ATS/JRS/ALAT Guidelines for Diagnosis of Humidifier Lung and Summer-Type Hypersensitivity Pneumonitis

doi:10.21203/rs.3.rs-1714948/v1

Background: The ATS/JRS/ALAT Guidelines for the Diagnosis of Hypersensitivity Pneumonitis (GL for HP) were published in 2020. Humidifier lung and summer-type HP are forms of HP, but it is unclear whether they can be diagnosed using the GL for HP. This study examined the level of confidence with which humidifier lung and summer-type HP can be diagnosed with the GL for HP.

Methods: Data from 23 patients with humidifier lung and 20 patients with summer-type HP (mean age, 67.3 and 57.4 years, respectively) diagnosed between October 2012 and January 2022 were retrospectively reviewed. We evaluated high resolution computed tomography (HRCT) patterns, bronchoalveolar lavage fluid (BALF) findings, exposures, and histopathological findings to determine the level of confidence with which a diagnosis of HP could be made using the GL for HP.

Results: HRCT pattern was classified as typical HP in 5 (22%) and compatible with HP in 18 (78%) patients with humidifier lung and judged as typical HP in 17 (85%) and compatible with HP in 3 (15%) summer-type-HP patients. The confidence level for diagnosis of HP was definite in 2 (8.7%), moderate in 14 (60.9%), and low in 7 (30.4%) patients with humidifier lung. It was definite in 12 (60%), high in 3 (15%), and moderate in 5 (25%) patients with summer-type HP.

Conclusions: The GL for HP showed utility in the diagnosis of humidifier lung in many patients with a moderate to low confidence. There was, however, a definite to high confidence for patients with summer-type HP.

Humidifier lung

Summer-type hypersensitivity pneumonitis

high-resolution CT

Bronchoalveolar lavage fluid

ATS/JRS/ALAT Guidelines for the Diagnosis of Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) is an inflammatory lung disorder caused by sustained or repeated inhalation of various antigens. Identification of irritating antigens is requisite for diagnosis of HP, and thus provocation tests are useful. For some patients, symptoms improve by avoiding antigen exposure, but others may require corticosteroid treatment [1–3]. The ATS/JRS/ALAT Guidelines for the Diagnosis of Hypersensitivity Pneumonitis (GL for HP) were published in 2020 [1]. While the incidence of HP is reported to range from 0.3–0.9 per 100,000 globally, claims-based analysis reports an incidence of 1.67 to 2.71 per 100,000 in the US population [1]. There are several phenotypes HP, and these are classified based on the causative antigen as summer-type HP, humidifier lung, bird breeders’ lung, hot-tub lung, and farmers’ lung [1–3]. Most cases of summer-type HP and humidifier lung are classified as acute non-fibrotic HP. The humid weather and traditional wooden houses in Japan are thought to increase exposure to Trichosporon asahii (T. asahii) a rare fungal pathogen common in immunocompromised patients. The incidence of summer-type HP in Japan was reported to be high—greater than 70%—and its characteristic features are thus well understood [4, 5].

In contrast, another study describes a low incidence of humidifier lung in Japan —less than 5%—and its characteristic features are thus poorly understood [4, 5]. Ultrasonic humidifiers are frequently used to prevent dry indoor environments during winter in the areas on the Pacific side of Japan. Humidifier lung is a phenotype of home environment HP. Humidifier use has been recommended for combating the spread of COVID-19 and so the frequency of humidifier lung is increasing. Contaminated ultrasonic humidifiers directly disperse causative antigens in 0.5-µm to 3-µm droplets that easily reach the distal airway. When ultrasonic humidifiers are not carefully cleaned the water is easily contaminated with microorganisms such as bacteria and fungi, including bacterial endotoxins [6–14]. In general, prolonged exposure to a contaminating fungal or bacterial antigen and/or endotoxin results in immune sensitization and causes immune-mediated lung injury in susceptible individuals [6–14].

