A deep learning framework for predicting the neutralizing activity of COVID-19 therapeutics and vaccines against evolving SARS-CoV-2 variants (preprint)

Understanding how viral variants evade neutralization is crucial for improving antibody-based treatments, especially with rapidly evolving viruses like SARS-CoV-2. Yet, conventional assays are limited in the face of rapid viral evolution, relying on a narrow set of viral isolates, and falling short in capturing the full spectrum of variants. To address this, we have developed a deep learning approach to predict changes in neutralizing antibody activity of COVID-19 therapeutics and vaccines against emerging viral variants. First, we trained a variational autoencoder (VAE) using all 67,885 unique SARS-CoV-2 spike protein sequences from the NCBI virus (up to October 31, 2022) database to encode spike protein variants into a latent space. Using this VAE and a curated dataset of 7,069 in vitro assay data points from the NCATS OpenData Portal, we trained a neural network regression model to predict fold changes in neutralizing activity of 40 COVID-19 therapeutics and vaccines against spike protein sequence variants, relative to their neutralizing activity against the ancestral strain (Wuhan-Hu-1). Our model also employs Bayesian inference to quantify prediction uncertainty, providing more nuanced and informative estimates. To validate the model\'s predictive capacity, we assessed its performance on a test set of in vitro assay data collected up to eight months after the data included in the model training (N = 980). The model accurately predicted fold changes in neutralizing activity for this prospective dataset, with an R2 of 0.77. Expanding our methodology to include all available data from NCBI virus and NCATS OpenData Portal up to date, we assessed predicted changes in activity for current COVID-19 monoclonal antibodies and vaccines against newly identified SARS-CoV-2 lineages. Our predictions suggest that current therapeutic and vaccine-induced antibodies will have significantly reduced activity against newer XBB descendants, notably EG.5, FL.1.5.1, and XBB.1.16. Using the model, we were able to primarily attribute the observed predicted loss in activity to the F456L spike mutation found in EG.5 and FL.1.5.1 sequences. Conversely, mRNA-bivalent vaccines are predicted to be less susceptible to the recent BA.2.86 variant compared to new XBB descendants. These findings align closely with recent research, underscoring the potential of deep learning in shaping therapeutic and vaccine strategies for emerging viral variants.

Physical activity and mental health during the COVID-19 pandemic among individuals with amputation.

The isolating nature of various COVID-19 mandates may have reduced physical activity (PA) and increased mental health symptomology among individuals with amputation. However, an investigation of mental health across PA levels before and after the onset of COVID-19 among this group has not been conducted. Therefore, the objective of this study was to investigate group differences in depression, anxiety, and post-traumatic stress symptomology among individuals with amputation who reported being physically "active," "somewhat active," or "inactivate" before and during the pandemic. Individuals with an amputation at any level (n = 91; 51% female; age = 52.5±15.5) completed an online questionnaire to assess demographic information, PA levels, and mental health throughout the pandemic. Group differences in self-reported PA before and after COVID-19 onset were assessed by the PA Guidelines for Americans recommendations. The Center for Epidemiologic Studies Depression Scale (CES-D), Generalized Anxiety Disorder (GAD-7), and Posttraumatic Stress Disorder Checklist (PCL-5) scales were used to assess group differences in mental health status. Before and after the onset of COVID-19, 33% and 42.9% of respondents reported that they were inactive, respectively. 58.2% of respondents reported decreased PA since the pandemic's onset. Prior to the pandemic, active individuals reported lower CES-D (14.21 vs. 19.07; Cohen's d: -0.414), GAD-7 (3.82 vs. 5.47; Cohen's d: -0.359), and PCL-5 (15.92 vs. 21.03; Cohen's d: -0.319) scores compared to inactive individuals. After the onset of COVID-19, scores remained lower for active respondents CES-D (12.67 vs. 20.03; Cohen's d: 0.-669), GAD-7 (3.17 vs. 5.87; Cohen's d: -0.598), and PCL-5 (13.39 vs. 19.90; Cohen's d: -0.430). Individuals with amputation reported decreased PA after the onset of COVID-19. Individuals reporting that they were "active" exhibited improved depression and anxiety symptomology scores compared to those reporting that they were "inactive."

