Hypersensitivity pneumonitis used to be classified into acute, subacute, and chronic, but because of difficulty in defining “subacute” [10], it is now classified into acute and chronic. Acute hypersensitivity pneumonitis has a characteristic history, clinical picture, and course, and it appears to be relatively easy to make the diagnosis. However, because the clinical picture and course of CHP are similar to the clinical picture and course of IPF and fibrotic nonspecific interstitial pneumonia (fNSIP), it is difficult to diagnose. In a prospective case-cohort study by Morell F. et al. [11], 20 (43 %) of 46 patients initially diagnosed as IPF were later diagnosed as CHP. None of the patients had a medical history of that included an occupational history of farming, mushroom growing, painting, etc., and there were no associations with residential humidity or humidifiers. The patients had just been using ordinary feather bedding. They appeared to have had feather duvet lung (FDL), and it seems very important to differentiate FDL from IPF.

Associations between feathers and respiratory tract lesions began to be reported around 1960 when there was a report of dyspnea developing in workers engaged in duck and goose feather processing [12], and in 1992 Haitjema T. et al. [13] reported the case of a 31-year-old female with CHP caused by a feather duvet. The event had developed in a nonsmoker during the 4th year of using a feather duvet. A chest x-ray showed reticulonodular shadows in both lower lung fields. After feather duvets came into widespread use worldwide, the pathological features of FDL/CHP became clear. In 2003, Inase et al. [14] reported a case of FDL/CHP in a 73-year-old woman. The patient had started using a feather duvet 8 years before, and she had a chronic course of illness that had developed 3 years before. The HRCT findings consisted of scattered consolidation, micronodules, and peribronchial ground-glass opacities. In 2008, Morell F. et al. [15] reported analyzing 86 cases of bird fancier’s lung and that 17 % were the chronic type and 3 cases were FDL/CHP. In 2010, Koschel D. et al. [16] analyzed 13 cases of FDL. In one case the patient had used only a feather pillow, and in the other 12 cases, the patients had either used a feather duvet or both a feather pillow and a feather duvet. The results of their analysis showed: “in all patients specific IgG antibodies to goose and/or duck feathers were detected. Pulmonary function tests revealed a moderate to severe reduced diffusion capacity and a mild restrictive pattern.” In 6 of the 11 cases in which HRCT was performed, the images revealed a PF pattern, and in one of the 9 cases in which an SLB was performed, it showed UIP. Based on these reports, cases that have been diagnosed as IPF have included a certain number of FDL/CHP cases. FDL/CHP pursues a chronic course and is slowly progressive and difficult to differentiate from IPF, but differential aspects have been pointed out based on both the HRCT and SLB findings.

Akashi T. et al. [17] assessed 16 autopsy cases of CHP and reported that the predominance of honeycombing in the lower lung fields resembled the findings in IPF/UIP, but that honeycombing that predominated in the upper lung fields and asymmetry of the honeycomb lesions were more common in CHP. They also reported that when there is centrilobular fibrosis in UIP, it is important to conduct a thorough investigation of the possibility of antigen exposure. Takemura T. et al. [18] compared 22 cases of CHP accompanied by UIP and 13 cases of IPF/UIP in which SLB had been performed. They reported that “bronchiolitis, centrilobular fibrosis, bridging fibrosis, organizing pneumonia, granulomas, giant cells and lymphocytic alveolitis were significantly more frequent among patients with CHP than among patients with IPF (all P < 0.01).” Silva C. I. et al. [19] described the HRCT image characteristics of CHP, thus: “The CT features that best differentiated CHP were lobular areas with decreased attenuation and vascularity, centrilobular nodules, and absence of lower-zone predominance of abnormalities.”

The values of the interstitial pneumonia markers KL-6 and SPD are both high in FDL and reflect disease activity, but they are not FDL specific. However, Ohnishi H. et al. [20] reported that the KL-6 levels were high in winter in bird-related HP (close to FDL) and that seasonal fluctuations in KL-6 values are a valid basis for making the diagnosis. The presence of specific IgG antibodies to goose feathers is useful for making the diagnosis of FDL [21], but evaluation is difficult when it is the chronic type. Antigen-induced lymphocyte proliferation in peripheral blood or bronchoalveolar lavage cells is positive in FDL. Its specificity is high, and it is said to be useful in making the diagnosis [22].

Cordeiro C. R. et al. [23] reported a case of CHF that was impossible to differentiate from IPF because the patient had clinical manifestations, including shortness of breath, which are common to IPF, and because testing was negative for parakeet-specific antibody, and because the SLB pathology findings were those of UIP. There were no significant findings in the pathological diagnosis or specific antibodies in their case. Nevertheless, the patient “had regular exposure to a parakeet and poultry,” and “chest imaging showed subpleural cystic lesions and traction bronchiectasis with a right side and upper level predominance.” The pathological findings in SLB specimens and the results of specific antibody testing do not always provide answers, and careful assessment of the medical history and findings is all that can be done.

