline characteristics are summarised by frequency and percent, and continuous characteristics are reported as the median (interquartile range, IQR). We compared baseline characteristics and therapy for nonfibrotic and fibrotic HP by Fisher's exact test or Wilcoxon test in accordance with nominal and continuous variables, respectively. Recurrence and/or fibrosis development in each patient group with or without CAA was estimated by Kaplan–Meier analysis. Because recurrence and/or fibrosis development occurred only in the IAA group, we investigated potential risk factors of recurrence and/or developing fibrosis only in these patients. We chose the following variables for entry into univariate Cox regression analysis: sex, age, smoking history, HP subtype, presence of fever, BAL lymphocytes, BAL neutrophils, BAL CD4/CD8, forced vital capacity (FVC) % predicted, diffusing capacity for carbon monoxide (DLCO) % predicted, partial pressure of arterial oxygen (PaO), partial pressure of arterial carbon dioxide (PaCO), alveolar–arterial oxygen difference (A-aDO), erythrocyte sedimentation rate, C-reactive protein (CRP), sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6), pulmonary surfactant protein D (SP-D) and steroid therapy. Survival times of patients with nonfibrotic and fibrotic HP were estimated by Kaplan–Meier analysis. All-cause mortality rates were compared with a log-rank test. To investigate potential risk factors of mortality of patients with fibrotic HP, we used the following variables for entry into univariate Cox regression analysis: sex, age, smoking history, type of disease onset, HP subtype, BAL lymphocytes, BAL neutrophils, BAL CD4/CD8, FVC % predicted, DLCO % predicted, PaO, PaCO, A-aDO, erythrocyte sedimentation rate, CRP, KL-6, SP-D, HRCT findings of honeycombing, traction bronchiectasis, and lung distortion, steroid therapy and CAA. We then performed univariate and multivariate Cox regression analysis with backward variable selection. Fibrotic HP can be divided clinically into two types of onset: insidious type, which develops without a history of acute episodes but is a slowly progressive chronic respiratory disease, and recurrent type, which develops after recurrent acute episodes. A p-value of <0.05 was considered to be statistically significant in all analyses. Missing data were categorised as “unknown” and were entered into each statistical analysis model. All data were analysed with SAS version 9.1.3 (SAS Institute, Cary, NC, USA). The Saitama Cardiovascular and Respiratory Center institutional review board approved this study (no. 2020034).

Results

Patient characteristics

Of the 121 patients, 60 (49.6%) were female. Median patient age was 63.0 years. Phenotypes included nonfibrotic (61.2%) and fibrotic (38.8%) HP. HP subtypes included summer-type (43.0%), bird-related (26.4%), home-related (14.0%), occupational (9.1%), humidifier lung (6.6%) and hot tub lung (0.8%) (table 3).

TABLE 3

Baseline characteristics and treatment of the 121 study patients with hypersensitivity pneumonitis (HP) according to nonfibrotic and fibrotic phenotypes

