Serological response to vaccination in post-acute sequelae of COVID.

BACKGROUND: Individuals with post-acute sequelae of COVID (PASC) may have a persistence in immune activation that differentiates them from individuals who have recovered from COVID without clinical sequelae. To investigate how humoral immune activation may vary in this regard, we compared patterns of vaccine-provoked serological response in patients with PASC compared to individuals recovered from prior COVID without PASC. METHODS: We prospectively studied 245 adults clinically diagnosed with PASC and 86 adults successfully recovered from prior COVID. All participants had measures of humoral immunity to SARS-CoV-2 assayed before or after receiving their first-ever administration of COVID vaccination (either single-dose or two-dose regimen), including anti-spike (IgG-S and IgM-S) and anti-nucleocapsid (IgG-N) antibodies as well as IgG-S angiotensin-converting enzyme 2 (ACE2) binding levels. We used unadjusted and multivariable-adjusted regression analyses to examine the association of PASC compared to COVID-recovered status with post-vaccination measures of humoral immunity. RESULTS: Individuals with PASC mounted consistently higher post-vaccination IgG-S antibody levels when compared to COVID-recovered (median log IgG-S 3.98 versus 3.74, P < 0.001), with similar results seen for ACE2 binding levels (median 99.1 versus 98.2, P = 0.044). The post-vaccination IgM-S response in PASC was attenuated but persistently unchanged over time (P = 0.33), compared to in COVID recovery wherein the IgM-S response expectedly decreased over time (P = 0.002). Findings remained consistent when accounting for demographic and clinical variables including indices of index infection severity and comorbidity burden. CONCLUSION: We found evidence of aberrant immune response distinguishing PASC from recovered COVID. This aberrancy is marked by excess IgG-S activation and ACE2 binding along with findings consistent with a delayed or dysfunctional immunoglobulin class switching, all of which is unmasked by vaccine provocation. These results suggest that measures of aberrant immune response may offer promise as tools for diagnosing and distinguishing PASC from non-PASC phenotypes, in addition to serving as potential targets for intervention.

Noncardiovascular Disease and Critical Care Delivery in a Contemporary Cardiac and Medical Intensive Care Unit.

BACKGROUND: Noncardiovascular comorbidities and critical illness are increasing in cardiovascular intensive care units (CICUs). There are limited data comparing critical care delivery, resource utilization, and costs between contemporary CICUs and medical intensive care units (MICUs). METHODS: All CICU (n = 6967; 22 748 patient-days) and MICU (n = 10 892; 39 211 patient-days) admissions to Cedars-Sinai Medical Center, a tertiary care academic medical center, between January 2011 and December 2016 were reviewed. Both the CICU and MICU admitted patients for primary cardiovascular or medical conditions during the study period, but not for postoperative surgical care. RESULTS: Patients admitted to the CICU were more frequently older, male, and had more preexisting cardiac disease ( P < .0001). More than one-fifth (21.4%) of CICU patients had a noncardiovascular primary admission diagnosis, compared to 89.2% of MICU patients. Cardiovascular intensive care unit patients had lower Acute Physiology and Chronic Health Evaluation III scores (51.1 [19.9] vs 61.1 [24.9], P < .0001) and shorter median hospital length of stay ( P < .001), but not in-unit stay, as compared to MICU patients. Mechanical ventilation, vasopressors, inotropes, renal replacement therapy, and/or blood transfusion were required in 35.0% of CICU patients compared with 62.2% of MICU patients ( P < .0001). The unit mortality rate was lower for CICU than MICU patients (4.8% vs 13.0%, P < .0001), as was the hospital mortality rate (9.3% vs 21.6%, P < .0001). The standardized mortality ratio was 0.73 for the CICU and 0.86 for the MICU. There was no difference in the mean direct cost of care per patient-day between the CICU and MICU ($4011 USD [376] vs $3990 USD [214], P = .77). CONCLUSIONS: The burden of noncardiovascular diseases and the requirement for critical care therapies are high in contemporary CICU patients but remain lower compared to the MICU population. Our findings support the growing complexity of care in tertiary CICUs. Further studies are required to explore the association between critical care delivery and outcomes in this evolving population.

Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease.

OBJECTIVE: To evaluate the generation of rheumatoid arthritis (RA)-related autoantibodies in the lung. METHODS: Simultaneous collection of serum and induced sputum was performed in 21 healthy controls, 49 at-risk subjects without inflammatory arthritis but at risk of RA due to family history or seropositivity for anti-citrullinated protein antibodies, and 14 subjects with early RA. Samples were tested for anti-cyclic citrullinated peptide 2 (anti-CCP2), anti-CCP3, anti-CCP3.1, rheumatoid factor isotypes IgM, IgG, and IgA, and total IgM, IgG, and IgA. RESULTS: One or more autoantibodies were present in sputum of 39% of at-risk seronegative subjects, 65% of at-risk seropositive subjects, and 86% of subjects with early RA. In at-risk seronegative subjects, the rate of anti-CCP3.1 positivity and the median number of autoantibodies were elevated in sputum versus serum. In subjects with early RA, the rate of positivity for several individual autoantibodies and the median number of autoantibodies were higher in serum than in sputum. Results in at-risk seropositive subjects were intermediate between these groups. In at-risk subjects with autoantibody positivity in sputum, the ratios of autoantibody to total Ig were higher in sputum than in serum, suggesting that these autoantibodies are generated or sequestered in the lung. CONCLUSION: RA-related autoantibodies are detectable in sputum in subjects at risk of RA and in subjects with early RA. In a subset of at-risk subjects, the presence of sputum autoantibodies in the absence of seropositivity, and the increased autoantibody-to-total Ig ratios in sputum, suggest that the lung may be a site of autoantibody generation in the early development of RA. These findings suggest an important role of the lung in the pathogenesis of RA.

Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?

OBJECTIVE: To evaluate the presence of pulmonary abnormalities in rheumatoid arthritis (RA)-related autoantibody-positive subjects without inflammatory arthritis. METHODS: Forty-two subjects who did not have inflammatory arthritis but were positive for anti-cyclic citrullinated peptide antibodies and/or ≥2 rheumatoid factor isotypes (a profile that is 96% specific for RA), 15 autoantibody-negative controls, and 12 patients with established seropositive early RA (<1-year duration) underwent spirometry and high-resolution computed tomography (HRCT) lung imaging. RESULTS: The median age of autoantibody-positive subjects was 54 years, 52% were female, and 38% were ever-smokers; these characteristics were not significantly different from those of autoantibody-negative control subjects. No autoantibody-positive subject had inflammatory arthritis based on joint examination. HRCT revealed that 76% of autoantibody-positive subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities, and air trapping, compared with 33% of autoantibody-negative controls (P = 0.005). The prevalence and type of lung abnormalities among autoantibody-positive subjects were similar to those among patients with early RA. In 2 autoantibody-positive subjects with airways disease, inflammatory arthritis classifiable as articular RA developed ∼13 months after the lung evaluation. CONCLUSION: Airways abnormalities that are consistent with inflammation are common in autoantibody-positive subjects without inflammatory arthritis and are similar to airways abnormalities seen in patients with early RA. These findings suggest that the lung may be an early site of autoimmune-related injury and potentially a site of generation of RA-related autoimmunity. Further studies are needed to define the mechanistic role of lung inflammation in the development of RA.

Comparison of clinical characteristics and outcomes of critically ill adults with SARS-CoV-2 infection during Delta and Omicron variant predominance periods: a single-hospital retrospective cohort study.