The criteria for diagnosing this rare condition have not been standardized, however, the ATS/JRS/ALAT Guidelines for the Diagnosis of Hypersensitivity Pneumonitis (GL for HP) were published in 2020 [1] followed by the CHEST Guidelines for the Diagnosis and Evaluation of Hypersensitivity Pneumonitis [2] in 2021. We previously reported on the clinical, laboratory, and chest CT features that distinguish humidifier lung from summer-type HP [15]. Another study also described differences between humidifier lung and summer-type HP [16]. Therefore, we hypothesize that it is difficult to diagnose and differentiate humidifier lung from summer-type HP by using the GL for HP. Few studies have comprehensively evaluated whether humidifier lung and summer-type HP can be diagnosed with these guidelines. Therefore, this study sought to examine the level of diagnostic confidence for humidifier lung using the GL for HP compared with summer-type HP.

2.1 Study Subjects

We retrospectively reviewed data from 23 patients with humidifier lung (mean age, 67.3 years) and 20 patients with summer-type HP (mean age, 57.4 years) diagnosed between October 2012 through January 2022. High resolution computed tomography (HRCT) patterns, bronchoalveolar lavage fluid (BALF) findings, exposures, and histopathological findings were also reviewed to determine the level of confidence with which the diagnosis of HP could be made based on the GL for HP. All confidence levels were classified by multidisciplinary discussion. Information from clinical records and physical examinations was analyzed, as were results from laboratory analyses, including serum white blood cell count (WBC), C-reactive protein (CRP), lactate dehydrogenase (LDH), Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) levels, and arterial blood gas analysis.

2.2 Initial diagnosis of humidifier lung and summer-type HP

Humidifier lung was diagnosed from clinical and radiological findings by using a previously reported method [15] and the following criteria: 1) sustained presence of respiratory symptoms (such as cough, sputum, and dyspnea) for longer than 1 week; 2) bilateral ground-glass opacity (GGO) or consolidation on chest CT; 3) history of home ultrasonic humidifier use; 4) a positive provocation test result; 5) bronchoalveolar lavage findings or histopathological findings consistent with HP; and 6) improved symptoms, laboratory findings, and chest HRCT images after cessation of home ultrasonic humidifier use. Humidifier lung was diagnosed based on the presence of criteria 1, 2, 3, 4, and 5; criteria 1, 2, 3, 5, and 6; criteria 1, 2, 3, and 4; or criteria 1, 2, 3, and 6 (probable). When diagnosed by using these criteria, the antigen exposure section of the GL for HP is judged “positive”. Summer-type HP was diagnosed based on typical clinical and chest HRCT findings as previously described [4, 5], and the presence of precipitating antibodies to T. asahii. Next, we evaluated the level of confidence of diagnosing non-fibrotic HP using the GL for HP.

2.3 Chest HRCT

Chest HRCT was performed on admission and during follow-up with a SOMATOM Definition AS, Flash and Edge scanner (Siemens Co., Ltd., Munich, Germany). The entire lung was scanned in 5-mm–thick sections. Additional thin-section CT (thickness, 1.0 mm) was performed for all patients to evaluate for parenchymal abnormalities. Thin-section CT images were reconstructed with a fixed window setting. Images were reviewed independently by one thoracic radiologist (A.K.) and three pulmonologists (H.S., M.M., S.S.), all blinded to the identity and clinical, physiological, and pathological characteristics of the patients. Additionally, we determined which of the HRCT pattern criteria (nonfibrotic HP pattern) in the GL for HP were met. HRCT pattern was classified as typical and compatible with HP accordingly.

2.4 Bronchoalveolar lavage (BAL) and bronchoscopic examination

BAL was performed by using a basic modality. BAL fluid (BALF) was subjected to density-gradient centrifugation by means of BD VacutainerÒ CPTÔ with Sodium Heparin mononuclear cell preparation tubes (Becton Dickinson and Company, Franklin Lakes, NJ). Cytocentrifuge-prepared smears were obtained for differential count of the BALF cells following Wright-Giemsa staining. We performed flow cytometric analysis of T cells recovered from BALF to establish the phenotype. Next, we performed transbronchial biopsy (TBLB), which yielded between 3 and 5 specimens during the 1-week hospitalization period. Further analysis of specimens obtained by TBLB revealed inflammatory findings involving the bronchioles and alveoli. Other findings were organizing pneumonia, eosinophilic infiltration, granulomatous change, alveolar epithelial cell hyperplasia, and giant cell formation. Thus, we categorized the pathological diagnosis as typical, probable, or indeterminate based on the GL for HP (nonfibrotic HP).