		HP phenotypes
Characteristics	Total	Nonfibrotic	Fibrotic	p-value
Subjects	121 (100)	74 (100)	47 (100)
Female	60 (49.6)	44 (59.5)	16 (34.0)	0.009
Age years	63.0 (52.0–71.0)	59.0 (49.0–66.0)	67.0 (60.0–73.0)	<0.001
Smoker	52 (43.0)	27 (36.5)	25 (53.2)	0.09
Symptoms
Duration of symptoms days	68 (38–150)	58 (30–90)	210 (90–850)	<0.001
Cough	101 (83.5)	67 (90.5)	34 (72.3)	0.012
Sputum	38 (31.4)	29 (39.2)	9 (19.1)	0.027
Dyspnoea	100 (82.6)	58 (78.4)	42 (89.4)	0.144
Fever	45 (37.2)	35 (47.2)	10 (21.3)	0.004
HP subtype				<0.001
Summer-type	52 (43.0)	43 (58.1)	9 (19.1)
Bird-related	32 (26.4)	9 (12.2)	23 (48.9)
Home-related	17 (14.0)	6 (8.1)	11 (23.4)
Occupational#	11 (9.1)	9 (12.2)	2 (4.3)
Humidifier	8 (6.6)	6 (8.1)	2 (4.3)
Hot tub	1 (0.8)	1 (1.4)	0 (0.0)
HRCT scan features
Ill-defined centrilobular nodules	90 (74.4)	69 (93.2)	21 (44.7)	<0.001
Ground-glass opacities	119 (98.3)	74 (100.0)	45 (95.7)	<0.001
Mosaic attenuation	72 (59.5)	58 (78.4)	14 (29.8)	<0.001
Honeycombing	26 (21.5)	0 (0.0)	26 (55.3)	<0.001
Traction bronchiectasis	45 (37.2)	0 (0.0)	45 (95.7)	<0.001
Lung distortion	45 (37.2)	0 (0.0)	45 (95.7)	<0.001
BALF
Lymphocyte %	64.9 (40.3–77.6)	69.0 (58.0–81.6)	45.0 (7.6–71.3)	<0.001
Neutrophil %	3.2 (1.4–8.3)	5.05 (1.6–12.0)	2.75 (1.1–6.4)	0.065
CD4/CD8 ratio	0.8 (0.3–2.1)	0.4 (0.2–0.8)	2.0 (1.2–4.0)	<0.001
Laboratory data
WBC per mm3	7700 (6400–9100)	7700 (6300–10 000)	7700 (6400–8900)	0.414
LDH IU·L−1	258 (210–307)	246 (205–314)	264 (217–307)	0.555
ESR mm·h−1	42 (22–59)	22 (42–58)	39 (22–60)	0.717
CRP mg·dL−1	1.0 (0.2–2.6)	1.7 (0.4–2.9)	0.5 (0.1–1.4)	<0.001
KL-6 U·mL−1	1832 (934–2732)	1496 (898–2711)	2121 (1414–3552)	0.07
SP-D ng·mL−1	243 (173–423)	197 (141–277)	354 (214–545)	<0.001
PaO2 Torr (room air)	70.1 (62.5–78.5)	67.6 (60.1–75.5)	74.5 (66.5–84.0)	0.005
PaCO2 Torr (room air)	38.6 (35.4–41.7)	37.0 (35.2–40.6)	39.2 (37.3–42.5)	0.042
A-aDO2	33.9 (22.9–42.8)	37.4 (28.9–45.0)	28.0 (19.1–35.3)	<0.001
Pulmonary function
FVC % predicted	67.4 (50.9–79.0)	70.4 (56.9–81.9)	63.6 (49.4–71.5)	0.039
DLCO % predicted	67.0 (55.1–80.7)	67.0 (56.3–81.5)	64.8 (52.0–80.7)	0.389
Treatment
Steroid¶	33 (27.3)	11 (14.9)	22 (46.8)	<0.001
Complete antigen avoidance	38 (31.4)	30 (40.5)	8 (17.0)	0.009

Data are given as the median (interquartile range) or n (%) unless otherwise indicated. HRCT: high-resolution computed tomography; BALF: bronchoalveolar lavage fluid; WBC: white blood cell count; LDH: lactate dehydrogenase; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; KL-6: Krebs von den Lungen-6; SP-D: surfactant protein D; PaCO: partial pressure of carbon dioxide in arterial blood; PaO: partial pressure of oxygen in arterial blood; A-aDO: alveolar–arterial oxygen difference; FVC: forced vital capacity; DLCO: diffusing capacity of lung for carbon monoxide. #: occupational includes cases of mushroom worker's lung (n=6), isocyanate alveolitis (n=3), farmer's lung (n=1) and workplace-associated HP due to Aspergillus fumigatus; ¶: steroid was given in nonfibrotic HP patients who did not improve enough after admission to hospital, and in fibrotic HP patients who did not improve enough after admission to hospital and had diffuse ground-glass opacities. Patients who were treated with steroid at relapse or at acute exacerbation were not included.

Compared with patients with fibrotic HP, those with nonfibrotic HP were significantly more likely to be female, nonsmokers, have a shorter duration of symptoms, and have fever and summer-type HP. HRCT scan features of ill-defined centrilobular nodules, ground-glass opacities, and mosaic attenuation, BAL lymphocytosis, low CD4/CD8 of BAL lymphocytes, higher CRP, lower SP-D, lower PaO, lower PaCO, higher A-aDO and higher FVC % predicted all occurred significantly more frequently in those with nonfibrotic HP. Steroid therapy was more frequently administered to patients with fibrotic versus nonfibrotic HP, but CAA was more frequently done by patients with nonfibrotic versus fibrotic HP.

