Humidifier lung and summer-type hypersensitivity pneumonitis in Japan: a nationwide retrospective observational study of clinical, radiological and pathological features.

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Learn more: PMC Disclaimer | PMC Copyright Notice BMJ Open Respir Res . 2026 Jun 2;13(1):e003694. doi: 10.1136/bmjresp-2025-003694 Humidifier lung and summer-type hypersensitivity pneumonitis in Japan: a nationwide retrospective observational study of clinical, radiological and pathological features Susumu Sakamoto 1, ✉ , Atsushi Kitamura 2 , Yuki Iijima 3 , Satoko Hanada 4 , Koshi Yokomura 5 , Masafumi Shimoda 6 , Hisashi Ohnishi 7 , Norio Kodaka 8 , Motoyasu Kato 9 , Makoto Nagata 10 , Hisako Matsumoto 11 , Teruaki Nishiuma 12 , Atsuko Kurosaki 13 , Yasuyuki Kurihara 14 , Toshimasa Uekusa 15 , Masashi Bando 16 , Yasunari Miyazaki 3 , Takafumi Suda 17 , Kazuma Kishi 1 , Sakae Homma 1 Author information Article notes Copyright and License information 1 Department of Respiratory Medicine, Toho University Omori Medical Center, Ota, Japan 2 Department of Pulmonary Medicine Thoracic Center, St Luke’s International Hospital, Chuo, Japan 3 Department of Respiratory Medicine, Institute of Science Tokyo, Bunkyo-ku, Tokyo, Japan 4 Division of Respiratory Medicine, Musashino Red Cross Hospital, Musashino, Japan 5 Department of Respiratory Medicine, Seirei Mikatahara General Hospital, Hamamatsu, Japan 6 Respiratory Disease Center, Japan Anti-tuberculosis Association, Fukujuji Hospital, Kiyose, Japan 7 Department of Respiratory Medicine, Akashi Medical Center, Akashi, Japan 8 Division of Respiratory Medicine, Toho University Ohashi Medical Center, Meguro, Japan 9 Graduate School of Medicine, Department of Respiratory Medicine, Juntendo University, Bunkyo, Japan 10 Department of Respiratory Medicine, Saitama Medical University Hospital, Saitama, Japan 11 Department of Respiratory Medicine & Allergology, Faculty of Medicine, Kindai University, Higashiosaka, Japan 12 Department of Respiratory Medicine, Kakogawa Central City Hospital, Kakogawa, Japan 13 Department of Diagnostic Radiology, Fukujuji Hospital, Kiyose, Japan 14 Department of Radiology, St Luke’s International Hospital, Chuo, Japan 15 Department of Pathology, Kanto Rosai Hospital, Yokohama, Japan 16 Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan 17 Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. Additional supplemental material is published online only. To view, please visit the journal online ( https://doi.org/10.1136/bmjresp-2025-003694 ). None declared. ✉ Dr Susumu Sakamoto; susumu1029@med.toho-u.ac.jp Received 2025 Aug 6; Accepted 2026 May 17; Collection date 2026. Copyright © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/ . PMC Copyright notice PMCID: PMC13239438  PMID: 42230300 Abstract Background Humidifier lung (HFL) is a rare subtype of hypersensitivity pneumonitis (HP); understanding of the clinical, radiological and pathological characteristics is limited. To clarify the phenotype of HFL, this study compared HFL with the more established summer-type HP (SHP). Methods This nationwide survey of patients with HFL was conducted in 214 participating facilities across Japan from January 2011 to December 2021. Clinical, radiological and histopathological findings were comparatively evaluated between patients diagnosed with HFL and those with SHP. Results Overall, 430 HFL and 784 SHP cases were identified, with an increasing trend over time and a marked rise in HFL during the COVID-19 pandemic. Detailed data from 278 HFL and 220 SHP cases showed that HFL patients were older and predominantly male. HFL exhibited higher serum C-reactive protein levels but lower Krebs von den Lungen-6 (KL-6) and surfactant protein D levels than SHP (all p<0.0001). Chest CT in both cohorts included ground-glass opacities and mosaic attenuation; centrilobular ground-glass nodules were less frequent in HFL, which more frequently showed airspace consolidation. Histopathology demonstrated alveolitis in both with more intra-alveolar organisation and fewer epithelioid cell granulomas in HFL. Cluster analysis identified an HFL cluster with either Acute Respiratory Distress Syndrome (ARDS)-like or organising pneumonia-like high-resolution CT findings and normal KL-6, hence diagnosis can be challenging. Conversely, the major cluster of SHP showed typical CT features and elevated KL-6. Conclusions HFL exhibits distinct clinical, radiological and pathological characteristics compared to SHP, suggesting a unique subtype. This holds relevance for diagnostic accuracy and improved patient outcomes. Keywords: Allergic Alveolitis WHAT IS ALREADY KNOWN ON THIS TOPIC Humidifier lung (HFL) is a type of home environmental hypersensitivity pneumonitis (HP). The criteria for diagnosing this rare condition are not standardised, and the clinical, laboratory and chest CT features of HFL are not well documented. WHAT THIS STUDY ADDS HFL exhibits distinct clinical, radiological and pathological characteristics compared with summer-type HP, suggesting a unique subtype. Cluster analysis further identified a subgroup characterised with ARDS-like or organising pneumonia-like imaging findings, which may complicate diagnosis. