Respiratory Medicine 174 (2020) 106196

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Respiratory Medicine
journal homepage: http://www.elsevier.com/locate/rmed

Clinical and radiological characteristics of ultrasonic humidifier lung and

summer-type hypersensitivity pneumonitis
Susumu Sakamoto a, *, Marie Furukawa a, Hiroshige Shimizu a, Muneyuki Sekiya a,
Shion Miyoshi a, Yasuhiko Nakamura a, Naohisa Urabe a, Takuma Isshiki a, Yusuke Usui a,
Kazutoshi Isobe a, Yujiro Takai a, Atsuko Kurosaki b, Kazuma Kishi a, Sakae Homma c
a
Division of Respiratory Medicine, Toho University Omori Medical Center, Ota-ku, Tokyo, Japan
b
Department of Diagnostic Radiology, Fukujuji Hospital, Kiyose, Tokyo, Japan
c
Department of Advanced and Integrated Interstitial Lung Diseases Research, School of Medicine, Toho University, Ota-ku, Tokyo, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Ultrasonic humidifier lung is a rare form of hypersensitivity pneumonitis (HP), and its clinical and
Humidifier lung radiological features are unclear. This study examined the clinical and radiological characteristics of humidifier
Summer-type hypersensitivity pneumonitis lung.
High-resolution CT
Methods: Data from 18 patients with humidifier lung (mean age, 67.3 years) diagnosed during October 2012
Bronchoalveolar lavage fluid
through April 2018 were retrospectively reviewed. We compared clinical, laboratory, and CT findings and
bronchoalveolar lavage fluid (BALF) characteristics of these patients with those of 19 patients with summer-type
HP (mean age, 57.4 years).
Results: Cough and dyspnea were the most common symptoms. White blood cell count and serum C-reactive
protein titers were higher for humidifier lung than for summer-type HP. Serum levels of Krebs von den Lungen-6
and surfactant protein D were significantly lower for humidifier lung than for summer-type HP. The most
common chest CT findings in humidifier lung were ground-glass opacities (88.9%) and mosaic attenuation
(50.0%). Centrilobular ground glass nodules were less common in humidifier lung than in summer-type HP
(27.8% vs 63.1%; P = 0.043). Peribronchovascular or subpleural nonsegmental consolidation was more frequent
in humidifier lung than in summer-type HP (44.4% vs 5.3%; P = 0.013). Lymphocyte fractions in BALF speci­
mens were significantly lower for humidifier lung than for summer-type HP (37.3% vs 69.0%; P < 0.001).
Neutrophil fractions were higher for humidifier lung, but the difference was not significant (22.1% vs 8.1%; P =
0.153). The CD4/8 ratio was higher for humidifier lung than for summer-type HP (1.7 vs 0.8; P = 0.003).
Conclusions: The clinical and radiological characteristics of humidifier lung differ from those of summer-type HP.

1. Introduction studies have assessed humidifier lung.

Hypersensitivity pneumonitis (HP) is caused by continuous inhala­
tion of various antigens. Because diagnosis of HP requires identification
of antigens, challenge tests are useful. Symptoms improve when patients
avoid antigen exposure, but some patients need corticosteroid (CS)
treatment. HP is classified in relation to the causative antigen as
summer-type HP, humidifier lung, bird breeders’ lung, hot-tub lung, and
farmers’ lung [1]. In Japan, humid weather and traditional wooden
houses increase exposure to Trichosporon asahii. The incidence of
summer-type HP in Japan was reported to be high—greater than 70%—
and its characteristics are thus well understood [2,3]. However, few
In Japan, ultrasonic humidifiers are frequently used to prevent dry
indoor environments during winter. Humidifier lung is a type of home
environmental HP. The term “humidifier lung”, also known as “hu­
midifier fever” or “Monday morning sickness”, is used to describe HP
caused by inhalational exposure to contaminated ventilation units. HP
associated with a contaminated humidifier was first reported in 1970
[4]. Contaminated ultrasonic humidifiers directly disperse causative
antigens in 0.5-μm to 3-μm droplets that easily reach distal airway
spaces. Water in ultrasonic humidifiers that are not carefully cleaned is
easily contaminated with microorganisms such as bacteria, fungi, and
nontuberculous mycobacteria, including endotoxins [4–11].

