A 27-year-old Caucasian male patient was initially evaluated in the allergy and immunology clinic in January 2019 for immunodeficiency. His initial symptoms started in June of 2017 when the patient started having recurrent episodes of pneumonia that were treated by his primary care physician (PCP). Incidentally at this time he was found to also have thrombocytopenia. He complained primarily of recurrent productive cough with green discharge over the past 1 ½ years. His other symptoms included: intermittent headaches, sinus pressure, nasal congestion, rhinorrhea, intermittent diarrhea, fatigue, and loss of smell but denied fever, chills, and night sweats. The patient had initially lost around 10-11 pounds at the start of his disease course. His family history was pertinent for a brother who also had thrombocytopenia and died from a brain aneurysm. Secondary to the above the patient was referred to hematology for further work up. Hematology completed further investigation during the Summer of 2017. This included monitoring of his platelet counts over a 12 month which showed varying levels between 91-108 x 109/l. The rest of his CBC with differential, complete metabolic panel and urinalysis were normal. Quantitative immunoglobulin panels were completed four times over an additional 12-month period revealing the following: IgG 256-308 mg/dl (700-1600), IgM 9-25 (40-230), IgA 23-33 (70-400). A CT chest and abdomen revealed mediastinal and upper abdominal lymphadenopathy, splenomegaly, and multiple pulmonary nodules. Secondary, to his hypogammaglobulinemia he was vaccinated with pneumovax by the hematologist which included 2 doses, 1 month apart in May 2018 and June 2018. His findings on imaging made hematology concerned about tuberculosis, fungal infections, malignancy, and granulomatous disease such as sarcoidosis as a potential underlying cause. He was referred to pulmonary clinic in July 2018 for a lung biopsy. During his work up pulmonary function tests showed moderate reduction of airflow (FEV1/FVC: 59%), normal vital capacity and moderate reduction of diffusion capacity. These findings were certainly consistent with obstructive lung disease. He underwent bronchoscopy and ultrasound guided endobronchial lymph node biopsy twice in the summer of 2018. A Bronchoalveolar lavage (BAL) with multiple node biopsies were negative for bacterial, fungal and TB as a cause of lung disease. Testing was also negative for malignancy. He was started on fluticasone furoate, umeclidinium & vilanterol for further management with improvement in FEV1/FVC ratio (85%). However, part of his work up included an aspergillus galactomannan test which ended up being positive leading to pulmonary to start him on oral isavuconazonium sulfate to treat him for aspergillus infection. His antifungal treatment was continued for 5 weeks but was stopped in November 2018 secondary to side effects (elevated liver enzymes, nausea, and vomiting). Upon his follow up a repeat CT chest was ordered in December 2018 showing progression of multifocal nodularity in his lung and unchanged mediastinal lymphadenopathy. (Figure 1a & 1b). Secondary to this he underwent VATS guided lung biopsy of his superior right lower lung segment in January 2019.
When the patient presented to A/I clinic a physical examination showed the following: Vital signs:110/80, P: 64/minute, Temp: 97, RR: 18/minute. ENT exam showed bilateral swollen pale nasal turbinate with light yellow drainage. The rest of his physical examination was unremarkable. Repeat laboratory testing was ordered in January 2019 and showed a platelet count of 96 K. The following tests were all negative CMP, urinalysis, stool ova and parasites, and HIV test. An Immunoglobulin panel showed an IgM 10 (40-230 mg/dl), IgG 520 (700-1600 mg/dl), IgA 26 (70-400 mg/dl), IgE < 2 (0-158 mg/dl). Lymphocyte subset are as followed: Absolute lymphocyte: 1126[1000-4000], CD3: 935 [960-2600] (83% [61-84]), CD4: 586[540-1660] (52% [32-60]), CD8: 304[270-930] (27[13-40%), CD19: 79[122-632] (7% [3-22]), CD16+56: 90 [70-480] (8% [3-22]). As the next step of work up a lymphocyte mitogen screen showed a low to PHA and a normal Con A & Pokeweed Mitogen. A sinus Xray was remarkable for left maxillary sinus disease showing mucosal thickening. Despite being vaccinated the patient had poor pneumococcal antibody titers with only 2/14 ≥ 1.3 ug/mL being responsive. His tetanus antibody titer was in the protective range of 1.3. The patient eventually did have a lung biopsy that showed lymphoid hyperplasia with interstitial fibrosis, patchy foci of organizing pneumonia, rare giant cells/histiocytes, acute bronchopneumonia and occasional fibrin exudates. Overall, the interstitial findings are compatible with the CVID-related interstitial lung disease, granulomatous lymphocytic interstitial lung disease (GLILD). Given the extensive lymphoid component, MALT lymphoma was considered; however, the immunohistochemistry profile, flow cytometry and molecular studies (per report) show no evidence of a clonal B-cell process. (Figure 2). Based on these findings, allergy/immunology service confirmed the diagnosis of CVID with coexisting immune thrombocytopenia and GLILD. The patient had been started on treatment with IVIG 30 gm every four weeks based on his initial immunoglobulins by hematology and this was continued by us. We obtained repeat quantitative IgG after therapy and the level was 600 (600-1640 mg/dl) on 10/1/2019. We subsequently increase his IVIG dose to 50 mg every 4 weeks because of decreasing lung function and decreased platelet count. The patient currently remains infection free since November 2018. His follow up chest x ray and CT chest in January 2020 showed further widespread lymphadenopathy and nodular lung densities. Allergy service referred him to rheumatology to begin treatment with Rituximab and mycophenolate mofetil for GLILD. While waiting for treatment with Rituxan, he developed high grade fever, headache, and body ache. He subsequently tested positive for COVID 19 (RT-PCR) through nasal swab. He slowly recovered without any complication at home. Of note the patient did have positive SAR-Cov-2 total antibody test: 207.3 [(0-0.9 index) (Roche ECLIA)] about 10 weeks after he tested positive for COVID-19. The patient eventually was able to start Rituximab infusion of 375 mg/m2 weekly for 4 weeks and completed four cycles of therapy without complication. He is now just on maintenance mycophenolate mofetil 1 gm and monthly IVIG and is doing well.