Shinshu M ed J, 60⑶ :149 〜156, 2012

Acute Exacerbation of Pulmonary Fibrosis in Syndrome of Combined
Pulmonary Fibrosis and Emphysema Following Lung Surgery:
A Report of Two Cases
Yoshiaki KITAGUCHI , Keisaku FUJIMOTO ＊, Shiro HORIE , Keiko ISHII
Jiro HIRAYAMA , Ryosuke MACHIDA , M asayuki HANAOKA and Keishi KUBO
1)
2)
3)
4)

Department of Internal Medicine, Okaya Municipal Hospital
Departments of Biomedical Laboratory Sciences, Shinshu University School of Health Sciences
Department of Pathology, Okaya Municipal HospitalFirst Department of Internal Medicine, Shinshu University School of Medicine

We herein report two cases of an acute exacerbation of pulmonary ﬁbrosis in the syndrome of combined
pulmonary ﬁbrosis and emphysema (CPFE)following lung surgery,and also review the relevant literature.One
is a 76‑year‑old man,who had been diagnosed with CPFE and lung cancer and undergone lobectomy.He wasadmitted to our hospital because of aggravation of dyspnea 50 days after lung surgery.The other is a 69 ‑year‑
old man who had been diagnosed with pulmonary bulla, pulmonary emphysema and idiopathic interstitial
pneumonia at 53 years old and was complicated by lung cancer. He underwent right lower lobectomy andpresented with slight fever and desaturation 18 days after lung surgery. In both cases, chest computed
tomography showed diﬀuse bilateral ground‑glass opacities superimposed on preceding reticular opacities in
the lower lung ﬁeld.Theywere diagnosed as acute exacerbation of pulmonaryﬁbrosis in CPFE.A strict follow‑
up is required, because the prevalence of lung cancer may be higher, and acute exacerbation may occur
following lung surgery in CPFE patients.HRCT plays an important role in evaluating the occurrence of lungcancer at an early stage and for determining whether there is an acute exacerbation of pulmonary ﬁbrosis in
CPFE patients. Shinshu Med J 60 : 149 ―156, 2012
(Received for publication November 9, 2011;accepted in revised form January 18, 2012)
Key words:combined pulmonary ﬁbrosis and emphysema, smoking‑related interstitial lung disease,lung cancer, acute exacerbation

Introduction
Emphysema and idiopathic interstitial pneu-

bined pulmonary ﬁbrosis and emphysema (CPFE) .
CPFE is a unique disorder described in several caseseries of upper lobe emphysema associated withmonias, including idiopathic pulmonary ﬁbrosis

lower lobe ﬁbrosis, and the distinct features of(IPF), are conditions deﬁned by distinct clinical,

CPFE in comparison with chronic obstructive pul-functional, radiological and pathological character-monary disease (COPD) and IPF

istics.However,the occurrence of both emphysema

reported. CPFE may also be a risk factor for lungand pulmonary ﬁbrosis in the same patient hascancer ,and the prevalence of lung cancer may bereceived increased attention as a syndrome of com-higher in CPFE patients than in COPD and IPF

have been

patients .CPFE is highlighted as a smoking‑related
Corresponding author:Keisaku Fujimoto
Departments of Biomedical Laboratory Sciences,Shinshu

interstitial lung disease , while it may be under‑

University School of Health Sciences, 3‑1‑1 Asahi,recognized because of its subnormal spirometry.We

Matsumoto, Nagano 390‑8621 Japan

herein report the cases of two patients with acuteNo. 3, 2012

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Kitaguchi.Fujimoto.Horie et al.

Fig. 1A

The histolopathological images of Case 1 (×1.25, HE). The histological diagnosis
obtained by lobectomy was emphysema,usual interstitial pneumonia (A)and squamous cell
carcinoma (B).

exacerbation of pulmonary ﬁbrosis in CPFE follow-

without fever increasing since 14 days before admis-

ing lung surgeryfor lung cancer,and also review thesion, although he had not visited the hospital until

relevant literature.

admission. Laboratory ﬁndings on admission
Case Reports

Case 1

showed white blood cell count (WBC) 8500 mm ;lactate dehydrogenase (LDH)455 IU/L ;C‑reactive
protein (CRP)18.27 mg/dl;KL‑6 1124 U/mL.Arte-

