Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity.

We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.

Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas.

RATIONALE: Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. OBJECTIVE: To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). METHODS: Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. RESULTS: Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. CONCLUSION: These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.

Suspected Heparin-Induced Thrombocytopenia in Patients Receiving Extracorporeal Membrane Oxygenation.

Heparin-induced thrombocytopenia (HIT) is an immune reaction usually secondary to unfractionated heparin. Anticoagulation management is critical in patients while on extracorporeal membrane oxygenation (ECMO) to prevent thromboembolism and for the optimal functioning of the circuit. We identified five patients with respiratory failure at our hospital managed with ECMO in the last 2 years that were treated for HIT. A brief clinical course and their management are discussed. We also briefly review the literature for best evidence for management of such patients.

Interstitial Lung Disease Mortality Disparities Along the United States - Mexico Border, 1999-2020.

BACKGROUND: Optimal diagnosis and management of interstitial lung diseases (ILD) needs access to specialized centers, frequent monitoring, and complex therapeutic options. In underprivileged areas, these necessities can often lead to barriers in delivering care. RESEARCH QUESTION: What are the ILD mortality disparities in the regions along the United States-Mexico (US-MX) border? STUDY DESIGN AND METHODS: We obtained ILD mortality information through death certificate queries from the Centers for Disease Control and Prevention repository. Death data were adjusted for age and stratified by US-MX border regions and non-border regions in the US. Log-linear regression models were utilized to analyze mortality trends in the period from 1999 to 2020 followed by calculation of annual percentage changes (APC). Age-adjusted mortality rates (AAMR) were compared across cumulative and sub-demographic populations. RESULTS: ILD-related mortality among border regions (AAMR 5.31) was higher compared to non-border regions (AAMR 4.86). Mortality within border regions remained unchanged from 1999 to 2020 (APC +0.3, p=0.269). Non-border regions experienced a significant rise in mortality rates (APC +2.6, p=0.017) from 1999 to 2005 and remained unchanged from 2005 to 2020. Mortality was higher within both men (AAMR 6.57) and women (AAMR 4.36) populations among border regions compared to their non-border counterparts (AAMR 6.27 and 3.87, respectively). Hispanic populations among the border regions experienced higher mortality rates (AAMR 6.15) compared to Hispanic populations within non-border regions (AAMR 5.44). Non-Hispanic populations encountered similar mortality rates between the two regions. Mortality rates among Hispanic (APC +0.0, p=0.938) and non-Hispanic (APC +0.2, p=0.531) populations in the border regions remained unchanged from 1999 to 2020. INTERPRETATION: These results revealed ILD-related mortality disparities among the US-MX border regions, emphasizing the importance of public health measures to increase access to equitable medical care and implement targeted interventions among these vulnerable populations.

Outcomes of Venovenous Extracorporeal Membrane Oxygenation in Viral Acute Respiratory Distress Syndrome.

Our study assessed the relationship between the duration of venovenous extracorporeal membrane oxygenation (V-V ECMO) and patient outcomes. We studied patients undergoing V-V ECMO support for acute respiratory distress syndrome (ARDS) between 2009 and 2017 who were reported to the Extracorporeal Life Support Organization registry. We evaluated survival, major bleeding, renal failure, pulmonary complications, mechanical complications, neurologic complications, infection, and duration of V-V ECMO support. Multivariable regression modeling assessed risk factors for adverse events. Of the 4,636 patients studied, the mean support duration was 12.2 ± 13.7 days. There was a progressive increase in survival after the initiation of V-VECMO, peaking at a survival rate of 73% at 10 days of support. However, a single-day increase in V-V ECMO duration was associated with increased bleeding events (odds ratio [OR] 1.038; 95% confidence interval [CI]: 1.029-1.047; p < 0.0001), renal failure (OR 1.018; 95% CI: 1.010-1.027; p < 0.0001), mechanical complications (OR 1.065; 95% CI: 1.053-1.076; p < 0.0001), pulmonary complications (OR 1.04; 95% CI: 1.03-1.05; p < 0.0001), and infection (OR 1.04; 95% CI: 1.03-1.05; p < 0.0001). V-V ECMO progressively increases survival for ARDS over the first 10 days of support. Thereafter, rising complications associated with prolonged durations of support result in a progressive decline in survival.

Airway Management in the Critically Ill Patient.

PURPOSE OF REVIEW: This paper will evaluate the recent literature and best practices in airway management in critically ill patients. RECENT FINDINGS: Cardiac arrest remains a common complication of intubation in these high-risk patients. Patients with desaturation or peri-intubation hypotension are at high risk of cardiac arrest, and each of these complications have been reported in up to half of all intubations in critically ill patient populations. SUMMARY: There have been significant advances in preoxygenation and devices available for performing laryngoscopy and rescue oxygenation. However, the risk of cardiovascular collapse remains concerningly high with few studies to guide therapeutic maneuvers to reduce this risk.

SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus.

SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.

Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused.

