Full text of DOI:10.1016/S1081-1206(10)62018-2

Trichosporon asahii-induced asthma in a family
with Japanese summer-type hypersensitivity
pneumonitis
Yoichi Hirakata, MD; Tomoko Katoh, MD; Yoshiki Ishii, MD; Satoshi Kitamura, MD; and
Yukihiko Sugiyama, MD
Background: Trichosporon species frequently induce summer-type hypersensi-
tivity pneumonitis (SHP), which is the most prevalent type of hypersensitivity
pneumonitis (HP) in Japan, but have not been reported to induce asthma.
Objective: Evaluation of a case of asthma induced by Trichosporon asahii.
Methods and Results: This report describes a 46-year-old Japanese man who
developed asthma induced by T. asahii, following symptoms of HP attributable to
the same pathogen, in a case of familial occurrence of SHP. This patient lacked
typical findings of HP in his radiograph but had an elevated level of eosinophils in
his bronchoalveolar lavage fluid. Open lung biopsy, however, revealed typical
pathologic findings of HP when he was free of asthmatic symptoms. His serum was
also positive for anti-T. asahii antibody, as are the sera of SHP patients. Neverthe-
less, provocation tests, including returning home and inhalations of T. asahii
antigen, reproduced asthmatic features such as airway hyperresponsiveness and
reversible bronchoobstruction, but not the features of HP. A skin test with the same
antigen also evoked an immediate allergic reaction. An IgE mechanism was sus-
pected but could not be proven by radioallergosorbent test. The patient’s son and
daughter displayed typical features of SHP, associated with compatible results in
their radiographs, bronchoalveolar lavage fluid analysis, serologic and pathologic
examinations, and provocation and skin tests.
agnosis of SHP was made in accor-
dance with the diagnostic criteria of
the Research Committee on Diffuse
Pulmonary Disease organized by the
7
Japanese Ministry of Welfare. Table 1
shows the symptoms and the serum
antibody activities against T. mucoides
TIMM 1573 (formerly T. cutaneum se-
rotype I) and T. asahii TIMM 1318
(
formerly T. cutaneum serotype II) an-
tigens for patient 1 and his family
members, including patients 2 and 3.
The antibodies in serum were detected
by the indirect fluorescent antibody
method (titers of 32ϫ or more were
2,7
considered positive).
Patient 1 was a 46-year-old male
farmer who was an ex-smoker and had
no previous history of allergic rhinitis
or asthma. In late July 1994, patient 1
experienced the insidious onset of a
cough with yellowish sputum; he felt
feverish and experienced general fa-
tigue. The symptoms repeatedly sub-
sided and recurred over a 1-month pe-
riod. On August 30, 1994, he
experienced shortness of breath and
was later admitted to our hospital when
asthmatic symptoms recurred on Octo-
ber 19.
Conclusions: To our knowledge, this is the first case of extrinsic asthma, and of
coexistent asthma and HP, induced by T. asahii. The patient initially displayed
symptoms typical of SHP, which were subsequently replaced by more typical
asthmatic symptoms.
Ann Allergy Asthma Immunol 2002;88:335–338.
INTRODUCTION
portant Trichosporon species, as they
Summer-type hypersensitivity pneu-
monitis (SHP), which is caused by the
inhalation of Trichosporon species
during the muggy summers after the
rainy season, is the most prevalent type
of hypersensitivity pneumonitis (HP)
in Japan and has also recently been
found in other Asian countries. Tri-
chosporon asahii and Trichosporon
mucoides (formerly termed Trichos-
poron cutaneum serotypes II and I, re-
spectively) are the most clinically im-
cause both SHP and deep-seated infec-
4
–6
tion. We report here the first case of
extrinsic asthma induced by T. asahii.
The asthmatic features in this patient ap-
peared following typical symptoms of
HP because of exposure to the same
pathogen over a period of several weeks.
This patient was a member of a family
with familial occurrence of SHP in Japan
caused by Trichosporon. Only 1 of the 3
patients in this family exhibited asth-
matic features on admission and exhib-
ited typical pathologic findings of HP
when he was asymptomatic of asthma.