The patient was a 78‑year‑old male who ﬁrst

rial blood gas analysis while on 100% oxygen at 3

presented with cough and hemosputum. He was

L/min showed severe hypoxia and hypocarbia (pHdiagnosed with CPFE clinically based on the imag-

7.34, PaCO 27.3 Torr, PaO 40.3 Torr). HRCT

ing criteria for CPFE as described by Cottin et al. .

showed new diﬀuse bilateral ground‑glass opacities

High‑resolution computed tomography (HRCT)

superimposed on a background of reticular opac-

revealed the coexistence of emphysema with anities and honeycombing with basal and peripheral

upper lung ﬁeld predominance and diﬀuse paren-

predominance (Fig.1B). Cultures of endotracheal

chymal lung disease with signiﬁcant pulmonary

aspirate and blood showed no evidence of either

ﬁbrosis with lower lung ﬁeld predominance.In addi-

pulmonary infection or sepsis. Echocardiographytion, there was a 4‑cm irregular mass about in theshowed no evidence of left heart failure.These dataleft lung S4.The patient was an ex‑smoker(50pack‑also conﬁrmed a diagnosis of acute exacerbation ofyears). Bronchoscopy was performed and a his-

IPF according to the diagnostic criteria of the IPF

tological examination revealed squamous cell car-Clinical Research Network .He was diagnosed as

cinoma. He underwent left upper lobectomy forhaving an acute exacerbation of pulmonary ﬁbrosis

lung cancer. The ﬁnal pathological diagnosis wasin CPFE.His clinical course is shown in Fig.1C.He

emphysema, usual interstitial pneumonia and pul-

was treated with steroid pulse therapy (1 g ofmonary squamous cell carcinoma T2bN0M0＝

methylprednisolone per day for 3 days), and antibi-

Stage IIA (Fig.1A). The patient was placed under

otics. Although the respiratory failure was severe,

observation without chemotherapy following sur-he and his familyat ﬁrst refused mechanical ventila-

gery. He did not receive either steroids or im-tion and non‑invasive positive pressure ventilation

munosuppressants before admission.He was admit-(NPPV). They gave permission to apply NPPV in

ted to the hospital 50 days after lung surgery

order to reduce distress and start sivelestat sodium

because of aggravation of dyspnea and desatura-

hydrate, and NPPV was applied on day 5 aftertion. He had complained of increased dry coughadmission. The respiratory failure progressed

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Acute exacerbation of pulmonary ﬁbrosis in CPFE following lung surgery

Fig. 1B

Chest HRCT images before left upper lobectomy(A and B),after upper lobectomy(C and
D)and on admission (E and F)of Case 1.
HRCT scans revealed the coexistence of emphysema with an upper lung ﬁeld predominance and diﬀuse parenchymal lung disease with signiﬁcant pulmonary ﬁbrosis with lower
lung ﬁeld predominance. There was a 4‑cm irregular mass in the left lung S4 (B). New
diﬀuse bilateral ground‑glass opacities superimposed on a background of reticular opacities and honeycombing with basal and peripheral predominance (E and F).

Fig. 1C

No. 3, 2012

Clinical course of Case 1. Abbreviations:PAPM :panipenem / betamipron, mPSL : methylprednisolone sodium succinate, PSL : prednisolone,
NPPV :non‑invasive positive pressure ventilation

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Kitaguchi.Fujimoto.Horie et al.

Fig. 2A

The histolopathological images of Case 2 (×1.25, HE). The histological diagnosis
obtained by lobectomy was emphysema,usual interstitial pneumonia (A)and squamous cell
carcinoma (B).

despite the therapy and he died due to respiratory

pneumothorax.The ﬁnal pathological diagnosis was

failure on day 19 after admission.

emphysema, usual interstitial pneumonia and pul-

Case 2monary squamous cell carcinoma T2aN1M0＝

The patient was a 69 ‑year‑old male who was ﬁrst

Stage IIA (Fig.2A). The intercostal tube wasreferred to Shinshu University Hospital because ofremoved on day 25 after admission. He presented

an abnormal chest abnormal shadow detected in anwith aggravation of dyspnea, slight fever andannual checkup and was diagnosed with pulmonary

desaturation on day 37 after admission (18 days

bulla, pulmonary emphysema and idiopathic inter-

after lung surgery). Laboratory ﬁndings showedstitial pneumonia at 53 years old. He was in the

