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1.
Aging Cell ; : e13544, 2022 Jan 12.
Article in English | MEDLINE | ID: covidwho-1621824

ABSTRACT

Coronavirus disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of ~3.4 million individuals, large-scale deep immune cell profiling data, and single-cell RNA-sequencing data from aged COVID-19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C-reactive protein, D-dimer, and neutrophil-lymphocyte ratio) are significantly associated with age-specific COVID-19 severities. We identified the reduced abundance of naïve CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22) in aged severe COVID-19 patients. Older individuals with severe COVID-19 displayed type I and II interferon deficiencies, which is correlated with SARS-CoV-2 viral load. Elevated expression of SARS-CoV-2 entry factors and reduced expression of antiviral defense genes (LY6E and IFNAR1) in the secretory cells are associated with critical COVID-19 in aged individuals. Mechanistically, we identified strong TGF-beta-mediated immune-epithelial cell interactions (i.e., secretory-non-resident macrophages) in aged individuals with critical COVID-19. Taken together, our findings point to immuno-inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID-19 patients.

2.
J Urol ; 207(1): 183-189, 2022 01.
Article in English | MEDLINE | ID: covidwho-1612716

ABSTRACT

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a disproportionately severe effect on men, suggesting that the androgen pathway plays a role in the disease. Studies on the effect of castration and androgen receptor blockade have been mixed, while 5α-reductase inhibitor (5ARI) use in men with COVID-19 (2019 novel coronavirus) have shown potential benefits. We assessed the association of 5ARI use on risk of community acquired SARS-CoV-2 infection. MATERIALS AND METHODS: A total of 60,474 males in a prospective registry of people tested for SARS-CoV-2 between March 8, 2020 and February 15, 2021 were included. Using a matched cohort design, men using 5ARIs were matched 1:1 to non5ARI users. Independent analysis using unconditional multivariable logistic regression on the entire unmatched data set was completed for validation. Primary outcome measures were the association of 5ARI use on rates of SARS-Cov-2 positivity and disease severity. RESULTS: Of the men 1,079 (1.8%) reported 5ARI use and 55,100 were available for matching. The final matched cohorts included 944 men each. Mean duration of use was 60.4 months (IQR 17-84 months). Absolute risk for infection was significantly lower in 5ARI users compared to nonusers, 42.3% (399/944) vs 47.2% (446/944), respectively (absolute risk reduction [ARR] 4.9%, OR 0.81, 95% CI 0.67-0.97, p=0.026). Unconditional multivariable logistic regression analysis of the entire study cohort of 55,100 men confirmed the protective association of 5ARI use (ARR 5.3%, OR=0.877, 95% CI 0.774-0.995, p=0.042). Use of 5ARIs was not associated with disease severity. CONCLUSIONS: Use of 5ARIs in men without prostate cancer was associated with a reduction in community acquired SARS-CoV-2 infection.


Subject(s)
5-alpha Reductase Inhibitors/therapeutic use , COVID-19 , COVID-19/prevention & control , Cohort Studies , Humans , Male , Registries , SARS-CoV-2
3.
JAMA Netw Open ; 4(11): e2134241, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1508587

ABSTRACT

Importance: The influence of sleep-disordered breathing (SDB) and sleep-related hypoxemia in SARS-CoV-2 viral infection and COVID-19 outcomes remains unknown. Controversy exists regarding whether to continue treatment for SDB with positive airway pressure given concern for aerosolization with limited data to inform professional society recommendations. Objective: To investigate the association of SDB (identified via polysomnogram) and sleep-related hypoxia with (1) SARS-CoV-2 positivity and (2) World Health Organization (WHO)-designated COVID-19 clinical outcomes while accounting for confounding including obesity, underlying cardiopulmonary disease, cancer, and smoking history. Design, Setting, and Participants: This case-control study was conducted within the Cleveland Clinic Health System (Ohio and Florida) and included all patients who were tested for COVID-19 between March 8 and November 30, 2020, and who had an available sleep study record. Sleep indices and SARS-CoV-2 positivity were assessed with overlap propensity score weighting, and COVID-19 clinical outcomes were assessed using the institutional registry. Exposures: Sleep study-identified SDB (defined by frequency of apneas and hypopneas using the Apnea-Hypopnea Index [AHI]) and sleep-related hypoxemia (percentage of total sleep time at <90% oxygen saturation [TST <90]). Main Outcomes and Measures: Outcomes were SARS-CoV-2 infection and WHO-designated COVID-19 clinical outcomes (hospitalization, use of supplemental oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation, and death). Results: Of 350 710 individuals tested for SARS-CoV-2, 5402 (mean [SD] age, 56.4 [14.5] years; 3005 women [55.6%]) had a prior sleep study, of whom 1935 (35.8%) tested positive for SARS-CoV-2. Of the 5402 participants, 1696 were Black (31.4%), 3259 were White (60.3%), and 822 were of other race or ethnicity (15.2%). Patients who were positive vs negative for SARS-CoV-2 had a higher AHI score (median, 16.2 events/h [IQR, 6.1-39.5 events/h] vs 13.6 events/h [IQR, 5.5-33.6 events/h]; P < .001) and increased TST <90 (median, 1.8% sleep time [IQR, 0.10%-12.8% sleep time] vs 1.4% sleep time [IQR, 0.10%-10.8% sleep time]; P = .02). After overlap propensity score-weighted logistic regression, no SDB measures were associated with SARS-CoV-2 positivity. Median TST <90 was associated with the WHO-designated COVID-19 ordinal clinical outcome scale (adjusted odds ratio, 1.39; 95% CI, 1.10-1.74; P = .005). Time-to-event analyses showed sleep-related hypoxia associated with a 31% higher rate of hospitalization and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.08-1.57; P = .005). Conclusions and Relevance: In this case-control study, SDB and sleep-related hypoxia were not associated with increased SARS-CoV-2 positivity; however, once patients were infected with SARS-CoV-2, sleep-related hypoxia was an associated risk factor for detrimental COVID-19 outcomes.


Subject(s)
COVID-19 , Cause of Death , Hospitalization , Severity of Illness Index , Sleep Apnea Syndromes/complications , Aged , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Case-Control Studies , Continuous Positive Airway Pressure , Delivery of Health Care, Integrated , Extracorporeal Membrane Oxygenation , Female , Florida , Hospital Mortality , Humans , Hypoxia , Logistic Models , Male , Middle Aged , Odds Ratio , Ohio , Respiration, Artificial , Risk Factors , SARS-CoV-2 , Sleep , Sleep Apnea Syndromes/pathology , Sleep Apnea Syndromes/therapy
4.
J Allergy Clin Immunol Pract ; 9(11): 3934-3940.e9, 2021 11.
Article in English | MEDLINE | ID: covidwho-1504841

ABSTRACT

BACKGROUND: Sites of entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly expressed in nasal epithelial cells; however, little is known about the impact of intranasal corticosteroids (INCS) on coronavirus disease 2019 (COVID-19)-related outcomes. OBJECTIVE: To determine the association between baseline INCS use and COVID-19-related outcomes. METHODS: Using the Cleveland Clinic COVID-19 Research Registry, we performed a propensity score matching for treatment with INCS before SARS-CoV-2 infection (April 1, 2020, to March 31, 2021). Of the 82,096 individuals who tested positive, 72,147 met inclusion criteria. Our endpoints included the need for hospitalization, admission to the intensive care unit (ICU), or in-hospital mortality. RESULTS: Of the 12,608 (17.5%) who were hospitalized, 2935 (4.1%) required ICU admission and 1880 (2.6%) died during hospitalization. A significant proportion (n = 10,187; 14.1%) were using INCS before SARS-CoV-2 infection. Compared with nonusers, INCS users demonstrated lower risk for hospitalization (adjusted odds ratio [OR] [95% confidence interval (CI)]: 0.78 [0.72; 0.85]), ICU admission (adjusted OR [95% CI]: 0.77 [0.65; 0.92]), and in-hospital mortality (adjusted OR [95% CI]: 0.76 [0.61; 0.94]). These findings were replicated in sensitivity analyses where patients on inhaled corticosteroids and those with allergic rhinitis were excluded. The beneficial effect of INCS was significant after adjustment for baseline blood eosinophil count (measured before SARS-CoV-2 testing) in a subset of 30,289 individuals. CONCLUSION: INCS therapy is associated with a lower risk for COVID-19-related hospitalization, ICU admission, or death. Future randomized control trials are needed to determine if INCS reduces the risk for severe outcomes related to COVID-19.


Subject(s)
COVID-19 , Adrenal Cortex Hormones/therapeutic use , COVID-19 Testing , Humans , Intensive Care Units , SARS-CoV-2
5.
Med (N Y) ; 2(9): 1050-1071.e7, 2021 Sep 10.
Article in English | MEDLINE | ID: covidwho-1482809