* Corresponding author. Division of Respiratory Medicine Toho University Omori Medical Center Address: Ota-ku Omori nisi 6Tokyo, 143, Japan.
E-mail address: susumu1029@med.toho-u.ac.jp (S. Sakamoto).

https://doi.org/10.1016/j.rmed.2020.106196
Received 13 August 2020; Received in revised form 10 October 2020; Accepted 15 October 2020
Available online 16 October 2020
0954-6111/© 2020 Published by Elsevier Ltd.
S. Sakamoto et al.
Thermophilic actinomycetes have been isolated from humidifier
water, and the precipitating antibodies have been implicated as a cause
of humidifier lung. However, several reports found that some cases of
humidifier lung were not caused by these organisms; thus, humidifier
lung might be caused by multiple antigens. In general, prolonged
exposure to a contaminating fungal or bacterial antigen and/or endo­
toxin results in immune sensitization and causes immune-mediated lung
injury in susceptible individuals [4–11].
The criteria for diagnosing this rare condition are not standardized,
and the clinical, laboratory, and chest CT features of humidifier lung are
not well documented. We hypothesize that the mechanism underlying
humidifier lung differs from that of common summer-type HP. However,
few studies have carefully evaluated humidifier lung [11,12]. The
objective of this study was therefore to compare the clinical, laboratory,
and CT findings of humidifier lung with those of summer-type HP, the
most common HP in Japan.
2. Methods
2.1. Study patients
Data from 18 patients with humidifier lung diagnosed at Toho Uni­
versity Omori Medical Center during the period October 2012 through
April 2018 were reviewed retrospectively. The clinical and radiological
characteristics of these patients, including chest CT images, histopa­
thology findings, BALF findings, and presence of precipitating anti­
bodies to T. asahii, were compared with those of patients with typical
summer-type HP (n = 19) during the same period. 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), surfactant protein
D (SP-D), and arterial blood gas analysis (ABG).
Lung volume and forced expiratory volume in 1 s (FEV 1) were
measured with standard methods by using a Chestac-8800 or Chestac-
8900 spirometer (Chest Co., Ltd., Tokyo, Japan) and are expressed as
a percentage of the predicted value. The measurements were conducted
at diagnosis and during follow-up.
2.2. Diagnosis of humidifier lung and summer-type HP
Humidifier lung was diagnosed from clinical and radiological find­
ings by using a previously reported method [11] and the following
criteria: 1) continuous presence of respiratory symptoms (such as cough,
sputum, and dyspnea) for longer than 1 week, 2) bilateral ground-glass
opacity or consolidation on a chest CT scan, 3) history of home ultra­
sonic humidifier use, 4) positive result on a provocation test, 5) bron­
choalveolar lavage findings or histopathological findings consistent with
HP, 6) improvement of symptoms, laboratory findings, and chest
high-resolution CT (HRCT) images after cessation of home ultrasonic
humidifier use. Humidifier lung was diagnosed when 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) were present. Summer-type HP was diagnosed on the basis
of typical clinical and chest HRCT findings, as previously described [2,
3], and the presence of precipitating antibodies to T. asahii.
2.3. Chest CT
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 sec­
tions. Additional thin-section CT (thickness, 1.0 mm) was performed for
all patients, to evaluate parenchymal abnormalities. Thin-section CT
images were reconstructed with a fixed window setting. CT images were
