We found that 66% of the COVID patients had thymus reactivation, associated with more severe pulmonary involvement but less mortality (8.6% versus 41.2%). These findings were not mentioned in previous reports of COVID-19-associated features, despite common thoracic CT-scan examination in patients with pulmonary symptoms. The emergency context in which scans of patients hospitalized in intensive care for severe forms of COVID-19 pneumonia were performed have probably contributed to underestimate changes occurring in the thymic area. Indeed, analysis of the CT-scan images of pulmonary parenchyma requires specific settings (for example, adjustment of grey levels), which are not suitable for mediastinum analysis causing a lack of contrast between the various mediastinal tissues.
In adults, thymus hyperplasia is rare and can be observed in a limited number of pathological conditions: auto-immune diseases such as myasthenia gravis  and Graves-Basedow disease , after high-dose chemotherapy associated or not with autologous stem cell transplantation ,, in lymphopenic human immunodeficiency virus (HIV)-infected patients with maintained naïve T-cell counts  or after antiretroviral therapy . In the setting of severe T-cell depletion, caused by HIV infection or cytoreductive transplant or chemotherapy regimens, thymus hyperplasia is critical for the restoration of peripheral T-cell populations .
In patients with severe forms of COVID-19, intense lymphopenia is frequent. In our study it was associated with overall reduced survival and inversely correlated with the intra-thymic proliferation of T-cell precursors. Together, these data indicate that the enhancement of thymic function observed in COVID patients is a beneficial adaptation to SARS-CoV-2-induced lymphopenia, associated with an increased thymic production. This adaptation, at least partly triggered by enhanced IL-7 levels, appears to decline in patients above 80y, likely contributing to the higher mortality observed among more senior patients. A similar progressive reduction of T-cell precursors with age was reported after autologous peripheral blood stem cell transplant , and in a systematic study of 1000 healthy individuals showing that age and sex strongly affect thymic function . Moreover, while potential genetic factors are currently under investigation in COVID-19 patients who develop severe forms despite the absence of risk factors, it should be noted that precursor T-cell proliferation is genetically determined ,. Surprisingly, contrarily to previous observations in lymphopenic patients, IL-7 plasma level was proportional to blood lymphocyte counts in COVID patients. This observation indicates that during acute SARS-Cov2 infection, high IL-7 plasma levels were not due to its low consumption by T-cells as previously suggested , but most probably originate from an active overproduction, as previously evidenced in acute SIV-infection in rhesus macaques . Contrary to thymic production, the actual size of thymus in CT-scans of patients belonging to subgroups A and B of thymus classification was not inversely correlated with lymphopenia. Nodular and/or minimal areas of hyperplastic thymus might be sufficient to restore an adequate amount of peripheral lymphocytes.
The finding that the pulmonary involvement of COVID-19 patients quantified by the CT-scan score was significantly higher in patients with thymus enlargement, appears contra-intuitive respective to data and hypotheses above. A plausible explanation of this apparent paradox is that in patients with an “activated productive” thymus, the influx of immune cell into infected lungs is different from that occurring in patients with “non-reactive” thymus. This hypothesis is supported by a recent study in which cells from broncho-alveolar lavage fluid of COVID-19 patients were characterized using single-cell RNA sequencing. Monocyte-derived inflammatory macrophages were found in severe forms of COVID-19 pneumonia contrasting with the clonal expansion of CD8+ T-cell effectors in mild cases, indicative of a role of CD8+ T-cells of the adaptive immune response in the clearance of SARS-CoV-2 .
This observational study, conducted in an emergency context, has some limitations. TRECs could only be evaluated in patients who were still hospitalized; some immunologic investigationq in the blood or broncho-alveolar lavage fluid had not been anticipated, and patient follow up was limited in time. Prospective studies will be necessary to further characterize the role of thymic function in the control of SARS-CoV-2 infection and the involved molecular and cellular mechanisms.