Outcomes of Prone Positioning in Mechanically Ventilated COVID-19 patients: A Prospective Observational Study (preprint)

Introduction Prone positioning in mechanically ventilated patients with severe acute respiratory distress syndrome (ARDS) is associated with improved mortality. More data is needed to fully understand its utility in those with ARDS due to COVID-19.Methods We conducted a single center prospective observational study inclusive of 100 consecutive patients intubated for ARDS from COVID-19 admitted to the ICU from September 2020 to December 2020. Data was collected daily from time of intubation for 7 days along with 30-day outcomes.Results The study included a total of 53 patients proned and 47 non-proned during their hospitalization. Proned patients were 61.8 years old, and 56.6% men compared to 66.3 years old and 57.4% male in the non-proned group. Other baseline characteristics and treatments were similar between both groups other than proned patients having a higher BMI than non-proned patients (34.1 ± 7.5 vs 30.5 ± 7.4, p = 0.02), and lower initial P/F ratios (119.1 ± 54.5 vs 154.0 ± 92.7, p = 0.047). Proned patients required more neuromuscular blockade (OR 6.63, 95% CI 3.25–13.12, p < 0.0001) and higher sedation levels (2 sedatives: OR = 3.00, 95% CI = 1.77,5.08; ≥3 sedatives: OR = 7.13, 95% CI = 3.96,12.81) with similar ICU length of stays, ventilator days, newly initiated renal replacement therapy, and 30-day outcomes when compared to non-proned patients. Proned patients were re-intubated substantially less than the non-proned group (1.9% vs 19.1%, p = 0.006).Conclusion Proning mechanically ventilated COVID-19 patients was associated with more frequent use of neuromuscular blockade and sedation, and required significantly lower rates of re-intubation for respiratory failure when compared to non-proned patients.

Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients.

Mechanisms of neutrophil involvement in severe coronavirus disease 2019 (COVID-19) remain incompletely understood. Here, we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls and perform bulk RNA sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between six distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G1 (IgG1)-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.

Rapid initiation of nasal saline irrigation to reduce severity in high-risk COVID+ outpatients.

OBJECTIVE: To determine whether initiating saline nasal irrigation after COVID-19 diagnosis reduces hospitalization and death in high-risk outpatients compared with observational controls, and if irrigant composition impacts severity. METHODS: Participants 55 and older were enrolled within 24 hours of a + PCR COVID-19 test between September 24 and December 21, 2020. Among 826 screened, 79 participants were enrolled and randomly assigned to add 2.5 mL povidone-iodine 10% or 2.5 mL sodium bicarbonate to 240 mL of isotonic nasal irrigation twice daily for 14 days. The primary outcome was hospitalization or death from COVID-19 within 28 days of enrollment by daily self-report confirmed with phone calls and hospital records, compared to the CDC Surveillance Dataset covering the same time. Secondary outcomes compared symptom resolution by irrigant additive. RESULTS: Seventy-nine high-risk participants were enrolled (mean [SD] age, 64 [8] years; 36 [46%] women; 71% Non-Hispanic White), with mean BMI 30.3. Analyzed by intention-to-treat, by day 28, COVID-19 symptoms resulted in one ED visit and no hospitalizations in 42 irrigating with alkalinization, one hospitalization of 37 in the povidone-iodine group, (1.27%) and no deaths. Of nearly three million CDC cases, 9.47% were known to be hospitalized, with an additional 1.5% mortality in those without hospitalization data. Age, sex, and percentage with pre-existing conditions did not significantly differ by exact binomial test from the CDC dataset, while reported race and hospitalization rate did. The total risk of hospitalization or death (11%) was 8.57 times that of enrolled nasal irrigation participants (SE = 2.74; P = .006). Sixty-two participants completed daily surveys (78%), averaging 1.8 irrigations/day. Eleven reported irrigation-related complaints and four discontinued use. Symptom resolution was more likely for those reporting twice daily irrigation (X2 = 8.728, P = .0031) regardless of additive. CONCLUSION: SARS-CoV-2+ participants initiating nasal irrigation were over 8 times less likely to be hospitalized than the national rate.

