Shinshu Med J, 71⑷：235～240, 2023

Nonfibrotic Hypersensitivity Pneumonitis Complicatedby Chronic Progressive Pulmonary Aspergillosis : A Case Report
Risa Kanayama, Yosuke Wada＊, Kazunari Tateishi, Yoshiaki Kitaguchi
Atsuhito Ushiki and Masayuki Hanaoka
First Department of Internal Medicine, Shinshu University School of Medicine

Diagnosis of chronic pulmonary aspergillosis in patients with nonfibrotic hypersensitivity pneumonitis is dif­ficult, especially after treatment with systemic corticosteroids has been initiated. Therefore, treatment for chronic
progressive pulmonary aspergillosis (CPPA) is often delayed. Although the chief complaint of non-fibrotic hyper­
sensitivity pneumonitis complicated by pulmonary aspergillosis is often fever, the fungus cannot be identified,even after repeated sputum culture tests. Herein, we report a case of pulmonary aspergillosis that developed
after initiating treatment with systemic corticosteroids and was difficult to diagnose. The patient had a feverthat continued after the introduction of steroids. CPPA was eventually diagnosed based on histopathologicalexamination of a bronchoscopy sample. When CPPA is suspected in patients with hypersensitivity pneumonitis,
bronchoscopy may improve their prognosis. Shinshu Med J 71 : 235―240, 2023
(Received for publication March 3, 2023 ; accepted in revised form March 30, 2023)
Key words : bronchoscopy, nonfibrotic hypersensitivity pneumonitis,
chronic progressive pulmonary aspergillosis, chronic cavitary pulmonary aspergillosis, voriconazole

Herein, we describe the clinical course of a patient

Ⅰ Introduction

with severe nonfibrotic HP complicated by CPPA

Hypersensitivity pneumonitis (HP) is a chronic lungand the response to treatment including intensive

disease of variable severity, clinical presentation, andcare, systemic corticosteroids, and antifungal drugs.

1）

natural history . Based on the presence or absenceof fibrosis on imaging or histopathologic examination,Ⅱ

Case Report

HP is classified as nonfibrotic (inflammatory only) or

A 78-year-old man was referred to our hospital

fibrotic (mixed inflammatory and fibrotic or fibrotic

due to dry cough for 8 months. Apart from the med­

2）only) . In humid environments, fungi, particularly

ical history of prostate cancer and postoperative right3）

Penicillium spp. and Aspergillus spp., can cause HP .

common iliac artery aneurysm, he was an otherwise

Not only fungi can cause HP, but fungal growth inhealthy non-smoker. He lived in a 40-year-old wood­

the lungs of patients with HP, manifesting as chronicen house, and had built a wooden hut on his property

progressive pulmonary aspergillosis (CPPA) is a rare

2 years previously, in which he grew plants. He had

4）

but serious complication . CPPA can occur as a com­

no history of keeping birds, and there were no bird

plication in patients with HP and prolonged systemic

nests around his residence. He had no history of5）

corticosteroid use .

drug allergies. Chest computed tomography (CT) re­vealed faint graund-glass opacities (GGO) in both＊

Corresponding author : Yosuke WadaFirst Department of Internal Medicine,
Shinshu University School of Medicine,
3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : yosuke@shinshu-u.ac.jp

No. 4, 2023

lungs (Fig. 1A, B). 148 days before this hospitaliza­
tion, bronchoalveolar lavage (BAL) was performed
during bronchoscopy of the right middle lobe of thelung for diagnosis. The lymphocyte percentage in the235Kanayama・Wada・Tateishi et al.