After decades of research, two therapies for chronic fibrotic lung disease are now approved by the FDA, with dozens more anti-fibrotic therapies in the pipeline. A great deal of enthusiasm has been generated for the use of these drugs, which are by no means curative but clearly have a favorable impact on lung function decline over time. Amidst a flurry of newly developed and repurposed drugs to treat the coronavirus disease 2019 (COVID-19) and its accompanying acute respiratory distress syndrome (ARDS), few have emerged as effective. Historically, survivors of severe viral pneumonia and related acute lung injury with ARDS often have near full recovery of lung function. While the pathological findings of the lungs of patients with COVID-19 can be diverse, current reports have shown significant lung fibrosis predominantly in autopsy studies. There is growing enthusiasm to study anti-fibrotic therapy for inevitable lung fibrosis, and clinical trials are underway using currently FDA-approved anti-fibrotic therapies. Given the relatively favorable outcomes of survivors of virus-mediated ARDS and the low prevalence of clinically meaningful lung fibrosis in survivors, this perspective examines if there is a rationale for testing these repurposed antifibrotic agents in COVID-19-associated lung disease.

Corrigendum: Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused.

[This corrects the article DOI: 10.3389/fmed.2020.00539.].

Correction to: SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes.

The affiliation of the second author (Kenneth S. Knox) should have been Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA instead of Department of Medicine, University of Arizona-Phoenix, Phoenix, AZ 85004, USA.

SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes.

SARS-CoV-2 virus, the causative agent of the coronavirus infectious disease-19 (COVID-19), is taking the globe by storm, approaching 500,000 confirmed cases and over 21,000 deaths as of March 25, 2020. While under control in some affected Asian countries (Taiwan, Singapore, Vietnam), the virus demonstrated an exponential phase of infectivity in several large countries (China in late January and February and many European countries and the USA in March), with cases exploding by 30-50,000/day in the third and fourth weeks of March, 2020. SARS-CoV-2 has proven to be particularly deadly to older adults and those with certain underlying medical conditions, many of whom are of advanced age. Here, we briefly review the virus, its structure and evolution, epidemiology and pathogenesis, immunogenicity and immune, and clinical response in older adults, using available knowledge on SARS-CoV-2 and its highly pathogenic relatives MERS-CoV and SARS-CoV-1. We conclude by discussing clinical and basic science approaches to protect older adults against this disease.

Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure.

We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.

The Association of Non-Cardiac ECMO With Influenza Incidence: A Time Series Analysis.

BACKGROUND: The 2009 H1N1 influenza epidemic saw a rise in the use of extracorporeal membrane oxygenation (ECMO) as a supportive therapy for refractory ARDS. We sought to determine whether ECMO utilization follows a seasonal pattern that matches the influenza season, and whether it can further be explained by the incidence of each influenza subtype. METHODS: We performed a longitudinal analysis of non-cardiac and cardiac-associated ECMO cases from the National In-patient Sample from 2005 to 2014, using overdispersed Poisson regression to evaluate associations with influenza incidence categorized by influenza-like illness and total positive influenza tests divided by subtype from the Centers for Disease Control and Prevention. RESULTS: Non-cardiac ECMO use was positively associated with influenza-like illness incidence in the current month (incidence risk ratio [IRR] 1.11, 95% confidence interval [CI] 1.07-1.15, P < .001) and with influenza-like illness in the previous month (IRR 1.09, 95% CI 1.05-1.14, P < .001). The 2009 H1N1 subtype had the strongest association with non-cardiac ECMO (IRR 1.19, 95% CI 1.09-1.31, P < .001). Cardiac ECMO was also positively associated with the incidence of influenza-like illness (IRR 1.05, 95% CI 1.01-1.09, P = .02). CONCLUSION: Non-cardiac and cardiac ECMO use in the United States were significantly associated with influenza incidence. The influenza A, H1N1 2009, subtype had the strongest association.

Decreased In-Hospital Mortality after Lobectomy Using Video-assisted Thoracoscopic Surgery Compared with Open Thoracotomy.

RATIONALE: There is a paucity of data regarding the optimal surgical approach for lung lobectomy. Lobectomy performed by video-assisted thoracoscopic surgery (VATS) has been associated with lower morbidity as compared with lobectomy performed by thoracotomy. However, no multicenter studies have shown improved mortality with VATS lobectomy compared with open surgical lobectomy. OBJECTIVES: We used data from the United States Healthcare Cost and Utilization Project Nationwide Inpatient Sample database from 2009 to 2012 to compare VATS with open lobectomy for in-hospital mortality and other short-term outcomes. METHODS: We used International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes to identify the patients undergoing lobectomy. We used 1:1 ratio propensity matching with the nearest neighbor method without replacement to generate matched pairs. MEASUREMENTS AND MAIN RESULTS: Over the 4-year period, 27,451 patients underwent lobectomy. The majority of these procedures were performed by thoracotomy (65%) as compared with VATS (35%). A total of 9,393 matched pairs were created. VATS lobectomy was associated with significantly lower in-hospital mortality when compared with thoracotomy (1.3% vs. 2.5%, P < 0.001). A shorter length of hospital stay was observed for those undergoing VATS lobectomy (6.21 vs. 8.75 d, P < 0.001). The overall rate of perioperative complications was low, with those undergoing VATS being less likely to have any perioperative morbidity. CONCLUSIONS: In recent years, the use of VATS for lobectomy has increased relative to thoracotomy. This trend has coincided with increased survival and shorter length of stay for VATS lobectomy compared with thoracotomy. Further studies are needed to identify comorbidities that identify ideal candidates for VATS lobectomy.