PUBLIC PERCEPTIONS OF TEST TRACE PROTECT WALES: UNDERSTANDING AND IMPROVING SELF-ISOLATION ADHERENCE

Introduction: Despite the ongoing roll-out of the vaccination programme in Wales, self-isolation remains a crucial strategy to reduce transmission of COVID-19, especially as cases remain high. Test, Trace, Protect (TTP) is Wales' contact tracing programme where people are asked to isolate and provided with information and resources. Public Health Wales ran a real-time text message survey of contacts of cases of COVID-19 to provide insight as people were starting a period of self-isolation after notification from NHS Wales Test Trace Protect (Adherence Confidence Text Survey (ACTS)). This research study was designed to investigate what those being asked to self-isolate felt was good about their experience with TTP and what do they feel could be done better based on their text responses. Method: Text responses between 15th November 2020 and 2nd May 2021 (N = 12,092) were analysed using an automated content analysis (ACA) and sentiment analysis using the software Leximancer. Next, we conducted a qualitative thematic analysis using the software NVivo to explore further the findings of the ACA, as well as to look more deeply into some of the reasons behind people's views of TTP at two time periods for comparison, T1: 15th November- 5th December 2020 (n=2956) and T2: 1st March - 31st 2021 (n = 515). Results: ACA revealed that there were substantially more (roughly ten times as many) instances of favorable (positive affective) (n=4,963) terms within the data than unfavorable (negative affective) (n=425). NVivo analysis were in keeping with this finding as the majority reported a positive experience with TTP (T1 N = 1717, 58%;T2 N = 355, 69%). One of the sources of confusion was the date of the end of required isolation (T1 N= 101, 3.4%;T2 N = 11, 2.1%) though clarity improved from T1 to T2. Another concern was the time it took to be contacted following a positive test (T1 N = 205, 6.9%, T2 N = 14, 2.7%) again improving with time. Less than 1% reported financial concerns at both time periods. Conclusions: The Welsh population responding to the text sent by PHW had a positive experience with TTP. Automated content analysis is a viable method to process large datasets of qualitative content such as text responses.

Impacts of the COVID-19 pandemic on pharmaceuticals in wastewater treated for beneficial reuse: Two case studies in central Pennsylvania.

During the COVID-19 pandemic, wastewater surveillance was leveraged as a powerful tool for monitoring community-scale health. Further, the well-known persistence of some pharmaceuticals through wastewater treatment plants spurred concerns that increased usage of pharmaceuticals during the pandemic would increase the concentrations in wastewater treatment plant effluent. We collected weekly influent and effluent samples from May 2020 through May 2021 from two wastewater treatment plants in central Pennsylvania, the Penn State Water Reclamation Facility and the University Area Joint Authority, that provide effluent for beneficial reuse, including for irrigation. Samples were analyzed for severe acute respiratory syndrome coronavirus 2 (influent only), two over-the-counter medicines (acetaminophen and naproxen), five antibiotics (ampicillin, doxycycline, ofloxacin, sulfamethoxazole, and trimethoprim), two therapeutic agents (remdesivir and dexamethasone), and hydroxychloroquine. Although there were no correlations between pharmaceutical and virus concentration, remdesivir detection occurred when the number of hospitalized patients with COVID-19 increased, and dexamethasone detection co-occurred with the presence of patients with COVID-19 on ventilators. Additionally, Penn State decision-making regarding instruction modes explained the temporal variation of influent pharmaceutical concentrations, with detection occurring primarily when students were on campus. Risk quotients calculated for pharmaceuticals with known effective and lethal concentrations at which 50% of a population is affected for fish, daphnia, and algae were generally low in the effluent; however, some acute risks from sulfamethoxazole were high when students returned to campus. Remdesivir and dexamethasone persisted through the wastewater treatment plants, thereby introducing novel pharmaceuticals directly to soils and surface water. These results highlight connections between human health and water quality and further demonstrate the broad utility of wastewater surveillance.

COVID-19 Vaccination Intention in a Community Cohort in Ponce, Puerto Rico.

