The immunopathogenesis of severe COVID-19 is incompletely understood. In contradistinction to the upper respiratory tract where replicating (culturable) SARS-CoV-2 is recoverable approximately ~ 4 to 8 days after symptom onset, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (the human lung). We undertook lung tissue sampling (needle biopsy), within ~2 hours of death, in 42 mechanically ventilated decedents during the Beta and Delta waves. Lung biopsy cores underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling, immunohistochemistry and cell-based flow cytometry of deconstructed tissue. 38% (16/42) of patients had culturable virus in the lung (persisting for up to 4 weeks after symptom onset). This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced pulmonary pro-inflammatory response and variant-specific increased rates of bacterial bronchopneumonia and accelerated death. These findings question existing paradigms and suggest that in a subset of patients, concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response. Our findings have potential implications for the design of therapeutic interventional strategies and clinical management of severe COVID-19 disease.

/pdf/sars-cov-2-viral-replication-persists-in-the-human-lung-for-1dgdgepq.pdf

SARS-CoV-2 viral replication persists in the human lung for several weeks after onset of symptomatic severe COVID-19 and is associated with attenuated pulmonary immunity and variant-specific clinical sequalae

Public health emergencies, from Zika to COVID-19, have underscored the importance of addressing the needs of pregnant people and their infants. Recent events have underlined the critical role of mother-infant-linked longitudinal surveillance to characterize and assess the impacts of emerging, re-emerging, and persistent threats, including infectious diseases, on these populations. In partnership with state, local, and territorial health departments, CDC's National Center on Birth Defects and Developmental Disabilities activated the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET) to capture information about pregnant people with laboratory-confirmed infection with SARS-CoV-2 (the virus that causes COVID-19) and their infants. SET-NET data were critical in recognizing the severe risks of COVID-19 during pregnancy, which ultimately informed clinical decisions and public health policy, specifically vaccine prioritization at the local, state, and national levels. This commentary describes the activation of SET-NET to monitor COVID-19 in pregnancy and highlights the experiences of health departments. We provide examples of how SET-NET findings informed COVID-19 prevention efforts and public health policy. Lastly, we identify opportunities to improve and advance surveillance efforts to protect the health of pregnant people and their infants in the United States from current and future threats.

Population-Based Linked Longitudinal Surveillance of Pregnant People and Their Infants: A Critical Resource for Emerging, Re-Emerging, and Persistent Threats.

RATIONALE
In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for ~ 4 to 8 days after symptom onset, however, there is paucity of data about the frequency or 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 patents served as a control group.


METHODS
Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry.


RESULTS
38% (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) 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% (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity.


CONCLUSIONS
Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory 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 COVID-19 disease. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

SARS-CoV-2 Viral Replication Persists in the Human Lung for Several Weeks after Symptom Onset.

COVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where the human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an ex vivo human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors, reflecting the heterogeneity of human populations. In particular, two cytokines (IP-10 and IL-8) were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei, not only inhibited virus replication but also production of pro-inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs. SIGNIFICANCE Here we established an ex vivo human precision-cut lung slice platform for assessing SARS-CoV-2 infection, viral replication kinetics, innate immune response, disease progression, and antiviral drugs. Using this platform, we identified early induction of specific cytokines, especially IP-10 and IL-8, as potential predictors for severe COVID-19, and uncovered a hitherto unrecognized phenomenon that while infectious virus disappears at late times of infection, viral RNA persists and lung histopathology commences. This finding may have important clinical implications for both acute and post-acute sequelae of COVID-19. This platform recapitulates some of the characteristics of lung disease observed in severe COVID-19 patients and is therefore a useful platform for understanding mechanisms of SARS-CoV-2 pathogenesis and for evaluating the efficacy of antiviral drugs.

/pdf/an-ex-vivo-human-precision-cut-lung-slice-platform-provides-2f4ww27v.pdf

An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy

Coronavirus disease 2019 (COVID-19) has claimed millions of lives since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and lung disease appears the primary cause of death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an 

An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy

The Surveillance for Emerging Threats to Mothers and Babies Network conducts longitudinal surveillance of pregnant persons in the United States with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection during pregnancy. Of 6,551 infected pregnant persons in this analysis, 142 (2.2%) had positive RNA tests >90 days and up to 416 days after infection.

/pdf/recurrent-sars-cov-2-rna-detection-after-covid-19-illness-25cz00no.pdf

Recurrent SARS-CoV-2 RNA Detection after COVID-19 Illness Onset during Pregnancy

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Recurrent SARS-CoV-2 RNA Detection after COVID-19 Illness Onset during Pregnancy