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY. These findings highlight varying radiological and pathological heterogeneity, which may potentially facilitate support more personalised diagnostic approaches. Introduction Hypersensitivity pneumonitis (HP) is an immune-mediated lung disease caused by prolonged antigen exposure. Identifying causative antigens is requisite for diagnosis, making challenge tests valuable diagnostic tools. Symptomatic improvement typically follows antigen avoidance, although corticosteroid therapy may be required. 1 2 HP is linked to various organic/inorganic antigens and classified according to causative antigens as summer-type HP (SHP), humidifier lung (HFL), bird breeder’s lung, hot-tub lung and farmer’s lung. 3 Japan’s humid climate and wooden houses increase exposure to Trichosporon asahii ( T. asahii ). SHP, comprising >70%, is well understood, 3 4 but studies on HFL remain scarce. HP incidence varies, potentially based on causative antigen, exposure, geography, climate and traditions. In Japan, humidifiers are widely used indoors during winter, increasing HFL risk, a home environment HP subtype. The first case was reported in 1970. 5 Inadequate cleaning promotes microbial contamination, including bacteria, fungi, non-tuberculous mycobacteria and endotoxins. 5 , 11 The increased incidence of HFL during the COVID-19 pandemic is attributable to the widespread humidifier use recommendations. 12 Diagnostic criteria remain undefined, with limited data on clinical, laboratory and CT findings. We hypothesised that HFL incidence is rising and differs mechanistically from the more common SHP, which often develops acutely and in a non-fibrotic manner, a characteristic it shares with HFL. Despite its significance, few studies have comprehensively evaluated this condition. 11 13 14 This nationwide survey compared clinical, laboratory and CT findings between HFL and SHP, the most prevalent non-fibrotic form in Japan, and assessed yearly trends, seasonal variation and regional differences. Methods Cases This nationwide survey (2011–2021) included HFL and SHP cases from 64 institutions across Japan (14 tertiary referral centres equipped with advanced emergency and critical care units and 50 secondary care hospitals) to elucidate the pathophysiology of HFL and SHP. A questionnaire was emailed to 715 hospitals with specialty respiratory medicine facilities, assessing incidence, trends, regional differences and onset months over 10 years. Data included clinical features, blood tests, pulmonary function tests (PFTs), bronchoalveolar lavage fluid (BALF) analysis, high-resolution CT (HRCT) scans and histopathology. Clinical and laboratory analysis Clinical records and laboratory findings were analysed, including white blood cell (WBC) count, arterial blood gas analysis and C reactive protein (CRP), lactate dehydrogenase (LDH), Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) levels. Diagnosis of HFL and SHP HFL was diagnosed using clinical and radiological findings with a pre-established method 11 13 and these criteria: (1) persisting respiratory symptoms (eg, productive cough, dyspnoea) >1 week; (2) bilateral ground-glass opacity (GGO) or consolidation on CT; (3) home humidifier use; (4) positive antigen provocation; (5) BALF or histopathology consistent with HP; and (6) symptom, laboratory and HRCT improvement after humidifier cessation. Diagnosis was confirmed by meeting criteria 1–5; 1–3, 5, and 6; 1–3, and 4; or 1–3, and 6 (probable). SHP diagnosis required typical clinical, HRCT and pathological findings, plus anti- T. asahii antibodies. 2 3 Recurrence of HP was defined as the reappearance of clinical symptoms, such as cough or dyspnoea, accompanied by radiological findings on chest imaging similar to those observed at the time of the initial diagnosis. Pulmonary function tests Vital capacity (VC), forced VC (FVC), forced expiratory volume in 1 s (FEV1) and diffusing capacity for carbon monoxide (DLco) data were obtained at diagnosis. BALF analysis BAL was performed using a standardised method. Wright-Giemsa-stained cytocentrifuged smears were used for differential cell counts; BALF T-cell phenotype was determined using flow cytometry. Data included total cells, BALF differentials, CD4/CD8 counts and CD4/CD8 ratio. Chest HRCT Admission HRCT scans were reviewed independently by two pulmonologists (SHa, SS) and two radiologists (AK and YK), blinded to demographic, clinical, and laboratory data. Discrepancies were resolved through consensus. Scans (5 mm sections) and thin-section CT (1.0–1.25 mm) were evaluated for parenchymal abnormalities and classified per Fleischner Society guidelines for GGO, centrilobular nodules, consolidation, at six levels, including the aortic arch bilaterally, carina and 1 cm supra-diaphragmatic. Findings were semiquantitatively scored (0=none; 1=1%–25%; 2=26%–50%; 3=51%–75%; and 4≥75%; other: 0=none; 1=presence). Histopathology Two pulmonary pathologists (SHa and TU) independently evaluated transbronchial lung biopsy (TBLB), transbronchial lung cryobiopsy (TBLC) or surgical lung biopsy (SLB) specimens for key features. These included cellular interstitial pneumonia (bronchiolocentric), chronic cellular bronchiolitis, organising pneumonia (OP), distinctive granulomas, eosinophilic infiltration, alveolar epithelial hyperplasia and giant cells. Findings were semiquantified per high-power field (0=none, 1=0%–33%, 2=34%–66%, 3=67%–100%, 4=indeterminable). Cluster analysis Cluster analysis was performed to explore phenotypic patterns among patients with HP using Ward’s method. Clinical differences between HFL and SHP were examined. Variables included HRCT findings (extent of GGO, centrilobular