As of January 20, 2022, > 247,000 confirmed COVID-19 cases and 3,400 deaths were reported in Puerto Rico (PR). We interviewed participants aged ≥ 14 years in the Communities Organized to Prevent Arboviruses (COPA) study, a community-based cohort in PR, about COVID-19 vaccine intention from November 12, 2020, to June 25, 2021. We used univariate and adjusted analyses to identify participant characteristics associated with vaccine intention. Among 1,542 respondents, the median age was 37 years (interquartile range 23-45) and 914 (59%) were female. Most participants (83%) reported a willingness to receive a COVID-19 vaccine. The most common reason for vaccine hesitancy was concern about the safety or side effects (64%). Willingness to receive the COVID-19 vaccine was associated with a later interview date, higher household income, previous COVID-19 diagnosis among household members, COVID-19 risk perception, influenza vaccine uptake, dengue vaccine intention, and general positive perceptions of vaccines. While parents with minors (< 21 years old) were less likely to report vaccine intention for themselves than participants without minor children, we observed similar characteristics associated with parents' willingness to vaccinate their children. Overall, COVID-19 vaccine intention was high among COPA participants. It is important that public health messaging in PR addresses COVID-19 vaccine safety and possible side effects.

The Kinetics of SARS-CoV-2 Antibody Development Is Associated with Clearance of RNAemia.

Persistent SARS-CoV-2 replication and systemic dissemination are linked to increased COVID-19 disease severity and mortality. However, the precise immune profiles that track with enhanced viral clearance, particularly from systemic RNAemia, remain incompletely defined. To define whether antibody characteristics, specificities, or functions that emerge during natural infection are linked to accelerated containment of viral replication, we examined the relationship of SARS-CoV-2-specific humoral immune evolution in the setting of SARS-CoV-2 plasma RNAemia, which is tightly associated with disease severity and death. On presentation to the emergency department, S-specific IgG3, IgA1, and Fc-γ-receptor (Fcγ R) binding antibodies were all inversely associated with higher baseline plasma RNAemia. Importantly, the rapid development of spike (S) and its subunit (S1/S2/receptor binding domain)-specific IgG, especially FcγR binding activity, were associated with clearance of RNAemia. These results point to a potentially critical and direct role for SARS-CoV-2-specific humoral immune clearance on viral dissemination, persistence, and disease outcome, providing novel insights for the development of more effective therapeutics to resolve COVID-19. IMPORTANCE We showed that persistent SARS-CoV-2 RNAemia is an independent predictor of severe COVID-19. We observed that SARS-CoV-2-targeted antibody maturation, specifically Fc-effector functions rather than neutralization, was strongly linked with the ability to rapidly clear viremia. This highlights the critical role of key humoral features in preventing viral dissemination or accelerating viremia clearance and provides insights for the design of next-generation monoclonal therapeutics. The main key points will be that (i) persistent SARS-CoV-2 plasma RNAemia independently predicts severe COVID-19 and (ii) specific humoral immune functions play a critical role in halting viral dissemination and controlling COVID-19 disease progression.

Telemedicine and Plastic Surgery: Principles from the American Society of Plastic Surgeons Health Policy Committee.

SUMMARY: In the wake of the recent coronavirus disease of 2019 public health emergency, care delivery by means of telemedicine using audiovisual virtual platforms has become an important tool for patient communication. There are many logistic, medicolegal, and practical aspects of telemedicine that should be considered by the practicing plastic surgeon. Successful virtual patient interactions require an understanding of medical licensure requirements to perform telemedicine visits in a certain region. In addition, it is imperative to be familiar with specific liability and malpractice concerns, in addition to Health Insurance Portability and Accountability Act regulations before conducting electronic visits. During consultations, providers should be aware of proper physician conduct and the potential role of chaperones. Furthermore, appropriate visit documentation, in addition to telemedicine billing and coding, has to be ensured. Lastly, plastic surgeons should adhere to the rules of controlled substance prescription by means of telemedicine platforms. This article describes these salient topics surrounding telemedicine visits that are faced by plastic surgeons and discusses strategies to optimize and ensure safe use of virtual platforms.

Early Experiences With COVID-19 Testing in Transplantation.