2.5 Statistical analysis

Continuous variables are presented as the median (range), except as otherwise indicated; the Mann–Whitney U test was used for comparison. For categorical variables, the χ² test was used for comparison. A value of P < 0.05 was considered indicative of statistical significance. Statistical analysis was performed by using SPSS Statistics for Windows version 11.0 (SPSS Inc., Chicago, IL).

2.6 Ethical approval

This retrospective study was approved by the Ethics Committee of Toho University Omori Medical Center in April 2022 (project approval number M20221). Considering the nature of the retrospective study, the informed consent was waived by the Ethics Committee of Toho University Omori Medical Center because of the anonymized patient data. The study protocol was performed in accordance with the relevant guidelines.

3.1 Patient characteristics

The characteristics of the 23 patients (17 men and 6 women) with humidifier lung and 20 patients (9 men and 11 women) with summer-type HP are shown in Table 1. Patients with humidifier lung were significantly older than those with summer-type HP (68.0±14.4 vs 57.4±17.6 years, respectively). Most patients with humidifier lung first visited the hospital in winter. Subacute to acute disease, with dyspnea, cough, and fever, was most common; the incidences of these symptoms did not differ significantly between patients with humidifier lung and summer-type HP (78.2% vs 85.0%, 87.0% vs 75.0%, and 73.9% vs 40.0%, respectively).

3.2 Laboratory findings

Table 2 shows the laboratory findings for both patient groups. Total WBC count as well as serum CRP and LDH levels were elevated in most patients. Both WBC count and CRP level were higher in humidifier lung than in summer-type HP (WBC: 13500±6500 vs 7500±2300/μL, P=0.003; CRP: 8.0±6.5 vs 2.1±2.7 mg/dL, P=0.004). Analysis of differential WBC cell counts showed a lower lymphocyte fraction for humidifier lung than for summer-type HP (13.2±7.2% vs 22.0±13.1%, P=0.008). Neutrophil fraction was higher in humidifier lung than in summer-type HP (79.4±9.5% vs 68.0±13.7%, P=0.003). Serum levels of KL-6 and SP-D were significantly lower in patients with humidifier lung than in those with summer-type HP (KL-6: 593.4±396.7 vs 2107.7±2029.7 U/mL, P=0.001; SP-D: 162.4±156.7 vs 579.8±505.8 ng/mL, P=0.001).

3.4 HRCT findings

Chest HRCT findings are shown in Table 3. The most common HRCT findings for humidifier lung and summer-type HP were faint GGO (95.6% vs 95.0%) and mosaic attenuation (52.2% vs 75.0%) (Fig. 1-A). Poorly-defined centrilobular micronodules were less common in humidifier lung than in summer-type HP (Fig. 2) (30.4% vs 65.0%, P=0.026). Diffuse non-segmental consolidation was seen bilaterally in 12 patients with humidifier lung; this is unusual in summer-type HP. This consolidation was more common in humidifier lung than in summer-type HP (52.1% vs 5.0%, P=0.002) (Fig. 1-B). HRCT pattern according to the GL for HP was typical HP in 5 (22%) and compatible with HP in 18 (78%) patients with humidifier lung and was typical HP in 17 (85%) and compatible with HP in 3 (15%) patients with summer-type HP (Fig. 3).

3.5 BALF

BAL was performed in 15 patients with humidifier lung and in all 19 patients with summer-type HP. BALF findings are shown in Table 4. Total BALF cell count was high in all patients with humidifier lung and those with summer-type HP. No significant difference was seen in total cell count, however, differential BALF cell count revealed lower increase in lymphocytes in humidifier lung than in summer-type HP (37.3±20.1% vs 69.0±22.6%, P<0.001). The percentage of patients with BALF lymphocyte count ratio greater than 20% was 15/19 (78.9%) in humidifier lung and 19/19 (100%) in summer-type HP. Neutrophil fraction was greater in humidifier lung than in summer-type HP (22.1±25.6% vs 8.1±13.6%, P=0.157). Furthermore, the phenotypes of BAL lymphocytes differed significantly. BAL lymphocytes in humidifier lung were predominantly CD4+ lymphocytes, whereas those in summer-type HP were predominantly CD8+ lymphocytes. Thus, the CD4/CD8 ratio was significantly higher for humidifier lung than for summer-type HP (1.7±1.2 vs 0.8±0.9, P=0.003).