WBC 13870 mm ;LDH 464 IU/L ;CRP 6.09 mg/dl;

outpatient clinic of Shinshu UniversityHospital andKL‑6 1123 U/mL.Arterial blood gas analysis whilethen diagnosed with CPFE based on the imaging

on 100% oxygen at 1 L/min showed hypoxia (pH 7.

criteria for CPFE described byCottin et al. .HRCT475, PaCO 38.4 Torr, PaO 55.6 Torr). HRCT

revealed the coexistence of emphysema with anshowed new diﬀuse bilateral ground‑glass opacities

upper lung ﬁeld predominance and diﬀuse paren-

superimposed on a background of reticular opac-

chymal lung disease with signiﬁcant pulmonary

ities and honeycombing with basal and peripheralﬁbrosis with lower lung ﬁeld predominance.He had

predominance (Fig.2B). Cultures of endotracheal

not received steroids and immunosuppressants. He

aspirate and blood showed no evidence of pulmo-

was an ex‑smoker (33 pack‑years). Follow‑upnary infection or sepsis. Echocardiography showed

HRCT revealed a 3‑cm irregular mass in the rightno evidence of left heart failure. These data alsolungS10, and right hilar and mediastinal

conﬁrmed a diagnosis of acute exacerbation of IPF

lymphadenopathy. Bronchoscopy was performed

according to the diagnostic criteria of the IPF

and a histological examination revealed adenocar-

Clinical Research Network .He was diagnosed as

cinoma. He was admitted to Shinshu University

having an acute exacerbation of pulmonary ﬁbrosis

Hospital because of sudden aggravation of dyspnea

in CPFE.His clinical course is shown in Fig. 2C.He

and chest pain after coughing. He was diagnosed

was treated with steroid pulse therapy (1 g ofwith right spontaneous pneumothorax and received

methylprednisolone per day for 3 days).Respiratory

intracostal tube drainage. Persistent leakage andfailure progressed and mechanical ventilation was

failure of lung expansion continued. He underwent

applied on day 39 after admission. The PaO /FiO

right lower lobectomy on day 20 after admission forratio improved to 251 after intensive treatment,andboth right lung cancer and right spontaneous

he was successfully weaned from mechanical venti-

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Acute exacerbation of pulmonary ﬁbrosis in CPFE following lung surgery

Fig. 2B

Chest HRCT images before admission (A and B)and 17 days after lung surgery (C andD)of Case 2.
HRCT scans revealed the coexistence of emphysema with an upper lung ﬁeld predominance and diﬀuse parenchymal lung disease with signiﬁcant pulmonary ﬁbrosis with lower
lung ﬁeld predominance. There was 3‑cm irregular mass in the right lung S10 (B). New
diﬀuse bilateral ground‑glass opacities superimposed on a background of reticular opacities and honeycombing with basal and peripheral predominance (C and D). The ground‑glass opacity on chest CT was ameliorated after treatment (E and F).

Fig. 2C

Clinical course of Case 2. Abbreviations: BS : bronchoscopy, mPSL :methylprednisolone sodium succinate, PSL :prednisolone

No. 3, 2012

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Kitaguchi.Fujimoto.Horie et al.

lation on day 45 after admission. Prednisolone (1pathology present in CPFE and the exact path-

mg/kg) was administered orally as maintenanceogenesis of CPFE are unknown,CPFE is consideredtherapy and was then tapered over the next one

to be included as a SRILD.

week. Chest X‑ray and HRCT showed an improve-

The present cases suggest that an acute exacerba-

ment of the ground‑grass opacities.He was dischar-tion may occur in CPFE, and that lung surgery forgedon on day 140 after admission.

lung cancer is able to trigger an exacerbation ofparenchymal lung disease, as well as in the other

Discussion

idiopathic interstitial pneumonias, including IPF.