micronodules, consolidation) as well as serum CRP and KL-6 levels. Cases with missing values were excluded prior to the analysis, and the remaining data were preprocessed and normalised. Among the 498 patients (220 with SHP and 278 with HFL), six patients (two with SHP and four with HFL) had missing data for variables used in the cluster analysis and were, therefore, excluded prior to analysis. The optimal number of clusters was initially assessed using the elbow method. The final number of clusters was subsequently determined by considering both statistical results and clinical interpretability. No formal internal validation or stability assessment of the clustering results was performed. Therefore, the reproducibility of the identified clusters could not be evaluated, and the results of the cluster analysis should be interpreted as exploratory. Statistical analysis Continuous variables are presented as mean±SD and compared using the Mann–Whitney U test; categorical variables using the χ 2 test. Comparisons among three or more groups were performed using the Kruskal-Wallis test. Cluster analysis was performed using Ward’s method. Statistical significance was set at p<0.05. For post hoc pairwise comparisons following the Kruskal-Wallis test, the Steel-Dwass test was used. In other analyses, the Bonferroni correction was applied. All analyses were conducted using IBM SPSS Statistics V.28 (IBM, Armonk, New York). Patient and public involvement Patients were involved in the development of the research questions, but not the study design, recruitment, outcome measures, dissemination plans and conduct of the study. The study findings will be disseminated through open access scientific publications, stakeholder networks and national/international meetings. Results Patient selection The primary questionnaire garnered responses from 214 of 715 hospitals (29.9%); identifying 430 patients with HFL and 784 with SHP for analysis ( online supplemental figure 1 ). The secondary survey collected clinical, radiological and pathological data for 295 patients with HFL and 321 patients with SHP. After excluding those with underlying disease on radiology, 278 HFL and 220 SHP cases proceeded to secondary analysis; pathology specimens were available for 92 and 166 patients, respectively. Yearly trends and seasonal variation Of 430 cases of HFL and 784 cases of SHP, yearly trends for both conditions increased over time with a notable rise in HFL cases post-2019 ( figure 1A ), coinciding with the COVID-19 pandemic. Figure 1. ( A ) Yearly trends in the number of patients with humidifier lung and summer-type HP. Both conditions show an overall increase over time, with a notable rise in cases of humidifier lung after the onset of the COVID-19 pandemic. ( B ) Seasonal variations in humidifier lung and summer-type HP over 10 years. Seasonal variation was observed in the distribution of hospitalisation. Humidifier lung hospitalisations peaked during winter and spring (February–March) and for summer-type HP in summer and fall (August–October). HP, hypersensitivity pneumonitis. Open in a new tab Seasonally, HFL hospitalisations peaked during winter–spring (February–March) while SHP hospitalisations predominated in summer–fall (August–October) but occurred year-round ( figure 1B ). Geographical variation Online supplemental figure 2 illustrates the 10-year geographical distribution by subtype. HFL incidence was higher in Pacific-side regions with drier winters (Tokyo, Shizuoka, Hyogo) and lower in heavy snowfall areas (Hokkaido, Tohoku, Sea of Japan regions) ( online supplemental figure 2A ). SHP was frequent in Tokyo and southwestern Japan (Osaka, Hyogo, Fukuoka, Kochi) but less so in Hokkaido, Tohoku, Hokuriku and the Sea of Japan regions ( online supplemental figure 2B ). Patient characteristics Table 1 summarises data from 278 HFL cases (200 men, 78 women) and 220 SHP cases (107 men, 113 women). The HFL cohort was significantly older, predominantly male, and had fewer non-smokers versus the SHP cohort (mean age 65.2 vs 59.6 years, 71.9% vs 48.6%, 39.9% vs 59.5%, respectively; p<0.0001). Among the included HFL patients, 203 were classified as definite and 74 as probable cases, and antigen provocation testing was positive in 115 patients. Table 1. Patient characteristics, treatment modalities and outcomes in humidifier lung and summer-type hypersensitivity pneumonitis (HP). Humidifier lung (n=278) Summer type HP (n=220) P value Age (years) 65.2±14.8 59.6±16.2 <0.0001** Male, n (%) 200 (71.9%) 107 (48.6%) <0.0001** Height (cm) 1.639±0.08 1.593±0.09 <0.0001** Weight (kg) 62.526±11.95 57.270±12.52 <0.0001** Body mass index (kg/m ２ ) 23.077±3.580 22.417±3.742 0.0362* Smoking history (never/former/current) 111/129/38 131/78/11 <0.0001** Smoking index 401.379±500.814 232.393±446.643 <0.0001** Season of first hospital visit (March–May/June–August/September–November/December–February) 51/8/19/200 28/111/64/15 <0.0001** Time from initial hospital visit to diagnosis (days) 40±75.4 48±132.1 0.4 Clinical presentation at onset (chronic/subacute/acute) 5/108/165 44/123/51 <0.0001** Vital signs Temperature (°C) 37.275±0.831 36.846±0.648 <0.0001** Blood pressure (systolic) 127.298±20.472 125.066±20.113 0.2431 Blood pressure (diastolic) 73.649±13.794 75.646±14.916 0.2046 Heart rate 91.742±16.713 90.939±16.195 0.6574 Respiratory rate 20.408±5.889 19.611±5.395 0.3727 SpO 2 (%) (ambient air) 93.797±3.694 93.134±4.170 0.1219 SpO 2 /FiO 2 402.897±89.121 417.409±70.214 0.6338 