BAL fluid (BALF) was 79.0 ％ , which is consistent

growing foliage plants was suspected to be the cause,with the BALF in HP. The BALF CD4/8 ratio wasand his doctor advised him not to use it. Subsequent­as high as 14.73, indicating that home-related hyper­ly, 79 days before this hospitalization, he developed asensitivity pneumonitis was more likely than otherfever and was readmitted to our hospital as his sec­

types of hypersensitivity pneumonitis, such as sum­ond hospitalization. He was started on prednisolone

mer-type hypersensitivity pneumonitis. Suspecting(PSL) 60 mg/day for flare-ups of nonfibrotic HP. A

home-related HP, the mold in his residence was re­chest CT scan taken after the initiation of PSL treat­

moved. No inhalation antigens associated with sum­ment showed improvement of the GGO in both lungmer-type hypersensitivity pneumonitis, bird fancierʼsfields (Fig. 1E, F). After discharge the PSL dose waslung, or humidifier lung were identified during thetapered to 15 mg/day. Although PSL-based pharma­

patientʼs interview. Nevertheless, 133 days before

cotherapy temporarily reduced GGO in both lungs,

this hospitalization, he was temporarily readmitted tohe visited our hospital because of fever and dyspnea,

our department with suspected worsened HP as his

was diagnosed with recurrence of nonfibrotic HP,

first hospitalization. CT showed worsening GGO in

and was urgently re-admitted to our department

both lungs (Fig. 1C, D). After hospitalisation his non­(hospital day 1). On admission, his body temperature

fibrotic HP improved without treatment, and he waswas 38.6 °C and his oxygen saturation (SpO2) was

discharged. The hut on his premises intended for

77 ％ on room air. Physical examination revealed fineFig. 1 Chest computed tomography (CT) over the clinical course of the patient’s disease. Figures A, C, E and G arecross-sectional CT images at the level of the carina trachea. Figures B, D, F and H are cross-sectional CT
images at the level of the diaphragm. Figures A and B are CT images taken on June 3 (148 days prior to theadmission). A : CT image showing segmental ground-glass opacities (GGO) in both upper lobes ; B : CT image
showing GGO in both lower lobes. Figures C and D are CT images taken on August 11 (79 days prior to theadmission). C : CT image showing increased concentrations of GGO in the dorsal upper lobes of both
lungs ; D : CT image showing posterior consolidation with air bronchograms in the posterior segments of thelower lobes of both lungs. Figures E and F are CT images taken on October 1 (28 days prior to this admis­sion). E : CT image showing disappearance of the GGO in the upper lobes of both lungs ; F : CT image show­
ing disappearance of the GGO in the lower lobes of both lungs. Figures G and H are CT images taken on
October 29 (hospital day 1). G : CT image showing worsening of the GGO in both upper lobes and dorsum of
the lungs ; H : CT image showing worsening of the dorsal GGO and the GGO in the lower lobes of the lungs.
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Nonfibrotic hypersensitivity pneumonitis with pulmonary aspergillosis
Table 1

Laboratory test results on admission

Parameter

ResultReference Range

Hematology
White blood cell count (/μL)
Neutrophil count (/μL)
Hemoglobin (g/dL)
Platelet count (×104/μL)

4210
3500
13.0

3300-8600
1170-6130
11.6-14.8

6.4

15.8-34.8

5.1
2.9
32.5
1.41
37
29
352
1.43
46
98.0
5.14
4304
586
0.99
2.2

6.6-8.1
4.1-5.1
8.0-20.0
0.65-1.07
13-30
10-42
124-2220.40-1.50
13-64
0-20
0.00-0.14
105-435

Blood chemistry
Total protein (g/dL)
Albumin (g/dL)
Blood urea nitrogen (mg/dL)
Creatinine (mg/dL)
AST (U/L)
ALT (U/L)LDH (U/L)
Total bilirubin (mg/dL)
γ-Glutamyl transferase (U/L)
BNP (pg/mL)
C-reactive protein (mg/dL)
KL-6 (U/mL)
SP-D (ng/mL)
PT-INR
D-dimer (μg/mL)
Serology
Rheumatoid factor
Beta-D-glucan
Aspergillus antigen
Aspergillus antibody
Arterial blood gas (FiO2 0.5)

pH
PaCO2 (Torr)

0.85-1.15
0.0-1.0

Negative
Negative
Negative
Negative
7.445

7.340-7.450

29.3

32.0-45.0

PaO2 (Torr)

