clinicopathological features of chronic hypersensitivity pneumonitis
TRANSCRIPT
ORIGINAL ARTICLE
Clinicopathological features of chronic hypersensitivity pneumonitis
H HAYAKAWA,1 M SHIRAI,1 A SATO,2 Y YOSHIZAWA,3 A TODATE,4
S IMOKAWA,4 T SUDA,4 K CHIDA,4 R TAMURA,5 K ISHIHARA,6
S SAIKI7 AND M ANDO8
1Department of Internal Medicine, National Tenryu Hospital, Hamakita, 2Kyoto Preventive Center, Kyoto,3Department of Pulmonary Medicine, Tokyo Medical and Dental University, Tokyo, 4Second Department
of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, 5Department ofPulmonary Medicine, Fujieda Municipal Hospital, Fujieda, 6Department of Respiratory Disease, Kobe City
General Hospital, Kobe, 7Department of Pathology, St. Luke’s International Hospital, Tokyo, 8FirstDepartment of Internal Medicine, Kumamoto University School of Medicine, Kumamoto, Japan
Clinicopathological features of chronic hypersensitivity pneumonitisHAYAKAWA H, SHIRAI M, SATO A, YOSHIZAWA Y, TODATE A, IMOKAWA S, SUDA T, CHIDA K,TAMURA R, ISHIHARA K, SAIKI S, ANDO M. Respirology 2002; 7: 359–364Objective: Only limited information exists concerning the clinical and pathological features ofchronic hypersensitivity pneumonitis (HP) in Japan and elsewhere. We present data on clinico-pathological features of chronic HP obtained through a Japanese nationwide survey.Methodology: We studied the clinical and pathological findings in 10 patients with chronic HPwho underwent surgical lung biopsy or postmortem examination.Results: There were three types of clinical course: six of the 10 patients had persistent symptomsfollowed by repeated acute episodes; two showed a subacute onset with persistent symptoms; andtwo exhibited an insidious onset. Five patients made no attempt to avoid antigen exposure and theyall had progressive disease. Pathological findings indicated that lesions were mainly centrilobularwith or without epithelioid cell granulomas in specimens obtained during the acute or subacutestage. In contrast, most patients in the chronic stage predominantly showed interstitial fibrosis witha usual interstitial pneumonia pattern.Conclusions: The pathological findings of chronic HP depend on the stage of the disease at tissuesampling.
Key words: chronic hypersensitivity pneumonitis, pathology, pulmonary fibrosis, usual interstitialpneumonia.
organic dusts and low molecular weight chemicals. It is clinically classified into acute, subacute andchronic forms based on the manner of its presenta-tion, and these forms may coexist in the samepatient.1 The prognosis of acute HP is generally good,but the long-term outcome of chronic HP is variable.Previous observations in patients with bird fancier’slung and farmer’s lung have indicated that thechronic disease can progress to a fatal outcome,although continued antigen exposure does notalways cause pulmonary dysfunction.2–8
Previous studies have demonstrated that thetypical pathological features of acute HP includepatchy infiltration of the alveolar walls with mononu-
Respirology (2002) 7, 359–364
INTRODUCTION
Hypersensitivity pneumonitis (HP) is an immunolog-ically induced lung disease caused by the repeatedinhalation of a variety of causative agents, such as
Correspondence: Dr Hiroshi Hayakawa, Departmentof Internal Medicine, National Tenryu Hospital, 4201-2Oro, Hamakita 434-8511, Japan. Email: [email protected]
Received 17 October 2001; revised 10 May 2002;accepted for publication 21 May 2002.
clear cells in a bronchocentric distribution, smallnon-necrotizing epithelioid granulomas, bron-chiolitis obliterans, and organizing pneumonia.9–13
However, only limited data are available on the patho-logical features of chronic HP.13
To investigate the clinical characteristics andcurrent status of HP in Japan, a research committeeorganized by the Japanese Ministry of Welfare conducted a nationwide study of the disease, whichproduced several relevant results.14–17 We report onthe clinicopathological features of chronic HP as evi-denced by patients identified in the nationwidesurvey.