Symptoms mMRC (0/1/2/3/4) 26/52/92/45/25 32/63/51/31/15 0.0035** Cough, n (%) (no/dry/wet) 27/133/60 21/195/62 0.0543 Chest sounds (fine crackles/coarse crackles/rhonchi/none/squawks/wheezes/other) 172/22/1/59/0/2/13 129/15/2/65/2/1/2 0.0299* Treatment Corticosteroid use, n (%) 56 (20.1) 97 (44.1) <0.0001** Initial dose of prednisolone (mg/day) 151.9±309.7 72.6±196.3 0.2487 Corticosteroid pulse therapy n (%) 25 (9.0) 21 (9.5) 0.5127 Duration of corticosteroid use (days) 36.5±189.3 212.4±610.1 <0.0001** Recurrence, n (%) 9 (3.2) 72 (32.7) <0.0001** Antigen avoidance, n (%) 278 (100) 178 (80.9) <0.0001** Treatment status (continued/completed/other) 14/243/16 43/132/45 <0.0001** Time from diagnosis to end of hospital visits (days) 342.2±496.7 723.6±889.4 <0.000** Open in a new tab *P<0.05; **p<0.01. mMRC, Modified Medical Research Council Dyspnea Scale. Patients with HFL sought medical attention in winter, whereas SHP peaked in the summer but occurred year-round. HFL ran a more acute clinical course, although time-to-diagnosis did not differ significantly. Of 278 patients with HFL, 185 used home ultrasonic humidifiers and 5 used steam humidifiers with tap water. Acute/subacute symptoms (dyspnoea, cough, fever) were more frequent in HFL (98.2% vs 79.1%, p<0.0001). Dyspnoea severity (modified Medical Research Council scale) and temperature were also significantly higher. Fine crackles were prominently noted in both groups. Laboratory findings Table 2 shows higher WBC counts and elevated serum CRP levels in most patients and significantly so in HFL (WBC: 13 843.4±6731.9 vs 9125.4±4446.1/µL, p<0.0001; CRP: 8.0±7.6 vs 2.6±3.5 mg/dL, p<0.0001). Conversely, KL-6, SP-D and LDH were significantly lower in HFL cases (KL-6: 701.6±807.4 vs 2234.7±2038.7 U/mL, p<0.0001; SP-D: 189.5±160.8 vs 337.7±321.9 ng/mL, p<0.0001; LDH: 239.1±72.9 vs 284.0±121.2 U/L, p<0.0001). Table 2. Laboratory, pulmonary function and bronchoalveolar lavage fluid analysis results in patients with humidifier lung and summer-type hypersensitivity pneumonitis (HP). Humidifier lung (n=278) Summer type HP (n=220) P value White blood cells (/μL) 13843.417±6731.920 9125.409±4446.062 <0.0001** Eosinophils (%) 1.959±2.187 2.986±2.393 <0.0001** Lymphocytes (%) 13.072±7.969 18.652±9.184 <0.0001** Neutrophils (%) 79.181±10.113 71.411±11.158 <0.0001** CRP (mg/dL) 8.037±7.570 2.593±3.500 <0.0001** LDH (U/L) 239.137±72.949 284.018±121.203 <0.0001** KL-6 (U/mL) 701.607±807.420 2234.707±2038.714 <0.0001** SP-D (ng/mL) 189.517±160.813 337.727±321.883 <0.0001** SP-A (ng/mL) 106.950±65.670 91.130±62.541 0.1214 Arterial blood gas analysis (n=153) (n=153) PaO 2 (mm Hg) (ambient air) 74.733±18.045 72.101±18.049 0.3010 PaCO 2 (mm Hg) 36.462±4.621 37.012±5.131 0.4809 PaO 2 /FiO 2 ratio 402.897±89.121 417.409±70.214 0.8613 Pulmonary function tests (n=134) (n=180) VC (L) 2.781±0.803 2.456±0.759 0.0002** %VC (%) 86.951±18.121 80.727±17.703 0.0018** FVC (L) 2.743±0.788 2.415±0.760 0.0002** %FVC (%) 84.990±19.203 80.456±18.428 0.0182* FEV1(L) 2.111±0.658 1.935±0.625 0.0126* %FEV1 (%) 78.384±13.833 80.358±10.729 0.0117* %DLco (%) 69.106±19.862 62.023±22.993 0.0136* %DLco/VA (%) 73.402±17.830 68.473±20.515 0.0163* BALF (n=158) (n=179) Total cell count, n/mL×10 5 2.55±7.18 3.30±1.17 0.0170* Neutrophils (%) 17.6±20.28 10.32±14.02 0.0041** Lymphocytes (%) 38.17±20.91 60.42±24.63 <0.0001** Eosinophils (%) 3.89±5.76 3.16±4.23 0.3214 Macrophages (%) 38.34±23.59 25.60±22.17 <0.0001** CD4 (%) 52.23±15.33 35.89±19.14 <0.0001** CD8 (%) 32.21±14.99 57.40±21.04 <0.0001** CD4/CD8 ratio 2.51±2.20 1.099±1.60 <0.0001** Open in a new tab *P < 0.05; **p < 0.01. BALF, Bronchoalveolar lavage fluid; BNP, brain natriuretic peptide; CRP, C reactive protein; %DLco, carbon monoxide diffusing capacity % of predicted value; FEV1, forced expiratory volume in 1 s; KL-6, Krebs von der Lungen-6; LDH, lactate dehydrogenase; SP-A, surfactant protein A; SP-D, surfactant protein D; VC, vital capacity; %VC, vital capacity % of predicted value. Pulmonary function tests Table 2 summarises PFT results. Reductions in VC, %VC, FVC, %FVC, %DLco and FEV1 were less severe in HFL versus SHP (VC: 2.78±0.8 vs 2.45±0.76 L, p=0.0002; %VC: 87.0%±18.1% vs 80.7%±17.7%, p=0.0018; FVC: 2.74±0.79 vs 2.41±0.76 L, p=0.0002; %FVC: 85.0%±19.2% vs 80.5%±18.4%, p=0.0182; %DLco: 69.1%±19.9% vs 62.0%±23.0%, p=0.0136; FEV1: 2.11±0.66 vs 1.94±0.63 L, p=0.0126). However, %FEV1 was slightly lower in HFL (78.4%±13.8% vs 80.4%±10.7%, p=0.0177), possibly due to the higher FVC in this group. BALF analysis BAL was performed in 158 HFL and 179 SHP cases ( table 2 ). Total BALF cell counts were elevated in both cohorts but significantly lower in HFL comparatively (2.56±7.18×10⁶/mL vs 3.30±1.17×10⁶/mL, p=0.017). Differential BALF cell counts in HFL showed lower lymphocytes (38.2%±20.9% vs 60.4%±24.6%, p<0.0001) but significantly higher neutrophil fractions (17.7%±20.3% vs 10.3%±14.0%, p=0.0041) than SHP. Phenotypically, CD4+ lymphocytes predominated in HFL vs CD8+ lymphocytes in SHP; resulting in a higher CD4/CD8 ratio in HFL (2.5±2.2 vs 1.1±1.6, p<0.0001). HRCT findings Figure 2 and table 3 summarise HRCT results. HFL commonly showed bilateral GGO and/or consolidation, often without centrilobular ground-glass micronodules ( figure 2A ) but occasionally with profuse centrilobular micronodules ( figure 2B ), some cases showed ARDS-like bilateral diffuse GGO and multifocal consolidation ( figure 2C ), or OP-like subpleural non-segmental consolidation ( figure 