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□ CASE REPORT □

Rapidly Progressive Respiratory Failure in MixedConnective Tissue Disease: Report of an Autopsy Case

Yasutaka Watanabe 1, Shinichiro Koyama 1, Masato Moriguchi 2, Chihiro Miwa 1,

Mamoru Shiraishi 1, Motoko Nomura 1, Mitsuhiro Nokubi 3,

Chihiro Terai 2 and Yoshinori Kawabata 4

Abstract

A 64-year-old woman presented with exertional dyspnea. The case was diagnosed as mixed connective tis-

sue disease (MCTD) due to presence of swollen fingers, Raynaud’s phenomenon, muscle weakness, positive

anti-U1RNP antibody, pericarditis and interstitial pneumonia. Although the histology from a transbronchial

lung biopsy (TBLB) indicated organizing pneumonia, corticosteroid therapy was postponed for two months at

the patient’s request. She died 8 weeks later from acute progressive interstitial pneumonia in spite of the ad-

ministration of intravenous cyclophosphamide combined with prednisolone. The autopsy revealed exudative

and organizing diffuse alveolar damage (DAD). Previous reports have shown that DAD is an extremely rare

pulmonary complication in MCTD. This report presents a case of MCTD with acute respiratory failure. This

case thus suggests that this therapy should be administered as soon as possible.

Key words: mixed connective tissue disease, diffuse alveolar damage, interstitial pneumonia, cytomegalo-

virus

(Intern Med 51: 3415-3419, 2012)(DOI: 10.2169/internalmedicine.51.8728)

Introduction

Mixed connective tissue disease (MCTD) is characterized

by the combined features of systemic lupus erythematosus

(SLE), scleroderma and polymyositis, and high titers of a

serum antibody to ribonucleoprotein antigen (anti-RNP-

antibody). Pulmonary involvement, such as pleuritis, usual

interstitial pneumonia (UIP), and pulmonary hypertension,

occurs in 20 to 85% of patients with MCTD (1-3). This re-

port presents an autopsy case of MCTD in a patient that

died from acute progressive interstitial pneumonia (IP). Or-

ganizing pneumonia was diagnosed by a transbronchial lung

biopsy (TBLB) before therapy; however, an autopsy showed

diffuse alveolar damage (DAD). The rare association of

MCTD and DAD is discussed in the pathological findings.

Case Report

A 64-year-old woman presented with a one-month history

of exertional dyspnea. She was a housewife, with a BMI of

20.2 and was an ex-smoker with a 45 pack-year history. The

patient had an eight-year history of diabetes mellitus, hyper-

tension and hyperlipidemia. She was diagnosed with IP 3

weeks after the first visit based on fine crackles on chest

auscultation, and chest computed tomography (CT) showing

a reticular pattern at bilateral lower lung fields (Fig. 1a, b).

The case was also diagnosed as scleroderma or MCTD be-

cause she had swollen fingers, Raynaud’s phenomenon,

positive anti-nuclear-antibody and a single high titer of anti-

RNP-antibody. She was admitted for the TBLB one month

later, and the pathological examination showed findings that

suggested organizing pneumonia with plug formation and a

１Division of Pulmonary Medicine, Jichi Medical University, Saitama Medical Center, Japan, ２Division of Reumatology, Jichi Medical University,

Saitama Medical Center, Japan, ３Division of Pathology, Jichi Medical University, Saitama Medical Center, Japan and ４Division of Pathology,

Saitama Cardiovascular and Respiratory Center, Japan

Received for publication August 1, 2012; Accepted for publication September 11, 2012

Correspondence to Dr. Yasutaka Watanabe, yasuyasu@omiya.jichi.ac.jp

Intern Med 51: 3415-3419, 2012 DOI: 10.2169/internalmedicine.51.8728

3416

Table　1.　Laboratory Data on Admission

ygoloreSCBCWBC 6800 / L CRP 0.77 mg/dL

Neu 75.3 % ESR 62 mm Lym 16.2 % MPO-ANCA <10 EU Mono 5.4 % RF <10 IU/L

RBC 426×104 / L ANA 1:40960 Hb 12.3 g/dL Anti-RNP-Ab 256 Index Ht 41.5 % Anti-SSA-Ab (-) Plt 26.9×104 / L Anti-Jo1-Ab (-)

bA-AND-itnAyrtsimehC (-) HbA1c 5.9 % KL-6 3140 U/mL TP 8.3 g/dL SP-D 250 ng/mL Alb 3.3 g/dL IC 1.5 pg/mL T.Bil 0.53 mg/dL CH50 40.9 U/mL AST 30 IU/L C3 87 mg/dL ALT 10 IU/L C4 22 mg/dL LDH 379 IU/L Arterial blood gas analysis ; room air CK 382 IU/L pH 7.422 Aldolase 7.6 IU/L PaO2 60.5 mmHg ALP 216 mU/mL PaCO2 35.3 mmHg BUN 7 mg/dL HCO3

- 22.5 mmol/L Cre 0.43 mg/dL Na 142 mEq/L K 3.3 mEq/L Cl 107 mEq/L

Figure　1.　a, b show chest computed tomography (CT) scan showed bilateral peripheral reticular shadows and broncho-vascular consolidation; c-f show CT findings 2 and 3. 3 months after a and b. Chest CT findings worsened with time.