INTRODUCTION: Initial reports suggest the B.1.1.529 (Omicron) variant of SARS-CoV-2 causes less severe disease compared with the B.1.617.2 (Delta) variant, though more widespread vaccination contributed to these findings. Little is known about clinical characteristics and outcomes of patients with SARS-CoV-2 infection requiring intensive care during periods of Delta and Omicron variant predominance. AIM: To examine and compare characteristics of critically ill adults with SARS-CoV-2 infection during periods of Delta and Omicron variant predominance. METHODS: We conducted a retrospective cohort study of critically ill adults with SARS-CoV-2 infection at one academic hospital in Los Angeles during Delta (15 July 2021-23 September 2021) and Omicron (21 December 2021-27 January 2022) predominance. Patient characteristics were compared between Delta-period and Omicron-period hospitalisations, overall and stratified by vaccination status. RESULTS: 79 adults required intensive care during the Delta predominance period and 116 during the Omicron predominance period. We found similar proportions of intensive care unit admissions occurring in fully vaccinated patients between the two periods, despite Los Angeles County data revealing an almost 60% increase in the proportion of SARS-CoV-2 hospitalisations occurring in fully vaccinated persons. There was no difference in the need for invasive mechanical ventilation (IMV). Among those who required IMV, the median duration of IMV was shorter overall (Delta=18 days; Omicron=8 days; p=0.006) and among unvaccinated persons (Delta=19 days; Omicron=8.5 days; p=0.018). Among unvaccinated persons, the median intensive care unit length of stay was shorter (Delta=12 days; Omicron=5 days; p=0.037) during Omicron predominance. There was no difference in the proportion of patients who died while hospitalised. CONCLUSIONS: In this single-hospital study, critically ill patients with SARS-CoV-2 infection experienced less severe respiratory disease during Omicron predominance, likely due to reduced variant-specific virulence. Vaccination likely reduced development of critical illness in adults with SARS-CoV-2 infection during Omicron predominance.

Perception of interdisciplinary collaboration between ICU nurses and resident physicians during the COVID-19 pandemic.

Multidisciplinary collaboration is the hallmark of quality critical care. Prior studies have shown that nurses and physicians have different perceptions on communication and collaboration in the ICU. The Covid-19 pandemic has served to both strain and strengthen relationships between nurses and resident physicians in the ICU. This study used a survey-based approach sought to identify the similarities and differences between perception of collaboration between ICU nurses and resident physicians taking care of patients during the pandemic, and to identify whether they felt that the pandemic impacted the collaborative spirit of critical care. Although findings from this study suggest that overall residents and nurses perceive collaboration similarly, the COVID-19 pandemic may be differentially affecting the interdisciplinary dynamics of the ICU.

Creation of a dedicated line team for critically ill patients with COVID-19: A multidisciplinary approach to maximize resource utilization during the COVID-19 pandemic.

BACKGROUND: Pandemics create challenges for medical centers, which call for innovative adaptations to care for patients during the unusually high census, to distribute stress and work hours among providers, to reduce the likelihood of transmission to health care workers, and to maximize resource utilization. METHODS: We describe a multidisciplinary vascular access team's development to improve frontline providers' workflow by placing central venous and arterial catheters. Herein we describe the development, organization, and processes resulting in the rapid formation and deployment of this team, reporting on notable clinical issues encountered, which might serve as a basis for future quality improvement and investigation. We describe a retrospective, single-center descriptive study in a large, quaternary academic medical center in a major city. The COVID-19 vascular access team included physicians with specialized experience in placing invasive catheters and whose usual clinical schedule had been lessened through deferment of elective cases. The target population included patients with confirmed or suspected COVID-19 in the medical ICU (MICU) needing invasive catheter placement. The line team placed all invasive catheters on patients in the MICU with suspected or confirmed COVID-19. RESULTS AND CONCLUSIONS: Primary data collected were the number and type of catheters placed, time of team member exposure to potentially infected patients, and any complications over the first three weeks. Secondary outcomes pertained to workflow enhancement and quality improvement. 145 invasive catheters were placed on 67 patients. Of these 67 patients, 90% received arterial catheters, 64% central venous catheters, and 25% hemodialysis catheters. None of the central venous catheterizations or hemodialysis catheters were associated with early complications. Arterial line malfunction due to thrombosis was the most frequent complication. Division of labor through specialized expert procedural teams is feasible during a pandemic and offloads frontline providers while potentially conferring safety benefits.

Endotracheal Application of Ultraviolet A Light in Critically Ill Patients with Severe Acute Respiratory Syndrome Coronavirus 2: A First-in-Human Study.