78.0

75.0-100.0

19.8

22.0-28.0

PaO2/FiO2 ratio

156

HCO3− (mmol/L)

ALT, alanine aminotransferase ; AST, aspartate aminotransferase ; BNP, Brain Natriuretic Peptide ;SP-D, surfactant protein D ; FiO2 , inspired oxygen fraction ; KL-6, Krebs von den Lungen-6 ; LDH,

lactate dehydrogenase ; PaCO2 , partial pressure of arterial carbon dioxide ; PaO2 , partial pressureof arterial oxygen ; PT-INR, prothrombin time-international normalised ratio.

crackles in both lower lungs. Blood tests showed

Considering the recurrence of nonfibrotic HP, ste-thrombocytopenia (64,000/μL) and elevated levels ofroid pulse therapy (intravenous methylprednisolone

blood urea nitrogen (BUN, 32.5 mg/dL), creatinine

1,000 mg/day for 3 days), followed by an increase in(1.41 mg/dL), C-reactive protein (CRP, 5.14 mg/dL),oral PSL administration to 60 mg/day, was initiated.

Krebs von den Lungen-6 (KL-6, 4304 U/mL), andHe required a high-flow nasal system for several days

lactate dehydrogenase (LDH, 352 U/L) (Table 1). As-

after starting treatment but was able to reduce his

pergillus antigen and antibody tests results were

oxygen requirements to 2 L/minute by nasal cannulaboth negative, and his beta-D-glucan level was with-on hospital day 5. Unfortunately, on hospital day 29,

in the normal range. Chest CT showed further dete-

he developed sepsis due to Streptococcus sanginus,

rioration of the GGO and consolidation (Fig. 1G, H).

probably due to dental caries, and an intravenous Sul-

No. 4, 2023

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Kanayama・Wada・Tateishi et al.

bactam / Ampicillin was started. On hospital day 38,

administer oral voriconazole owing to difficulties ina CT scan revealed a new cavitary nodule at the apex

establishing intravenous access. A CT scan per­of the right lung (Fig. 2A, B). A complex fungal in­formed on hospital day 97 showed shrinkage of thefection was suspected and micafungin was adminis­right apical cavitary nodule (Fig. 2C). Although his

tered intravenously ; however, his fever did not subside.

pulmonary aspergillosis improved, his physicalA blood sample on hospital day 60 was positive forstrength gradually declined during his long hospital

Aspergillus antigen. On hospital day 77, bronchoscopy

stay, and he was transferred to another hospital for

was performed because of suspected worsening of his

rehabilitation.

pulmonary aspergillosis, and a transbronchial lung biop­
sy was obtained from the upper lobe of the right lung.

Ⅲ

Discussion

The biopsy specimens showed numerous hyphae,

Herein, we describe a case of pulmonary aspergil­

consistent with pulmonary aspergillosis (Fig. 3). A

losis that worsened after the beginning of systemic

culture with bronchial lavage fluid was negative ;

corticosteroids treatment for HP. PSL 0.5-1 mg/kg/

therefore, antifungal drugs were considered effective.

day corticosteroids have been shown to be effective

Based on the serologic findings of Aspergillus antigen

for nonfibrotic hypersensitivity pneumonitis that re­conversion and the transbronchial lung biopsy find­curs despite efforts to avoid inhalation antigens ; thisings, the diagnosis of CPPA was made. After thepatient was also at risk of respiratory failure and was

bronchoscopy, the antifungal drug was changed fromstarted on PSL 60 mg/day (1 mg/kg/day)6）7）. After

intravenous micafungin to oral voriconazole and his

the oral administration of PSL was started, PSL wasfever improved. Intravenous voriconazole was con­gradually tapered to 15 mg/day at a relatively rapid

sidered as an alternative ; however, we decided topace because CT showed rapid improvement in