then independently reviewed by one thoracic radiologist (A.K.) and 2
pulmonologists (M.F., S⋅S.) who were blinded to the identity and
2
Respiratory Medicine 174 (2020) 106196
clinical, physiological, and pathological characteristics of the patients.
2.4. Bronchoalveolar lavage (BAL) and bronchoscopy
BAL was performed by using a standard method. Briefly, 50 mL of
sterile 0.9% NaCl was administered 3 times to the right medial lobe or
left lingular lobe through a fiberoptic bronchoscope and collected by
gentle suction. BAL fluid (BALF) was purified by density-gradient
centrifugation with BD vacutainer mononuclear cell preparation tubes
and sodium heparin (Becton Dickinson and Company, NJ, USA). A dif­
ferential count of the BALF cells was performed on cytocentrifuged
smears stained with Wright-Giemsa. Flow cytometric analysis was used
to determine the phenotype of T cells recovered from BALF. Trans­
bronchial biopsy (TBLB) was performed after BAL, and 3 to 5 specimens
were obtained within 1 week of hospital admission. TBLB specimens
were evaluated for alveolitis, organization, eosinophilia, granuloma,
alveolar epithelial cell hyperplasia and giant cells. The severity of
alveolitis and epithelial cell hyperplasia was classified as − , +, and 2+,
and a classification of 2+ was considered severe.
2.5. Provocation tests
Nine patients underwent a provocation test with their humidifier.
The humidifier was operated in a hospital room measuring approxi­
mately 20 m2, with every window and door closed. The patient’s hu­
midifier was placed at their bedside, and the patient was exposed to the
humidifier mist for 2 h. If they developed symptoms during exposure,
the challenge test was stopped. During the next 24 h, the patient’s
symptoms and vital signs were observed, and information was collected
on body temperature, WBC, serum CRP, LDH, KL-6, SP-A, SP-D level,
ABG, pulmonary function test results, and HRCT image findings. Pa­
tients who developed symptoms from inhaling ultrasonic humidifier
mist were classified as positive. All patients tested gave their written
informed consent.
2.6. Statistical analysis
Continuous variables are expressed as median (range), unless
otherwise stated, and were compared with the Mann–Whitney U test.
Categorical variables were compared with the χ2 test. A P value of less
than 0.05 was considered to indicate statistical significance. All statis­
tical analyses were performed by using SPSS version 11.0 (SPSS Inc.,
Chicago, IL, USA).
Ethical approval
This retrospective study was approved by the Institutional Review
Board of Toho University Omori Medical Center in October 2017
(project approval number M17189).
3. Results
3.1. Patient characteristics
The characteristics of the 18 patients (13 men and 5 women) with
humidifier lung and 19 patients (9 men and 10 women) with summer-
type HP are shown in Table 1. The patients with humidifier lung were
slightly older than those with summer-type HP (67.3 ± 15.5 vs 57.4 ±
17.6 years, respectively). Most patients with humidifier lung first visited
the hospital in winter. The duration of symptoms ranged from 1 to 9
weeks (median, 2 weeks). All patients had home ultrasonic humidifiers
and used tap water in the humidifiers. The period of humidifier use
ranged from 1 to 4 months during the period September through March.
The duration of humidifier use on a daily basis was 6–24 h. The mean
interval from symptom onset to first hospital visit was 9.5 ± 19.5 days.
Subacute to acute disease, with dyspnea, cough, and fever, was most
S. Sakamoto et al. Respiratory Medicine 174 (2020) 106196

