Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19

The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.Graphical AbstractIn BriefIn severe COVID-19 cytotoxic CD4+ T cells accumulate in draining lymph nodes and in the lungs during the resolving phase of the disease. Re-activated cytotoxic CD4+ T cells and cytotoxic CD8+ T cells are present in roughly equivalent numbers in the lungs at this stage and these cells likely collaborate to eliminate virally infected cells and potentially induce fibrosis. A large fraction of epithelial and endothelial cells in the lung express HLA class II in COVID-19 and there is temporal convergence between CD4+CTL accumulation and apoptosis in the lung.HighlightsIn severe COVID-19, activated CD4+ CTLs accumulate in the lungs late in diseaseThese cells likely participate in SARS-CoV-2 clearance, collaborating with CD8+ T cells many of which exhibit an exhausted phenotypeT cells likely contribute to the late exacerbation of inflammationCD4+CTLs have been linked to fibrosis in many disorders and could also be responsible for the eventual induction of fibrosis in a subset of COVID-19 patientsSummaryThe contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.

Effects of Prone Ventilation on Oxygenation, Inflammation, and Lung Infiltrates in COVID-19 Related Acute Respiratory Distress Syndrome: A Retrospective Cohort Study

Patients receiving mechanical ventilation for coronavirus disease 2019 (COVID-19) related, moderate-to-severe acute respiratory distress syndrome (CARDS) have mortality rates between 76–98%. The objective of this retrospective cohort study was to identify differences in prone ventilation effects on oxygenation, pulmonary infiltrates (as observed on chest X-ray (CXR)), and systemic inflammation in CARDS patients by survivorship and to identify baseline characteristics associated with survival after prone ventilation. The study cohort included 23 patients with moderate-to-severe CARDS who received prone ventilation for ≥16 h/day and was segmented by living status: living (n = 6) and deceased (n = 17). Immediately after prone ventilation, PaO2/FiO2 improved by 108% (p < 0.03) for the living and 150% (p < 3 × 10−4) for the deceased. However, the 48 h change in lung infiltrate severity in gravity-dependent lung zones was significantly better for the living than for the deceased (p < 0.02). In CXRs of the lower lungs before prone ventilation, we observed 5 patients with confluent infiltrates bilaterally, 12 patients with ground-glass opacities (GGOs) bilaterally, and 6 patients with mixed infiltrate patterns; 80% of patients with confluent infiltrates were alive vs. 8% of patients with GGOs. In conclusion, our small study indicates that CXRs may offer clinical utility in selecting patients with moderate-to-severe CARDS who will benefit from prone ventilation. Additionally, our study suggests that lung infiltrate severity may be a better indicator of patient disposition after prone ventilation than PaO2/FiO2.

Pulmonary Silicosis Presents with Pleural Effusion

Silica and silicate mineral dust inhalation can cause a variety of histopathological changes in the lungs and pleura. These include pulmonary silicotic nodules, interstitial infiltrate, fibrosis, and pleural thickening. Pleural effusion is an extremely rare presentation of silicosis. To our best knowledge, there have been only 2 cases of silicosis with pleural effusion reported in medical literature. Herein, we describe a case of a 77-year-old male with almost 50 years’ history of occupational silica exposure. He presented with a 4-week history of exertional shortness of breath. He is a lifetime nonsmoker, with no known other significant pulmonary disease. He had chest X-ray which showed a right lung infiltrate and bilateral pleural thickening and effusion. Chest CT showed moderate-sized bilateral pleural effusion and thickening with multiple bilateral intrapulmonary nodules seen. He had undergone extensive workup and was diagnosed with silicosis.

Drug therapy for children with tuberculosis

The scientific basis of drug treatment for both active tuberculosis (TB) disease and TB infection, has been established, with treatment in children being largely extrapolated from adult active disease trials. It is essential that active TB disease is excluded before asymptomatic TB infection is diagnosed and treated. Nearly half of all children with active TB disease are found as asymptomatic tuberculin, or interferon gamma release assay (IGRA), positive contacts on screening by local TB services, usually of sputum TB microscopy positive adult relatives or other index cases, but with evidence of lung infiltrate or mediastinal lymphadenopathy on the child's chest x-ray. New drug regimens for both active disease and latent infection are in development, and also some novel drugs. However, none of these have yet been tested in children, and so again data will need to be extrapolated from adult results. In addition, there are issues regarding pharmacokinetics and dosing for current drugs, particularly isoniazid.