Abstract Rationale Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has been documented in immuno-compromised patients, especially in patients with hematologic malignancies. The understanding of peripheral and pulmonary immune response in these patients is limited. Methods We conducted a cohort analysis on hospitalized patients with persistent SARS-CoV-2 infection, defined as continuous PCR positive for more than 2 months, and presenting with persistent pulmonary symptoms and chest imaging abnormalities. Patients were recruited from two tertiary teaching hospitals in China. We also included recovered patients in convalescent stage as controls. Peripheral blood and bronchoalveolar lavage fluid samples were collected for further analysis. Results A total of 34 persistent infection patients were enrolled. All patients were deficient in B-cells in their peripheral blood and the majority (91.2%) had received anti-B-cell treatment. Therefore, they are termed chronic active SARS-CoV-2 infection in B-cell Immuno-deficiency (CASBI). There was an absence of antibody response against SARS-CoV-2. Although antigen-specific CD4+ and CD8+ T cell response was developed in CASBI patients, the total CD4+T cell count was significantly decreased, and the percentage of Tnaïve cells was lower but that of Treg was higher in CASBI patients than in convalescent controls. These patients also have slightly higher IL-6 and IL-10 levels than control. To further understand the pulmonary immune response in persistent SARS-CoV-2 infection, we collected paired BALF and peripheral blood sample from CASBI patients and convalescent controls for single-cell transcriptomic analysis. We found clonal expansion of a group of GZMK-expressing CD8+T cells in CASBI patients, which was absent in convalescent controls. These clonally-expanded GZMK+cells are recruited from the peripheral blood, and are predicted to be antigenically specific to SARS-CoV-2 according to their T-cell receptor sequences. They exhibit an inflammatory characteristic, and interact with cytotoxic CD8+T cells through CCL5-CCR5/CXCR3 axis. Conclusion We reported that SARS-CoV-2 may lead to persistent infection in patients with deficient B-cell response, tentatively termed CASBI. The combined defect in B-cell and CD4+ T-cell response cause delayed viral clearance in these patients. A group of GZMK-expressing CD8+T cells may be responsible for the inflammatory pulmonary environment in these patients, and serve as potential treatment target. This abstract is funded by: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, New Cornerstone Science Foundation, Beijing Natural Science Foundation, Distinguished Clinical Study Project, and Beijing Association for Science and Technology
Xu et al. (Fri,) studied this question.