INTRODUCTION: Our previous preclinical experiments show that under specific and monitored conditions, ultraviolet A (UVA) exposure reduces certain bacteria, fungi, and viruses including coronavirus-229E without harming mammalian columnar epithelial cells. The goal of this study was to evaluate the safety and effects of narrow-band UVA therapy administered by a novel device via endotracheal tube in critically ill subjects with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Newly intubated, mechanically ventilated adults with SARS-CoV-2 infection and an endotracheal tube size of at least 7.50 mm were eligible for inclusion in the study. Subjects were treated with UVA for 20 min daily for 5 days and followed for 30 days. RESULTS: Five subjects were enrolled (mean age 56.60 years, three male). At baseline, all subjects scored 9/10 on the World Health Organization (WHO) clinical severity scale (10 = death), with predicted mortality ranging from 21% to 95%. Average endotracheal viral load significantly reduced from baseline to day 5 (- 2.41 log; range - 1.16 to - 4.54; Friedman p = 0.002) and day 6 (- 3.20; range - 1.20 to - 6.77; Friedman p < 0.001). There were no treatment-emergent adverse events, with no changes in oxygenation or hemodynamics during the 20-min treatments. One subject died 17 days after enrollment due to intracranial hemorrhagic complications of anticoagulation while receiving extracorporeal membrane oxygenation. The remaining subjects clinically improved and scored 2, 4, 5, and 7 on the WHO scale at day 30. In these subjects, clinical improvement correlated with reduction of viral load (Spearman's rho = 1, p < 0.001). CONCLUSIONS: In this first-in-human study, endotracheal narrow-band UVA therapy, under specific and monitored settings, appears to be safe and associated with a reduction in respiratory SARS-CoV-2 viral burden over the treatment period. UVA therapy may provide a novel approach in the fight against COVID-19. CLINICAL TRIAL NUMBER: NCT04572399.

An International Virtual COVID-19 Critical Care Training Forum for Healthcare Workers.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic resulted in redeployment of non-critical care-trained providers to intensive care units across the world. Concurrently, traditional venues for delivery of medical education faced major disruptions. The need for a virtual forum to fill knowledge gaps for healthcare workers caring for patients with coronavirus disease (COVID-19) was apparent in the early stages of the pandemic. Objective: The weekly, open-access COVID-19 Critical Care Training Forum (CCCTF) organized by the American Thoracic Society (ATS) provided a global audience access to timely content relevant to their learning needs. The goals of the forum were threefold: to aid healthcare providers in assessment and treatment of patients with COVID-19, to reduce provider anxiety, and to disseminate best practices. Methods: The first 13 ATS CCCTF sessions streamed live from April to July 2020. Structured debriefs followed each session and participant feedback was evaluated in planning of subsequent sessions. A second set of 14 sessions streamed from August to November 2020. Content experts were recruited from academic institutions across the United States. Results: As of July 2020, the ATS CCCTF had 2,494 live participants and 7,687 downloads for a total of 10,181 views. The majority of participants had both completed training (58.6%) and trained in critical care (53.8%). Physicians made up a majority (82.2%) of the audience that spanned the globe (61% were international attendees). Conclusion: We describe the rapid and successful implementation of an open-access medical education forum to address training and knowledge gaps among healthcare personnel caring for patients with COVID-19.

Development of a National Academic Boot Camp to Improve Fellowship Readiness.