METHODS
The Research Committee on Diffuse PulmonaryDisease organized by the Japanese Ministry of Welfareconducted a nationwide survey of chronic HP. A ques-tionnaire was sent to the relevant hospitals through-out Japan and data were compiled by members of theResearch Committee or members of the JapaneseRespiratory Society on the staff of these hospitals. Adiagnosis of chronic HP was made according to pre-viously described criteria.17 Briefly, more than three of the following findings were needed for diagnosisand have included (v), either (ii) or (iii), and either (i)or (vi): (i) reproduction of the symptoms of HP byenvironmental provocation or laboratory-controlledinhalation of the causative antigen; (ii) evidence of pulmonary fibrosis with or without granulomas;(iii) honeycombing on chest CT; (iv) progression ofrestrictive impairment of pulmonary function over 1year; (v) respiratory symptoms related to HP persist-ing for longer than 6 months; and (vi) antibodiesand/or lymphocyte proliferation in response to thepresumptive antigen. The survey detected 36 patientswith chronic HP, and an earlier report summarizedtheir clinical findings.17 The present study included 10patients who underwent surgical lung biopsy (openor video-assisted thoracoscopy) or postmortemexamination. Data on nine cases were obtained fromthe above-mentioned nationwide survey and anadditional recent case was also included. The patientsunderwent surgical biopsy because they showedatypical clinical features for HP including progressivedisease or chest images suggestive of idiopathic pulmonary fibrosis such as lung volume loss andhoneycombing, although provocation tests and/orimmunological tests were positive and indicative ofHP.
The specimens were stained with haematoxylinand eosin stain as well as elastica van Gieson stain.Pathological findings were reviewed by at least two ofthe authors (HH and SS) without knowledge of thepatient’s clinical course. Each patient was evaluatedfor cellular bronchiolitis, bronchiolitis obliterans,centrilobular fibrosis, alveolitis, organizing pneumo-nia, interstitial fibrosis, lymphoid aggregation, andepithelioid cell granulomas. When interstitial fibrosiswas the predominant finding, its pathological classi-fication was determined.18
RESULTS
Clinical features
The clinical findings are summarized in Table 1. The patients’ mean age was 54.8 years, with two menand eight women. Only two of the 10 patients weresmokers. The major presenting symptoms includedcough, sputum, dyspnoea, and fever. There werethree types of clinical course: six of the 10 patientshad persistent symptoms followed by repeated acuteepisodes (two summer-type, two home-related, oneoccupation-related and one farmer’s lung); twoshowed a subacute onset with persistent symptoms(one wheat flour and one home-related); and twoexhibited an insidious onset (both had bird fancier’slung).
Chest X-ray, CT scan and BAL findings prior to the tissue sampling are shown in Table 1. Chest X-ray findings revealed small nodular shadows in allpatients and volume loss was seen in four patients at the subacute or chronic stage. CT scan was per-formed in six cases and also frequently revealed small nodules. Honeycomb change was observed intwo patients at the chronic stage. BAL lymphocytosiswas seen in three out of four patients at the acute orsubacute stage, but in neither of the two patients atthe chronic stage. Five patients made no attempt toavoid antigen exposure by failing to comply with thephysician’s suggestions for improving the environ-ment. All five had progressive disease, and threedeveloped respiratory failure.
Pathological findings
The pathological findings obtained from biopsy orautopsy specimens are summarized in Table 2. Thepathological findings varied depending on the stageof the disease.
Biopsy was carried out at the acute stage in Cases1, 2 and 3, and all of them showed the typical findingscommonly seen in acute HP such as bronchiolitis,organizing pneumonia, and epithelioid cell granulo-mas, with changes mainly in the centrilobular area.Because Cases 2 and 3 had acute exacerbations ofchronic illness, it is reasonable that they showed mildinterstitial fibrosis. Case 2 underwent video-assistedthoracoscopic lung biopsy twice; the first biopsy wasperformed during the second acute episode, and asecond biopsy was done during the subsequent acuteexacerbation 4 years later. Although both specimensshowed bronchiolar lesions and epithelioid cell gran-ulomas, these HP-related findings were less distinctin the second biopsy specimen compared with thefirst one (Fig. 1).