BACKGROUND: The early effects of coronavirus disease 2019 (COVID-19) on transplantation are dramatic: >75% of kidney and liver programs are either suspended or operating under major restrictions. To resume transplantation, it is important to understand the prevalence of COVID-19 among transplant recipients, donors, and healthcare workers (HCWs) and its associated mortality. METHODS: To investigate this, we studied severe acute respiratory syndrome coronavirus 2 diagnostic test results among patients with end-stage renal disease or kidney transplants from the Johns Hopkins Health System (n = 235), and screening test results from deceased donors from the Southwest Transplant Alliance Organ Procurement Organization (n = 27), and donors, candidates, and HCWs from the National Kidney Registry and Viracor-Eurofins (n = 253) between February 23 and April 15, 2020. RESULTS: We found low rates of COVID-19 among donors and HCWs (0%-1%) who were screened, higher rates of diagnostic tests among patients with end-stage renal disease or kidney transplant (17%-20%), and considerable mortality (7%-13%) among those who tested positive. CONCLUSIONS: These findings suggest the threat of COVID-19 for the transplant population is significant and ongoing data collection and reporting is critical to inform transplant practices during and after the pandemic.

Long-term ecological research and the COVID-19 anthropause: A window to understanding social-ecological disturbance.

The period of disrupted human activity caused by the COVID-19 pandemic, coined the "anthropause," altered the nature of interactions between humans and ecosystems. It is uncertain how the anthropause has changed ecosystem states, functions, and feedback to human systems through shifts in ecosystem services. Here, we used an existing disturbance framework to propose new investigation pathways for coordinated studies of distributed, long-term social-ecological research to capture effects of the anthropause. Although it is still too early to comprehensively evaluate effects due to pandemic-related delays in data availability and ecological response lags, we detail three case studies that show how long-term data can be used to document and interpret changes in air and water quality and wildlife populations and behavior coinciding with the anthropause. These early findings may guide interpretations of effects of the anthropause as it interacts with other ongoing environmental changes in the future, particularly highlighting the importance of long-term data in separating disturbance impacts from natural variation and long-term trends. Effects of this global disturbance have local to global effects on ecosystems with feedback to social systems that may be detectable at spatial scales captured by nationally to globally distributed research networks.

Impact of the COVID-19 Pandemic on the Wellness of Canadian Plastic Surgery Residents.

On top of preexisting burnout, depression, and anxiety among trainees, the COVID-19 pandemic has introduced novel stressors. The objectives of this study were to determine the effects of the COVID-19 pandemic on Canadian plastic surgery residents' practice, wellness, and overall training. Methods: Surveys for program directors and residents were created and disseminated to all English-speaking Canadian plastic surgery residency training programs. Survey results were pooled and presented as a percentage of responses for each question. Results: Response rates were 50% (n = 5/10) and 25% (n = 19/77) for program directors and residents, respectively. All program directors believed that the pandemic has a negative effect on resident wellness, 80% (n = 4/5) of which believed that their residents were coping effectively. They rated program support for resident wellness as neutral or supportive. Most programs (80%; n = 4/5) introduced strategies to support resident well-being. Most trainees (84%; n = 16/19) reported the pandemic as having a negative effect on their well-being, with approximately 50% endorsing worse emotional, social, psychological, and physical wellness, as well as feelings of burnout. Some reported difficulties coping (21%; n = 4/19). Residents felt that their wellness was supported externally by their own resilience (89%; n = 17/19), family members (74%; n = 14/19), friends (74%; n = 14/19), their partner (68%; n = 13/19), or co-residents (53%; n = 10/19). Internal support by their program was rated as neutral or negative (63%; n = 12/19). Conclusions: Our findings of negative effects of the COVID-19 pandemic on the wellness of Canadian plastic surgery trainees are concerning. Programs must implement appropriate identification and support strategies to improve resident well-being.

Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions.

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

Prevention Research Centers and COVID-19: Models of a Community-Engaged Response to a Public Health Emergency.

