A new study conducted by researchers from Weill Cornell Medicine, New York – USA has found SARS-CoV-2 viral presence in the lung up to 359 days after acute phase of disease, even in patients with negative nasopharyngeal swab tests.
The study findings were published on a preprint server and are currently being peer reviewed.
Our analysis of post-mortem lung tissue from the microanatomical to single-cell level with multiplexed imaging provides a thorough examination of acute infection and host response, as well as the chronic pathological processes that manifest at long-term after acute infection.
In post-acute COVID-19 (PC) patients followed for a period of up to 399 days, we identified surprisingly persistent loss of lung lacunarity (as a proxy for pulmonary capacity), fibrosis, and perturbed immune and structural cellular components of the lung. Of particular note, we identified persistent presence of SARS-CoV-2 epitopes in the lung of PC patients, which did not necessarily agree with the status of the last nasopharyngeal test of the patients.
It however agrees with recent reports showing viral factors present in circulation43 and in the gut44 of PASC patients. We also observed that SARS-CoV-2 presence is linked with the activation of senescence in AT-2, mesenchymal, endothelial, and fibroblast cells as detected by the upregulation of p16INK4A, uPAR, and IL-6 which is part of the senescence associated secretory profile (SASP).
SARS-CoV-2 induction of senescence in AT-2 cells had been suggested in acute disease45–47, but its long-term persistence after the acute disease raises the question of whether AT-2 senescence provides a reservoir for SARS-CoV-2 -something that would require future validation using viral replication assays.
Furthermore, the fact that mesenchymal cells in addition to AT-2s display increased senescence suggests a “double-hit” for the maintenance of epithelial cells in the lung since they can promote AT-2 self-renewal48,49 and relieve AT-2 senescence50.
Overall, we observed that PC cases showed distinct features in comparison to healthy lung or acute COVID-19, with extensive derangement of the vascular network characterized by increased microvascularization and NET-induced vascular damage. Thrombosis as well as intussusceptive and sprouting angiogenesis have been found in acute COVID-1951 at higher levels than in Influenza patients.
The fact that in our data we find the level of vascular derangement higher in post-acute than in acute COVID-19 suggests that vascular remodeling is a continuously acting process during post-acute COVID disease.
While UIP/IPF and sequelae of SARS-CoV-2 infection develop at largely different time scales (years and months respectively), we identified several common aspects between the diseases such as increased fibrosis and fibroblast abundance, vascular remodeling, increase of Mast cells, and upregulation of CC16/SCGB1A1 secretion.
Mast cells play a pivotal role in IPF, with particular importance to the establishment of the fibrotic phenotype52,53. Mast cell involvement in PASC has been suggested based on comparative analysis of symptomatic questionnaires54 and molecular analysis of circulatory factors55.
The secreted Club cell marker CC16/SCGB1A1 is overexpressed in IPF42 but it was recently linked to negative regulation of the microbial response of alveolar macrophages. This feedback may however not function similarly in the host response to COVID-19 which is characterized by high influx of interstitial macrophages to the lung and may not be responsive to CC16 inhibition.
Overall, our comparative analysis suggests that while pathologically distinct entities, prolonged lung disease after acute COVID-19 may depend on the use of common features as IPF. Our study’s use of tissue from fatal cases of post-acute COVID-19 patients may not allow complete extrapolation to the full diversity of the PASC syndrome.
It does however represent an extremely timely and valuable resource to study lung pathology of acute and post-acute COVID-19 from the microanatomical to single cell level and highlights persistent pathological derangement of lung structure in patients with prolonged lung disease post-acute COVID-19.