Q:

2/16/2013
I have a 41 yo male with h/o papillary thyroid cancer, recurrent pneumonia and sinusitis, pancytopenia, night sweats, fatigue, non-caseating granulomas on mediastinal biopsy x 2, now meeting criteria for diagnosis of CVID (IgG 68, IgA, IgM both to low to be measured and no Ab response to S pneumo or tetanus, decreased B cells on flow, normal T cells, and normal mitogens with hypermetabolic splenomegaly (approx 20 cm) and hypermetabolic retroperitoneal nodes via PET scan. Bone marrow shows no evidence of malignancy. His chest CT shows global micronodular interstitial pattern. He has restrictive lung disease on PFTs. After giving IVIG (3 doses over 3 days of 400 mg/kg/day given because we were preparing for a possible surgery that ultimately did not occur) he developed worsening of his WBC and platelets. WBC of 1.8, ANC 600 and platelets 38,000. Also dypsneic with O2 sat of 92% with ambulation and negative CTPA ruling out PE. Considering an open lung biopsy to evaluate for a BALT lymphoma or GLILD. Is this something that is recommended because of the patients declining status even though we have already shown non-caseating granulomas (indicating sarcoid-like illness?) in which case we would begin steroids now, instead of open lung biopsy. Also should I give steroids before next IVIG dose in 4 wks to prevent worsening cytopenias? Thank you.

A:

Thank you for your inquiry.

I am forwarding your inquiry to Dr. Jack Routes, a nationally known expert in immunodeficiency disorders, and author of a recent series of common variable immunodeficiency patients with granulomas and interstitial lung disease treated with combination chemotherapy. I have copied the abstract from this article below along with a fairly recent review of common variable immunodeficiency with granulomatous-interstitial lung disease.

As soon as we hear from Dr. Routes, we will forward his reply to you.

Thank you again for your inquiry.

J Clin Immunol. 2013 Jan;33(1):30-9. doi: 10.1007/s10875-012-9755-3. Epub 2012 Aug 29.
Use of Combination Chemotherapy for Treatment of Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) in Patients with Common Variable Immunodeficiency (CVID).
Chase NM, Verbsky JW, Hintermeyer MK, Waukau JK, Tomita-Mitchell A, Casper JT, Singh S, Shahir KS, Tisol WB, Nugent ML, Rao RN, Mackinnon AC, Goodman LR, Simpson PM, Routes JM.
Source
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Abstract
Purpose: A subset of patients with common variable immunodeficiency (CVID) develops granulomatous and lymphocytic interstitial lung disease (GLILD), a restrictive lung disease associated with early mortality. The optimal therapy for GLILD is unknown. This study was undertaken to see if rituximab and azathioprine (combination chemotherapy) would improve pulmonary function and/or radiographic abnormalities in patients with CVID and GLILD.
Methods: A retrospective chart review of patients with CVID and GLILD who were treated with combination chemotherapy was performed. Complete pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans of the chest were done prior to therapy and >6 months later. HRCT scans of the chest were blinded, randomized, and scored independently (in pairs) by two radiologists. The differences between pre- and post-treatment HRCT scores and PFT parameters were analyzed.
Results: Seven patients with CVID and GLILD met inclusion criteria. Post-treatment increases were noted in both FEV1 (p = 0.034) and FVC (p = 0.043). HRCT scans of the chest demonstrated improvement in total score (p = 0.018), pulmonary consolidations (p = 0.041), ground-glass opacities (p = 0.020) nodular opacities (p = 0.024), and both the presence and extent of bronchial wall thickening (p = 0.014, 0.026 respectively). No significant chemotherapy-related complications occurred.
Conclusions: Combination chemotherapy improved pulmonary function and decreased radiographic abnormalities in patients with CVID and GLILD.

Clin Immunol. 2010 Feb;134(2):97-103. doi: 10.1016/j.clim.2009.10.002. Epub 2009 Nov 8.
Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID).
Park JH, Levinson AI.
Source
Section of Allergy and Immunology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Abstract
Infectious complications of the lung occur quite frequently in patients with common variable immunodeficiency (CVID), a clinical syndrome that represents a primary immunodeficiency. However, there appears to be noninfectious pulmonary complications in association with CVID as well, and recently the term granulomatous-lymphocytic interstitial lung disease (GLILD) has been created to describe these noninfectious, diffuse lung disease complications that develop in CVID patients. They exhibit both granulomatous and lymphoproliferative histologic patterns, consisting of lymphocytic interstitial pneumonia (LIP), follicular bronchiolitis, and lymphoid hyperplasia. There are many unanswered questions surrounding this relatively unstudied entity. In an attempt to answer some of these questions, this review discusses in detail pathologic and clinical features of GLILD and its proposed pathogenesis with a particular attention to potential role of human herpesvirus 8 (HHV-8). Lastly, therapeutic approach is discussed to generate novel treatment strategy to better care for a subgroup of CVID patients afflicted with this entity.

Sincerely,
Phil Lieberman, M.D.

Dear Dr. Cole:

We have received a response from Dr. John Routes. Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. John Routes:
With non-caseating granulomas on mediastinal biopsy, your patient most likely has GLILD. I enclose our recent paper on the treatment of this disorder. The decision on whether to obtain an open lung bx is a difficult one. If the patient’s restrictive lung disease is severe and you worry about significant complications, you could treat with a presumptive diagnosis of GLILD. I have seen pure BALT lymphoma that looks like GLILD—so we do try to get a bx if possible. If you do get a thoracoscopic lung biopsy, make sure you characterize the infiltrate for at least T cells, B cells and macs as well as stains to check for remodeling.

In my experience of treating many patients with GLILD, steroids never clear the disease (as noted in the paper below). In some patients you may see a temporary improvement, but the disease recurs and typically you need to continue an unacceptably high dose of prednisone in an attempt to stabilize lung function. Because the infiltrate in GLILD contains B cells and T cells, we now use rituximab and azathioprine to treat these patients. Our experience has been excellent. We typically check the TPMT gentoype before beginning aza (see paper for how we do the immunosuppressive therapy.

Use of Combination Chemotherapy for Treatment of Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) in Patients with Common Variable Immunodeficiency (CVID)

Sincerely,
John M. Routes, MD
Chief, Section of Allergy and Clinical Immunology
Co-Director, Clinical and Translational Science Institute of Southeast WI
Professor of Pediatrics, Medicine, Microbiology and Molecular Genetics
Department of Pediatrics
Children's Hospital of Wisconsin
Medical College of Wisconsin

AAAAI - American Academy of Allergy Asthma & Immunology