Figure　2.　Hematoxiin and Eosin staining (a) and Elastica van Gieson staining (b) of transbronchial lung biopsy 2 months before therapy showing plug formation and foamy macrophage reaction-like OP pattern.

foamy macrophage reaction (Fig. 2). Steroid therapy was

recommended, but she rejected it because of her diabetes

mellitus. However, her dyspnea gradually worsened after

discharge. She was re-admitted because of a worsened opac-

ity on chest CT one and a half months after the TBLB,

(Fig. 1c, d).

A physical examination showed proximal muscle weak-

ness of the extremities. Laboratory data (Table 1) showed

positive anti-nuclear antibody (ANA) with a titer higher than

Intern Med 51: 3415-3419, 2012 DOI: 10.2169/internalmedicine.51.8728

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Figure　3.　Clinical course of chest X ray, laboratory data of KL-6 and LDH, and therapies. Abbre-viation: PSL: prednisolone, CPA: cyclophosphamide

Figure　4.　An autopsy section with Elastica van Gieson stain-ing. (a) Panoramic view (×0.5). Outer area(※) shows organi-zation of the lung with a few foci of ectatic air space (arrow). There is pleural fibrosis in part(★). Inner area shows diffuse alveolar damage. (b) Plugformation like Organizing Pneumo-nia without honeycomb change (×20). (c) Hyaline membrane (×20).

1:40960; positive anti-U1-RNP antibody with a titer higher

than 1:256; LDH 379 IU/L; KL-6 3,140 U/mL; SP-D 250

ng/mL; CRP 0.77 mg/dL; and CK 382 IU/L. Echocardiogra-

phy revealed mild pulmonary hypertension at 56 mmHg

with a tricuspid regurgitation pressure gradient, and slight

pericardial effusion without asynergy and an abnormal ejec-

tion function. These symptoms and signs fulfilled the crite-

ria of MCTD. She was then started on 50 mg/body/day oral

prednisolone (PSL) and 50 mg/body/day cyclophosphamide

(CPA) 2 months after the TBLB diagnoses. Her clinical

course is shown in Fig. 3. Her symptoms and chest X-ray

film improved transiently 2 weeks after treatment. However

her hypoxia and chest images worsened a month after treat-

ment. Her symptoms suggested acute exacerbation of IP or

infection without the use of drugs, which induced pneumo-

nia. The administration of high dose intravenous corticoster-

oid therapy with a daily dose of 1,000 mg/body methylpred-

nisolone for three days, high dose of cyclophosphamide

therapy with a daily dose of 500 mg/body, and broad spec-

trum antibiotic drugs were started. Negative findings of Gro-

cotte stain and β-D glucan suggested no evidence of a pneu-

mocystis infection, but cytomegalovirus (CMV) infection

was suspected due to the high level of the pp65 antigenemia

assay for CMV. Therefore, gancyclovir was started 6 days

after acute exacerbation.

However, the respiratory failure rapidly worsened, and she

was intubated at 9 days and died 15 days after the acute ex-

acerbation. Partial autopsy of only the heart and lung was

performed with the consent of her family. The autopsy re-

Intern Med 51: 3415-3419, 2012 DOI: 10.2169/internalmedicine.51.8728

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Table　2.　Reports of Acute Courses of Pulmonary Diseases Except Pulmonary Hypertension Complicated with MCTD

Reference number Age, Sex Histopathology(type of specimen)

Therapy Prognosis

5 37, M Modest interstitial fibrosis(TBLB, open lung biopsy & autopsy)

PSL&CPA dead

5 66, M Distortion of alveolar architecture by patchy interstitial fibrosis, recently organizing(open lung biopsy)

chlorambucil & PSL

alive

6 43, F unknown mPSL alive

7 33, F UIP&OP(open lung biopsy)

PSL & CsA Y UT

alive

8 49, F DAD(open lung biopsy)

mPSL & CPA alive

Abbreviations. TBLB: transbronchial lung biopsy, UIP: usual interstitial pneumonia, OP: organizingpneumonia, UIP: usual interstitial pneumonia, DAD: diffuse alveolar damage, PSL: Prednisolone, CPA: oral cyclophosphamide, CsA: cyclosporine A, Y: intravenous cyclophosphamide, UT: Ulinastatin, mPSL: methylprednisolone, : intravenous immunoglobulin, MC micafungin,

megalovirus

vealed the occlusion of alveoli, hyaline membranes, mem-

branous organization in the alveoli, and dilation of the al-

veolar ducts. Some lesions were associated with subpleural

fibrosis, but no honeycombing was found. In addition, an in-

traluminal organizing process was noted (Fig. 4). Her autop-

sied lung revealed acute or exudative DAD. There were no

features associated with DAD caused by CMV pneumonia,

although there were a few CMV inclusion bodies. There

were no findings to implicate other organisms such as bacte-

ria, pneumocystis jirovecii, and fungus. In addition, no vas-

cular changes of pulmonary hypertension with plexiform le-

sion were found, although there were a few arterializations

of small blood vessels. She was clinically diagnosed with

fatal interstitial pneumonia associated with MCTD.