3.6 Pathological findings

Among the 15 patients with humidifier lung who underwent bronchoscopy, TBLB was performed in 9 because of worsening respiratory failure after BAL. Pathological findings of both groups are shown in Table 5. TBLB specimens from 9 patients with humidifier lung revealed alveolar septal wall thickening with lymphocyte infiltration (alveolitis) in all patients. Intra-alveolar organization was observed in 4 of the 9 patients with granulomatous inflammation and in 2 patients with summer-type HP. No patient had characteristics of epithelioid cell granuloma.

In both humidifier lung and summer-type HP, TBLB specimens showed alveolitis in all patients. However, there was no evidence of obvious cellular chronic bronchiolitis in TBLB specimens in all patients, because it was difficult to obtain sufficient bronchiolocentric area due to the small size of TBLB specimens. Thus, the pathological pattern was classified as indeterminate in all patients based on the GL for HP.

3.7 Guideline-based diagnosis of humidifier lung and summer-type HP

HRCT classification, precipitating IgG antibodies, exposures, pathological classification BALF lymphocyte count ratio, and total grade of confidence of HP diagnosis in all patients are shown in Figure 4. Definite or high level of confidence is depicted in dark green, while low level of confidence is highlighted in yellow. HRCT patterns were classified as typical HP in 5 (22%) and compatible with HP in 18 (78%) patients with humidifier lung and classified as typical HP in 17 (85%) and compatible with HP in 3 (15%) patients with summer-type HP. All patients with humidifier lung showed a clear correlation with exposure. Precipitating antibodies to T. asahii were confirmed present in all patients with summer-type HP. The percentage of patients with BALF lymphocyte count ratio of more than 20% was 15/19 (78.9%) in humidifier lung and 18/18 (100%) in summer-type HP. In both humidifier lung and summer-type HP, TBLB specimens showed cellular interstitial pneumonia (alveolitis) in all patients. However, there was no evidence of obvious cellular chronic bronchiolitis and granulomatous inflammation. Thus, the pathological pattern was classified as indeterminate in all patients based on GL for HP classification. The confidence level for the diagnosis of HP was definite in 3 (13.0%), moderate in 14 (60.9%), and low in 6 (26.1%) patients with humidifier lung and definite in 12 (60%), high in 3 (15%), and moderate in 5 (25%) patients with summer-type HP (Fig. 5).

A few reports have suggested characteristic clinical and radiological differences between humidifier lung and summer-type HP [15,16]. These differences might depend on the nature or amount of inhaled causative antigens and the duration of inhalation. We hypothesize that it is difficult to diagnose humidifier lung with high confidence using the GL for HP. However, few studies have carefully evaluated the utility of these guidelines for diagnosing humidifier lung and summer- type HP.

In our study, the diagnostic confidence for HP based on HRCT differed significantly between summer-type HP and humidifier lung. In the GL for HP, HRCT pattern was classified as typical and compatible for non-fibrotic HP according to specific HRCT findings [1]. Typical HP pattern consists of diffusely distributed HRCT findings including lung infiltration plus at least one HRCT abnormality suggestive of small airway disease. HRCT findings of small airway disease include ill-defined centrilobular nodules on inspiratory images and air trapping on expiratory images. These parenchymal patterns are usually bilateral and symmetric with a diffuse distribution, both axially and craniocaudally. A combination of parenchymal abnormalities and features of small airway disease is highly suggestive of nonfibrotic HP. In our study, most summer-type HP patients had parenchymal abnormalities and features of small airway disease, such as ill-defined centrilobular nodules, on HRCT. Therefore, many summer-type HP cases were classified as typical HP on HRCT.

