CVID is a primary immunodeficiency characterized by decreased IgG two standard deviations below the lower limits of normal and reduced IgA and/or IgM with impaired specific antibody response measured via vaccine titers and variable T cell defects [3], that cause recurrent infections, particularly upper and lower respiratory tract infections [2]. GL-ILD is a non-infectious complication of CVID that manifests various lung findings on CT imaging that have not been previously well characterized with respect to morphology and distribution. Additionally, there are several histological patterns including granulomatous inflammation, lymphoid hyperplasia/lymphocytic interstitial pneumonia (LIP) and follicular bronchiolitis [2, 9, 11] that can be confusing to the pathologist. A retrospective series that examined lung pathology in 34 patients with CVID demonstrated benign lymphoid proliferation and granulomas in 23 patients who did not have a clinical and radiological diagnosis of GL-ILD [5]. Over-diagnosing GL-ILD in patients histologically without tight clinical, historical and radiological criteria and multidisciplinary agreement does not provide useful information in managing patients. Patients with CVID may have other pulmonary manifestations such a bronchiectasis, necrotizing granulomas from infection, lymphocytic intestinal pneumonia (LIP) from coexisting autoimmune disease[5, 12], scarring and pneumonia that may overlap with GL-ILD [13]. Some of the CT imaging features associated with GL-ILD are common to sarcoidosis [14], and are thus often misdiagnosed as sarcoidosis, especially histologically [6, 7, 14]. Histology may not be the “gold standard” in diagnosing GL-ILD rather a multidisciplinary ILD conference is the most optimal method to obtain a diagnosis of GL-ILD with the radiologist raising GL-ILD in the differential diagnosis. In centers with multidisciplinary ILD teams, a lung biopsy can be reserved to resolve disagreements and ambiguity.
Although GL-ILD suggests a pulmonary process, it actually encompasses a multi-systemic granulomatous inflammatory disease that may affect the liver, spleen, lymph nodes and any organ/organ system [15]. Due to the lymphocytic dysregulation in GL-ILD, patients are at high risk of lymphoma [16]. Several theories have been proposed to explain the pathogenesis of GL-ILD in CVID, including dysfunctional antigen handling (due to impaired T cell function) and aberrant immune response to viruses (potentially HHV-8). Due to improved life expectancy and reduced rate of infection with immunoglobulin replacement therapy, non-infectious manifestations of CVID such as GL-ILD are becoming more emergent [6, 11]. GL-ILD treatment requires immunomodulatory therapy (rituximab, azathioprine), as well as high dose immunoglobulin replacement therapy [13, 17] to reduce the disease progression and potentially reverse some of the radiological disease [9]. Some patients diagnosed with GL-ILD with normal lung functions and mild disease may not need treatment unless there is radiological and clinical progression [18].
The main goal of our case series was to identify predominant clinical and imaging findings in this cohort of GL-ILD patients that can be used to identify patients with CVID who have developed GL-ILD. The lower lobe predominant ground glass opacities (GGOs) (7 out of the 8 patients) were a finding more common in prior CT scans that tend to evolve into solid nodules in the subsequent scans. While longitudinal imaging studies are not available, it can be theorized that these GGOs are nodules in evolution, based on their distribution. There was 98% agreement between the two independent chest radiologists for the individual radiological findings of bronchocentric nodules with an apical to basal gradient, most numerous in the lower lobes.
When a PFT abnormality was present, the predominant finding was a moderate to severe reduction in the diffusion capacity, two patients who had severe impairment of diffusion capacity had hypoxia (Table 1). Restrictive lung functions are the predominant finding in GL-ILD in keeping with previous studies and case reports [11, 12, 18]; no patient had airflow limitation/ obstructive physiology that would implicate airway involvement[12]. Splenomegaly and ITP were important predictors of GL-ILD in CVID patients that were identified by the case control study by Hartano et al (69%) [6]. Splenomegaly was also an important clinical finding towards establishing a diagnosis of GL-ILD in the BLS/UKPIN statement [1], five patients in our series demonstrated splenomegaly while the other three patients had a splenectomy (Table 2). Features of ITP were present in five patients. Mild to moderate cylindrical bronchiectasis that was found in six patients is representative of the sequel of recurrent infections in CVID rather than a feature of GL-ILD.
Limitations of the GL-ILD case series is the small sample size of eight, but representative of the prevalence of this rare disease and the strict case selection by the multidisciplinary ILD team. Additional cohorts in a multicenter approach would be necessary to validate these findings. This study has the restrictions of a retrospective chart review and our data is limited by the availability of test results and documentation in the chart. One of the strengths that stand out in this study is the in-depth explanation of the radiological findings with CT imaging examples from our cohort.
Future studies should focus on multi-center database approach to increase the sample size of this rare disease. HRCT and better defined radiological criteria are replacing the need for biopsy in the field of ILD. GL-ILD has distinct radiological findings that can be useful in centers with multidisciplinary ILD teams.