Fig. 2 The clinical course according to the day of hospitalisation. Chest computed tomography (CT) showing
progression of ground-glass opacities with cavitation (A, B). CT after starting voriconazole showing a reduc­tion in the size of the abnormal opacities (C).
 CTRX, ceftriaxone ; MEPM, meropenem ; MCFG, micafungin ; mPSL, methylprednisolone ; SBT/ABPC, sul­
bactam, ampicillin ; VRCZ, voriconazole.
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Nonfibrotic hypersensitivity pneumonitis with pulmonary aspergillosis

Fig. 3 Histopathology of a bronchoscopy biopsy specimen of the upper lobe of the right lung collected bytransbronchial biopsy showing numerous hyphae, consistent with pulmonary aspergillosis. Thin, septate
hyphae with regular branching can be seen in each section (arrows). A : Hematoxylin and eosin stain(×40) ; B : Grocott stain (×60).

pulmonary GGO. The patient had repeated exacerba­

antigens to confirm seroconversion is important intions of HP and developed CPPA after the dose ofdetermining the appropriate timing of bronchoscopy.

steroids was increased. Long-term steroid use is a

When pulmonary aspergillosis is suspected, timely

risk factor for pulmonary aspergillosis. Other risk

bronchoscopy is key to obtaining a correct diagnosis.

factors include diabetes mellitus, malnutrition, alco­

Patients with HP and chronic pulmonary aspergillo­

8）holism, and advanced age . To accomplish steroid

sis often have decreased physical strength, and at­dose reduction, it is essential to concentrate on thetending physicians are often reluctant to perform

avoidance of hypersensitivity pneumonitis recurrence.

bronchoscopy. Repeated Aspergillus antigen testing

If the causative antigen is presumed to be present into confirm positive conversion is an alternative if

the house or residential environment, as in this case,bronchoscopy is unavailable. Antibiotics and antifun­

measures such as relocation or deep cleaning are

gal drugs are frequently administered at an earlyrequired to prevent the recurrence of hypersensitivi­stage to severely immunocompromised patients withty pneumonitis.

fungal infections, and it is often difficult to determine

A positive serum Aspergillus immunoglobulin G

the cause of fever. Even if a fungus cannot be identi­(IgG) antibody test is important for the diagnosis offied on culture, as in this case, a definitive diagnosis

9）

CPPA . In Japan, Aspergillus antigen tests, which

can be made based on a bronchoscopy biopsy.

are covered by national health insurance, are often

In this case, even after beginning the intravenous

used as an alternative to Aspergillus IgG antibody

infusion of micafungin, the aspergilloma opacity wors­

tests. However, in this case, the Aspergillus antigen

ened, and the patient’s condition only improved after

and antibody test results on admission were nega­

switching to voriconazole. Micafungin or voriconazole

tive. After recognizing that the Aspergillus antigen

should only be used in severely ill patients who do nottest had changed to positive, a bronchoscopy was per­respond to other azole therapy, such as itraconazole10）11）.

formed, and following a confirming diagnosis, the med­

However, intravenous antifungal drugs are required

ication was changed from micafungin to voriconazole.

in patients with severe disease. Micafungin infusion

This case suggests that retesting for Aspergillus

has fewer side effects than voriconazole infusion, andNo. 4, 2023

239

Kanayama・Wada・Tateishi et al.

the response rates are similar9）. In this case, intrave­

diagnosing CPPA in a patient with HP, a re-exami­

nous micafungin and oral voriconazole did not cause

nation of Aspergillus antigens can help, and a broncho­

any significant side effects, and after switching

scopy that looks for tissue diagnosis may improveto oral voriconazole, the patient’s fever and cavi­

the prognosis.

tary nodule were reduced. Oral administration of

Acknowledgements

voriconazole may be effective as an initial treatment

We thank the patient, and the nurses and otherin patients with severe Aspergillus infections who

clinical staff who provided intensive care to the pa­

can take oral medications, as in this case.
In summary, we have described the clinical courseof severe nonfibrotic HP complicated by CPPA. Whentient. We would like to thank Editage (www.editage.
com) for English language editing.

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