Table 1 Serum levels of WBC and CRP were higher for humidifier lung than for
Characteristics of patients with humidifier lung and summer-type hypersensi­ summer-type HP (WBC: 13327.8 ± 7380.0 vs 7463.2 ± 2311.1/μl, P =
tivity pneumonitis (HP). 0.003; CRP: 5.6 ± 6.5 vs 2.1 ± 2.7 mg/dl, P = 0.244). Analysis of dif­
Humidifier lung Summer-type p- ferential WBC cell counts showed that the lymphocyte fraction was
(n = 18) HP (n = 19) value lower for humidifier lung than for summer-type HP (13.9 ± 7.9% vs
Age (yrs) 67.3 ± 15.5 57.4 ± 17.6 0.098 22.0 ± 13.1%, P = 0.002). The neutrophil fraction was higher for hu­
Male, n (%) 13 (72.2) 9 (47.3) 0.074 midifier lung than for summer-type HP (79.0 ± 9.5% vs 68.0 ± 13.7%, P
Body height (cm) 159.9 ± 7.85 162 ± 9.97 0.477 = 0.003). Serum levels of KL-6 and SP-D were significantly lower in
Body weight (kg) 59.3 ± 7.81 59.6 ± 15.0 0.817
patients with humidifier lung than in those with summer-type HP (KL-6:
Body mass index (kg/m2) 21.5 ± 6.2 18.8 ± 9.5 0.975
Smoking (Current/Former/ 1,7,8 0,9,10 0.471 665.4 ± 428.8 vs 2107.7 ± 2029.7 U/ml, P = 0.001; SP-D: 179.7 ±
Never) 156.7 vs 579.8 ± 505.8 ng/mL, P = 0.001). Serum LDH levels did not
Smoking index 498.2 ± 811.3 246.5 ± 385.0 0.639 significantly differ between the groups. The differences in PaO2 and
Season of first hospital visit 4/0/1/13 1/10/6/1 0.003* PaCO2 were not significant (PaO2: 74.1 ± 13.2 vs 72.2 ± 14.3; PaCO2:
(Mar–May/Jun–Aug/
Sep–Nov/Dec–Feb)
37.1 ± 4.0 vs 38.2 ± 4.7). Among the 18 patients with humidifier lung, 2
Interval from first hospital visit to 11.2 ± 7.3 10.3 ± 7.3 0.333 had respiratory failure (PaO2 <60 mm Hg) at admission, and 1 devel­
diagnosis (days) oped respiratory failure after provocation testing.
Symptoms
mMRC 2.1 ± 0.8 2.5 ± 0.9 0.281
Dyspnea, n (%) 14 (77.8) 17 (89.5) 0.31 3.3. Pulmonary function testing
Cough, n (%) 14 (77.8) 14 (73.7) 0.772
Fever, n (%) 11 (61.1) 8 (42.1) 0.248 The results of pulmonary function testing are shown in Table 2. Two
Sputum, n (%) 7 (38.9) 6 (31.6) 0.642
of 18 (11.1%) patients with humidifier lung and 8 of 19 (42.1%) patients
with summer-type HP had restrictive impairment of respiratory func­
common, and the incidences of these symptoms did not significantly tion. One of 18 (5.6%) patients with humidifier lung and 2 of 19 (10.5%)
differ between patients with humidifier lung and summer-type HP patients with summer-type HP exhibited obstructive impairment of
(77.8% vs 89.5%, 77.8% vs 73.7%, and 61.1% vs 42.1%, respectively). respiratory function. The differences between groups were not signifi­
Although other family members were exposed to the humidifiers, none cant. The decrease in DLco was significantly less severe for humidifier
developed humidifier lung. Fine crackles were the most prominent lung than for summer-type HP (84.2 ± 37.9% vs 60.0 ± 14.8%, P =
physical finding in 12 of 18 patients. 0.025).