HP recurrence/fibrosis in nonfibrotic HP

Of the 74 patients with nonfibrotic HP, 30 did CAA and experienced no recurrence or fibrosis development, and complete resolution was maintained at the last follow-up regardless of whether short-course steroid therapy was administered (figure 1a). In the remaining 44 patients not doing CAA, recurrence and/or fibrosis development occurred in 24 (54.5%) patients, and the median time to recurrence and/or developing fibrosis was 3.7 years. Of the 20 patients who did not experience a recurrence or develop fibrosis, all maintained complete resolution. The log-rank test showed a significant difference between event-free curves in the patients with CAA and IAA (p<0.001) (figure 2). Among the 24 patients with recurrence and/or fibrosis development, recurrence occurred in 22 patients and fibrosis developed in seven (figure 1b). The first episode of recurrence or fibrosis development was recurrence only in 21 patients, fibrosis only in two patients, and both in one patient. Of the 21 patients with recurrence, three did CAA, and none experienced recurrence or developed fibrosis. Of the remaining 18 patients without CAA, 11 patients experienced a second recurrence, and three experienced recurrence and developed fibrosis. Of the 11 patients with a second recurrence, two patients did CAA, and neither experienced recurrence nor developed fibrosis. Of the remaining nine patients without CAA, two patients experienced a third recurrence, and one patient experienced recurrence and developed fibrosis. Among the 74 patients in the nonfibrotic HP group, none of the seven patients with fibrosis development died, but six patients had progressive lung fibrosis, for which two required home oxygen therapy.

FIGURE 1

a) Patient flow diagram detailing the relationship between “complete antigen avoidance” and “recurrence and/or developing fibrosis” in patients with nonfibrotic hypersensitivity pneumonitis (HP). Of the 74 patients with nonfibrotic HP, 30 patients did complete antigen avoidance (CAA), and these patients experienced no recurrence nor developed fibrosis. Of the nonfibrotic HP patients without CAA (n=44), 24 experienced recurrence and/or developed fibrosis. b) Patient flow diagram detailing the clinical course of nonfibrotic HP patients with incomplete antigen avoidance who experienced an episode of recurrence and/or developed fibrosis. Of the 21 patients with recurrence at the 1st episode, three did CAA after the 1st episode and none had a recurrence thereafter. Of the 18 patients who did not do CAA after the 1st episode, 11 had a recurrence only and three had a recurrence and developed fibrosis (2nd episode). Of the 11 patients with a 2nd episode of recurrence, two patients did CAA, and neither experienced recurrence nor developed fibrosis thereafter. Of the nine patients not doing CAA and who did not develop fibrosis at the 2nd episode, two had recurrence only and one had recurrence and subsequently developed fibrosis (3rd episode). In total, seven patients developed fibrosis during the observation period: six developed progressive pulmonary fibrosis, and two required home oxygen therapy. A: humidifier lung; B: bird-related HP; H: home-related HP; N: number; O: occupational HP; S: summer-type HP; T: hot tub lung.

FIGURE 2

Kaplan–Meier curves of the probability of recurrence and/or development of fibrosis in patients with nonfibrotic hypersensitivity pneumonitis (HP) with or without complete antigen avoidance. None of the 30 patients with complete antigen avoidance experienced recurrence and/or developed fibrosis, whereas 24 of the 44 patients without complete antigen avoidance experienced recurrence and/or developed fibrosis.

In a univariate Cox proportional hazard model, no factor was found to be a risk factor for recurrence and/or fibrosis development among the patients with nonfibrotic HP who did not do CAA (table 4).

TABLE 4

Univariate analysis of predictors of recurrence and/or developing fibrosis in 43 patients with nonfibrotic hypersensitivity pneumonitis who did not do complete antigen avoidance

Variables	Univariate analysis
	HR	95% CI	p-value
Male sex	1.04	0.43–2.50	0.937
Age ≥60 years	1.91	0.84–4.34	0.122
Ever-smoker	0.80	0.32–2.01	0.631
HP subtype
Summer-type	Reference
Bird-related	0.60	0.20–1.76	0.349
Household	0.32	0.043–2.40	0.267
Occupational#	0.65	0.14–3.03	0.991
Fever	0.64	0.27–1.51	0.307
BALF
Lymphocytes <50%	0.62	0.21–1.81	0.381
Neutrophil ≥5%	0.58	0.26–1.30	0.186
CD4/CD8 ≥2.0	1.68	0.66–4.25	0.274
PFT
% FVC <70%	0.62	0.26–1.47	0.279
% DLCO <70%	0.87	0.36–2.10	0.759
Arterial blood gas analysis
PaO2 Torr (room air) <70	0.51	0.22–1.17	0.112
PaCO2 Torr (room air) ≥35	0.42	0.13–1.42	0.164
A-aDO2 ≥40	0.696	0.31–1.61	0.397
Laboratory findings
ESR mm·h−1 ≥40	0.57	0.24–1.33	0.190
CRP mg·dL−1 ≥1.0	0.59	0.26–1.33	0.201
KL-6 U·mL−1 ≥2000	0.90	0.37–2.19	0.822
SP-D ng·mL−1 ≥250	0.65	0.23–1.88	0.426
Treatment
Steroid	1.55	0.62–3.92	0.351

