Hypersensitivity pneumonitis (HP) is a complex syndrome caused by the repeated exposure and sensitization to a wide variety of antigens. The etiology is diverse with more than 100 different sources of antigens currently known to produce the disease .1,2 The clinical course is variable but a number of patients with chronic disease evolve to a fibrotic progressive disorder which is associated with substantial worse prognosis .1–5 In this context, a recent report indicates that patients with chronic HP (cHP) showed a 5-year mortality of 31.5%.6 Aging, persistence of the inciting antigen, and smoking have been associated with chronicity, but the mechanisms involved in the development of chronic fibrotic HP are unclear.

Since HP is considered an inflammatory-driven lung disorder, corticosteroids and immunosuppressive drugs are frequently used, mainly in patients with disease progression. However, there are no prospective studies to confirm this approach and there is no consensus on an optimal regimen.7 A recent retrospective study suggested that treatment with mycophenolate mofetil or azathioprine allowed the reduction in prednisone dose and was associated with improvement in diffusion capacity of the lung for carbon monoxide (DLCO) after one year without effect of forced vital capacity in patients with fibrotic HP.8

In 2014, two drugs, pirfenidone and nintedanib were accepted as anti-fibrotic therapy for idiopathic pulmonary fibrosis (IPF).9,10 In addition to anti-fibrotic effects, pirfenidone has also anti-inflammatory properties, such as down-regulation of NLRP3 inflammasome activation and subsequent IL-1β secretion, and decreasing the expression of tumor necrosis factor alpha (TNFα).11,12 These effects may be important in HP, since they are upregulated in this disease and seems to be involved in the pathogenesis.13,14

On these bases, we performed an open-label, proof of concept study, to evaluate the efficacy and safety of pirfenidone added to immunosuppressive drugs on the treatment of cHP.

From July 2015 to March 2018, a total of 34 patients were enrolled for the study. Twelve patients were excluded for different causes, most of them because the diagnosis was not confirmed after multidisciplinary discussion (Fig. 1). Twenty-two patients were included in the study; nine were assigned to the Group 1 and thirteen patients were assigned to the Group 2 (Fig. 1). Demographic and baseline characteristics are summarized in Table 1. There were no significant imbalances in clinically relevant baseline characteristics between two study groups. Most patients were female (56% in group 1 and 85% in group 2) with a mean age of 57 (±9) and 55 (±7) years respectively. The proportion of identified exposure sources (mostly birds) was similar between the groups.

Fig. 1.

Patient disposition. ILD: interstitial lung disease. PFTs: pulmonary function test. Group 1 received prednisone plus azathioprine and Group 2 received prednisone plus azathioprine and pirfenidone. MT: multidisciplinary team.

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A total of 19 patients (83%) completed the study: 8 patients in the Group 1 and 11 patients in the Group 2. One patient was missed after 3 months of treatment in the Group 1, and 2 patients discontinued prematurely the treatment, one before and the other after 3 months in the Group 2.

Primary efficacy analysis

No significant changes were observed in the predicted value of FVC (%) from baseline to 12 months in any of the groups. An improvement was observed in FVC in ml in both groups with a small (non significant) tendency to be higher in Group 2 (Table 2, Fig. 2A and B).

Table 2.

Primary and secondary efficacy outcomes.

Variable	Group 1	Group 2	p
Pulmonary function tests (Δ±SD; baseline to 12 months)
FVC (% predicted)	35±152	79±328	0.7
FVC (ml)	1.25±5	3.91±14	0.6
DLCO (% predicted)	−1.63±10.1	10.8±15.1	0.06
Quality of life questionnaires (Δ±SD or IQR; baseline to 12 months)
Total SGRQ score	1.50±4.5	−2.36±2.29	0.02
ATAQ-IPF score	3 (−9 to 23)	−7 (−17 to −2)	0.1
VAS score	−10 (−18 to 10)	5 (0–18)	0.07
HRCT score (Δ, IQR; baseline to 12 months)
Total extension	−9 (−11 to −4)	−4 (−18 to −2)	0.8
Ground Glass	−8.8 (−13 to −6)	−10.1 (−18 to −2)	1.0
Fibrosis	0.45 (−0.7 to 2)	−1.8 (−4.2 to 3.5)	0.4

Δ: Delta change; FVC: forced vital capacity; SD: standard deviation; DLCO: carbon monoxide diffusing capacity; IQR: interquartile range; SGRQ: St. George's Respiratory Questionnaire; ATAQ-IPF: A Tool to Assess Quality of life in idiopathic pulmonary fibrosis; VAS: visual analogue score; HRCT: high resolution computed tomography.

Fig. 2.