Physical examination showed only
diffuse wheezing. Laboratory studies
9
showed: leukocyte count, 6.8 ϫ 10 /L,
1
–3
with 7.0% eosinophils; C-reactive pro-
tein, 0.221 mg/dL; erythrocyte sedi-
mentation rate, 25 mm in the first hour;
hepatic and renal function test results,
normal. The total serum level of im-
munoglobulin (Ig)E was normal at 15
U/mL. Arterial blood gas analysis in
Department of Pulmonary Medicine, Jichi Med-
ical School, Minamikawachi, Tochigi, Japan.
Received for publication August 23, 2001.
Accepted for publication in revised form Octo-
ber 17, 2001.
room air showed pH 7.465, PaO 65.6
2
CASE REPORTS
We examined a family living together
in an 18-year-old wooden house. Di-
mm Hg, and PaCO 37.1 mm Hg. Pul-
2
monary function testing showed per-
centage of vital capacity was 86.5%,
VOLUME 88, MARCH, 2002
335

Table 1. Symptoms on Admission, and Anti-Trichosporon Antibody Activities of the Patients and an Asymptomatic Family Member
Anti-Trichosporon antibodies
Subject
Sex
Age
Symptoms on admission
T. asahii TIMM1318
T. mucoides TIMM1573
Patient 1
Patient 2 (son of patient 1)
Patient 3 (daughter of patient 1)
Asymptomatic family member
Male
Male
Female
Female
46
17
21
43
shortness of breath, stridor
fever, cough, sputum
fever, cough, sputum
none
ϫ 64
ϫ 64
ϫ 256
ϫ 8
ϫ 8
ϫ 64
ϫ 64
ϫ 8
(wife of patient 1)
percentage of forced expiratory vol-
asthmatic symptoms but not the HP
symptoms. An inhalation test and a
sulfate. In the second inhalation test,
ume in 1 second (FEV ) 30.2%, and
%FEV was monitored, and decreased
1
1
2
,7
percentage of diffusing capacity of
lung for carbon monoxide 70.8%, in-
dicating obstructive respiratory dys-
function. Neither x-ray nor thoracic
computed tomography showed typical
findings of HP. The bronchoalveolar
lavage fluid (BALF) exhibited an ex-
tremely high percentage of eosino-
phils, a slightly elevated percentage of
lymphocytes, and a decreased CD4/
CD8 ratio when the patient displayed
the symptoms of asthma (Table 2).
The symptoms and signs subsided on
the second day and disappeared on the
third day of hospitalization. Open bi-
opsy of the lung was performed when
the patient was asymptomatic 1 week
after the last asthma attack. Tissue sec-
tions were stained with hematoxylin
and eosin. Microscopic examination of
the sections revealed diffuse focal non-
foamy histiocytes associated with al-
veolar and interstitial infiltration of
plasma cells. Giant cells and Masson
bodies, typical findings of HP, were
also observed. Fungal cultures of
sputum, BALF, and material from
the lung biopsy were negative. Se-
rum anti-Aspergillus fumigatus anti-
body was negative.
skin test were administered to patient
1 to determine whether provocation
produced immediate, late, or both
kinds of allergic reaction. First, patient
1 inhaled a total of 2.0 mg of T. asahii
TIMM1318 antigen (0.2 mg/mL). This
is widely used as the standard method
for inhalation challenge and skin tests
to diagnose SHP attributable to T. asa-
in value from 46.5% to 28.7% 30 min-
utes after the challenge. Respiratory
resistance also increased from 3.2 to
4.8 cm H O/L/second during the same
2
time period. After the inhalation of or-
ciprenaline sulfate, %FEV and the re-
1
spiratory resistance improved to the
initial levels, indicating airway hyper-
responsiveness and reversible bron-
choobstruction. Over the 48-hour pe-
riod after the asthmatic symptoms had
improved, no cough or fever were ob-
served in either (2 and 20 mg antigen)
inhalation test. There was also no in-
crease in peripheral leukocytes and no
elevation of C-reactive protein. A skin
test involving intradermal injection of
0.02 mL of a 1-mg/mL solution of
culture-filtrate antigen of T. asahii
TIMM1318 was performed. Reactions
7
hii in Japan. The culture-filtrate anti-
gen was prepared by the double dialy-
8
sis method of Edwards, and the
lyophilized crude antigen was dis-
solved in sterile phosphate-buffered
saline at a concentration of 10 mg/
2
,7
mL. The antigen was used after ap-
propriate dilution in sterile phosphate-
buffered saline. During the next 48
hours, symptoms and signs were re-
corded, and body temperature, periph-
eral leukocytes, and C-reactive protein
were measured. One week later, the
patient inhaled 20 mg of culture-fil-
trate antigen (2 mg/mL). In both inha-
lation tests, the patient complained of a
sore throat just after inhalation; short-
ness of breath with stridor occurred 15
minutes after the beginning of the in-
halation, suggesting that an immediate
reaction had occurred. Diffuse wheez-
ing became audible in the lung fields.