2D ) patterns, atypical for SHP. SHP typically showed diffuse GGO, with/without poorly defined micronodules, predominantly in the upper middle lung zones ( figure 2E,F ). Figure 2. Representative images showing chest HRCT findings in humidifier lung ( A, B, C, D ) and summer-type HP ( E, F ). ( A ) Diffuse faint ground-glass opacities (GGO) and mosaic attenuation, without poorly defined centrilobular micronodules (diffuse GGO type). ( B ) Diffuse GGO with poorly defined micronodules and mosaic attenuation (typical HP type). ( C ) Diffuse bilateral diffuse GGO and consolidation (ARDS-like type). ( D ) Diffuse or focal non-segmental consolidation bilaterally, with minimal ground-glass opacities (organising pneumonia-like type). ( E ) Diffuse bilateral diffuse GGO (diffuse GGO type). ( F ) Diffuse GGO with poorly defined micronodules and mosaic attenuation (typical HP type). ARDS, Acute Respiratory Distress Syndrome; HP, hypersensitivity pneumonitis; HRCT, high-resolution CT. Open in a new tab Table 3. High-resolution CT findings showing mean scores for each level of parenchymal involvement. Humidifier lung (n=278) Summer-type HP (n=220) P value Upper Middle Lower Upper Middle Lower Ground-glass opacity 2.67 2.77 2.78 3.66 3.74 3.74 <0.0001** Centrilobular nodule 0.87 0.88 0.75 2.09 1.99 1.55 <0.0001** Consolidation 0.24 0.27 0.30 0.06 0.08 0.08 <0.0001** Mosaic attenuation 0.66 0.74 0.82 0.89 0.94 0.95 <0.0001** Bronchial wall thickening 0.26 0.51 0.50 0.51 0.78 0.79 <0.0001** Interlobular septal thickening 0.24 0.24 0.33 0.08 0.08 0.25 <0.0001** Reticulation 0.13 0.17 0.17 0.01 0.01 0.02 <0.0001** Bronchiectasis 0.14 0.28 0.30 0.07 0.25 0.29 0.0205* Distribution: Cranio-caudal, n Upper dominant Lower dominant Diffuse Upper dominant Lower dominant Diffuse 27 52 199 5 17 198 <0.0001** Distribution: axial, n Peripheral Central Diffuse Peripheral Central Diffuse 61 3 213 4 2 214 <0.0001** Pleural effusion, n Right Left Bilateral Right Left Bilateral 10 13 45 1 8 3 <0.0001** Mediastinal lymphadenopathy +, n (%) 143 (51.4) 41 (18.6) <0.0001** Open in a new tab Semiquantification of parenchymal abnormality severity (ground-glass opacities, centrilobular nodules, consolidation): 0=none; 1=1–25%; 2=26–50%; 3=51–75%; and 4 >75%. Other lung parenchymal findings: 0=none; 1=present. *:P<0.05; **p<0.01. HP, hypersensitivity pneumonitis. Both subtypes showed faint GGO and mosaic attenuation; HFL had less extensive GGO and fewer poorly defined centrilobular micronodules (p<0.0001). Airspace consolidation was more frequent in HFL, but atypically rare in SHP (p<0.0001). Consolidation was primarily peripheral, then multifocal. Pleural effusion and mediastinal lymphadenopathy were more common in HFL. Pathological findings Histopathology is summarised in table 4 and figure 3 . Lung biopsy was performed in 102 of 278 HFL cases (*92 specimens analysed; 2 (TBLC), 1 (SLB) and others (TBLB); 13 were deemed inadequate and excluded) and in 176 of 220 SHP cases (*136 specimens analysed; 3 (cryobiopsy), others (TBLB); 38 were deemed inadequate and excluded). Table 4. Pathological findings in patients with humidifier lung and summer-type hypersensitivity pneumonitis (HP). Humidifier lung (n=92) Summer-type HP (n=136) P value Score 0 1 2 3 0 1 2 3 Alveolitis, n 6 24 22 39 6 36 32 61 0.6633 Intra-alveolar organisation, n 26 32 18 16 50 58 21 7 0.0110* Cellular bronchiolitis, n 11 3 1 0 4 7 0 1 0.0564 Epithelioid cell granulomas, n 82 9 0 1 76 36 14 10 <0.0001** Multinucleated histiocytes, n 92 33 9 1 84 8 1 0 <0.0001** Eosinophilia, n 83 7 1 1 126 8 2 0 0.5214 Alveolar epithelial cell hyperplasia, n 37 32 15 8 65 47 17 7 0.1554 Intra-alveolar macrophage, n 12 49 20 11 12 68 37 18 0.2368 Cholesterol clefts, n 91 1 0 0 131 4 0 1 0.2304 Open in a new tab Semiquantification of severity of pathological findings per high-magnification field: 0=none; 1=0–33%; 2=34%–66%; 3=67%–100%; 4=indeterminable. *P<0.05; **p<0.01. Figure 3. ( A ) Representative images showing histopathological findings in humidifier lung. Transbronchial lung biopsy specimen: section showing diffuse alveolitis with lymphocytic infiltration and intra-alveolar organisation (arrows) (H&E; scale bar=200 µm). Chest HRCT demonstrated diffuse bilateral ground-glass opacities (GGO) and consolidation, resembling acute respiratory distress syndrome. ( B ) Representative images showing histopathological findings in summer-type HP. Transbronchial lung biopsy specimen: section showing diffuse alveolitis with lymphocytic infiltration and features of epithelioid cell granuloma (arrowheads). (H&E; scale bar=200 µm). Chest HRCT demonstrated diffuse GGO with poorly defined micronodules and mosaic attenuation, consistent with typical HP. HP, hypersensitivity pneumonitis; HRCT, high-resolution CT. Open in a new tab Both subtypes showed alveolitis with septal thickening and lymphocytic infiltration. Intra-alveolar organisation was greater in HFL (p=0.011) ( figure 3A ), but epithelioid cell granulomas (p<0.0001) ( figure 3B ) and multinucleated histiocytes (p<0.0001) were fewer. Cellular bronchiolitis was minimal in TBLB samples, attributable to minuscule bronchiolocentric TBLB specimens. Cluster analysis Cluster analysis identified four distinct radiological and serological subtypes in both HFL and SHP, as shown in figure 4 . In HFL, cluster 1 (39.4%) was characterised by diffuse GGO on HRCT with moderately elevated CRP (4.2 mg/dL) and KL-6 (846.1 U/mL) and was designated the diffuse GGO type. Cluster 