Some of the patients with humidifier lung had nonspecific features but also had compatible HRCT findings, as compared with summer-type HP. Many cases of humidifier lung had parenchymal abnormalities such as uniform and subtle GGO and airspace consolidation, but did not have features of small airway disease such as ill-defined centrilobular nodules. Therefore, many patients with humidifier lung were classified as compatible with HP on HRCT. Consolidation on chest HRCT might be attributable to strong inflammatory reaction, including lung injury due to exposure to high levels of antigen and/or endotoxin [17-20].

For patients with newly identified interstitial lung disease for whom the differential diagnosis includes nonfibrotic HP, the GL for HP recommend BAL with lymphocyte cellular analysis. In our study, the percentage of patients with a BALF lymphocyte count ratio of more than 20% was 15/19 (78.9%) in those with humidifier lung and 19/19 (100%) in those with summer-type HP. Furthermore, in humidifier lung, the increase in BALF neutrophil fraction was greater than that for summer-type HP [15, 16]. Most HP patients, including those with summer-type HP, exhibit increased BAL T lymphocytes, predominantly CD8⁺ lymphocytes, thus decreasing the CD4/CD8 ratio. However, CD4/CD8 ratio is higher in farmers’ lung indicating that BAL lymphocyte phenotypes vary depending on the type of HP [1-5, 21-23]. Few studies of humidifier lung have evaluated BAL lymphocyte phenotypes [13, 15, 16]. They reported a significantly higher CD4/CD8 ratio for humidifier lung than for summer-type HP, which is consistent with our results. The reasons for these differences in WBC fractions and BAL lymphocyte phenotypes in HP are unclear and as mentioned above, may be attributed to the nature or amount of inhaled causative antigens and endotoxins.

In our study, diagnostic confidence for HP based on histopathological criteria did not differ between summer-type HP and humidifier lung. In the GL for HP, histopathological diagnostic confidence for nonfibrotic HP requires the presence of the following typical histopathological features: 1) Cellular interstitial pneumonia accentuated around small airways (bronchiolocentric) accompanied by 2) Chronic cellular bronchiolitis, 3) A distinctive pattern of granulomatous inflammation, and 4) No histopathological features suggestive of a more likely alternative. The term indeterminate HP refers to cases where either cellular bronchiolocentric interstitial pneumonia or an otherwise unexplained chronic cellular bronchiolitis is present, but without the characteristic granulomatous inflammation [1]. Yet, in our study, the histopathological features in both humidifier lung and summer-type HP were classified as indeterminate in all patients. TBLB specimens showed cellular interstitial pneumonia (alveolitis) in all patients. There was no evident cellular chronic bronchiolitis. This is because of the difficulty in obtaining specimens with adequate bronchiolocentric area from TBLB. Therefore, we could not obtain sufficiently-sized TBLB specimens in the bronchiolocentric area to facilitate an accurate diagnosis of cellular bronchiolitis.

The GL for HP make no recommendations or suggestions for or against transbronchial lung cryobiopsy (TBLC) for patients with newly identified ILD whose differential diagnosis includes nonfibrotic HP. Several studies reported higher diagnostic yield with TBLC than with TBLB, although the incidence of bleeding was also higher with TBLC [24, 25]. TBLC allows for obtaining specimens with adequate bronchiolocentric area. Wider use and improved safety of TBLC in the future would facilitate a more straightforward pathological evaluation of bronchiolocentric area, and more accurate pathological diagnosis of nonfibrotic HP.

The GL for HP provide robust criteria for establishing a diagnosis of HP. This is based on the incorporation of HRCT imaging, exposure assessment, BAL lymphocytosis, and histopathological features. In our study, 75% of summer-type HP patients were diagnosed with definite or high confidence, even though the pathological pattern was indeterminate, based on typical HRCT findings, increased BALF lymphocytosis, and the presence of precipitating T. asahii antibodies. However, only 13% of patients with humidifier lung were definitively diagnosed as HP, based on nonspecific features. But these could be compatible with nonfibrotic HP HRCT findings and the increased BALF neutrophil fraction. Thus, a unique set of criteria might be preferred for the accurate diagnosis of humidifier lung.