Background: Pulmonary and critical care medicine (PCCM) fellowship requires a high degree of medical knowledge and procedural competency. Gaps in fellowship readiness can result in significant trainee anxiety related to starting fellowship training.Objective: To improve fellowship readiness and alleviate anxiety for PCCM-bound trainees by improving confidence in procedural skills and cognitive domains.Methods: Medical educators within the American Thoracic Society developed a national resident boot camp (RBC) to provide an immersive, experiential training program for physicians entering PCCM fellowships. The RBC curriculum is a 2-day course designed to build procedural skills, medical knowledge, and clinical confidence through high-fidelity simulation and active learning methodology. Separate programs for adult and pediatric providers run concurrently to provide unique training objectives targeted to their learners' needs. Trainee assessments include multiple-choice pre- and post-RBC knowledge tests and confidence assessments, which are scored on a four-point Likert scale, for specific PCCM-related procedural and cognitive skills. Learners also evaluate course material and educator effectiveness, which guide modifications of future RBC programs and provide feedback for individual educators, respectively.Results: The American Thoracic Society RBC was implemented in 2014 and has grown annually to include 132 trainees and more than 100 faculty members. Mean knowledge test scores for participants in the 2019 RBC adult program increased from 55% (±14% SD) on the pretest to 72% (±11% SD; P < 0.001) after RBC completion. Similarly, mean pretest scores for pediatric course attendees increased from 54% (±13% SD) to 62% (±19% SD; P = 0.17). Specific content domains that improved by 10% or more between pre- and posttests included airway management, bronchoscopy, pulmonary function testing, and code management for adult course participants, and airway management, pulmonary function testing, and extracorporeal membrane oxygenation for pediatric course participants. Trainee confidence also significantly improved across all procedural and cognitive domains for adult trainees and in 10 of 11 domains for pediatric course attendees. Course content for the 2019 RBC was overwhelmingly rated as "on target" for the level of learner, with <4% of respondents indicating any specific session was "much too basic" or "much too advanced."Conclusion: RBC participation improved PCCM-bound trainee knowledge, procedural familiarity, and confidence. Refinement of the RBC curriculum over the past 7 years has been guided by educator and course evaluations, with the ongoing goal of meeting the evolving educational needs of rising PCCM trainees.

Pre-existing traits associated with Covid-19 illness severity.

IMPORTANCE: Certain individuals, when infected by SARS-CoV-2, tend to develop the more severe forms of Covid-19 illness for reasons that remain unclear. OBJECTIVE: To determine the demographic and clinical characteristics associated with increased severity of Covid-19 infection. DESIGN: Retrospective observational study. We curated data from the electronic health record, and used multivariable logistic regression to examine the association of pre-existing traits with a Covid-19 illness severity defined by level of required care: need for hospital admission, need for intensive care, and need for intubation. SETTING: A large, multihospital healthcare system in Southern California. PARTICIPANTS: All patients with confirmed Covid-19 infection (N = 442). RESULTS: Of all patients studied, 48% required hospitalization, 17% required intensive care, and 12% required intubation. In multivariable-adjusted analyses, patients requiring a higher levels of care were more likely to be older (OR 1.5 per 10 years, P<0.001), male (OR 2.0, P = 0.001), African American (OR 2.1, P = 0.011), obese (OR 2.0, P = 0.021), with diabetes mellitus (OR 1.8, P = 0.037), and with a higher comorbidity index (OR 1.8 per SD, P<0.001). Several clinical associations were more pronounced in younger compared to older patients (Pinteraction<0.05). Of all hospitalized patients, males required higher levels of care (OR 2.5, P = 0.003) irrespective of age, race, or morbidity profile. CONCLUSIONS AND RELEVANCE: In our healthcare system, greater Covid-19 illness severity is seen in patients who are older, male, African American, obese, with diabetes, and with greater overall comorbidity burden. Certain comorbidities paradoxically augment risk to a greater extent in younger patients. In hospitalized patients, male sex is the main determinant of needing more intensive care. Further investigation is needed to understand the mechanisms underlying these findings.

Mucosal immune responses to microbiota in the development of autoimmune disease.

The etiology of most systemic autoimmune diseases remains unknown. There is often a preclinical period of systemic autoimmunity prior to the onset of clinically classifiable disease; established and emerging data suggest that dysregulated immune interactions with commensal microbiota may play a role in the initial generation of autoimmunity in this preclinical period. This article reviews potential mechanisms by which alterations of healthy microbiota may induce autoimmunity as well as mucosal microbial associations with autoimmune diseases. If mucosal microbiota lead to the development of autoimmunity, these mucosal sites, microorganisms, and immunologic mechanisms can be targeted to prevent the onset of systemic autoimmune disease.