Systemic Granulomatous Disease in CVID With LRBA Deficiency: Long-term Management Strategies

Abstract INTRODUCTION – Granulomatous disease, predominantly involving the lungs, liver, lymph nodes and skin has been frequently associated with common variable immunodeficiency (CVID). While the management of CVID itself revolves around IVIG, there is no consensus on treatment of choice for its associated granulomatous complications. CASE – A 12-year-old female with no significant past medical history initially presented with a 2 month history of failure to thrive, nocturnal sweats and generalized malaise. Lab work was remarkable for leukopenia, hypogammaglobulinemia with low CD2, CD3, CD8, NK cells, CD19, CD45RA, no T-reg cells and absent vaccination titres. Meanwhile, she continued to have dyspnea, productive cough and fevers despite being on antibiotics and bronchodilators. HRCT chest showed multiple pulmonary nodules superimposed on diffuse reticulonodular interstitial infiltrate with hilar and axillary lymphadenopathy. Extensive infectious workup remained negative. Lung biopsy revealed diffuse lymphoid hyperplasia/lymphoid interstitial pneumonia (LIP) complex, consistent with CVID. She was started on IVIG and mycophenolate mofetil. Genetic testing revealed 2 variants of unknown significance related to the lipopolysaccharide-responsive beige-like anchor (LRBA) gene, a gene known to cause autosomal recessive LRBA deficiency. Over the next 6 years, the patient continued to have intermittent autoimmune cytopenias, episodic worsening of lymphoid interstitial pneumonia/interstitial lung disease and chronic pansinusitis. She also developed granulomatous hepatitis and lymphadenitis (biopsy proven). After significant trial and error, patient is currently stable on monthly IVIG infusions, weekly abatacept for LRBA deficiency, rituximab weekly for four weeks every six months for GLILD and pentamidine for PJP prophylaxis due to her low CD4 counts. DISCUSSION – Presence of granulomas on tissue biopsy can result in delayed management of CVID if other etiologies such as sarcoidosis are favored, and also results in 50% diminished median survival. The presence of autoimmunity (most commonly ITP or AIHA) is almost 2.5 times more common in presence of granulomatous disease. Our case highlights the challenges of managing granulomatous complications associated with CVID. The absence of LRBA gene has been associated dramatically reduced levels of CTLA4 protein and development of CVID, autoimmunity and chronic inflammation. Abatacept mimics the function of CTLA4 protein and has been crucial in halting our patient's granulomatous disease. We strongly believe that early diagnosis and prompt immunosuppression could prevent future development of granulomas.