Discussion

This report presented a MCTD case with rapidly fatal res-

piratory failure showing DAD at autopsy. IP is the most

common pulmonary manifestation of MCTD. The reported

frequency of IP in MCTD is between 21 and 50% (1, 4).

Sullivan et al. described chest X-ray abnormalities in 10 of

34 MCTD patients (3). However, rapid pulmonary complica-

tions associated with MCTD, other than pulmonary hyper-

tension, are very rare and there are few previous reports, as

shown in Table 2 (5-8). Patients with DAD generally have a

poor prognosis in comparison to other histopathological pat-

terns of IP. DAD can be seen in patients with UIP, pneumo-

nias, sepsis, drug-induced lung disease, inhalation injuries,

and various other conditions (9). Although the current pa-

tient received oxygen treatment, it was difficult to regard

oxygen therapy as the most probable origin of DAD because

her severe respiratory failure occurred before intubation. In

addition, there were no findings induced by drugs, sepsis

and so on in her clinical course and there were few CMV

inclusions or other pathogens found in the autopsy. There-

fore, the origin of DAD was first suspected to have been

caused by MCTD itself. Parambil et al. reported that DAD

can occasionally occur as a presenting manifestation of con-

nective tissue diseases (CTDs) (8). Their study population

indicated that DAD occurs in patients with or without preex-

isting CTD-related chronic IP and is a de novo manifesta-

tion of CTD in some patients. The CTD-related IP findings

prior to the onset of DAD showed organizing pneumonia

(OP) in 3 of 9 patients. The current patient’s TBLB finding

before therapy showed OP-like findings with plugs of granu-

lation tissue filling airspaces. It was possible that the first

pathological finding was not accurate for a diagnosis of IP

because very small samples were obtained by the TBLB. In

other words, her TBLB sample might be a part of DAD

showing granulation tissue in both the airspace and intersti-

tium (organizing pattern) (10). The pathological findings

might have progressed during the two months after the

TBLB. Another possibility is that acute exacerbation was su-

perimposed on the preexisting OP (8, 11). The TBLB speci-

men showed organizing pneumonia, and the autopsy find-

ings were DAD. Therefore, the cause of DAD seems most

likely to be related to her underlying MCTD.

On the other hand, this case had a high titer of CMV an-

tigenemia. Hanaoka et al. reported that CMV reactivation in-

dicates poor prognosis in CTD patients and might cause

subclinical CMV pneumonia in CTD patients that die by ex-

acerbation of IP (12). CMV infection could have caused

DAD in the current patient, because there was a high CMV

antigen titer. In addition, there were few CMV inclusions in

her autopsy, although previous reports said that their pres-

ence at autopsy might be a secondary phenomenon during

the terminal episode following treatment with high-dose cor-

ticosteroids (10). It is difficult to entirely exclude a viral in-

fection as a trigger for her course of DAD.

Case reports have described successful therapeutic use of

cyclosporine A combined with PSL or CPA, or human uri-

Intern Med 51: 3415-3419, 2012 DOI: 10.2169/internalmedicine.51.8728

3419

nary trypsin inhibitor (5-7). Cyclophosphamide combined

with prednisolone was administered in the present case, but

was not effective.

IP associated with CTD can be fatal even in patients

treated with high-dose corticosteroids (13, 14). In particular,

DAD has been described most commonly in patients with

polymyositis (PM)-dermatomyositis (DM) in whom DAD

implies a poor prognosis. Most of these patients die within a

few months of the onset of DAD despite corticosteroid ther-

apy (15). However, the drug seems to be effective for IP in

PM-DM, particularly when used early in the course of the

disease (16, 17). MCTD has features of PM or DM. DAD

might be related to PM or DM in the current patient. The

only therapy that might have helped this patient before exac-

erbation was to intervene earlier. Early immunosuppressive

therapy might have improved the clinical course of this pa-

tient although the autopsy finding suggested that her condi-

tion was irreversible and refractory.

It is sometimes difficult to determine whether the clinical

manifestations related to pulmonary involvement are due to

CTD or to an infectious process under immunosuppressive

therapy. However, early therapeutic intervention may be

preferable to avoid the deterioration of pulmonary lesions

associated with MCTD.

MCTD patients could be further compromised by respira-

tory deterioration and need early examination to determine

the optimal therapy. The duration of remission is uncertain.

The authors state that they have no Conflict of Interest (COI).

AcknowledgementThe authors thank Dr. Jack Hildebrandt and Wayne Lamm at

the University of Washington in Seattle, for their editorial assis-

tance.

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