We herein describe two cases of acute exacerba-

An acute exacerbation of idiopathic interstitialtion of pulmonary ﬁbrosis in CPFE. CPFE is apneumonia is occasionally observed following lungunique disorder described in several case series.

surgery, and it has a high mortality over a short

Almost all of the patients were male and heavy

course in IPF .The triggers of acute exacerbation

smokers.CPFE is characterized by subnormal spir-

following lung surgery are considered to be pro-ometry (mild airﬂow limitations and mild lung

longed ventilation at a large tidal volume withhyperinﬂation), severe impairment of gas exchange

oxygen supplementation at a high concentration .

and desaturation during exercise.The chest HRCT

A high concentration of supplemental oxygen leads

shows the coexistence of emphysema with an upper

to the production of endogenous oxygen radicals

lung ﬁeld predominance and diﬀuse parenchymal

from cells such as inﬂammatory cells, and the oxy-lung disease with signiﬁcant pulmonaryﬁbrosis withgen radicals could inactivate various enzymes

lower lung ﬁeld predominance.We previouslyrepor-within the alveolar epithelial and capillary endoth-

ted that twenty‑two of a series of 47 CPFE patients

elial cells to damage not only the cellular mem-

(46.8%)had lung cancer,and the prevalence of lungbranes, but also the genes within the nuclei .

cancer may be higher in CPFE patients than in

Therefore, lung‑protected mechanical ventilation

COPD and IPF patients .CPFE has therefore been

under appropriate anesthesia is deﬁnitely

suggested to possibly be an important risk factor

required . Case 1 and Case 2 were diagnosed as

for lung cancer.

having an acute exacerbation of pulmonary ﬁbrosis

Tobacco smoking is best known for causing not

in CPFE 50 days and 18 days after lung surgery,only pulmonary emphysema, but also idiopathic

respectively. There was thus a diﬀerence in thepulmonary ﬁbrosis. While the exact path-

duration of developing acute exacerbation. How-ogenesis of CPFE is unknown, tobacco smoking isever,Case 1 had complained of increased dry coughthought to be the major risk factor for the develop-

without fever increasing since 14 days before admis-

ment of CPFE,as well as COPD .In addition,CPFE

sion, although he had not visited the hospital until

has been highlighted as a smoking‑related inter-

admission.There was a possibility that acute exac-

stitial lung disease (SRILD) . The SRILDs include

erbation had already developed 14 days before

DIP, respiratory bronchiolitis‑related interstitialadmission,that is,36 days after lung surgeryin Caselung disease (RB‑ILD),pulmonary Langerhansʼcell

1. There was no cause which could have produced

histiocytosis (LCH)

and IPF . Pathologicalthe acute exacerbation other than lung surgery,ﬁndings of diﬀuse interstitial lung disease in CPFE

such as infection or receiving drugs which could

have been reported to be heterogeneous, such as

induce lung injury.

usual interstitial pneumonia (UIP), non‑speciﬁc

Usui et al. retrospectively reviewed the data forinterstitial pneumonia (NSIP), desquamative inter-

1143 patients with lung cancer. CPFE, emphysema

stitial pneumonia (DIP) or organizing pneumo-

and ﬁbrosis were identiﬁed in 8.9 %, 35.3% andnia,while UIP is the most common pathological

1.3% of patients with lung cancer,respectively.Theﬁnding . While the reason for the heterogeneous

median overall survival of CPFE patients was154

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Acute exacerbation of pulmonary ﬁbrosis in CPFE following lung surgery

signiﬁcantly lower than that of normal patients or

imposed on a background of reticular opacities andthat of patients with emphysema alone. It is ofhoneycombing on chest radiograph or HRCT.

interest that 76% of lung cancers in patients with

Therefore, strict follow‑up is required for these

CPFE were diagnosed at an advanced stage. In

patients, and HRCT plays an important role inaddition, fatal severe acute lung injury occurred

evaluating the occurrence of lung cancer in the

more frequently (19.8%) in CPFE patients, irre-

early stage.

spective of the treatment modality. In particular,

In summary,CPFE is considered to be one variant

postoperative lung injury occurred in nine of 33

of smoking‑related interstitial lung disease. An

patients with CPFE (27.3%). Therefore, the pres-acute exacerbation may occur in CPFE, as well as

ence of CPFE may result in a higher risk for pos-in the other interstitial pneumonias.A strict follow‑

toperative lung injury, as well as the presence of

up is therefore required, because the prevalence ofinterstitial lung disease. Therefore, strict observa-

lung cancer may be higher,and acute exacerbation

tion may be needed following lung surgery.

may occur following lung surgery. HRCT plays an

When patients with CPFE are complicated byimportant role in evaluating the occurrence of lunglung cancer, this may have a profound inﬂuence on

cancer at an early stage and for determining

their prognosis because of the poor operability andwhether there is an acute exacerbation of pulmo-

diﬃculties in administering chemotherapy. Occa-

nary ﬁbrosis in CPFE patients.

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