Limitations

This was a single-center retrospective study with a small sample size. A large-scale multicenter study is needed to confirm these findings as to whether humidifier lung and summer-type HP can be diagnosed with the GL for HP.

Using the GL for HP, diagnostic confidence was moderate to low for many humidifier lung patients, but was definite-to-high for patients with summer-type HP. Therefore, a unique set of criteria is beneficial for the diagnosis of humidifier lung.

Ethical approval and consent to participate

This retrospective study was approved by the Ethics Committee of Toho University Omori Medical Center in April 2022 (project approval number M20221). Considering the nature of the retrospective study, the informed consent was waived by the Ethics Committee of Toho University Omori Medical Center because of the anonymized patient data. The study protocol was performed in accordance with the relevant guidelines.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interest

We declare that we have no conflict of interest.

Funding

None.

Author contributions:

S.S. served as principal author and had access to, and takes responsibility for, the integrity of the data and the accuracy of the data analysis. S.S. and S.H. contributed to the design of the study; S.S., M.M., S.H., T.I., Y.T., Y.U., K.K., N.U., M.S., S.M., and K.I. contributed to data collection; S.S., T.I., Y.N., and S.H. contributed to interpretation of the study; S.S., M.M., T.I., and S.H. contributed to the study analysis; and A.K., S.S., T.I., H.S., Y.U., Y.N., and S.H. contributed to evaluation of HRCT images. All authors were involved in drafting and revising this report and gave their ﬁnal approval of the version to be published. All authors vouch for the accuracy of the content included in the ﬁnal report.

Acknowledgments:

We thank Florence Ene, MD, PhD for medical English language editing of this article. This study was partially supported 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.

Conflict of interest:

None declared.

Support statement:

None.

Raghu G, Remy-Jardin M, Ryerson CJ, et al. Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med 2020; e36-e69. doi: 10.1164/rccm.202005-2032ST
Fernández Pérez ER, Travis WD, Lynch DA, et al. Diagnosis and Evaluation of Hypersensitivity Pneumonitis: CHEST Guideline and Expert Panel Report. Chest 2021; e97-e156. doi: 10.1016/j.chest.2021.03.066
Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: Current concepts and future questions. J Allergy Clin Immunol 2001; 108: 661-670.
Ando M, Suga M, Kohrogi H. A new look at hypersensitivity pneumonitis. Curr Opin Pulm Med 1999; 5: 299-304.
Ando M, Konishi K, Yoneda R, et al. Difference in the Phenotypes of Bronchoalveolar Lavage Lymphocytes in Patients with Summer-Type Hypersensitivity Pneumonitis, Farmer's Lung, Ventilation Pneumonitis, and Bird Fancier's Lung: Report of a Nationwide Epidemiologic Study in Japan. J Allergy Clin Immunol 1991; 87: 1002- 1009.
Banaszak, E.F., Thiede, W.H., Fink, J.N. Hypersensitivity pneumonitis due to contamination of an air conditioner. N. Engl. J. Med 1970; 283: 271-276.
Marinkovich VA, Novey HS. Humidifier lung. Clin Rev Allergy 1983; 1: 533-536.
Fink JN, Banaszak EF, Theide WH, et al. Interstitial pneumonitis due to hypersensitivity to an organism contaminating a heating system. Ann Intern Med 1971; 74: 80-83.
Sweet LC, Anderson JA, Callies QC, et al. Hypersensitivity pneumonitis related to a home furnace humidifier. J Allergy Clin lmmunol 1971; 48: 171-178.
Fink JN, Banaszak EF, Barboriak JJ, et al. Interstitial lung disease due to contamination of forced air systems. Ann Intern Med 1976; 84: 406-413.
Burke GW, Carrington CB, Strauss R, et al. Allergic alveolitis caused by home humidifiers. JAMA 1977; 238: 2705-2708.
Robertson AS, Burge PS, Wieland GA, et al. Extrinsic allergic alveolitis caused by a cold water humidifier. Thorax 1987; 42: 32-37.
Suda T, Sato A, Ida M, et al. Hypersensitivity pneumonitis associated with home ultrasonic humidifiers. Chest 1995; 107: 711-717.
Gemma H, Nihashi F, Kitahara Y, et al. Three Cases of Humidifier Lung Associated with Respiratory Failure. The Japanese journal of sarcoidosis and other granulomatous disorders 2018; 38: 80-83
Sakamoto S, Furukawa M, Shimizu H, et al. Clinical and radiological characteristics of ultrasonic humidifier lung and summer-type hypersensitivity pneumonitis. Respir Med 2020; 174:106196.
Shimoda M, Morimoto K, Tanaka Y, et al. Features of humidifier lung and comparison with summer-type hypersensitivity pneumonitis. Respirology 2021; 26: 394-395.
Suga M，Yamasaki H，Nakagawa K, et al．Mechanisms accounting for granulomatous response in hypersensitivity pneumonitis．Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: 131-138．
Flaherty DK, Deck FH, Cooper J, et al. Bacterial endotoxin isolated from a water spray air humidification system as a putative agent of occupation- related lung disease. Infect lmmun 1984; 43: 206-211.
Rylander R, Haglind P, Lundholm M, et al. Humidifier fever and endotoxin exposure. Clin Allergy 1978; 8: 511-516.
Ohnishi H, Yokoyama A, Hamada H, et al. Humidifier lung: possible contribution of endotoxin-induced lung injury. Intern Med 2002; 41: 1179-1182.
Leatherman JW, Michael AF, Schwartz BA, et al. Lung T cells in hypersensitivity pneumonitis. Ann Intern Med 1984; 100: 390-392.
Costabel U, Bross KJ, Ruhle KH, et al. Ia-like antigens on T cells and their subpopulations in pulmonary sarcoidosis and in hypersensitivity pneumonitis: analysis of bronchoalveolar and blood lymphocytes. Am Rev Respir Dis 1985; 131: 337-342.
Semenzato G, Agostini C, Zambello R, et al. Lung T cells in hypersensitivity pneumonitis: phenotypic and functional analyses. J Immunol 1986; 137: 1164-1172.
Pajares V, Puzo C, Castillo D, et al. Diagnostic yield of transbronchial cryobiopsy in interstitial lung disease: a randomized trial. Respirology 2014; 19: 900–906.
Ramaswamy A, Homer R, Killam J, et al. Comparison of transbronchial and cryobiopsies in evaluation of diffuse parenchymal lung disease. J Bronchology Interv Pulmonol 2016; 23: 14–21.