HR: hazard ratio; BALF: bronchoalveolar lavage fluid; PFT: pulmonary function test; FVC: forced vital capacity; DLCO: diffusing capacity of lung for carbon monoxide; PaO: partial pressure of oxygen in arterial blood; PaCO: partial pressure of carbon dioxide in arterial blood; A-aDO: alveolar–arterial oxygen difference; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; KL-6: Krebs von den Lungen-6; SP-D: surfactant protein D. #: occupational includes one case of mushroom worker's lung.

Mortality and causes of death

Death from any cause occurred in 28 (23.1%) patients over a median follow-up period of 5.6 years (IQR, 2.7–9.2 years), and the overall cumulative 5- and 10-year mortality rates were 19.3% and 31.0%, respectively. The respective overall cumulative 5- and 10-year mortality rates were 0.0% and 2.9% in the nonfibrotic HP group and 47.8% and 79.6% in the fibrotic HP group. The log-rank test showed a significant difference between survival curves in patients with nonfibrotic versus fibrotic HP (p<0.001, figure 3). Three patients with nonfibrotic HP died from non-pulmonary malignancy (two patients), and unknown cause (one patient), and 25 patients with fibrotic HP died from respiratory failure due to HP progression (13 patients), acute exacerbation of HP (11 patients) and pulmonary tuberculosis (one patient).

FIGURE 3

Kaplan–Meier survival curves of all-cause mortality in all patients and those with nonfibrotic and fibrotic hypersensitivity pneumonitis (HP). Overall cumulative 5- and 10-year mortality rates were 19.3% and 31.0%, respectively. Respective 5- and 10-year all-cause mortality rates in the nonfibrotic HP patients were 0% and 2.9% versus 47.8% and 79.6% in the fibrotic HP patients. A log-rank test showed a significant difference between survival curves in the patients with nonfibrotic HP and fibrotic HP (hazard ratio 65.7, 95% CI 8.8–490.1, p<0.001). Median survival time for fibrotic HP patients was 5.25 years (95% CI 3.81–9.09).

Prognostic factors of HP-specific mortality

In a multivariate Cox proportional hazard model, <50% lymphocytes in BAL and HRCT features of honeycombing were found to be negative prognostic factors of HP-specific mortality in the patients with fibrotic HP (table 5). IAA showed a tendency to be related to poorer survival according to the multivariate analysis (hazard ratio 3.452, 95% CI 0.964–12.359, p=0.057).

TABLE 5

Univariate and multivariate Cox regression models of the risk of hypersensitivity pneumonitis (HP)-related mortality in 47 patients with fibrotic HP

Variables	Univariate analysis			Multivariate analysis
	HR	95% CI	p-value	Adjusted HR	95% CI	p-value
Male sex	1.44	0.57–3.7	0.442
Age ≥60 years	1.13	0.47–2.74	0.789
Ever-smoker	1.25	0.55–2.86	0.599
Insidious type# (versus recurrent)	2.1	0.93–4.75	0.075
HP subtype
Summer-type	Reference
Bird-related	0.97	0.28–3.39	0.966
Household	0.65	0.14–3.03	0.586
Occupational¶	<0.01		0.991
Humidifier	0.41	0.04–4.28	0.459
BALF
Lymphocytes <50%	2.65	1.02–6.84	0.044	3.128	1.15–8.53	0.026
Neutrophil ≥5%	2.02	0.81–5.02	0.130
CD4/CD8 ≥2.0	0.77	0.31–1.91	0.576
PFT
% FVC <70%	1.41	0.56–3.59	0.468
% DLCO <70%	1.92	0.66–5.58	0.231
Arterial blood gas analysis
PaO2 Torr (room air) <70	1.51	0.64–3.55	0.350
PaCO2 Torr (room air) ≥35	0.58	0.13–2.54	0.471
A-aDO2 ≥40	0.96	0.28–3.29	0.953
Laboratory findings
ESR mm·h−1 ≥40	1.45	0.59–3.60	0.422
CRP mg·dL−1 ≥1.0	0.65	0.24–1.75	0.394
KL-6 U·mL−1 ≥2000	0.793	0.34–1.87	0.597
SP-D ng·mL−1 ≥250	0.93	0.36–2.45	0.855
HRCT findings
Honeycombing	3.08	1.26–7.54	0.014	3.081	1.26–7.54	0.014
Treatment
Steroid	0.778	0.35–1.74	0.541
No antigen avoidance	2.695	0.80–9.10	0.110	3.452	0.96–12.36	0.057