2 (6.9%) showed diffuse GGO with centrilobular micronodules, typical of HP and exhibited markedly elevated KL-6 (1517.1 U/mL). Cluster 3 (21.5%) displayed diffuse GGO with multifocal consolidation, markedly elevated CRP (16.9 mg/dL), normal KL-6 (491.4 U/mL) and impaired oxygenation (mean P/F ratio=230), resembling an ARDS-like presentation. In this study, the term ‘ARDS-like pattern’ was used to describe a radiological phenotype that resembles ARDS on CT, particularly as observed during the acute exudative phase, rather than to indicate that the patients fulfilled the clinical diagnostic criteria for ARDS. None of the patients demonstrated fibrotic features, such as fibroproliferative changes or extensive architectural distortion, at the time of initial presentation. Cluster 4 (32.1%) presented with non-segmental consolidation and minimal GGO, consistent with an OP-like pattern. Clusters 3 and 4 posed diagnostic challenges due to atypical imaging features and discordant biomarker profiles ( figure 4 ). Figure 4. Cluster analysis of HRCT and serological findings in humidifier lung and summer-type HP. Analysis included HRCT features, extent of GGO, centrilobular micronodules and consolidation, as well as serum CRP and KL-6 levels. Humidifier lung: cluster 1 defined by diffuse GGO on HRCT with moderately elevated CRP and KL-6 (diffuse GGO type). Cluster 2 showed diffuse GGO with centrilobular micronodules and exhibited markedly elevated KL-6 consistent with typical HP. Cluster 3 displayed GGO with consolidation, markedly elevated CRP and normal KL-6, resembling ARDS. Cluster 4 featured non-segmental consolidation with minimal GGO (OP-like type). Summer-type HP: cluster 1 featured diffuse GGO with markedly elevated KL-6 and mildly elevated CRP (1.8 mg/dL), while cluster 2 displayed typical HP findings with centrilobular nodules. Clusters 3 and 4 were less common and resembled ARDS and focal GGO patterns, respectively. Definition of biomarker elevations: CRP: mild (<3 mg/L), moderate (3–10 mg/L), marked (>10 mg/L) KL-6: normal (<500 U/mL), moderate (500–1000 U/mL), marked (>1000 U/mL). CRP, C reactive protein; GGO, ground-glass opacity; HP, hypersensitivity pneumonitis; HRCT, high-resolution CT; KL-6, Krebs von der Lungen-6. Open in a new tab SHP exhibited a comparable cluster distribution. Cluster 1 (57.8%) displayed diffuse GGO with markedly elevated KL-6 (2709.1 U/mL) and mildly elevated CRP (1.8 mg/dL). Cluster 2 (33.0%) showed classic HP findings with centrilobular nodules. Clusters 3 (4.1%) and 4 (5.0%) were less common, with imaging patterns resembling ARDS and focal GGO, respectively. Clusters 1 and 2 accounted for the majority of SHP cases and exhibited characteristic CT features alongside elevated serum KL-6 levels, allowing for a relatively straightforward diagnosis ( figure 4 ). Treatment and outcomes The mean follow-up duration was significantly longer in patients with SHP than in those with HFL (723.4±892.1 days vs 346.9±498.8 days, p<0.0001). The proportion of patients who completed treatment was also significantly higher in HFL than in SHP (88.9% vs 59.6%, p<0.001). During the observation period, one death occurred in the HFL group, and no cases progressed to pulmonary fibrosis. Conversely, six deaths occurred in the SHP group, including three attributable to SHP due to progressive pulmonary fibrosis and respiratory failure. The remaining deaths were due to other causes (two pneumonia, one lung cancer and one unknown cause). Table 1 presents treatments used for both conditions. Of 278 HFL cases, 56 (20.1%) required corticosteroids (prednisolone 0.5–1.0 mg/kg, tapered) while 222 (79.9%) improved (symptoms, blood tests, imaging) following humidifier avoidance, with minimal recurrence. Severe cases (respiratory failure) received methylprednisolone pulse therapy (1000 mg/day×3 days). Corticosteroid use was higher and more prolonged in SHP (44.1% vs 20.1%, p<0.0001; 36.5 days vs 212.4 days, p<0.0001). Initial prednisolone dosing was similar; recurrence was significantly higher in SHP (32.7% vs 3.2%, p<0.0001). Some HFL cases presented with severe respiratory failure (ARDS-like cluster) required high-dose corticosteroid therapy. Most of these cases showed favourable response and resolved without progressing to fibrosis. Discussion Both HFL and SHP have increased over time, with a notable increase in HFL post-COVID-19. Ando et al reported SHP as the most prevalent (74.4%), whereas HFL comprised only 4.3% of 835 acute non-fibrotic HP cases. 4 Traditionally rare, HFL cases surged during the pandemic, surpassing SHP. Increased incidence has been reported although in limited sample sizes 12 likely due to stay-at-home mandates, social distancing and widespread recommendations for humidifier use to prevent viral spread. Based on the current data, a direct causal relationship between the increase in HFL cases and the surge in humidifier sales during the COVID-19 pandemic cannot be established. However, the marked increase in humidifier sales in Japan suggests that prolonged time spent indoors and increased humidifier use could have contributed to the observed rise in HFL cases. The rising SHP incidence may stem from improved diagnostics, particularly after the 2013 commercial availability of T. asahii- specific IgG testing. This testing increasingly aids diagnosis in challenging cases. 