Biopsy was performed during the subacute stage inCases 4 and 5. In these patients, bronchiolar lesionsand centrilobular organizing pneumonia were char-acteristically seen (Fig. 2), but there were no epithe-lioid cell granulomas.
In the remaining five patients (Cases 6–10), tissuesamples were obtained during the chronic stage. Only
360 H Hayakawa et al.
Clinicopathological features of CHP 361
Tab
le1
Clin
ical
fin
din
gs
Dat
a at
tis
sue
sam
plin
gM
easu
res
for
Man
ner
Ch
est
X-r
ayC
hes
t C
T s
can
avo
idin
g ca
usa
tive
Cas
eA
geo
f cl
inic
alC
linic
al s
tatu
sSm
all
Volu
me
BA
Lan
tige
n e
xpo
sure
No.
(yea
rs)
Sex
Dis
ease
cou
rse
at e
xam
inat
ion
no
du
lar
loss
Ho
ney
com
bin
gLy
m (
%)
afte
r d
iagn
osi
sO
utc
om
e
150
FSu
mm
er-t
ype
RA
EÆ
PS
Acu
te+
-N
DN
DN
on
eD
evel
op
ed C
RE
an
d d
ied
du
rin
g an
ear
thq
uak
e2
62F
Ho
me-
rela
ted
RA
EÆ
PS
Acu
te+
-N
D22
.0N
on
eD
eter
iora
ted
355
FH
om
e-re
late
dR
AE
ÆP
SA
cute
-on
-ch
ron
ic+
--
64.6
Cle
aned
th
e h
om
eD
eter
iora
ted
446
MW
hea
t fl
ou
rSO
ÆP
SSu
bac
ute
++
-55
.2W
ore
a m
ask
du
rin
g w
ork
Det
erio
rate
d5
51F
Ho
me-
rela
ted
SOÆ
PS
Sub
acu
te+
+-
5.0
Cle
aned
th
e h
om
eIm
pro
ved
654
FSu
mm
er-t
ype
RA
EÆ
PS
Ch
ron
ic+
-N
DN
DN
on
eD
evel
op
ed C
RF
an
d d
ied
of
pn
eum
on
ia7
66F
Bir
d f
anci
er’s
lun
gIn
sid
iou
sC
hro
nic
++
+10
.4St
op
ped
kee
pin
g b
ird
sD
eter
iora
ted
849
MB
ird
fan
cier
’s lu
ng
Insi
dio
us
Ch
ron
ic+
-+
9.0
No
ne
Un
chan
ged
972
FFa
rmer
’s lu
ng
RA
EÆ
PS
Ch
ron
ic+
+N
DN
DN
on
eD
ied
of
CR
F10
43F
Occ
up
atio
n-r
elat
edR
AE
ÆP
SC
hro
nic
+-
-N
DA
void
ed v
isit
ing
the
Imp
rove
dca
usa
tive
pla
ce
RA
E, R
epea
ted
acu
te e
pis
od
es; P
S, p
ersi
ten
t sy
mp
tom
s; S
O, s
ub
acu
te o
nse
t; N
D, n
ot
do
ne;
CR
F, c
hro
nic
res
pir
ato
ry f
ailu
re.