Collagen-related diseases and PF that precedes collagen disease present problems in making the differential diagnosis. Cases of interstitial lung disease (ILD) in which there is suspicion of a collagen disease have been debated by the American College of Rheumatology (ACR), and thus far three concepts have been proposed. Diseases that do not fulfill the diagnostic criteria established for collagen diseases have been classified as unclassified connective tissue disease (UCTD) [24–26], cases with meager systemic findings other than lung lesions have been classified as lung-dominant connective tissue disease (LD-CTD) [27, 28], and cases with some sort of autoimmune abnormality that do not fulfill the diagnostic criteria for collagen disease have been classified as autoimmune-featured interstitial lung disease (AIF-ILD) [29]. Lung diseases associated with them consist of many cases of NSIP in UCTD, ILD as a whole in LD-CTD, and many cases of UIP in AIF-ILD. Thus, there seems to be a high degree of need to differentiate AIF-ILD from IPF. In 2011, Vij et al. [29] conducted a comparative study in which, based on replies to a questionnaire and the results of serologic tests, they divided 200 ILD cases into three groups: an AIF-ILD group (63 cases, 32 %), an ordinary IPF group (58 cases, 29 %), and a so-called collagen-disease-lung lesion (connective tissue disease – interstitial lung disease [CTD-ILD]) group that had already been diagnosed with collagen disease (37 cases, 19 %). HRCT revealed a classic UIP pattern in 62 % of the AIF-ILD cases, and in 81 % of the cases in which an SLB had been performed, it showed a UIP pattern. Moreover, the outcome of the AIF-ILD cases was the same as the outcome of the IPF cases. Based on the findings they reported to have obtained in these cases by HRCT and SLB, which are important tools in making the diagnosis, it is impossible to reliably distinguish between AIF-ILD and IPF. Points that have been cited to differentiate AIF-ILD from IPF have been as follows: female gender; in terms of clinical manifestations, dry eye, gastroesophageal reflux disease (GERD), foot swelling, joint pain, and the Raynaud phenomenon; and in terms of clinical laboratory test findings, the presence of antinuclear antibody (ANA) and rheumatoid factor (RF).

In research conducted on IPF, Kono et al. [30] reported a study in which they followed up 111 IPF cases for a mean period of 6.4 years. The result was the discovery that a definite collagen disease had developed in ten (9 %) of the cases, and the collagen diseases consisted of rheumatoid arthritis (RA) in four cases, microscopic polyangiitis (MPA) in four cases, and systemic sclerosis (SSc) in one case. There were two factors at the time the diagnosis of IPF was made that were important predictors of the future onset of a collagen disease: female gender and biopsy specimen histology showing the presence of lymph follicles with germinal centers. In addition, the outcome of the IPF accompanied by collagen disease was significantly better than that of the IPF not accompanied by collagen disease. Thus, whether or not a collagen disease will develop in IPF in the future appeared to be a factor related to the prognosis. In research conducted on RA, Lee et al. [31] assessed 18 cases of ILD associated with RA. In 3 of the 18 cases, the pulmonary lesions developed first. In two of the three cases, they were UIP lesions, and in one case they were NSIP lesions. However, the pulmonary lesions had developed 1.6–7 years in advance, earlier than the 1.1–4.3 years in the report by Kono et al. [30]. Ultimately, they may fall into the AIF-ILD category before a definitive diagnosis is made.

A drug-induced type of PF caused by anticancer drugs (e.g., bleomycin) is known. Since an underlying disease is present, when treatment with one of the drugs that fall into this category is considered necessary, it is possible to make the differential diagnosis of ILD that develops relatively soon after starting the drug. However, development of a wide variety of drugs is proceeding, and the drug situation has been changing. The problem is PF that develops after treating patients with molecularly targeted drugs, anti-arrhythmia drugs, etc., and a certain period of time has passed.

Herpesvirus involvement, in particular, has been pointed out among cases of PF caused by persistent infection by viruses and other pathogens [42]. Hepatitis C virus [43], adenovirus [44], human cytomegalovirus (HCMV) [45], and Epstein-Barr virus (EBV) [46] have also been associated with the development of PF. These viruses cause persistent latent infections and do not produce any clear clinical manifestations of an infection. Dworniczak S. et al. [45] compared newly diagnosed PF patients and 16 healthy volunteers and tested their alveolar lavage fluid cells for the presence of HCMV DNA. Both groups tested positive for HCMV DNA, but the number of DNA copies in the PF group was significantly higher. Endoplasmic reticulum (ER) stress has been hypothesized to increase as a result of persistent infection and induce alveolar epithelial-cell apoptosis [47]. Lawson et al. [48] discovered that the markers of endoplasmic reticulum (ER) stress were elevated in alveolar epithelial cells lining areas of the fibrosing portion of IPF using the immunostain. They also discovered the antigen proteins of three herpesviruses (EBV, CMV, or HHV-8) to the same area seen with the same distribution for the ER stress markers. These findings were the interesting reports which suggest the hypothesis implicating alveolar epithelial-cell apoptosis in the pathogenesis of PF. There was also a report of PF being observed in an SLB 1 year after Mycoplasma pneumoniae pneumonia [49], and there is a possibility of PF developing as a result of a pathogen that causes a latent infection. However, there were some reports which were not able to discover the antigen of herpesviruses from the tissue of PF [50, 51]. It is still unknown that the infection of viruses and others may play the role to IPF. The relationship between latent infections (such as viruses and others) and IPF will be probably confirmed in the near future.