Pulmonary Embolism with Right Ventricular Dysfunction: Who Should Receive Thrombolytic Agents?

BACKGROUND: Appropriate management of pulmonary embolism patients with right ventricular dysfunction is uncertain. Recent guidelines have stressed the need for more data on the use of thrombolytic agents in the stable pulmonary embolism patient with right ventricular dysfunction. The objective of this study is to investigate the hypothesis that thrombolytic therapy in hemodynamically stable pulmonary embolism patients with right ventricular dysfunction is not associated with improved mortality. METHODS: We did a retrospective analysis using multi-institutional observational data from the Nationwide Inpatient Sample database. International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes were used to identify the patients with pulmonary embolism and right ventricular dysfunction. In-hospital mortality was defined as the primary outcome of interest. RESULTS: Over the 4 years of the study period, 3668 patients with right ventricular dysfunction and pulmonary embolism were found, of which 3253 patients were identified as having hemodynamically stable right-sided heart failure with pulmonary embolism. There was no significant difference in mortality between hemodynamically stable pulmonary embolism patients with right ventricular dysfunction who received thrombolytic agents compared with those who did not. When outcomes were assessed for patients with right ventricular dysfunction and hemodynamic instability, a significant improvement in mortality was noted for patients with right ventricular dysfunction who received thrombolytic agents, which confirmed previous reports that thrombolytic therapy decreases mortality in pulmonary embolism patients who are hemodynamically unstable. CONCLUSION: Our data support the use of less aggressive treatment for stable pulmonary embolism patients with right ventricular dysfunction. These results argue against the reflexive use of thrombolytic agents in stable pulmonary embolism patients with right ventricular dysfunction.

Failure to achieve first attempt success at intubation using video laryngoscopy is associated with increased complications.

The purpose of this investigation was to investigate the association between first attempt success and intubation-related complications in the Intensive Care Unit after the widespread adoption of video laryngoscopy. We further sought to characterize and identify the predictors of complications that occur despite first attempt success. This was a prospective observational study of consecutive intubations performed with video laryngoscopy at an academic medical Intensive Care Unit. Operator, procedural, and complication data were collected. Multivariable logistic regression was used to examine the relationship between the intubation attempts and the occurrence of one or more complications. A total of 905 patients were intubated using a video laryngoscope. First attempt success occurred in 739 (81.7 %), whereas >1 attempt was needed in 166 (18.3 %). One or more complications occurred in 146 (19.8 %) of those intubated on the first attempt versus 107 (64.5 %, p < 0.001) of those requiring more than one attempt. Logistic regression analysis shows that >1 attempt is associated with 6.4 (95 % CI 4.4-9.3) times the adjusted odds of at least one complication. Pre-intubation predictors of at least one complication despite first attempt success include vomit or edema in the airway as well as the presence of hypoxemia or hypotension. There are increased odds of complications with even a second attempt at intubation in the Intensive Care Unit. Complications occur frequently despite a successful first attempt, and as such, the goal of airway management should not be simply first attempt success, but instead first attempt success without complications.

Extracorporeal Membrane Oxygenation for ARDS: National Trends in the United States 2008-2012.

INTRODUCTION: Recent advances in technology and protocols have made the use of extracorporeal membrane oxygenation (ECMO) a viable rescue therapy for patients with ARDS who present with refractory hypoxemia. Despite the lack of strong evidence supporting the use of ECMO in ARDS, its use seems to be increasing. We sought to determine recent trends in the use of ECMO for ARDS. We also assessed trends in mortality among patients with ARDS in whom ECMO was used. METHODS: We performed a retrospective analysis using the largest all-payer in-patient healthcare database in the United States, the Healthcare Cost and Utilization project, the National In-patient Sample database from 2008 to 2012. Subjects with ARDS were identified using carefully chosen International Classification of Diseases, Ninth Revision codes. RESULTS: We found that in 2008, about 1 in 1,000 subjects with ARDS underwent ECMO. Over the subsequent 4-y time period, there was a 0.19% absolute increase and 70% relative increase in the use of ECMO for ARDS. The mortality rate among subjects with ARDS in whom ECMO was used declined from 78% in 2008 to 64% in 2012. We also found a trend toward a reduction in hospital stay among survivors. CONCLUSION: In the United States, between 2008 and 2012, there was an increasing trend toward the use of ECMO in patients with ARDS that coincided with a slight increase in survival among these patients.