No changes were observed in FVC (ml) [A], FVC (% predicted) [B] and DLCO (% predicted) [C] between both groups.

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Quality of life

The median change from baseline to 12 months in total score on the SGRQ was 1.5±4.5 in the Group 1, and −2.36±2.29 in Group 2, p=0.02 (Table 2 and Fig. 3A). VAS score was −10 (−18 to 10) in Group 1 and 5 (0–18) in the Group 2 (p=0.07) (Table 2 and Fig. 3B). ATAQ-IPF score was 3 (−9 to 23) in the Group 1 versus −7 (−17 to −2) in Group 2 without statistical difference (Table 2 and Fig. 3C).

Fig. 3.

Mean change in quality of life questionnaires scores in both groups from baseline to 12 months of treatment. [A] ATAQ-IPF score, [B] VAS score and [C] SGRQ score.

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High resolution computed tomography (HRTC)

The analysis of HRCT showed a slight/moderate decrease of the extent of the lesions, as well as of the ground glass attenuation without changes in the fibrotic lesions and without differences in both groups (Table 2 and Fig. 4).

Fig. 4.

Mean change in HRCT in both groups from baseline to 12 months of treatment. [A] Mean observed change in the HRCT total extension score. [B] Mean observed change in the HRCT fibrosis score. [C] Mean observed change in the HRCT ground glass score.

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A substantial number of patients with chronic HP evolve to fibrosis which leads to progressive clinical deterioration and worsened quality of life. Although there are no randomized, double-blind, placebo-controlled clinical trials, these patients are usually treated with prednisone, and more recently, with immunosuppressive therapy either azathioprine or mycophenolate mofetil, with controversial results.8,20 Some studies suggest that rituximab, a human/murine, chimeric monoclonal antibody, with specific affinity for the B-lymphocyte transmembrane protein, CD20, may be effective in selected patients that are refractory to other systemic immunosuppressive drugs.21,22 However, the experience is scanty.

In this context, there is an urgent need to identify new therapeutic approaches for this disease mainly focused on the fibrotic progressive phase.

In the last years, two anti-fibrotic drugs pirfenidone and nintedanib, have been approved for the treatment of idiopathic pulmonary fibrosis, an epithelial-driven disease and certainly the most aggressive fibrotic lung disorder.9,10 More recently, these drugs are being explored for use in several inflammatory-driven fibrotic lung diseases such as systemic sclerosis, non-specific interstitial pneumonia and others.23,24 Importantly, some of the chronic fibrotic HP patients present a usual interstitial pneumonia (UIP) like pattern, characteristic of IPF either in the HRCT or in the lung biopsy, and these patients can be indistinguishable and are often misdiagnosed as IPF.4,25

With these bases we conducted this open-label, proof of concept study, adding pirfenidone, which also has some anti-inflammatory properties, to the immunosuppressive therapy that we usually indicate in HP patients with chronic progressive disease.

Our results showed that after a year, the addition of pirfenidone to prednisone and azathioprine was associated with some improvement compared with the immunosuppressive treatment alone. Among all the primary and secondary pre-specified efficacy end-points, the addition of pirfenidone resulted in a marginal tendency to improvement in gas exchange (DLCO), a significant improvement in quality of life according to the total score on the SGRQ with a tendency to be significant in VAS. No effect was observed on lung mechanics and fibrotic opacities in HRCT. However, it is important to emphasize that in this proof of concept study, the sample size is too small and underpowered (0.506) to make a definitive conclusion. Nevertheless, we consider that these preliminary results are encouraging, mainly because the effect on quality of life a relevant aspect for the patients with chronic respiratory diseases.

Importantly, there was an acceptable safety profile. Actually, although gastrointestinal adverse events were more frequently observed in the group receiving pirfenidone, no differences were observed between both groups, and no serious AEs leading to discontinuation of pirfenidone were observed.

This study has several limitations to be considered. First, the sample size was small and all the patients were enrolled from one reference Center. Second, investigators were not blinded to treatment. Third, this was an uncontrolled open-label trial (without a placebo group).

In conclusion, combination therapy with immunosuppressive drugs (azathioprine and prednisone) plus pirfenidone seems to provide a benefit as compared with immunosuppressive drugs alone in patients with chronic fibrotic HP, and may improve the outcome with acceptable safety profile. However, further investigation of the effect of pirfenidone and other anti-fibrotic drugs through a randomized, double-blind, placebo-controlled clinical trial is needed.

One of the authors: Jonathan Castillo-Pedroza serves partial time with Cell Pharma, the Company that gave us the pirfenidone. He did not participate in the interpretation/integration of the data.

None of the other authors have conflict of interests regarding this manuscript.