For more than 30 years, the network of Centers for Disease Control and Prevention (CDC)-funded Prevention Research Centers (PRCs) has worked with local communities and partners to implement and evaluate public health interventions and policies for the prevention of disease and promotion of health. The COVID-19 pandemic tested the PRC network's ability to rapidly respond to multiple, simultaneous public health crises. On April 28, 2020, to assess the network's engagement with activities undertaken in response to the early phase of the pandemic, PRC network leadership distributed an online survey to the directors of 34 currently or formerly funded PRCs, asking them to report their PRCs' engagement with predetermined activities across 9 topical areas and provide case studies exemplifying that engagement. We received responses from 24 PRCs, all of which reported engagement with at least 1 of the 9 topical areas (mean, 5). The topical areas with which the greatest number of PRCs reported engagement were support of frontline agencies (21 of 24, 88%) and support of activities related to health care (21 of 24, 88%). The mean number of activities with which PRCs reported engagement was 11. The PRCs provided more than 90 case studies exemplifying their work. The results of the survey indicated that the PRCs mobilized their personnel and resources to support the COVID-19 response in less than 6 weeks. We posit that the speed of this response was due, in part, to the broad and diverse expertise of PRC personnel and long-standing partnerships between PRCs and the communities in which they work.

Alveolar, Endothelial, and Organ Injury Marker Dynamics in Severe COVID-19.

Rationale: Alveolar and endothelial injury may be differentially associated with coronavirus disease (COVID-19) severity over time. Objectives: To describe alveolar and endothelial injury dynamics and associations with COVID-19 severity, cardiorenovascular injury, and outcomes. Methods: This single-center observational study enrolled patients with COVID-19 requiring respiratory support at emergency department presentation. More than 40 markers of alveolar (including receptor for advanced glycation endproducts [RAGE]), endothelial (including angiopoietin-2), and cardiorenovascular injury (including renin, kidney injury molecule-1, and troponin-I) were serially compared between invasively and spontaneously ventilated patients using mixed-effects repeated-measures models. Ventilatory ratios were calculated for intubated patients. Associations of biomarkers with modified World Health Organization scale at Day 28 were determined with multivariable proportional-odds regression. Measurements and Main Results: Of 225 patients, 74 (33%) received invasive ventilation at Day 0. RAGE was 1.80-fold higher in invasive ventilation patients at Day 0 (95% confidence interval [CI], 1.50-2.17) versus spontaneous ventilation, but decreased over time in all patients. Changes in alveolar markers did not correlate with changes in endothelial, cardiac, or renal injury markers. In contrast, endothelial markers were similar to lower at Day 0 for invasive ventilation versus spontaneous ventilation, but then increased over time only among intubated patients. In intubated patients, angiopoietin-2 was similar (fold difference, 1.02; 95% CI, 0.89-1.17) to nonintubated patients at Day 0 but 1.80-fold higher (95% CI, 1.56-2.06) at Day 3; cardiorenovascular injury markers showed similar patterns. Endothelial markers were not consistently associated with ventilatory ratios. Endothelial markers were more often significantly associated with 28-day outcomes than alveolar markers. Conclusions: Alveolar injury markers increase early. Endothelial injury markers increase later and are associated with cardiorenovascular injury and 28-day outcome. Alveolar and endothelial injury likely contribute at different times to disease progression in severe COVID-19.

Severe COVID-19 infection is associated with aberrant cytokine production by infected lung epithelial cells rather than by systemic immune dysfunction (preprint)

The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation or over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 to FiO2) as a physiologic measure of disease severity. Machine learning algorithms integrating 139 parameters identified IL-6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti-IL6-R antibody treatment. However, transcripts encoding these cytokines were not detected among circulating immune cells. Rather, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL-6 and CCL2 were dominantly produced by infected lung type II pneumocytes. Severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. These results refine our understanding of severe COVID-19 pathophysiology, indicating that aberrant cytokine production by infected lung epithelial cells is a major driver of immunopathology. We propose that these factors cause local immune regulation towards the benefit of the virus.

Influenza and SARS-CoV-2 Co-infections in California, USA, September 2020-April 2021.

During September 1, 2020-April 30, 2021, the California Department of Public Health, Richmond, California, USA, received 255 positive influenza molecular test results that matched with severe acute respiratory syndrome coronavirus 2 molecular test results; 58 (23%) persons were co-infected. Influenza activity was minimal in California, and co-infections were sporadic.