3.4. HRCT findings

3.2. Laboratory findings
Chest HRCT findings are shown in Table 3. The most common HRCT
The laboratory findings for both patient groups are shown in Table 2.
findings for humidifier lung were faint ground-glass opacities (88.9%)
Serum levels of WBC, CRP, and LDH were elevated in most patients.
and mosaic attenuation (50.0%) (Fig. 1-A). Poorly defined centrilobular
micronodules were less common in humidifier lung than in summer-type
Table 2 HP (Fig. 2) (27.8% vs 63.1%, P = 0.043). Eight patients with humidifier
Laboratory and pulmonary function test results for patients with humidifier lung
lung had diffuse nonsegmental consolidation bilaterally, which is un­
and summer-type hypersensitivity pneumonitis (HP).
usual for summer-type HP (peribronchovascular consolidation in 7,
Humidifier lung (n Summer-type HP (n p- subpleural nonsegmental consolidation in 1). These consolidations were
= 18) = 19) value
more frequent in humidifier lung than in summer-type HP (44.4% vs
Blood test 5.3%, P = 0.013) (Fig. 1-B). During follow-up, HRCT findings gradually
White blood cells 13.3 ± 7.4 × 103 7.5 ± 2.3 × 103 0.003 * improved with avoidance of humidifier exposure and were almost
(/μL)
Eosinophils (%) 2.3 ± 3.7 3.1 ± 3.4 0.042 *
normal at the end of follow-up. Ground-glass opacities developed after
Lymphocytes (%) 13.9 ± 7.9 22 ± 13.1 0.002 * provocation testing but improved with avoidance of humidifier expo­
Neutrophils (%) 79.0 ± 9.5 68.0 ± 13.7 0.003 * sure or after CS treatment.
CRP (mg/dL) 5.6 ± 6.5 2.1 ± 2.7 0.244
LDH (U/L) 259.6 ± 72.8 294 ± 89.0 0.346
KL-6 (U/mL) 665 ± 429 2108 ± 2030 0.001 * 3.5. BALF
SP-D (ng/mL) 179.7 ± 156.7 579.8 ± 505.8 0.001 *
SP-A (ng/mL) 101.9 ± 55.7 95.7 ± 62.2 0.589 BAL was performed in 15 patients with humidifier lung and in all
Arterial blood gas
patients with summer-type HP. BALF findings are shown in Table 4. All
test
PaO2 (Torr) 74.1 ± 13.2 72.2 ± 14.3 0.551 patients with humidifier lung had high BALF total cell counts, as did
PaCO2 (Torr) 37.1 ± 4.0 38.2 ± 4.7 0.597
PaO2/FiO2 ratio 345 ± 99.2 331 ± 88.0 0.422 Table 3
Aa-DO2 (Torr) 29.6 ± 15.7 29.8 ± 14.0 0.851
High-resolution computed tomography (HRCT) findings for patients with hu­
midifier lung and summer-type hypersensitivity pneumonitis (HP).
Pulmonary function test
VC (L) 2.6 ± 0.6 2.7 ± 0.8 1.000 Chest HRCT findings Humidifier Summer- p-
%VC (%) 90.6 ± 11.9 86.4 ± 17.4 0.486 lung (n = 18) type HP (n = value
FEV1(L) 1.95 ± 0.50 2.20 ± 0.67 0.215 19)
%FEV1 79.4 ± 11.0 84.2 ± 8.5 0.057
Ground-glass opacity, n (%) 16 (88.9) 17 (89.5) 0.954
%DLco (%) 84.2 ± 37.9 60.0 ± 14.8 0.025 *
Centrilobular nodule, n (%) 5 (27.8) 12 (63.1) 0.043 *
%DLco/VA (%) 77.6 ± 18.9 67.6 ± 18.1 0.683
Peribronchovascular or 8 (44.4) 1 (5.3) 0.013 *
KL-6: Krebs von der Lungen-6, SP-D: surfactant protein D, SP-A: surfactant subpleural nonsegmental
protein A, LDH: lactate dehydrogenase, CRP: C-reactive protein, BNP; brain consolidation, n (%)
natriuretic peptide, VC: vital capacity, %VC; vital capacity % of predicted value, Mosaic attenuation, n (%) 9 (50.0) 14 (73.7) 0.138
Subpleural curve linear opacity, n 2 (11.1) 5 (26.3) 0.181
FEV1; forced expiratory volume in 1 s, %DLco: carbon monoxide diffusing ca­
(%)
pacity % of predicted value.

3
S. Sakamoto et al. Respiratory Medicine 174 (2020) 106196

Fig. 1. Representative chest HRCT findings for hu­

midifier lung.
A) Diffuse faint ground-glass opacities and mosaic
attenuation, without poorly defined centrilobular
micronodules. This case was diagnosed by provoca­
tion test. B) Diffuse nonsegmental peri­
bronchovascular consolidation bilaterally, with
intralobular septal thickening—an unusual finding
for summer-type HP. This case was diagnosed by
provocation test.