Tab
le2
Det
ails
of
tiss
ue
sam
plin
g an
d p
ath
olo
gica
l fin
din
gs
Path
olo
gica
l fin
din
gsB
ron
chio
lar
lesi
on
sA
lveo
lar
lesi
on
sSa
mp
ling
Clin
ical
sta
tus
Cel
lula
rB
ron
chio
litis
Cen
trilo
bu
lar
Org
aniz
ing
Inte
rsti
tial
Lym
ph
oid
Ep
ith
elio
id c
ell
Cas
e N
o.m
eth
od
at s
amp
ling
bro
nch
iolit
iso
blit
eran
sfi
bro
sis
Alv
eolit
isp
neu
mo
nia
fib
rosi
sag
greg
atio
ngr
anu
lom
as
1B
iop
syA
cute
++
-+
+-
++
2–1*
Bio
psy
Acu
te+
++
++
++
+2–
2*B
iop
syA
cute
–on
–ch
ron
ic+
-+
++
++
+3
Bio
psy
Acu
te–o
n–c
hro
nic
++
++
++
++
4B
iop
sySu
bac
ute
+-
-+
+-
--
5B
iop
sySu
bac
ute
++
++
++
+-
6A
uto
psy
Ch
ron
ic+
-+
++
+-
-7
Bio
psy
Ch
ron
ic-
--
++
+(U
IP)
--
8B
iop
syC
hro
nic
--
-+
++
(UIP
)+
-9
Au
top
syC
hro
nic
--
++
-+
(UIP
)+
-10
Bio
psy
Ch
ron
ic-
--
+-
+(U
IP)
+-
*C
ase
2–1
and
Cas
e 2–
2 w
ere
the
sam
e p
atie
nt,
wh
o u
nd
erw
ent
vid
eo-a
ssis
ted
th
ora
cosc
op
ic lu
ng
bio
psy
tw
ice.
Th
e se
con
d b
iop
sy w
as d
on
e 4
year
s af
ter
the
firs
t o
ne
was
per
form
ed.
one patient predominantly exhibited bronchiolarlesions. In contrast, the other four predominantlyshowed interstitial fibrosis (three were without appar-ent bronchiolar lesions and one had only a single siteof centrilobular fibrosis). According to the pathologi-cal classification of interstitial fibrosis, all of them hada usual interstitial pneumonia (UIP) pattern (Fig. 3)and none had epithelioid cell granulomas.
DISCUSSION
The subjects in the present study were collected in a considerably biased manner because selection ofpatients for surgical biopsy appeared to dependlargely on the diagnostic criteria for chronic HP ineach institute. Thus, the results should be carefullyevaluated. Nevertheless, the present study providesseveral points of interest.
The present study clearly indicated that the patho-logical findings of chronic HP depended on the
362 H Hayakawa et al.
(a)
(c)
(b)
(d)
Figure 1 Pathological findings in Case 2 who underwent lung biopsy twice. (a, b) The first biopsy, which was performedduring the patient’s second acute episode. Lesions are centrilobular (a, HE ¥ 5), and scattered epithelioid cell granuloma(arrow) is seen (b, HE ¥ 50). (c, d) The second biopsy, done during the subsequent acute exacerbation 4 years later. The cen-trilobular pattern is not distinct (c, HE ¥ 5). A tiny granuloma can be seen (d, HE ¥ 90).
Figure 2 Pathological findings in Case 5. Biopsy was doneat the subacute stage. There is massive centrilobularinvolvement, with organizing pneumonia and fibrosis. Elas-tica van Gieson ¥ 6.6.
HP may advance to the chronic stage under certainconditions. The present study also confirmed thatboth repeated intermittent antigen exposure (causingrepeated acute or subacute episodes in the earlyhistory) and continuous low-grade exposure (insidi-ous onset) could lead to chronic HP.3–8
Five patients made no attempt to avoid antigenexposure and they all had progressive disease. These results suggest that continuing antigen expo-sure may largely contribute to a poor prognosis of chronic HP and indicate that chronic HP should be carefully distinguished from other interstitial lung diseases, because complete avoidance of thecausative antigen may prevent progression of thedisease.
ACKNOWLEDGEMENT
This study was supported by the Research Committeeof the Japanese Ministry of Health and Welfare onDiffuse Pulmonary Diseases, Grant-in-Aid for scien-tific research 09670604 from the Japanese Ministry ofEducation.
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Clinicopathological features of CHP 363
(a) (b)
Figure 3 Photomicrographs of specimens obtained in the chronic stage. (a) Lung biopsy in Case 7. There is marked varia-tion in the degree of lung involvement, indicating usual interstitial pneumonia (UIP). HE ¥ 4. (b) Postmortem examinationof a lung specimen from Case 9. Honeycomb change and normal lung tissue are both seen, indicating UIP. HE ¥ 2.5.
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