15 ATS and CHEST guidelines suggest that IgG detection enhances HP diagnosis when combined with other data. 16 17 IgG detection also supports the diagnosis of fibrotic SHP, contributing to rising case numbers. Geographically, HFL incidence was higher in the eastern Japan Pacific coastal regions with drier winters and was lower in humid, snow-prone regions—likely reflecting regional differences in humidifier use, from climate variation and humidity. SHP was more frequent in Tokyo and southwestern Japan, where warm humid climates apparently favour SHP. This is because T. asahii, the primary causative antigen of SHP, proliferates rapidly at 25°C–28°C and approximately 80% relative humidity. 18 Environmental conditions in the southwest Pacific Ocean border favour T. asahii proliferation during summer. 19 Although 74 HFL cases were categorised as probable, all demonstrated clinical evidence supporting humidifier exposure as the cause of disease, including worsening of clinical and radiological findings after exposure or improvement after avoidance. These cases were clinically diagnosed as HFL at each institution, suggesting that diagnostically uncertain cases were unlikely to be included. Microbiological confirmation of humidifier contamination was not evaluated in this survey because identification of specific causative microorganisms from humidifier water is often difficult in clinical practice. HFL and other HP subtypes share a similar pathogenesis, involving type III and IV hypersensitivity reactions (HSR) to bacterial and/or fungal antigens. However, type IV HSR predominates in HP. 1 2 20 Some HFL cases display specific immune-mediated responses, including precipitating antibodies and lymphocyte proliferation on exposure to humidifier water. Clinical and radiological differences between these subtypes possibly reflect antigen type, concentration and exposure duration. SHP results from prolonged low-level fungal exposure. HFL often develops acutely from high-dose exposure to bacteria, fungi and/or endotoxins, in contaminated humidifiers. In HFL, acute exposure to contaminated water triggers type III HSR, with complement activation, neutrophil recruitment, 21 22 acute lung injury and intra-alveolar organisation. Conversely, SHP develops gradually through type IV HSR, characterised by sustained lymphocyte infiltration and granuloma formation. 23 , 27 These pathophysiological processes align with observed differences in BALF neutrophil and lymphocyte fractions. However, direct immunological measurements were not performed in the present study. Therefore, these interpretations remain hypothesis-generating and are not mechanistically proven, and further studies are needed to elucidate the underlying mechanisms. Endotoxins also contribute to the pathophysiology of HFL. Contaminated humidifiers often harbour Gram-negative bacteria whose endotoxins drive lung injury HFL. 28 , 32 These potent lung injury mediators induce inflammatory cytokines (eg, interleukin-1, tumour necrosis factor-alpha) and increase neutrophil and lymphocyte counts in BALF and blood. 33 34 Heterogeneity in endotoxin sensitivity stems from polymorphisms in pro-inflammatory cytokine, CD14 and Toll-like receptor genes, potentially influencing clinical, radiological and pathological differences. 35 , 38 HRCT findings in large HFL and SHP cohorts remain under-reported. Consistent with prior small case series, 13 14 some patients with HFL in this study showed atypical HRCT patterns. OP-like subpleural non-segmental consolidation or ARDS-like bilateral diffuse GGO and consolidation were more frequent, implying severe inflammation from high-level antigen and endotoxin exposure. In contrast, SHP typically displays diffuse GGO and poorly defined micronodules, predominantly in the upper and middle lung zones, 13 14 consistent with the typical HRCT pattern of HP. Serum KL-6 levels were mildly elevated in HFL but significantly lower than in SHP. High KL-6 and SP-D levels are hallmarks of SHP and farmers’ lung, 3 4 39 although some HFL cases showed normal levels. In SHP, chronic low-dose antigen exposure drives subacute or chronic disease characterised by type IV HSR, granuloma formation and fibrosis, with elevated KL-6 and SP-D levels. Acute-onset HFL, resulting from short-term, high-dose antigen exposure, induces type III HSR, with earlier symptom-onset and minimal lymphocytic alveolitis, likely explaining the lower KL-6 and SP-D levels. 1 2 Cluster analysis identified a distinct subgroup of HFL cases characterised by ARDS-like or OP-like findings on HRCT, normal serum KL-6 levels and moderately to markedly elevated CRP levels, indicating that diagnosis in such cases can be challenging. These atypical clusters may reflect endotoxin-induced lung injury rather than classic HP. Notably, only a small proportion of cases showed typical HP features on HRCT with elevated KL-6 levels. Conversely, the major cluster of SHP exhibited characteristic HRCT findings and elevated serum KL-6 levels, supporting a relatively straightforward diagnosis. BAL lymphocyte surface phenotypes in HP have been extensively studied. Most patients with SHP show increased BALF T-cell lymphocytes, predominantly CD8+, with a decreased CD4/CD8 ratio. In contrast, farmers’ lung is associated with a higher CD4/CD8 ratio. Similarly, in bird fancier’s lung, the BALF CD4/CD8 ratio is often normal or elevated. These findings indicate variability in BALF immunophenotypes across HP subtypes. 4 11 13 14 40 Few studies have investigated BALF lymphocyte phenotypes in HFL; however, a significantly higher CD4/CD8 ratio, consistent with our findings, has been reported. 