Fig. 2. Representative chest HRCT scan for typical summer-type HP showing diffuse ground-glass opacities with poorly defined micronodules and mosaic
attenuation.

Table 4 Table 5a
Bronchoalveolar lavage fluid findings from patients with humidifier lung and Pathological findings from patients with humidifier lung and summer-type hy­
summer-type hypersensitivity pneumonitis (HP). persensitivity pneumonitis (HP).
Humidifier lung (n Summer-type HP (n p-value Humidifier lung Summer-type p-
= 15) = 19) (n = 9) HP (n = 15) value

Total cell count, n/ 3.0 ± 2.3 × 105 3.3 ± 2.4 × 105 0.60 Alveolitis n (%) 9 (100) 15 (100) 1.000
mL Severe alveolitis n (%) 1 (11) 10 (66.7) 0.013 *
Neutrophils (%) 22.1 ± 25.6 8.1 ± 13.6 0.16 Organization n (%) 4 (44.4) 11 (73.3) 0.212
Lymphocytes (%) 37.3 ± 20.1 69.0 ± 22.6 <0.001 * Eosinophilia n (%) 2 (22.2) 3 (20) 1.000
Eosinophils (%) 9.47 ± 19.0 3.1 ± 2.8 1.00 Granuloma n (%) 0 (0) 2 (13.3) 0.511
Macrophages (%) 31.2 ± 22.2 20.0 ± 19.6 0.05 Alveolar epithelial cell 8 (88.9) 14 (93.3) 1.000
CD4 (%) 51.2 ± 11.9 32.9 ± 17.9 0.002 * hyperplasia n (%)
CD8 (%) 34.7 ± 9.4 60.8 ± 21.0 0.002 * Severe alveolar epithelial 2 (22.2) 8 (53.3) 0.134
CD4/CD8 ratio 1.7 ± 1.2 0.8 ± 0.9 0.003 * cell hyperplasia n (%)
Giant cell n (%) 0 (0) 6 (40) 0.052
Intra-alveolar macrophage n 1 (11.1) 10 (66.7) 0.013 *
those with summer-type HP. Although there was no significant differ­ (%)
ence in total cell count, in BALF differential cell counts, the increase in The severity of alveolitis and alveolar epithelial cell hyperplasia was classified as
lymphocytes was less for humidifier lung than for summer-type HP − , +, and 2+, and a classification of 2+ was considered severe.
(37.3 ± 20.1% vs 69.0 ± 22.6%, P < 0.001). The neutrophil fraction was
greater for humidifier lung than for summer-type HP (22.1 ± 25.6% vs
8.1 ± 13.6%, P = 0.157). Furthermore, the phenotypes of BAL lym­ Table 5b
phocytes significantly differed. BAL lymphocytes in humidifier lung Treatments and outcome for patients with humidifier lung and summer-type
were predominantly CD4+ lymphocytes, whereas those in summer-type hypersensitivity pneumonitis (HP).
HP were predominantly CD8+ lymphocytes. Thus, the CD4/CD8 ratio Treatment Humidifier lung Summer-type HP p-
was significantly higher for humidifier lung than for summer-type HP (n = 18) (n = 19) value
(1.7 ± 1.2 vs 0.8 ± 0.9, P = 0.003). Corticosteroid use, n (%) 5 (27.8) 15 (78.9) 0.002 *
Initial dose of 8.1 ± 13.8 95.8 ± 245.4 0.012 *
prednisolone (mg/day)
Duration of corticosteroid 4.31 ± 7.1 15.1 ± 24.7 0.007 *
3.6. Pathological findings
use (months)
Recurrence, n (%) 0 (0) 6 (31.6%) 0.043 *
Among the 15 patients with humidifier lung who underwent bron­
choscopy, TBLB was performed in 9 because of worsening respiratory
failure after BAL. The pathological findings of both groups are shown in severe than in summer-type HP.
Table 5a. TBLB specimens from 9 patients with humidifier lung revealed
alveolar septal wall thickening with lymphocyte infiltration (alveolitis) 3.7. Provocation tests
in all patients (Fig. 3). Intra-alveolar organization was observed in 4 of
the 9 patients. No patient had characteristics of epithelioid cell granu­ Nine patients underwent provocation testing with their humidifier; 5
loma. Alveolitis and intra-alveolar macrophage infiltration were less exhibited a positive response. Two hours after exposure to humidifier

