Share this article on:

IgG4-related Pleural Disease Presenting as a Massive Bilateral Effusion

Ishida, Atsuko MD*; Furuya, Naoki MD*; Nishisaka, Takashi MD; Mineshita, Masamichi MD*; Miyazawa, Teruomi MD, PhD*

Journal of Bronchology & Interventional Pulmonology: July 2014 - Volume 21 - Issue 3 - p 237–241
doi: 10.1097/LBR.0000000000000082
Case Reports

A 74-year-old woman with massive bilateral pleural effusion, which was exudative in nature, and with mononuclear cell predominance underwent a pleuroscopy. Parietal pleura were thickened and partly reddish in color. Biopsy specimens taken from the parietal pleura revealed lymphoplasmacytic inflammation with fibrosis. As her performance status rapidly worsened with thoracentesis, we performed bilateral pleurodesis using talc. Pathologic evaluation of the pleural biopsy specimen with immunohistochemical staining revealed 91 IgG4-positive plasma cells per high-power field and an IgG4/IgG ratio of 91%. Thus, the diagnosis of pleuritis from IgG4-related disease was established. Our case suggests that IgG4-related disease is one of the causes of pleural effusion, and it should be included in the differential diagnosis of unexplained pleuritis.

*Department of Internal Medicine, Division of Respiratory and Infectious Diseases, St Marianna University School of Medicine, Kawasaki

Department of Pathology, Hiroshima Prefectural Hospital, Hiroshima, Japan

Disclosure: There is no conflict of interest or other disclosures.

Reprints: Teruomi Miyazawa, MD, PhD, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Japan 216-8511 (e-mail:

Received July 9, 2013

Accepted April 29, 2014

IgG4-related disease is a recently recognized condition characterized by lymphoplasmacytic inflammation including IgG4-positive plasma cells.1 IgG4-related disease has been reported in various organs.1 Of these, there are few reports describing pleuritis as IgG4-related disease, and its clinical features are not well understood. We herein report a patient who became critically ill with massive bilateral pleural effusion.

Back to Top | Article Outline


A 74-year-old woman complaining of mild dyspnea on exertion and leg edema was found to have a bilateral pleural effusion of 5 months’ duration before visiting our institution. She had a history of liposarcoma involving the retroperitoneum, which was initially resected 23 years ago and reoperated on 3 other times because of its repetitive local recurrence. The patient had a family history of tuberculosis, with the father having had pulmonary tuberculosis, and her mother had tuberculous spondylitis. She denied exposure to either asbestos or ionizing radiation. She was consuming unknown herbal medication for the past 3 months. Despite several diagnostic examinations including cytologic and microbial analysis of pleural effusion, no specific diagnosis could be achieved. She was placed on diuretics and underwent therapeutic thoracentesis as needed until she became progressively dyspneic and eventually hypotensive and hemodynamically unstable owing to rapidly increasing bilateral pleural effusion.

She was emergently referred to our hospital because her pulse oxygen saturation at room air was 75%. She also presented with excessive bilateral leg edema, and her Karnofsky Performance Status (KPS) was 40. Chest radiograph in an upright position revealed large bilateral pleural effusion (Fig. 1A). A computed tomography (CT) scan of the chest obtained after the placement of left-side and right-side drainage tubes demonstrated bilateral pleural thickening and residual pleural effusion (Fig. 1B) but without evidence of pulmonary infiltrates, tumors, or intrathoracic lymphadenopathy. Routine laboratory examinations revealed hypoproteinemia of 5.4 g/dL and hypoalbuminemia of 2.4 g/dL, with normal renal and liver functions. There was no evidence of any infection. Serum autoantibodies and tumor markers were also negative for collagen vascular disease (CVD) or malignancy, respectively. Her brain natriuretic peptide was elevated to 161.1 pg/mL; however, cardiac function was well preserved on echocardiography. Analyses of left and right pleural effusions revealed exudative fluid based on Light’s criteria (2.8 g/dL pleural fluid protein for the left side; 3.2 g/dL for the right side), mononuclear cell predominance (88% for the left side; 94% for the right side), normal range for adenosine deaminase, and negative results for cytologic and bacteriological culture.



