ARS-CoV-2 is the causal agent for COVID-19, and the World Health Organization classifies this virus as an airborne pathogen transmitted by asymptomatic, pre-symptomatic and symptomatic individuals through close contact via exposure to infected droplets and aerosols 1,2 . Although SARS-CoV-2 transmission can occur by activities involving the oral cavity, such as speaking, breathing, coughing, sneezing and even singing [3][4][5] , most attention has focused on the nasal-lung axis of infection 6 . Oral manifestations, such as taste loss, dry mouth and oral lesions, are evident in about half of COVID-19 cases [7][8][9] , although it remains unknown whether SARS-CoV-2 can directly infect and replicate in oral tissues, such as the salivary glands (SGs) or mucosa. This is critical because, if these are sites of early infection, they could play an important role in transmitting the virus to the lungs or the gastrointestinal tract via saliva, as has been suggested for other microbial-associated diseases, such as pneumonia 10 and inflammatory bowel diseases 11,12 (Extended Data Fig. 1a).SARS-CoV-2 uses host entry factors, such as ACE2 and TMPRSS family members (TMPRSS2 and TMPRSS4) 13,14 , and understanding the cell types that harbor these receptors is important for determining infection susceptibilities throughout the body [15][16][17] . ACE2 and TMPRSS2 expression has been reported in oral tissues 18,19 ; however, there are no comprehensive descriptions of viral entry factor expression nor direct confirmation of SARS-CoV-2 infection in oral tissues. We hypothesized that SGs and barrier epithelia of the oral cavity and oropharynx can be infected by SARS-CoV-2 and contribute to the transmission of SARS-CoV-2. To test this, we generated two human oral single-cell RNA sequencing (scRNA-seq) atlases to predict cell-specific susceptibilities to SARS-CoV-2 infection. We confirmed ACE2 and TMPRSS expression in SGs and oral mucosa epithelia. SARS-CoV-2 infection was confirmed using autopsy and outpatient samples. Saliva from asymptomatic individuals with COVID-19 demonstrated the potential for viral transmission. In a prospective clinical cohort, we found a positive correlation between salivary viral load and taste loss; we also demonstrated persistent salivary antibody responses to SARS-CoV-2 nucleocapsid and spike proteins. ResultsOral tissue atlases reveal resident immune cells and niche-specific epithelial diversity. The SGs and the barrier mucosa of the oral cavity and oropharynx are likely gateways for viral infection, replication SARS-CoV-2 infection of the oral cavity and saliva

Background The COVID-19 pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well-described. Methods We performed a multi-center cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. Results Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (IQR 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [aOR 3.0, 95%CI 1.7-5.5, p<0.001], congestive heart failure [aOR 3.2, 95%CI 1.4-7.0, p=0.004], chronic lung disease [aOR 2.5, 95%CI 1.2-5.2, p=0.018], obesity [aOR 1.9, 95% CI 1.0-3.4, p=0.039]) and presenting findings (lymphopenia [aOR 1.9, 95%CI 1.1-3.5, p=0.033], abnormal chest imaging [aOR 2.9, 95%CI 1.1-7.5, p=0.027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. Conclusions Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality.

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction 1 – 3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4 , 5 ). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain 3 , 6 – 14 . Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

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SummaryBackgroundInfluenza causes significant morbidity and mortality despite currently available treatments. Anecdotal reports suggest plasma with high antibody titers towards influenza may be of benefit in the treatment of severe influenza.MethodsWe conducted a randomized, open-label, multicenter phase 2 trial at 29 academic medical centers in the United States to assess the safety and efficacy of anti-influenza plasma with hemagglutination inhibition (HAI) antibody titers of ≥ 1:80 to the infecting strain. Hospitalized children and adults (including pregnant women) with severe influenza A or B (defined as hypoxia or tachypnea) were randomly assigned to receive either 2 units (or pediatric equivalent) of anti-influenza plasma plus standard care (P+S), versus standard care alone (S), and were followed for 28 days. The primary endpoint was time to normalization of patients’ respiratory status (respiratory rate of ≤ 20 for adults or age defined thresholds of 20–38 for children), and a room air saturation of oxygen ≥ 93%. ClinicalTrials.gov Identifier: NCT01052480FindingsBetween January 13, 2011 and March 2, 2015, 113 participants were screened, and 98 were randomized. Of the participants with confirmed influenza, 28 of 42 (67%) of P+S participants normalized their respiratory status by Day 28, as compared to 24 of 45 (53%) of S participants (p=0·069). The estimated hazard ratio comparing P+S to S was 1·71 (95% CI: 0·96 to 3·06). Six participants died, 1 (2%) and 5 (10%) from the P+S and S arms respectively (p=0·093). P+S participants had non-significant reductions in days in hospital (median 6 vs. 11 days, p=0·13) and days on mechanical ventilation (median 0 vs. 3 days, p=0·14), and significantly improved clinical status at Day 7 (p=0·020). Fewer P+S participants experienced SAEs compared to S recipients (20% vs. 38%, p= 0·041), the most frequent of which were acute respiratory distress syndrome (1 [2%] vs 2 [4%]) and stroke (1 [2%] vs 2 [4%]).InterpretationResults from this Phase II randomized trial of immune plasma for the treatment of severe influenza provides support for a possible benefit of immunotherapy across the primary and secondary endpoints. A Phase III randomized trial is now underway to further evaluate this intervention.

COVID-19 is known to cause multi-organ dysfunction1-3 in acute infection, with prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS-CoV-2 (PASC)4-5. However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain3,6-14. We performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple extrapulmonary tissues early in infection. Further, we detected SARS-CoV-2 RNA in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset. Despite extensive distribution of SARS-CoV-2 in the body, we observed a paucity of inflammation or direct viral cytopathology outside of the lungs. Our data prove that SARS-CoV-2 causes systemic infection and can persist in the body for months.

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Background We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. Methods In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov , NCT04501978 . Findings Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–...