4
S. Sakamoto et al.
Fig. 3. Histopathological findings of transbronchial lung biopsy specimen
showing diffuse alveolitis with lymphocytes infiltration and intraalveolar or­
ganization (hematoxylin and eosin; scale bar = 200 μm).
mist, they developed cough, dyspnea, and fever. In addition, serum WBC
and CRP levels increased. In all cases, humidifier avoidance or removal
resulted in resolution of both respiratory symptoms and abnormalities in
blood test results. One patient developed acute respiratory failure and
needed CS treatment after the provocation test. The humidifiers of the 4
patients who did not exhibit a positive response had been cleaned before
the provocation test.
3.8. Treatments and outcomes
The treatments for patients with humidifier lung and summer-type
HP are shown in Table 5b. Among the 18 patients with humidifier
lung, only 5 (29.4%) needed CS treatment. Prednisolone was given at an
initial dose of 0.5 mg/kg, which was decreased gradually. One patient
received methylprednisolone pulse therapy (1000 mg/day, 3 days) for
treatment of severe respiratory failure. Although 1 patient did not
require CS treatment on admission, he developed respiratory failure
after provocation testing and was treated with CS. For the other 13
(72.2%) patients, symptoms and blood test and HRCT findings improved
after humidifier avoidance and never recurred. Among patients with
summer-type HP, 15 (78.9%) needed CS treatment and 4 improved
without CS, after moving to a new home. Therefore, CS treatment was
more frequent and longer for summer-type HP than for humidifier lung
(78.9 vs 27.8%; P = 0.002).
4. Discussion
The pathogenesis of humidifier lung and other types of HP is believed
to be similar. Type III and type IV hypersensitivity reactions to bacteria
and/or fungal antigens are involved; however, previous studies found
that the type IV hypersensitivity reaction was more important [1,13].
Persons with humidifier lung sometimes have detectable specific
immune-mediated reactions, such as precipitating antibodies and pro­
liferation of lymphocytes against humidifier water. The present findings
suggest characteristic clinical and radiological differences between hu­
midifier lung and summer-type HP. These differences might depend on
the nature or amount of inhaled causative antigens and the duration of
inhalation.
Summer-type HP seems to be caused by continuous exposure to a
small amount of fungal antigens. In contrast, patients with humidifier
lung may develop pulmonary and systemic symptoms after direct
exposure to a large amount of highly antigenic particles, such as bacteria
5
Respiratory Medicine 174 (2020) 106196
and fungi and/or endotoxins, while using humidifiers with highly
polluted water. The pathophysiology of humidifier lung may thus
encompass not only hypersensitivity reactions as HP but also lung injury
caused by endotoxins. Gram-negative bacteria and their associated en­
dotoxins may be involved in the pathogenesis of humidifier lung, as the
humidifier water contains high levels of endotoxins [14–17]. Endotoxins
are an extremely potent agent of lung injury, and endotoxin inhalation
can cause pulmonary and systemic symptoms by inducing inflammatory
cytokines such as interleukin-1 and tumor necrosis factor-alpha, in
addition to increases in neutrophils as well as lymphocytes in BALF and
peripheral blood [18,19]. Recent studies reported considerable inter­
individual variability in endotoxin responsiveness. This variability de­
pends on polymorphisms in genes encoding proinflammatory cytokines
and the LPS receptor CD14 in humans, and the Toll-like receptor.
Variability in endotoxin sensitivity may contribute to differences in
clinical and radiological features among patients with humidifier lung
[20–23].
Some of the present patients with humidifier lung had unusual
findings, as compared with summer-type HP. Chest HRCT scans showed
bilateral ground-glass opacities and/or consolidation, without cen­
trilobular ground-glass micronodules, in humidifier lung. In contrast,