Subsequently, pleuroscopy was performed on the left side using a pleura videoscope (LTF-260; Olympus; Tokyo, Japan) under local anesthesia. Adhesions were observed in the lower part of the pleural space, and the parietal pleura were thickened and partly reddish in color (Fig. 2). No nodules or tumors were seen on the pleura. Biopsy specimens retrieved from the parietal pleura revealed lymphoplasmacytic inflammation associated with fibrosis by hematoxylin-eosin stain (Figs. 3A, B), and microbial culture was negative. The initial results obtained from pleuroscopic biopsy suggested pleuritis but did not give us further information about specific cause. We administered levofloxacin empirically, but it was ineffective. Meanwhile, the patient required daily pleural fluid drainage from both sides of 800 to 1200 mL/d in total to maintain her respiratory status stable. The serum albumin level decreased to 1.4 g/dL in 2 weeks, and her general condition worsened to KPS 30 from anasarca. Therefore, we decided to perform talc pleurodesis as we confirmed that both the lungs were well reexpanded on chest radiograph after the drainage. At first we performed right pleuroscopy, which showed almost the same findings as the previous left pleuroscopy, and insufflated 4 g of sterile talc. Left pleurodesis was also carried out with 4 g of sterile talc under thoracoscopy to control pleural effusion and to improve her general condition. Both left and right pleural effusions disappeared on chest radiograph, and 1 month after the pleurodesis she was discharged from our hospital on foot. Five months later, she visited us again complaining of dry cough. A chest CT scan showed ground glass opacity in the right lower lobe. Serum levels of pulmonary surfactant, protein-D, and IgG4 were elevated to 1220 U/mL, 517 ng/mL, and 740 mg/dL, respectively. Being diagnosed as having interstitial pneumonia, the patient was administered prednisone at 25 mg/d (0.5 mg/kg/d). Reevaluation of pleuroscopic biopsy specimens for immunohistochemical staining demonstrated 91 IgG4-positive plasma cells per high-power field, and an IgG4/IgG ratio of 91% (Figs. 3C, D). A diagnosis of pleuritis from IgG4-related disease was established, and a metachronous involvement of the lung was suggested. The ground glass opacity on chest CT scan resolved soon after the commencement of prednisone, which was gradually tapered to 5 mg/d as a maintenance dose, and her general condition improved to KPS 100. At present, she has continued prednisone for over 1 year with no recurrence of pleural effusion and interstitial pneumonia and maintains a good quality of life.





Back to Top | Article Outline


IgG4-related disease is a newly recognized condition. Although it can affect various organ systems, to the best of our knowledge, there are only 3 reported cases describing pleuritis from IgG4-related disease.2–4 We have summarized these 3 cases and the present case in Table 1. Three patients had bilateral pleural effusion, whereas 1 patient had unilateral process. Our patient is the first case to present massive bilateral pleural effusion resulting in hemodynamic instability.



The IgG4-related disease could have systemic presentation involving the submandibular glands, orbits, and lungs that can occur either simultaneously or metachronously.1 Of the 4 pleuritis cases of IgG4-related disease shown in Table 1, 2 cases had extrapleural lesions. Our patient also developed interstitial infiltrates 1 year after her initial presentation. A lung biopsy was not performed; however, in view of the elevated level of serum IgG4, and in the absence of conditions such as CVD, drug toxicity, occupational exposure, or radiation therapy, the infiltrates were felt to be due to metachronous interstitial pneumonia from the IgG4 disease. In our opinion, the patients with IgG4-related disease should be followed up over years for the possibility of developing systemic involvement.

To diagnose IgG4-related disease, evaluations to prove appropriate pathologic appearance and increased numbers of IgG4-positive plasma cells in the involved tissue are essential.5 A consensus statement mentions that histopathologic diagnosis of the IgG4 disease requires 2 of the following 3 major features: (1) dense lymphoplasmacytic infiltrate, (2) fibrosis arranged at least focally in a storiform pattern, and (3) obliterative phlebitis. In addition, the presence of >50 IgG4-positive plasma cells per high-power field and IgG4/IgG plasma cell ratio of >40% on the pleural biopsy specimen is highly suggestive for pleuritis from IgG4-related disease. Other conditions exhibiting lymphoplasmacytic infiltrates with increased IgG4-positive plasma cells in the tissue include inflammatory diseases such as CVD rheumatoid arthritis, lymphoproliferative disorders such as multicentric the Castleman’s disease or lymphoma, and malignancies. However, such condition can be easily differentiated by pathologic findings, in addition to the patient’s history, objective findings, and the biomarkers such as serum autoantibodies and interleukin-6. Low-grade B-cell lymphomas should also be excluded. They are characterized by proliferated CD20-posirive B cells, although the majority of lymphocytes in IgG4-related disease are T lymphocytes.5 Malignant diseases can be differentiated by obvious histopathologic features.5

For the diagnosis of pleural effusion of unknown etiology, rigid thoracoscopy has been the gold standard because of its simplicity and efficacy with the diagnostic yield of 93% to 97%.6–8 Recently, it has been reported that the diagnostic yield of pleuroscopy using a flexirigid videothoracoscope is also over 90%.9,10 Rigid equipments allow us to obtain larger biopsy specimens and facilitate management of difficult loculated empyema. On the contrary, flexirigid videothoracoscope allows application of narrow band imaging to detect superficial subtle vascular changes.11 We performed pleuroscopy using a flexirigid videothoracoscope. The initial standard pathologic assessment of the pleuroscopic biopsy specimens by hematoxylin-eosin stain revealed only lymphoplasmacytic inflammation, suggesting idiopathic pleuritis. Despite improvement in the diagnostic techniques and the yield, significant number (29% to 40%) of pleuroscopy performed for the effusion of unknown etiology may just reveal nonspecific pleuritis.11,12 Among the patients who are initially diagnosed as idiopathic pleuritis, in 15% to 20%12,13 of the cases true diagnosis can be achieved with long-term follow-up. Thus, it is necessary to continue to follow-up the patients diagnosed as idiopathic pleuritis. The IgG4-related disease should be considered in the differential diagnosis of recurrent pleuritis.14 Besides, to diagnose IgG4-related disease, serological examination alone is not sufficient as approximately 30% of the patients may have normal serum IgG4.1 Therefore, pathologic reevaluation including immunohistochemical staining should be considered when IgG4-related disease is suspected.

For the treatment of IgG4-related disease, glucocorticoids are the main stay.1 Of the 4 IgG4-related pleuritis cases depicted in Table 1, 1 case responded well to glucocorticoids therapy alone. Depending on the amount of pleural effusion, patients may require therapeutic thoracentesis. Our patient’s health actually worsened after thoracentesis, although her diagnosis was still in dilemma and eventually required pleurodesis. As she was started on glucocorticoids therapy 5 months after the talc pleurodesis, we believe that there was no negative effect of steroids on the pleurodesis. Our case has been maintained on a small dose of prednisone, and we consider it effective as she has suffered with recurrence of neither pleural effusion nor interstitial pneumonia. We plan to continue this therapy indefinitely.

Back to Top | Article Outline


The authors thank Mr Jason Tonge for his English review of this manuscript.

Back to Top | Article Outline


1. Stone JH, Zen Y, Deshpande V.IgG4-related disease.N Engl J Med.2012;366:539–551.
2. Yamamoto H, Suzuki T, Yasuo M, et al..IgG4-related pleural disease diagnosed by a re-evaluation of chronic bilateral pleuritis in a patient who experienced occasional acute left bacterial pleuritis.Intern Med.2011;50:893–897.
3. Sekiguchi H, Horie R, Utz JP, et al..IgG4-related systemic disease presenting with lung entrapment and constrictive pericarditis.Chest.2012;142:781–783.
4. Yamashita K, Haga H, Kobashi Y, et al..Lung involvement in IgG4-related lymphoplasmacytic vasculitis and interstitial fibrosis: report of 3 cases and review of the literature.Am J Surg pathol.2008;32:1620–1626.
5. Deshpande V, Zen Y, Chan JK, et al..Consensus statement on the pathology of IgG4-related disease.Mod Pathol.2012;25:1181–1192.
6. Boutin C, Astoul P.Diagnostic thoracoscopy.Clin Chest Med.1998;19:295–309.
7. Blanc FX, Atassi K, Bignon J, et al..Diagnostic value of medical thoracoscopy in pleural disease: a 6-year retrospective study.Chest.2002;121:1677–1683.
8. Loddenkemper R.Thoracoscopy—state of the art.Eur Respir J.1998;11:213–221.
9. Munavvar M, Khan MA, Edwards J, et al..The autoclavable semirigid thoracoscope: the way forward in pleural disease?Eur Respir J.2007;29:571–574.
10. Lee P, Hsu A, Lo C, et al..Prospective evaluation of flex-rigid pleuroscopy for indeterminate pleural effusion: accuracy, safety and outcome.Respirology.2007;12:881–886.
11. Ishida A, Ishikawa F, Nakamura M, et al..Narrow band imaging applied to pleuroscopy for the assessment of vascular patterns of the pleura.Respiration.2009;78:432–439.
12. Janssen JP, Ramlal S, Mravunac M.The long-term follow up of exudative pleural effusion after nondiagnostic thoracoscopy.J Bronchol.2004;11:169–174.
13. Ferrer JS, Munoz XG, Orriols RM, et al..Evolution of idiopathic pleural effusion: a prospective, long-term follow-up study.Chest.1996;109:1508–1513.
14. Medford AR.Recurrent pleuritis: consider IgG4-related systemic disease.Respiration.2013;85:265.

IgG4-related disease; pleuritis; pleuroscopy; pleural effusion

© 2014 by Lippincott Williams & Wilkins.