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At the stroke of the New Year 2020, COVID-19, a zoonotic disease that would turn into a global pandemic, was identified in the Chinese city of Wuhan. Although unique in its transmission and virulence, COVID-19 is similar to zoonotic diseases, including other SARS variants (e.g., SARS-CoV) and MERS, in exhibiting severe flu-like symptoms and acute respiratory distress. Even at the molecular level, many parallels have been identified between SARS and COVID-19 so much so that the COVID-19 virus has been named SARS-CoV-2. These similarities have provided several opportunities to treat COVID-19 patients using clinical approaches that were proven to be effective against SARS. Importantly, the identification of similarities in how SARS-CoV and SARS-CoV-2 access the host, replicate, and trigger life-threatening pathological conditions have revealed opportunities to repurpose drugs that were proven to be effective against SARS. In this article, we first provided an overview of COVID-19 etiology vis-à-vis other zoonotic diseases, particularly SARS and MERS. Then, we summarized the characteristics of droplets/aerosols emitted by COVID-19 patients and how they aid in the transmission of the virus among people. Moreover, we discussed the molecular mechanisms that enable SARS-CoV-2 to access the host and become more contagious than other betacoronaviruses such as SARS-CoV. Further, we outlined various approaches that are currently being employed to diagnose and symptomatically treat COVID-19 in the clinic. Finally, we reviewed various approaches and technologies employed to develop vaccines against COVID-19 and summarized the attempts to repurpose various classes of drugs and novel therapeutic approaches.

Established technology, operational infrastructure, and nursing resources were leveraged to develop a remote patient monitoring (RPM) program for ambulatory management of patients with COVID-19. The program included two care-delivery models with different monitoring capabilities supporting variable levels of patient risk for severe illness. The primary objective of this study was to determine the feasibility and safety of a multisite RPM program for management of acute COVID-19 illness. We report an evaluation of 7074 patients served by the program across 41 US states. Among all patients, the RPM technology engagement rate was 78.9%. Rates of emergency department visit and hospitalization within 30 days of enrollment were 11.4% and 9.4%, respectively, and the 30-day mortality rate was 0.4%. A multisite RPM program for management of acute COVID-19 illness is feasible, safe, and associated with a low mortality rate. Further research and expansion of RPM programs for ambulatory management of other acute illnesses are warranted.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive pulmonary disease characterized by aberrant tissue remodeling, formation of scar tissue within the lungs and continuous loss of lung function. The areas of fibrosis seen in lungs of IPF patients share many features with normal aging lung with cellular senescence being one. The contribution of the immune system to the etiology of IPF remains poorly understood. Evidence obtained from animal models and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. Currently, there is only modestly effective pharmacotherapy for IPF. Mesenchymal stem cells (MSCs)-based therapies have emerged as a potential option treatment of IPF. This study explores the possibility of using autologous MSCs as an IPF therapy and present an attempt to determine if the disease occurring in the lungs can be reflected on peripheral blood immune status. MethodsComprehensive characterization of autologous adipose derived MSCs (aMSCs) from five IPF patients and five age and gender matched Healthy Controls (HC) was done using flow cytometry, Droplet Digital PCR (ddPCR), Multiplex Luminex xMAP technology and confocal microscopy. For assessing the self renewal capacity and osteogenic differentiation IncuCyte Live Cell Imaging technology was used. Multi-parameter quantitative flow cytometry of un-manipulated whole blood of another group of 15 IPF patients and 87 (30 age and gender matched) HC was used to analyze 110 peripheral phenotypes.ResultsThere are no differences between autologous aMSCs from IPF patients and HC in their stem cell properties, self renewal capacity, plasticity for osteogenic differentiation, secretome content, cell cycle inhibitor marker levels and mitochondrial health. IPF patients had altered peripheral blood immunophenotype including reduced B cells subsets, increased T cell subsets, and increased granulocytes among others demonstrating clear and significant differences.ConclusionsOur results indicate that there is no difference in aMSCs properties from IPF patients and HC, suggesting that autologous aMSCs may be an acceptable option for IPF therapy.Characterization of peripheral immune phenotype may be a valuable indicator for successful therapy, and for potentially staging the disease.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive pulmonary disease characterized by aberrant tissue remodeling, formation of scar tissue within the lungs and continuous loss of lung function. The areas of fibrosis seen in lungs of IPF patients share many features with normal aging lung including cellular senescence. The contribution of the immune system to the etiology of IPF remains poorly understood. Evidence obtained from animal models and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. Currently, there is only modest effective pharmacotherapy for IPF. Mesenchymal stem cells (MSCs)-based therapies have emerged as a potential option treatment of IPF. This study characterizes the functionality of autologous MSCs for use as an IPF therapy and presents an attempt to determine whether the disease occurring in the lungs is associated with an alterated immune system. Methods Comprehensive characterization of autologous adipose-derived MSCs (aMSCs) from 5 IPF patient and 5 age- and gender-matched healthy controls (HC) was done using flow cytometry, PCR (ddPCR), multiplex Luminex xMAP technology, confocal microscopy self-renewal capacity and osteogenic differentiation. Additionally, multi-parameter quantitative flow cytometry of unmanipulated whole blood of 15 IPF patients and 87 (30 age- and gender-matched) HC was used to analyze 110 peripheral phenotypes to determine disease-associated changes in the immune system. Results There are no differences between autologous aMSCs from IPF patients and HC in their stem cell properties, self-renewal capacity, osteogenic differentiation, secretome content, cell cycle inhibitor marker levels and mitochondrial health. IPF patients had altered peripheral blood immunophenotype including reduced B cells subsets, increased T cell subsets and increased granulocytes demonstrating disease-associated alterations in the immune system. Conclusions Our results indicate that there are no differences in aMSC properties from IPF patients and HC, suggesting that autologous aMSCs may be an acceptable option for IPF therapy. The altered immune system of IPF patients may be a valuable biomarker for disease burden and monitoring therapeutic response

Objective To report the Mayo Clinic experience with coronavirus disease 2019 (COVID-19) related to patient outcomes. Methods We conducted a retrospective chart review of patients with COVID-19 diagnosed between March 1, 2020, and July 31, 2020, at any of the Mayo Clinic sites. We abstracted pertinent comorbid conditions such as age, sex, body mass index, Charlson Comorbidity Index variables, and treatments received. Factors associated with hospitalization and mortality were assessed in univariate and multivariate models. Results A total of 7891 patients with confirmed COVID-19 infection with research authorization on file received care across the Mayo Clinic sites during the study period. Of these, 7217 patients were adults 18 years or older who were analyzed further. A total of 897 (11.4%) patients required hospitalization, and 354 (4.9%) received care in the intensive care unit (ICU). All hospitalized patients were reviewed by a COVID-19 Treatment Review Panel, and 77.5% (695 of 897) of inpatients received a COVID-19–directed therapy. Overall mortality was 1.2% (94 of 7891), with 7.1% (64 of 897) mortality in hospitalized patients and 11.3% (40 of 354) in patients requiring ICU care. Conclusion Mayo Clinic outcomes of patients with COVID-19 infection in the ICU, hospital, and community compare favorably with those reported nationally. This likely reflects the impact of interprofessional multidisciplinary team evaluation, effective leveraging of clinical trials and available treatments, deployment of remote monitoring tools, and maintenance of adequate operating capacity to not require surge adjustments. These best practices can help guide other health care systems with the continuing response to the COVID-19 pandemic.

Background Sarcoidosis is a systemic granulomatous disease that may affect the myocardium. This study evaluated the diagnostic and prognostic value of 2-dimensional speckle tracking echocardiography in cardiac sarcoidosis (CS). Methods Eighty-three patients with extracardiac, biopsy-proven sarcoidosis and definite/probable diagnosis of cardiac involvement diagnosed from January 2005 through December 2016 were included. Strain parameters in early stages of CS, in a subgroup of 23 CS patients with left ventricular ejection fraction (LVEF) within normal limits (LVEF> 52% for men: > 54% for women, mean value: 57.3% ± 3.8%) and no wall motion abnormalities was compared with 97 controls (1:4) without cardiac disease. LV and right ventricular (RV) global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain and strain rate (SR) analyses were performed with TomTec software and correlated with cardiac outcomes (including heart failure and arrhythmias). This study was approved by the Mayo Clinic Institutional Review Board, and all patients gave informed written consent to participate. Results Mean age of CS patients was 53.6 ± 10.8 years, and 34.9% were women. Mean LVEF was 43.2% ± 12.4%; LV GLS, − 12.4% ± 3.7%; LV GCS, − 17.1% ± 6.5%; LV GRS, 29.3% ± 12.8%; and RV wall GLS, 14.6% ± 6.3%. In the 23 patients with early stage CS with normal LVEF and RV systolic function, strain parameters were significantly reduced when compared with controls (respectively: LV GLS, − 15.9% ± 2.5% vs − 18.2% ± 2.7% [P = .001]; RV GLS, − 16.9% ± 4.5% vs − 24.1% ± 4.0% [P − 14%). Conclusion Reduced strain values in the LV GLS and RV GLS can be used in the diagnostic algorithm in patients with suspicion of cardiac sarcoidosis. These values also correlate with adverse cardiovascular events.

Idiopathic pulmonary fibrosis is a progressively fatal disease with limited treatments. The bleomycin mouse model is often used to simulate the disease process in laboratory studies. The aim of this study was to develop an ex vivo technique for assessing mice lung injury using lung ultrasound surface wave elastography (LUSWE) in the bleomycin mouse model. The surface wave speeds were measured at three frequencies of 100, 200, and 300 Hz for mice lungs from control, mild, and severe groups. The results showed significant differences in the lung surface wave speeds, pulse oximetry, and compliance between control mice and mice with severe pulmonary fibrosis. LUSWE is an evolving technique for evaluating lung stiffness and may be useful for assessing pulmonary fibrosis in the bleomycin mouse model.

CD8+ tissue-resident memory T (TRM) cells provide frontline immunity in mucosal tissues. The mechanisms regulating CD8+ TRM maintenance, heterogeneity, and protective and pathological functions are largely elusive. Here, we identify a population of CD8+ TRM cells that is maintained by major histocompatibility complex class I (MHC-I) signaling, and CD80 and CD86 costimulation after acute influenza infection. These TRM cells have both exhausted-like phenotypes and memory features and provide heterologous immunity against secondary infection. PD-L1 blockade after the resolution of primary infection promotes the rejuvenation of these exhausted-like TRM cells, restoring protective immunity at the cost of promoting postinfection inflammatory and fibrotic sequelae. Thus, PD-1 serves to limit the pathogenic capacity of exhausted-like TRM cells at the memory phase. Our data indicate that TRM cell exhaustion is the result of a tissue-specific cellular adaptation that balances fibrotic sequelae with protective immunity.

Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations.The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus.Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab.The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.

Introduction: Short telomere syndromes (STS) are accelerated aging syndromes affecting hematopoietic, pulmonary, hepatobiliary and/or immunological systems. Clinical assessment of age-appropriate telomere length (TL) is performed using flow cytometry & fluorescence in-situ hybridization (flowFISH). Screening for germline variants in STS-related genes is guided by flowFISH-determined centile categories of TL, with screening recommended for TL 10th centile and integration of clinical phenotype with flowFISH data in predictive algorithms is currently unclear. Methods: FlowFISH testing was done at reference laboratories in Vancouver (Repeat Diagnostics; Canada) & Johns Hopkins University (JHU, USA). Salient clinical features were pre-determined as, personal history of premature hair greying (onset at age < 30 years), idiopathic pulmonary fibrosis (IPF) or IPF/emphysema overlap (in smokers), cryptogenic cirrhosis or NRH, unexplained cytopenias &/or immunodeficiency, & family history of the above (in >1 1st or 2nd degree relatives). Clinical likelihood score (CLS) was assigned as low (1), intermediate (int, 2) or high (>2), based on the number of aforementioned clinical features present prior to flowFISH testing. Genetic testing was performed using either an in-house or commercial bone marrow failure-specific next generation sequencing (NGS) panel or whole exome sequencing (WES), and data for known variants affecting telomerase or telomeric function (TERT, TERC, DKC1, TINF2, NHP2, NOP10, TCAB1, NAF1, & RTEL1) was recorded. Results: One hundred forty-nine patients at our institution underwent TL assessment at Repeat diagnostics (n=38) and JHU (n=111) laboratories, respectively. Median age was 56 (range: 7-79) years; 88 (59%) being males. Significant family history was present in 40 (27%) patients, while premature greying of hair was present in 13 (9%) patients. Organ-specific clinical features included unexplained cytopenias (n=89, 60%) IPF (n=71, 48%), cryptogenic cirrhosis or NRH (n=21, 14%), & unexplained immunodeficiency (n=14, 9%). CLS stratification included low (n=74, 50%), int (n=54, 36%), & high (n=21, 14%), with higher CLS significantly correlating with lower delta TL for L (p=0.0005) but not G (p=0.3). Genetic testing was performed in 51 (35%) patients (NGS-51, WES-1) among which 13 (26%) patients had a telomere-associated variant; 5 (10%) pathogenic (pv, all TERT). CLS alone was unable to predict likelihood of finding a telomere-associated variant (p=0.4). Based on age-appropriate centile categorization of L & G TL (information for both available in 134 patients), patients were stratified into six groups (table 1). TL 1-90th centile in G [C2, n=36, CLS low-19 (53%), 16 (44%), 1 (3%)] of whom 8 (22%) underwent NGS with 1 TERTpv and 2 VUS in TINF2TL >10th centile in L & 1-90th centile in G (n=43, 32%): CLS stratification in this group included 27 (63%) low, 12 (28%) int, 4 (9%) high. NGS testing was done in 13 (30%) patients [CLS low-9(69%), int 2(15%), high 2 (15%)], of whom only 2 (15%) had VUS in TINF2 and TERT gene, but no pathogenic variants (figure 1). Conclusion: Our study demonstrates the importance of using a flowFISH assay based predictive algorithm to screen patients with suspected STS for telomere-related genetic alternations, in comparison to a clinical likelihood score. We also demonstrate a limited role for genetic testing in patients with lymphocyte TL >10th centile, regardless of the clinical likelihood score. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.