BALF: bronchoalveolar lavage fluid; PFT: pulmonary function test; FVC: forced vital capacity; DLCO: diffusing capacity of lung for carbon monoxide; PaO: partial pressure of oxygen in arterial blood; PaCO: partial pressure of carbon dioxide in arterial blood; A-aDO: alveolar–arterial oxygen difference; ESR: erythrocyte sedimentation rate; HR: hazard ratio; CRP: C-reactive protein; KL-6: Krebs von den Lungen-6; SP-D: surfactant protein D; HRCT: high-resolution computed tomography. #: fibrotic HP can be divided clinically into two types: insidious type develops HP without a history of acute episodes but has a slowly progressive chronic respiratory disease, and recurrent type develops HP after recurrent acute episodes; ¶: occupational includes cases of mushroom worker's lung (n=1) and workplace-associated HP due to Aspergillus fumigatus.

Discussion

The patients in the present study with nonfibrotic HP who did CAA did not experience recurrence or develop fibrosis and sustained their clinical improvement, whereas those with fibrotic HP not doing CAA showed a trend towards poor prognosis. Although antigen avoidance has long been the first line of treatment for HP, its impact on prognosis has been poorly reported.

De Sadeleer et al. [9] reported that antigen avoidance improved the lung function trajectory (FVC % predicted, DLCO % predicted) in patients with nonfibrotic HP but did not improve mortality in patients with nonfibrotic or fibrotic HP. Gimenez et al. [18] investigated the relationship of antigen avoidance and survival in patients with fibrotic HP. Among their 112 patients, 61 (54.4%) patients reported antigen avoidance and 25 (41%) reported sustained clinical improvement. Clinical improvement with antigen avoidance (not just antigen avoidance itself) was associated with reduced mortality. Some patients with insidiously progressive fibrotic HP do not show significant improvement of symptoms even with antigen avoidance [20], and in the Gimenez et al. study, survival was compared in patients who achieved sustained clinical improvement after avoiding exposure and in patients who did not achieve clinical improvement and those not avoiding exposure. Fernández Pérez et al. [7] found that identifying an antigen was associated with improved survival in patients with chronic HP. In this report, antigens could be identified only in 67 (47%) of 142 patients with HP, and at least 27 patients (40%) had occupational HP or hot tub lung, for which the antigen could easily be completely avoided, and had a good prognosis [21, 22]. In the present study, the inciting antigen was identified in nearly all patients other than five of the 17 patients with home-related HP.

Unfortunately, appropriate means of antigen avoidance are not well defined [23]. Craig et al. [24] and Sema et al. [25] reported that high levels of bird antigen can be detected for a prolonged period after bird removal and environmental clean-up in patients with bird-related HP. In fact, two of our four patients with bird-related nonfibrotic HP who continued to live in the same house after bird removal experienced a recurrence. Tsutsui et al. [26] reported that the amount of avian antigen in household dust is related to disease progression and prognosis in chronic bird-related HP, indicating that fibrosis development and prognosis in patients with HP depend on the degree of antigen avoidance. Therefore, to clearly classify whether CAA was done, we defined CAA in each type of HP (table 2). Especially for summer-type, bird-related and home-related HP, we defined changing home to be the only complete change of environment satisfying CAA. CAA is straightforward for patients with occupational HP (job change or relocation), humidifier lung (no use) and hot tub lung (no use). When limited to the patients with these types of HP, only 15 of the 58 patients with nonfibrotic HP and six of the 45 patients with fibrotic HP actually changed homes.