The symptoms and wheezing resolved
after the patient inhaled orciprenaline
2
with indurations of 100 mm or larger
7
were considered to be positive. The
skin test was positive 15 minutes after
2
provocation (234-mm diameter). The
induration 3 hours after challenge di-
2
minished to 91 mm and then enlarged
2
to 120 mm 6 hours after the challenge.
The indurations 12, 24, and 36 hours
after provocation were 513, 1,140, and
2
600 mm , respectively. The results
A provocation test consisting of the
return of the patient to his home was
positive for causing recurrence of the
demonstrated that immediate, late, and
delayed allergic reactions all occurred.
Specific IgE levels against T. asahii
Table 2. BALF Findings of the Patients
Total cell
number
%
%
%
%
CD4/CD8
ratio
Subject
macrophages
lymphocytes
neutrophils
eosinophils
Patient 1, with symptoms
Patient 1, without symptoms
Patient 2
5.5 ϫ 106
2.1 ϫ 10
3.3 ϫ 106
2.4 ϫ 106
47.0
79.0
13.0
15.6
12.0
8.0
79.0
83.9
0.0
3.0
2.0
0.0
41.0
10.0
6.0
0.50
ND
0.38
0.19
6
Patient 3
0.5
ND, not done.
3
36
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

TIMM 1318 and other mold antigens
were measured by radioallergosorbent
test (RAST) using a capsulated hydro-
philic carrier polymer (Pharmacia,
the house was found to be damp and
dusty, especially in the room of patient
2. Decayed wood was observed in the
bathroom, kitchen, and dining room.
in this patient were IgE-mediated, but
we could not prove this because the
RAST failed to detect the specific IgE
in serum and BALF. However, the sen-
sitivity of RAST was probably too low
because the crude antigen used for
RAST was not IgE-specific. In addi-
tion, it is a general finding that RAST
has high specificity, but lower sensi-
9
Uppsala, Sweden) system. For this
study, capsulated hydrophilic carrier
polymer was newly produced by the
coating of freeze-dried T. asahii
TIMM 1318 cells (Pharmacia). RAST
values were arbitrarily classified into
categories corresponding to those used
for the Phadebas RAST system (Phar-
macia). Specific IgE against T. asahii
TIMM 1318 was not detected in the
serum or BALF of patient 1 in this
study. IgE RAST for house dust, Der-
matophagoides pteronyssinus, Der-
matophagoides farinae, Penicillium
notatum, Cladosporidium herbarum,
A. fumigatus, and Candida albicans
were also all negative in patient 1.
Patients 2 and 3, who were the 17-
year-old son and 21-year-old daughter
of patient 1, experienced fever, cough,
and yellowish sputa during the summer
of 1994 and were admitted to our hos-
pital on September 7 and October 26,
DISCUSSION
It is well known that inhalation of di-
isocyanates can produce the features of
1
0–12
both asthma and HP.
A case of a
1
6
farmer with coexistent HP and extrin-
tivity than the provocation test. In
particular, RAST has been considered
to be less sensitive than the skin test
1
3
sic asthma has also been reported.
However, it is generally recognized
that asthma is an unusual concomitant
1
7
for mold antigens. It is also possible
that an IgG antibody (most likely
1
4
of HP. Further, SHP patients have
normal IgE levels, eosinophilia is usu-
ally absent, and the incidence of SHP
is not higher in atopic than in nona-
1
8
IgG4)-mediated immediate response
to Trichosporon was involved.
