Discussion

CVID is the most common primary immunodeficiency disorder. It is characterised by impaired B cell differentiation and inadequate Ig production. The common defect in CVID is a block in the normal differentiation of lymphocytes into antigen-producing plasma cells. The exact mechanisms involved in this defect are still unknown and could include intrinsic defects in the ability of B cells to synthesise or secrete Ig, as well as abnormalities in regulatory T cells. Clinical manifestations are heterogenous and typically involve multiple organ systems.5 The lung is commonly affected in this disorder. The majority of the patients tend to have recurrent rhinosinusitis, bronchitis and pneumonia. Chronic lung disease is also a common problem and approximately one-third of the patients will have some type of chronic lung disease by the time the diagnosis is made. These include obstructive lung disease associated with asthma and bronchiectasis, restrictive disease associated with granulomatous and lymphocytic infiltrative disease and, less commonly, interstitial lung diseases like lymphoid hyperplasia, follicular bronchiolitis and lymphoid interstitial pneumonia (LIP).1 OP, formerly known as bronchiolitis obliterans OP or BOOP, is a relatively rare presentation in CVID. OP refers to a non-specific response to an initial injury to bronchial epithelium. These initial insults can be from inhalational injury, infections or drug exposures. OP is called cryptogenic OP when it is idiopathic. Histologically this disorder is characterised by excessive proliferation of granulation tissue consistent of loose collagen-embedded fibroblasts and myofibroblasts. Plugs of granulation tissue are found in alveolar ducts and alveolar spaces with or without bronchiolar intraluminal polyps. Inflammatory cells, mainly lymphocytes and plasma cells, are commonly found in the interstitium. BAL typically reveals an increase in all cell types with lymphocyte prevalence. OP is clinically characterised by a subacute illness with dyspnoea, cough, fever, malaise and weight loss. A typical pattern of bilateral patchy alveolar infiltrates is seen on chest CT scan. PFTs reveal a mild-to-moderate restrictive defect. The histological diagnosis can be made by transbronchial lung biopsy but open lung biopsy might be sometimes required as diagnosis can be missed on small specimens.6 Several of these clinical and histopathological features are shared by LIP, which is more commonly seen in association with CVID, and therefore constitute the main differential diagnosis from OP. Like OP, LIP manifest clinically with non-specific symptoms of dyspnoea, cough and fever. Radiographs show typically reticular and reticulonodular infiltrates but alveolar opacities can be seen. PFTs show a similar restrictive pattern with impaired diffusion and BAL reveals increased lymphocytes. Histology reveals similar infiltration of the interstitium and alveolar spaces by lymphocytes and plasma cells; however, granulation plugs and polyps are not present and would be the most helpful element in differentiating between the two entities.7

The pathogenetic mechanism of OP in CVID is unknown. The exact pathogenesis of OP itself remains not well-defined. It is thought that OP is a consequence of epithelial injury that leads to leakage of plasma proteins, recruitment of fibroblasts and fibrin formation within the alveolar lumen.8 Also dysregulation of vascular endothelial growth factor and matrix metalloproteinase has been associated with OP.9 One could speculate on the presence of a pathogenetic relationship between the recurrent infections in CVID and the initial epithelial lung injury that leads to OP. Perhaps we could also speculate on the presence of a relation between the B cell dysregulation and T cell imbalance in CVID and the dysregulation in angiogenesis seen in OP.

The diagnosis of CVID in our case was based on a medical history of recurrent respiratory infections since childhood and low serum IgG and IgA levels. The presence of bilateral lung infiltrates and mediastinal lymphadenopathy raised initially the suspicion for either an infectious process or lymphoproliferative disorder. Also a granulomatous disorder was in the differential. This led to the initial diagnostic procedure that included biopsies from the lymph nodes. BAL cell differential was not typical. Because of the uncertainty of the diagnosis, surgical lung biopsies were performed via VATS and OP was diagnosed. Interestingly the diagnosis of OP required surgical lung biopsy in the all three cases previously reported.2–4 The clinical picture and pulmonary function tests were compatible with the diagnosis as well. Once the diagnosis was established, corticosteroid therapy was promptly instituted and resulted in dramatic clinical, radiographic and physiological response.