Although the efficacy of antigen avoidance in patients with nonfibrotic HP is well established [9, 22, 27, 28], some reports suggest that their symptoms do not progress and their pulmonary function does not always decline even without adequate antigen avoidance [29-31]. Of our 44 patients with nonfibrotic HP without CAA, 24 experienced recurrence and/or developed fibrosis, whereas the remaining 20 patients had no recurrence afterward and achieved sustained clinical improvement (figure 1a). Five patients did CAA after one or two recurrences, and none of them had recurrence or fibrosis after CAA (figure 1b). These results suggest that if a patient who could not do CAA at the time of diagnosis still has a recurrence after efforts to reduce the antigen level, CAA might be recommended again at the new recurrence. Sema et al. [25] found that the amounts of avian antigens in household dust were related to disease progression and poor prognosis in chronic bird-related HP, and even if changing homes is not possible for various reasons, efforts should be made to thoroughly reduce the amounts of antigen by clean-up and renovation.

Patients with nonfibrotic HP have a low mortality rate [9, 11, 18], and none of the present study patients died of HP-related causes. Among the 74 patients with nonfibrotic HP, some experienced repeated recurrences without developing fibrosis, but seven patients also developed fibrosis. Recently, genomics has begun to have an important role in researching the mechanisms underlying the susceptibility to and progression of pulmonary fibrosis [32]. Ley et al. [33] found that among patients with chronic HP, the mucin 5B (MUC5B) minor allele and shorter telomere length measured in peripheral blood leukocytes were associated with the extent of radiographic fibrosis. Future studies are needed to determine whether the background genetics of patients with nonfibrotic HP may influence the onset of pulmonary fibrosis.

Fibrosis in HP is a poor prognostic factor, with median survival time ranging between 4.9 and 9.2 years [7–9, 11, 17–19]. The prognosis of honeycomb HP is even poorer, with Salisbury et al. [11] reporting a survival time of 2.8 years, similar to that for idiopathic pulmonary fibrosis with honeycombing. Twenty-six of the 47 patients with fibrotic HP had honeycomb HP, and their median survival was 3.69 years, similar to that of Salisbury et al. Of the eight patients with fibrotic HP with CAA, all three patients who died during the follow-up period had honeycombing. The median survival times of patients with honeycomb HP with CAA (n=4) and with IAA (n=22) were 4.54 years and 3.15 years, respectively, but the difference was not significant (p=0.508) because of the small number of patients. Additional study is needed to clarify whether CAA should be recommended for honeycomb HP.

An important strength of this study was that HP was diagnosed by the new diagnostic criteria of the ATS/JRS/ALAT guideline, all patients could be classified into six HP subtypes, and the decrease in exposure to inciting agents was divided into the grades of CAA or IAA by HP subtype. So, although this was a retrospective study performed in a single hospital, these results could have some generalisability.

Our study has some limitations. First, the distinction between CAA and IAA was strictly defined in this study. Although the definition of CAA in occupational HP, humidifier lung and hot tub lung was not so difficult, the distinction between CAA and IAA is not so easily defined for summer-type, bird-related and home-related HP. Actually, in summer-type and home-related HP, after the colonising places in the patients’ houses were intensively cleaned and the patients returned home, some experienced recurrence whereas others did not. Thus, in patients without recurrence, this type of intensive cleaning would be considered CAA. Similarly, in bird-related HP, some patients experienced recurrence after stopping the breeding of birds but others did not. However, at least no one experienced a recurrence or developed fibrosis after CAA according to our definition. The accuracy of our distinction between CAA and IAA should be re-evaluated. Second, because only eight of the 47 patients with fibrotic HP did CAA, the conclusion from the multivariate analysis that IAA tended to be related to poorer survival could indicate bias due to the small sample size. Third, although 20–53% of patients included in previous reports had unknown inciting antigen [7-9], all patients in the present study had an inciting antigen or an identified site of exacerbation by inhalation provocation tests and specific antibodies. We carefully judged the indication for surgical lung biopsy in fibrotic diffuse lung diseases and performed it in only 10 of the 121 patients. Because most patients with unknown inciting antigen and no histopathological findings are considered “low confidence” or “not excluded” in the ATS/JRS/ALAT guidelines, this study did not include patients with unknown inciting antigen without histopathological findings of HP pattern and thus may not reflect the whole population of HP.

Conclusions

In this analysis, CAA done by patients with nonfibrotic HP was related to no recurrence and/or no fibrosis development. Moreover, CAA was useful after a second or third recurrence. However, nearly all of these patients with fibrosis development developed progressive lung fibrosis. In the patients with fibrotic HP, <50% lymphocytes in BAL and radiographic honeycombing were negative prognostic factors for HP-related mortality, and CAA was suggested to be related to longer survival. These findings may have important implications for the care of patients with HP in terms of the need for CAA.