SARS-CoV-2 Viral Replication Persists in the Human Lung for Several Weeks after Symptom Onset
Michele Tomasicchio, Shameem Z. Jaumdally, Lindsay Wilson, Andrea Kotze, Lynn Semple, Stuart Meier, Anil Pooran, Aliasgar Esmail, Komala Pillay, Riyaadh Roberts, Raymond Kriel, Richard Meldau, Suzette Oelofse, Carley Mandviwala, Jessica Burns, Rolanda Londt, Malika Davids, Charnay van der Merwe, Aqeedah Roomaney, Louié Kühn, Tahlia Perumal, Alex Scott, Martin Hale, Vicky L. Baillie, Sana Mahtab, Carolyn Williamson, R Joseph, Alex Sigal, I Joubert, Jenna Piercy, David Thomson, David Fredericks, Malcolm Miller, Marta C. Nunes, Shabir A. Madhi, Keertan Dheda
Abstract
Abstract Rationale In the upper respiratory tract, replicating (culturable) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recoverable for ∼4–8 days after symptom onset, but there is a paucity of data about the frequency and duration of replicating virus in the lower respiratory tract (i.e., the human lung). Objectives We undertook lung tissue sampling (needle biopsy) shortly after death in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patients served as a control group. Methods Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling, and immunohistochemistry. Measurements and Main Results Thirty-eight percent (16 of 42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 wk) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (P < 0.05). Nasopharyngeal culture was negative in 23.1% (6 of 26) of decedents despite lung culture positivity. This hitherto undescribed biophenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary proinflammatory response but with concurrent viral culture positivity. Conclusions Concurrent rather than sequential active viral replication continues to drive a heightened proinflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe coronavirus disease (COVID-19).