summer-type HP was generally associated with diffuse ground-glass
opacities and poorly defined micronodules, predominantly in the mid­
dle to lower lungs [2,3]. Furthermore, some patients with humidifier
lung exhibited peribronchovascular or subpleural nonsegmental
consolidation, an unusual finding for acute or subacute summer-type HP
[24]. Consolidation on chest HRCT might be attributable to strong in­
flammatory reactions, including lung injury due to exposure to high
levels of antigen and/or endotoxin.
Serum KL-6 levels were not elevated during the clinical course of
most patients with humidifier lung. Increases in serum KL-6 and SP-D
are thought to be a hallmark of summer-type HP and farmers’ lung [2,
3,25]. However, serum SP-D level was elevated in almost all patients
with humidifier lung. In summer-type HP, prolonged low-level antigen
exposure leads to subacute or chronic disease and, ultimately, to type IV
allergy. Chronic inflammation causes alveolar fibrosis due to lympho­
cyte infiltration, formation of epithelioid granulomas, and activation of
fibroblasts. As fibrosis insidiously progresses, serum levels of interstitial
lung disease markers such as KL-6 and SP-D increase and diffusion ca­
pacity decreases. In contrast, because a large amount of antigen is
inhaled during a short period of time in humidifier lung, onset of
symptoms was early and many did not develop pulmonary fibrosis.
Thus, increases in serum KL-6 and SP-D levels were lower for humidifier
lung than for summer-type HP.
Many studies have examined the surface phenotypes of BAL lym­
phocytes in HP. Most HP patients exhibit an increase in BAL T lym­
phocytes, which are predominantly CD8+ lymphocytes, thus decreasing
the CD4/CD8 ratio. However, the CD4/CD8 ratio is higher in farmers’
lung, which indicates that BAL lymphocyte phenotypes may depend on
the type of HP [2,3,11,26–28]. Few studies of humidifier lung evaluated
the phenotypes of BAL lymphocytes [3,11]. Suda et al. reported that the
CD4/CD8 ratio was significantly higher for humidifier lung than for
summer-type HP, which is consistent with our results [11]. Furthermore,
the increase in the BALF neutrophil fraction was greater than that for
summer-type HP. The reasons for these differences in WBC fractions and
phenotypes of BAL lymphocytes in HP are unclear. As mentioned above,
the nature or amount of inhaled causative antigens and endotoxins may
explain these findings.
4.1. 4.1Limitations
This was a single-center retrospective study with a small sample size.
A large-scale multicenter study is needed in order to confirm the present
clinical and radiological characteristics of humidifier lung.
S. Sakamoto et al.
5. Conclusion
The clinical and radiologic findings of humidifier lung differed from
those of summer-type HP. Humidifier lung is sometimes difficult to di­
agnose as HP. Rapid diagnosis depends on obtaining a detailed envi­
ronmental history.
Credit author statement
Susumu Sakamoto: served as principal author and had access to, and
takes responsibility for the integrity of, the data and the accuracy of the
data analysis. Susumu Sakamoto and Sakae Homma contributed to the
design of the study; Susumu Sakamoto, Marie Furukawa, Shigehiro
Shimizu, Takuma Isshiki, Yujiro Takai, Yusuke Usui, Kazuma Kishi,
Naohisa Urabe, Muneyuki Sekiya, Shion Miyoshi, and Kazutoshi Isobe
contributed to data collection; Susumu Sakamoto, Takuma Isshiki,
Yasuhiko Nakamura and Sakae Homma contributed to interpretation of
the study; Susumu Sakamoto, Marie Furukawa, Takuma Isshiki and
Sakae Homma contributed to the study analysis; and Atsuko Kurosaki,
Susumu Sakamoto, Takuma Isshiki, Yusuke Usui, Yasuhiko Nakamura
and Sakae Homma contributed to evaluation of HRCT images. All au­
thors 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.
Funding/support statement
None.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
We thank David Kipler, ELS, for reviewing the language of the
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 Intrac­
table Disease.
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