11 13 14 BALF neutrophil fractions were also higher in HFL. These differences may reflect antigen type, concentration and exposure duration. Histopathological findings in HFL and SHP are infrequently reported in large case series. Both conditions demonstrated alveolitis in smaller case series; 13 14 however, intra-alveolar organisation is more prominent in HFL, reflecting its association with acute lung injury. In the ARDS-like cluster, organisation within the alveolar spaces was observed relatively frequently, and intra-alveolar fibrin deposition was noted in several cases, suggesting that acute lung injury may have been present in a subset of patients. However, no cases demonstrated definite hyaline membrane formation and diffuse alveolar damage was not identified. Conversely, SHP, driven by type IV HSR, more commonly presents with epithelioid granulomas and multinucleated histiocytes. These differences may highlight variations in disease progression phase or antigen type. HFL usually resolves with antigen avoidance, and mild cases improve rapidly. Similarly, clinical and radiological findings improve after humidifier avoidance and most patients have no recurrence. In our study, only ~20% required corticosteroids. In contrast, patients with SHP often had ongoing unavoidable antigen exposure or limited improvement, leading to more frequent and prolonged corticosteroid use. Some patients with HFL developed severe respiratory failure requiring high-dose corticosteroid therapy; however, these cases generally responded well to treatment and did not progress to fibrosis. Limitations This study has several limitations. First, the response rate to the nationwide survey was 29.9%, raising the possibility of selection bias, which may have affected the representativeness of the reported incidence and clinical spectrum. However, all participating institutions were accredited training facilities of the Japanese Respiratory Society staffed by board-certified pulmonologists, and the diagnosis of HP in Japan generally requires specialised investigations such as HRCT and bronchoscopic procedures. Therefore, the institutional composition of the participating centres is unlikely to have substantially influenced the diagnostic approach. Second, although 74 cases were classified as probable according to the diagnostic framework for HFL, the inclusion of probable cases may introduce some degree of diagnostic uncertainty and potential misclassification. However, all cases showed consistent exposure–response relationships, such as worsening after exposure or improvement following avoidance, supporting the diagnostic validity of these cases. Third, the cluster analysis was exploratory. No formal validation or stability assessment was performed. Therefore, the reproducibility of the identified clusters could not be evaluated, and further studies are needed to confirm these findings. Finally, in severe HFL presenting with respiratory failure, PFTs and bronchoscopy are often impracticable, hindering BAL or lung biopsy. Also, the heterogeneity of HFL subtypes with varying clinical and imaging characteristics warrants further study. These limitations may have influenced our results and may pose potential confounding factors. Conclusion The incidence of both subtypes has risen, with surges in HFL cases during the pandemic. HFL presents distinct clinical, radiological and pathological features from SHP. Diagnosis remains challenging due to atypical presentation; thus, a comprehensive environmental exposure history is requisite for expediting accurate diagnosis. Supplementary material online supplemental file 1 bmjresp-13-1-s001.tif (37.7MB, tif) DOI: 10.1136/bmjresp-2025-003694 online supplemental file 2 bmjresp-13-1-s002.tif (36.8MB, tif) DOI: 10.1136/bmjresp-2025-003694 online supplemental file 3 bmjresp-13-1-s003.tif (36.8MB, tif) DOI: 10.1136/bmjresp-2025-003694 Acknowledgements The authors acknowledge Chiaki Nishimura of CN Medical Research Inc. (Tokyo Japan) for the statistical analysis, and Florence Ene, MBBS, PhD, of Platinum Medical Consulting Japan for editing a draft of this manuscript. This study was supported in part by a grant from the Ministry of Health, Labour and Welfare of Japan, awarded to the Study Group on Diffuse Pulmonary Disorders, Scientific Research/Research on Intractable Disease. Footnotes Funding: This study was partially supported by a grant from The Japanese Respiratory Society Research Grants Program 2022 by Boehringer Ingelheim. Provenance and peer review: Not commissioned; externally peer-reviewed. Patient consent for publication: Not applicable. Ethics approval: This study was approved by the Toho University Omori Medical Center Institutional Review Board (Approval Number: M21280 , October 2022). The Ethics Committee waived informed consent due to anonymised retrospective data. Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. 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Supplementary Materials online supplemental file 1 bmjresp-13-1-s001.tif (37.7MB, tif) DOI: 10.1136/bmjresp-2025-003694 online supplemental file 2 bmjresp-13-1-s002.tif (36.8MB, tif) DOI: 10.1136/bmjresp-2025-003694 online supplemental file 3 bmjresp-13-1-s003.tif (36.8MB, tif) DOI: 10.1136/bmjresp-2025-003694 Data Availability Statement All data relevant to the study are included in the article or uploaded as supplementary information. 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