Table 1

Characteristics of patients with humidifier lung and summer-type hypersensitivity pneumonitis (HP)

	Humidifier lung (n=23)	Summer-type HP (n=20)	P value
Age (y)	68.0±14.4	57.4±17.6		0.035*
Male, n (%)	17 (70.1)	9 (47.3)		0.118
Body height (cm)	160±7.85	162±9.97		0.477
Body weight (kg)	58.3±7.81	59.6±15.0		0.817
Body mass index (kg/m^２)	21.5±6.2	18.8±9.5		0.975
Smoking (Current/Former/Never)	1/11/11	0/10/10		0.606
Smoking index	498.2±811.3	246.5±385.0		0.639
Season at the time of first hospital visit (Mar-May/Jun-Aug/Sep-Nov/ Dec-Feb)	4/0/1/18	1/10/7/1		0.003*

Symptoms
mMRC	2.0±0.4	2.5±0.9		0.281
Dyspnea, n (%)	18 (78.2)	17(85.0)		0.310
Cough, n (%)	20 (87.0)	15 (75.0)		0.772
Fever, n (%)	17 (73.9)	8 (40.0)		0.248
Sputum, n (%)	11 (47.8)	6 (30.0)		0.642

*mMRC: Modified Medical Research Council Dyspnea Scale

Table 2

Laboratory and pulmonary function test results for patients with humidifier lung and summer-type hypersensitivity pneumonitis (HP)

	Humidifier lung (n=23)	Summer-type HP (n=20)	P value
Blood tests
White blood cells (/μL)	13.5±6.5× 10³	7.5±2.3 × 10³	0.003	*
Eosinophils (%)	2.4±3.1	3.1±3.4	0.042	*
Lymphocytes (%)	13.2±7.2	22±13.1	0.008	*
Neutrophils (%)	79.4±9.5	68.0±13.7	0.003	*
CRP (mg/dL)	8.0±6.5	2.1±2.7	0.004	*
LDH (U/L)	258.5±69.8	294±89.0	0.346
KL-6 (U/mL)	593.4±396.7	2107.7±2029.7	0.001	*
SP-D (ng/mL)	162.4±156.7	579.8±505.8	0.001	*
SP-A (ng/mL)	99.7±52.0	95.7±62.2	0.812
Arterial blood gas analysis
PaO₂ (Torr)	69.4±16.0	72.2±14.3	0.551
PaCO₂ (Torr)	37.8±4.2	38.2±4.7	0.597
PaO₂/FiO₂ ratio	323.9±100.4	331±88.0	0.422
Aa-DO₂ (Torr)	29.6±15.7	29.8±14.0	0.851

KL-6: Krebs von der Lungen-6; SP-D: surfactant protein D; SP-A: surfactant protein A; LDH: lactate dehydrogenase; CRP: C-reactive protein.

Table 3

High-resolution computed tomography (HRCT) findings in patients with humidifier lung and summer-type hypersensitivity pneumonitis (HP)

Chest HRCT findings	Humidifier lung (n=23)	Summer-type HP (n=20)	P value
Ground-glass opacity, n (%)	22 (95.6)	19 (95.0)	0.806
Centrilobular nodule, n (%)	7 (30.4)	12 (65.0)	0.026	*
Peribronchovascular or subpleural nonsegmental consolidation, n (%)	12 (52.1)	1 (5.0)	0.002	*
Mosaic attenuation, n (%)	12 (52.2)	15 (75.0)	0.115
Subpleural curve linear opacity, n (%)	4 (17.4)	5 (25.0)	0.363

Table 4

Bronchoalveolar lavage fluid findings in patients with humidifier lung and summer-type hypersensitivity pneumonitis (HP)

	Humidifier lung (n=15)	Summer-type HP (n=19)	P value
Total cell count, n /mL	3.0±2.3 × 10⁵	3.3±2.4 × 10⁵	0.60
Neutrophils (%)	22.1±25.6	8.1±13.6	0.16
Lymphocytes (%)	37.3±20.1	69.0±22.6	<0.001	*
Eosinophils (%)	9.47±19.0	3.1±2.8	1.00
Macrophages (%)	31.2±22.2	20.0±19.6	0.05
CD4 (%)	51.2±11.9	32.9±17.9	0.002	*
CD8 (%)	34.7±9.4	60.8±21.0	0.002	*
CD4/CD8 ratio	1.7±1.2	0.8±0.9	0.003	*

Table 5

Pathological findings in patients with humidifier lung and summer-type hypersensitivity pneumonitis (HP)

	Humidifier lung (n=9)	Summer-type HP (n=15)	P-value
Alveolitis n (%)	9 (100)	15 (100)	1.000
Severe alveolitis n (%)	1 (11)	10 (66.7)	0.013	*
Organization n (%)	4 (44.4)	11 (73.3)	0.212
Eosinophilia n (%)	2 (22.2)	3 (20)	1.000
Granuloma n (%)	0 (0)	2 (13.3)	0.511
Alveolar epithelial cell hyperplasia n (%)	8 (88.9)	14 (93.3)	1.000
Severe alveolar epithelial cell hyperplasia n (%)	2 (22.2)	8 (53.3)	0.134
Giant cells n (%)	0 (0)	6 (40)	0.052
Intra-alveolar macrophages n (%)	1 (11.1)	10 (66.7)	0.013	*
Cellular chronic bronchiolitis n (%)	0 (0)	0 (0)	1.000

The severity of alveolitis and alveolar epithelial cell hyperplasia was classified as −, +, and 2+, and a classification of 2+ was considered severe.

No competing interests reported.

ATS/JRS/ALAT Guidelines for Diagnosis of Humidifier Lung and Summer-Type Hypersensitivity Pneumonitis

Status:

Version 1

Abstract

Figures

1. Background

2. Methods

3. Results

4. Discussion

5. Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1