Patients with mild cases of HP
sometimes have normal chest x-rays,
and the chronic form of HP may show
relatively mild symptoms in response
to natural or bronchial inhalation chal-
1
5
topic patients. In SHP patients, the
inhalation test with 15 mg of Trichos-
poron antigen generally produces
symptoms and signs that appear 4 to 6
hours after the challenge and subside 2
to 6 hours thereafter, whereas an im-
mediate allergic reaction has not been
1
9
lenges with the offending antigens.
Further, it has been reported that even
high-resolution computed tomography
did not reveal abnormal findings in 6
of 11 HP patients who were swimming
7
reported hitherto in SHP patients. The
time course of the skin test response is
identical to that of the symptoms and
2
0
pool employees. Therefore, it is pos-
sible that patient 1 developed sponta-
neous chronic SHP after the recurrence
of typical SHP and showed no typical
findings in radiographs, and that spe-
cific IgE against T. asahii was pro-
duced during the repeated natural in-
halation. Allergic bronchopulmonary
fungosis was also suspected but ruled
out because the radiographs of the pa-
tient lacked central bronchiectasis,
which is thought to be the most spe-
cific finding for allergic bronchopul-
monary aspergillosis according to the
7
1
994, respectively. The total IgE levels
signs that appear after inhalation.
in patients 2 and 3 were 48 and 154
U/mL, respectively. The serum of pa-
tient 2 showed high RAST values for
house dust (14.16 Ua/mL), D. pteron-
yssinus (13.73 Ua/mL), and D. farinae
An immediate asthma-type reaction
attributable to inhalation of T. asahii
occurred in the Japanese farmer de-
scribed here (patient 1) during the
summer, when two of his children liv-
ing in the same house experienced typ-
ical SHP. Patient 1 initially displayed
symptoms typical of SHP, which re-
curred and subsided over a period of
several weeks, and were then replaced
by more typical asthmatic symptoms.
The patient had obvious wheezing and
had 7% eosinophils in his blood when
he arrived at our hospital and also
showed an elevated percentage of eo-
sinophils in his BALF, in line with
diagnosis of asthma. The asthmatic
symptoms recurred upon the inhalation
of the T. asahii antigen widely used in
standard sensitivity tests for the diag-
nosis of SHP and by the returning-
home test. A skin test also showed an
immediate allergic reaction to this an-
tigen. To our knowledge, extrinsic
asthma induced by T. asahii has not
been reported. We suspect that the
asthma and the immediate allergic re-
actions in the inhalation and skin tests
(
9.05 Ua/mL). Both patients 2 and 3
improved a few days after admission
without any medication. Typical find-
ings of SHP were observed in the ra-
diographs, anti-Trichosporon antibody
assays (Table 1), BALF (Table 2), and
pathologic examinations of the trans-
bronchial lung biopsy materials of
these patients. Upon the provocation
test consisting of returning home, both
patients were positive for recurrence of
the features of HP. They were negative
for an immediate allergic reaction
against T. asahii by the skin test per-
formed as described above.
2
1
diagnostic criteria of Rosenberg et al.
HLA-DQw3 antigens are frequently
2
2
detected in SHP patients. This sug-
gests that the susceptibility of hosts to
the antigens inducing HP may be ge-
netically controlled. In our study, how-
ever, HLA-DQw3 was not detected in
the patients (data not shown). Addi-
tionally, we found no HLA antigen
specific to the wife, suggesting that she
did not have a genetically specified
resistant phenotype (data not shown).
The other family member, the wife
of patient 1, was negative for anti-
Trichosporon antibodies and had no
symptoms during the summer season.
Environmental examination was per-
formed in October 1994. Although no
live Trichosopron species were iso-
lated from their house environment,
ACKNOWLEDGMENTS
We thank Professor Masayuki Ando,
and Drs. Kazuko Arima and Yuriko
VOLUME 88, MARCH, 2002
337

Nishiura of the First Department of
Internal Medicine, Kumamoto Univer-
sity Medical School, for their generos-
ity in providing T. asahii TIMM 1318
antigen, and for kindly measuring anti-
Trichosporon antibodies activity.
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ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY