Non-tuberculous, adenosine deaminase-positive lymphocytic pleural effusion: Consider immunoglobulin G4-related disease

Abstract

Objective:

Immunoglobulin G4-related disease (IgG4-RD) is a recently described systemic disorder. Pleural effusion is considered an uncommon manifestation of the disease. We describe a case series of patients with IgG4-RD and clinically significant pleural effusions.

Methods:

A retrospective analysis of patients with histologically proven IgG4-RD treated for pleural effusion in our clinic.

Results:

We identified 4 male patients with pleural effusion caused by IgG4-RD. The effusions were lymphocytic exudates, with especially high protein concentrations. All patients had hyperglobulinemia, elevated serum immunoglobulin G (IgG) levels and elevated levels subclasses IgG1 and IgG4. In two patients, levels of adenosine deaminase (ADA) were measured in the effusion and were elevated (309 and 108 IU/L). Tuberculosis was excluded in both cases by pleural biopsy. Involvement of other organs by IgG4-RD was the rule, especially thoracic lymphadenopathy which was prominent in all patients. In all cases, effusion responded to corticosteroids therapy. One patient developed radiological findings compatible with rounded atelectasis during remission.

Conclusions:

IgG4-RD may cause an ADA-positive, lymphocytic exudate with a high protein concentration, characteristics resembling tuberculous effusion. Thoracic lymphadenopathy, hyperglobulinemia, and an increased total IgG, IgG1, IgG4 may suggest the diagnosis. Not previously described, IgG4-RD pleural inflammation may result in rounded atelectasis. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 225-230)

Introduction

Immunoglobulin G4 related disease (IgG4-RD) is a systemic disorder with involvement of various organs. The condition is characterized by lymphoplasmacytic infiltration of single or multiple organs, resulting in mass lesions and/or organ dysfunction. Additional histological features include: storiform fibrosis and obliterative phlebitis, and abundance of IgG4-positive plasma cells in involved organs, often with elevated IgG4 serum levels [1-2]. Pulmonary manifestations of IgG4-RD may include involvement of the lung parenchyma, airways, vasculature, pleural spaces, and thoracic lymph nodes [1]. Pleural effusion is considered an uncommon manifestation of IgG4-RD, mainly mentioned in case reports.

Methods

We conducted a retrospective analysis of patients with a pleural effusion secondary to IgG4-RD who were treated in our clinic from January 2009 to December 2017. We assessed patients’ clinical, radiographic, laboratory and pathological data, treatment and outcome. We included only cases with an established diagnosis of IgG4-RD (based on accepted criteria, including both the Boston pathologic criteria and the Japanese comprehensive and organ-specific criteria [2-3]), who had pleural effusions requiring evaluation or management with pleurocentesis. The study was approved by the Rabin Medical Center Institution Review Board (application No. RMC-0869-17) and in accordance with the Declaration of Helsinki and with Good Clinical Practice guidelines. Due to the retrospective nature of the study, a written informed consent was not required.

Results

We identified four patients with pleural effusion caused by IgG4-RD. All patients were males, mean age 74-years at time of diagnosis. One of the patients was a smoker with a history of chronic obstructive pulmonary disease (COPD). None of the patients had a history of other respiratory diseases, relevant occupational or environmental exposure, and none had known exposure to tuberculosis (TB). Human Immunodeficiency Virus (HIV) status was negative for all cases. All cases presented with dyspnea. Additional clinical and laboratory data are detailed in Table 1.

Table 1.

Data of patients with pleural effusion due to IgG4-RD

4	3	2	1	Case No.
68	84	68	75	Age
M	M	M	M	Sex
				Serum studies (normal range)
5.2	3.9	4	5.2	Globulins g/dL (2.0-3.5)
3030	2620	2491	4520	IgG mg/dL (700-1600)
1851	2010	NA	1967	IgG1 mg/dL (405-1011)
297	1420	NA	1170	IgG4 mg/dL (3-201)
				Effusion studies (normal range in serum)
bilateral	bilateral	bilateral	right	Side
1326	2385	2900	NA	White blood cells
85	88	96	NA	Lymphocytes%
272/428 (0.64)	382/287 (1.33)	908/866 (1.05)	770/359 (2.15)	LDH (effusion/serum) U/L (230-460) (ratio)
6.9/8.7 (0.79)	7.4/7 (1.06)	7.0/7.1 (0.99)	5.6/9.0 (0.62)	Protein (effusion/serum) g/dL (6.0-8.2) (ratio)
107/121 (0.88)	69/98 (0.70)	273/294 (0.93)	115/120 (0.96)	Glucose (effusion/serum) mg/dL (70-100) (ratio)
7.41	7.34	7.39	7.30	pH
108	NA	309	NA	ADA IU/L
				Pleural biopsy
+	-	+	-	Performed?
-	NA	+	NA	Diagnostic of IgG4-RD?
Probable (Highly)	Established	Established	Established	Level of diagnostic certainty for IgG4-RD
Peripheral lymph node	Transbronchial biopsy	Pleural and transbronchial biopsy	Liver biopsy	Histopathological confirmation for IgG4-RD derived from
Generalized LNE	Lung parenchymal, thoracic LNE	Lung parenchymal, thoracic LNE	Liver and biliary, thoracic LNE	Additional organ involvement by IgG4-RD
+	+	+	+	Response to steroid treatment

LNE – lymph nodes enlargement

All patients had polycloncal hyperglobulinemia, with elevated serum concentrations of immunoglobulin G (IgG) and subclasses IgG4 and IgG1.

Radiographically, pleural effusions were bilateral in 3 cases and right-sided only in one case. Prominent enlargement of mediastinal and hilar lymph nodes was demonstrated in all patients. Two patients had additional parenchymal involvement in the form of diffuse ground glass opacities (GGO) consolidations.

Diagnosis of IgG4-RD was based on accepted criteria, including: organ involvement, elevated serum levels of IgG4, pathological features supporting the diagnosis and exclusion of other alternative diagnoses [2-3]. One patient had a prior diagnosis of IgG4-RD cholangitis and liver involvement supported by a liver biopsy. In the 3 other cases, pleural effusions were part of the initial presentation of IgG4-RD. Diagnosis of IgG4-RD was supported by a surgical pleural biopsy in case 2, by an excisional biopsy of a peripheral lymph node in case 4, and in cases 2 and 3 by a transbronchial biopsy. In case no. 3, transbronchial biopsies demonstrated a lymphoplasmacytic infiltrate with areas suggesting organizing pneumonia pattern, and abundant IgG4 positive cells. Thus, in all cases a diagnosis of definite or probable IgG4-Related respiratory disease was established [2-3].

Pleural effusions were exudates in all cases, with especially high protein concentrations and elevated concentrations of lactate dehydrogenase (LDH). There was a striking lymphocytic predominance in the cell counts, with no decrease in glucose and pH levels. In all cases bacterial and mycobacterial cultures were negative, and cytological evaluation was negative for malignancy.

Levels of adenosine deaminase (ADA) were measured in two patients and were elevated at 309 and 108 IU/L, respectively. In both cases TB was excluded by negative tissue cultures and histology of pleural biopsies specimens. In case no. 2, histological and immunohistochemical evaluation of the pleura fulfilled criteria for the diagnosis of definite IgG4-RD, specifically, a lymphoplasmacytic infiltrate with increased number of IgG and IgG4 positive cells was demonstrated in pleural biopsy specimens as well as in transbronchial biopsy specimens of the lung. In case no. 4 pleural biopsy demonstrated signs of non-specific chronic lymphocytic inflammation and a diagnosis of probable IgG4-RD was established by an excisional biopsy of an inguinal lymph node [2-3]. In both cases, Acid Fast stains and tissue cultures of the pleura were negative, and no granulomas were identified.

All four patients were treated with oral prednisone 0.5-1mg/kg daily as initial dose. All had good responses to steroid therapy with clinical improvement, as well as significant reduction in the size of pleural effusion and volume of lymph nodes, occurring within 4 weeks of therapy, and prednisone dosing was therefore gradually tapered down over several months. Patients no. 1 and 2 were able to stop prednisone completely after 9 and 7 months respectively. Patient 3 required ongoing immunosuppression, and azathioprine was added after 6 months of prednisone therapy, ultimately allowing complete steroid withdrawal. In case no. 4, steroid dose was quickly tapered down due to uncontrolled diabetes. His initial elevated level of ADA (108 IU/L) in the effusion was reduced (32 IU/L) with repeated therapeutic pleurocentesis. He was then treated with rituximab as a steroid sparing agent, with two doses of 1g given 14-days apart, resulting in long-term remission of his illness. However, follow-up computed tomography 6 months later demonstrated the development of rounded atelectasis in the right lung (Figure 1).

Fig. 1.

Rounded atelectasis in a patient with IgG4-RD

CT of the chest from patient no. 4, demonstrating thickened pleura and a small effusion with signs of rounded atelectasis on the right (arrow).

Discussion

Indeed, intrathoracic involvement in IgG4-RD is common, while pleural effusions are an unusual, yet a clinically significant manifestation [4-8]. In a prospective study by Fei et al., intrathoracic lesions were identified in 87/248 cases with IgG4-RD, yet with pleural effusions in only 4 cases [8]. In a UK study by Corcoran et al., 22/53 (42%) patients were categorized according to thoracic cross-sectional imaging studies as having thoracic involvement by IgG4-RD, yet only three patients had pleural effusions [9].

We have reviewed the literature for studies of large cohorts of patients with IgG4-RD (n > 20) and which report pulmonary or pleural involvement. We’ve identified 24 such studies from different countries, including a total of 1796 patients with IgG4-RD [8-9, 19-40]. The prevalence of pulmonary involvement in those series varied widely, from 3.6% to 59%, and was defendant on the study’s design. Thus, the percentage of patients with pulmonary involvement was higher in studies in which CT of the chest was routine. The presence of pleural effusions was not addressed at all in six of the reviewed studies. From the remaining 18 studies which comprise 1228 patients, the prevalence of pleural effusions reached up to 5.7%, but was 0% in 14/18 studies. Thus, in the majority of large series of patients with IgG4-RD, no cases of pleural effusion were reported, while in a few studies they were very uncommon

Patients with IgG4-RD and pleural effusions have mostly been described in case reports. In addition to reporting two new cases, a literature review from 2016 also identified 13 previous case reports. In their review, 72% of patients were male with a mean age of 65, 55% had bilateral effusions and all cases had elevated serum levels of IgG4. In the majority (83%), additional organs involvement was described, mostly lungs, pericardium, and mediastinum. The authors suggest that serosal involvement by IgG4-RD, including pleural effusion, might be more common than previously considered [10]. This concurs to our experience, thus we agree that pleural effusions secondary to IgG4-RD are probably under-recognized and subsequently under-reported.

ADA, an enzyme involved in purine metabolism, catalyzes the deamination of adenosine to inosine and of deoxyadenosine to deoxyinosine. The enzyme is involved in the proliferation and differentiation of lymphocytes, specifically the T-lymphocytes. T-cells activation in the presence of live intracellular pathogens includes the release ADA, thus considered a marker of cell-mediated immune response [11]. Nonetheless, interpretation of ADA measurements in the evaluation of lymphocytic pleural effusions is complex. In endemic areas, positive results (> 35-40 IU/L) are highly sensitive and specific for tuberculosis (TB) and anti-tuberculous therapy is usually indicated [11]. Even in populations with a low incidence of TB, a positive ADA in a lymphocytic effusion, although very uncommon, still strongly suggests TB, while a negative result can exclude tuberculous pleural effusion [12]. In a large prospective study among 410 patients, pleural fluid ADA was elevated in only 7 (1.7%) patients with nontuberculous lymphocytic effusions [13]. Thus, an undiagnosed ADA-positive lymphocytic effusion in a low incidence population should prompt further evaluation including pleural biopsy. There are a few case reports of patients with IgG4-RD and an elevated pleural fluid ADA. A recent report from 2018 describes such a case and reviews 4 additional case reports [14].

In TB, stimulation of T cells by mycobacterial antigens results in increased ADA levels. However, the mechanisms associated with elevations of ADA levels in the pleural fluid of patients with IgG4-RD are unknown. In IgG4-RD, Th2-cell responses are predominantly activated at affected sites. While in contrast, in classic autoimmune conditions, the function of regulatory T-cells (Treg) cells is impaired. The mechanisms involved in IgG4-RD pathophysiology are supported by large infiltrates of CD4⁺CD25⁺ Treg cells at affected sites [15]. Interestingly, similar to observations in TB patients [16], suggesting a possible common pathway of immune response inducing high ADA levels.

To the best of our knowledge, we describe the first case of rounded atelectasis solely attributed to IgG4-RD. In one other report, the patient had significant long-term occupational exposure to asbestos, resulting in stable round atelectasis for 8 years before the first symptoms of IgG4-RD emerged [17].

Many of the findings from our single center case series correlate with previous reports of cases with IgG4-RD pleural effusion. Most patients with IgG4-RD in general are elderly men, frequent clinical findings include elevated serum levels of IgG and IgG4 (in our series also of IgG1), and additional organ involvement of the disease, most commonly thoracic lymphadenopathy [18, 41]. Thus, our report adds significant information to the little data available regarding pleural effusions in IgG4-RD.

In summary, although uncommon, pleural effusion can be a manifestation of IgG4-RD, and even part of the initial presentation of the disease. IgG4-RD may cause an ADA-positive lymphocytic exudate, resembling tuberculous effusion. Clinicians should consider IgG4-RD in the differential diagnosis of an ADA-positive pleural effusion, which are very uncommon in areas with a low incidence of TB. In the absence of extra-thoracic involvement, clinical signs suggesting such diagnosis are mediastinal and hilar lymphadenopathy, polyclonal hyperglobulinemia, and elevated levels of IgG, IgG1 and IgG4. A pleural biopsy can aid in confirming the diagnosis. Pleural inflammation by IgG4-RD may also result in the development of rounded atelectasis.

The authors report no conflict of interest regarding this manuscript. The study was self-funded by the Pulmonary Institute of Rabin Medical Center.