ABSTRACT

Background: T cells control viral infection, promote vaccine durability, and in coronavirus disease 2019 (COVID-19) associate with mild disease. We investigated whether prior measles-mumps-rubella (MMR) or tetanus-diphtheria-pertussis (Tdap) vaccination elicits cross-reactive T cells that mitigate COVID-19. Methods: Antigen-presenting cells (APC) loaded ex vivo with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MMR, or Tdap antigens and autologous T cells from COVID-19-convalescent participants, uninfected individuals, and COVID-19 mRNA-vaccinated donors were co-cultured. T cell activation and phenotype were detected by interferon-γ (IFN-γ) enzyme-linked immunospot (ELISpot) assays and flow cytometry. ELISAs (enzyme-linked immunosorbant assays) and validation studies identified the APC-derived cytokine(s) driving T cell activation. TCR clonotyping and single-cell RNA sequencing (scRNA-seq) identified cross-reactive T cells and their transcriptional profile. A propensity-weighted analysis of COVID-19 patients estimated the effects of MMR and Tdap vaccination on COVID-19 outcomes. Findings: High correlation was observed between T cell responses to SARS-CoV-2 (spike-S1 and nucleocapsid) and MMR and Tdap proteins in COVID-19-convalescent and -vaccinated individuals. The overlapping T cell population contained an effector memory T cell subset (effector memory re-expressing CD45RA on T cells [TEMRA]) implicated in protective, anti-viral immunity, and their detection required APC-derived IL-15, known to sensitize T cells to activation. Cross-reactive TCR repertoires detected in antigen-experienced T cells recognizing SARS-CoV-2, MMR, and Tdap epitopes had TEMRA features. Indices of disease severity were reduced in MMR- or Tdap-vaccinated individuals by 32%-38% and 20%-23%, respectively, among COVID-19 patients. Conclusions: Tdap and MMR memory T cells reactivated by SARS-CoV-2 may provide protection against severe COVID-19. Funding: This study was supported by a National Institutes of Health (R01HL065095, R01AI152522, R01NS097719) donation from Barbara and Amos Hostetter and the Chleck Foundation.

6.
PLoS One ; 16(8): e0255343, 2021.
Article in English | MEDLINE | ID: covidwho-1344153

ABSTRACT

BACKGROUND: Social and ecological differences in early SARS-CoV-2 pandemic screening and outcomes have been documented, but the means by which these differences have arisen are not well understood. OBJECTIVE: To characterize socioeconomic and chronic disease-related mechanisms underlying these differences. DESIGN: Observational cohort study. SETTING: Outpatient and emergency care. PATIENTS: 12900 Cleveland Clinic Health System patients referred for SARS-CoV-2 testing between March 17 and April 15, 2020. INTERVENTIONS: Nasopharyngeal PCR test for SARS-CoV-2 infection. MEASUREMENTS: Test location (emergency department, ED, vs. outpatient care), COVID-19 symptoms, test positivity and hospitalization among positive cases. RESULTS: We identified six classes of symptoms, ranging in test positivity from 3.4% to 23%. Non-Hispanic Black race/ethnicity was disproportionately represented in the group with highest positivity rates. Non-Hispanic Black patients ranged from 1.81 [95% confidence interval: 0.91-3.59] times (at age 20) to 2.37 [1.54-3.65] times (at age 80) more likely to test positive for the SARS-CoV-2 virus than non-Hispanic White patients, while test positivity was not significantly different across the neighborhood income spectrum. Testing in the emergency department (OR: 5.4 [3.9, 7.5]) and cardiovascular disease (OR: 2.5 [1.7, 3.8]) were related to increased risk of hospitalization among the 1247 patients who tested positive. LIMITATIONS: Constraints on availability of test kits forced providers to selectively test for SARS-Cov-2. CONCLUSION: Non-Hispanic Black patients and patients from low-income neighborhoods tended toward more severe and prolonged symptom profiles and increased comorbidity burden. These factors were associated with higher rates of testing in the ED. Non-Hispanic Black patients also had higher test positivity rates.


Subject(s)
COVID-19 Testing/trends , COVID-19/diagnosis , Socioeconomic Factors , Adult , Aged , COVID-19/economics , COVID-19/psychology , COVID-19 Testing/methods , Cohort Studies , Comorbidity , Female , Hospitalization , Humans , Male , Mass Screening/methods , Mass Screening/psychology , Middle Aged , Ohio/epidemiology , Pandemics , Risk Factors , SARS-CoV-2/pathogenicity
7.
Signal Transduct Target Ther ; 6(1): 292, 2021 07 30.
Article in English | MEDLINE | ID: covidwho-1333904

ABSTRACT

Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial, and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied. Here we inspected sex differences in SARS-CoV-2 infection, hospitalization, admission to the intensive care unit (ICU), sera inflammatory biomarker profiling, and single-cell RNA-sequencing (scRNA-seq) profiles across nasal, bronchoalveolar lavage fluid (BALF), and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with varying degrees of disease severities. Our propensity score-matching observations revealed that male individuals have a 29% elevated likelihood of SARS-CoV-2 positivity, with a hazard ratio (HR) 1.32 (95% confidence interval [CI] 1.18-1.48) for hospitalization and HR 1.51 (95% CI 1.24-1.84) for admission to ICU. Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers (C-reactive protein and procalcitonin). We found that SARS-CoV-2 entry factors, including ACE2, TMPRSS2, FURIN, and NRP1, have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19. We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples, which offers potential molecular mechanism for sex-biased susceptibility to viral infection. Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19. Mechanistically, monocyte-elevated expression of Toll-like receptor 7 (TLR7) and Bruton tyrosine kinase (BTK) is associated with severe outcomes in males with COVID-19. In summary, these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.


Subject(s)
COVID-19/immunology , Cell Communication/immunology , Leukocytes, Mononuclear/immunology , Nasal Mucosa/immunology , SARS-CoV-2/immunology , Sex Characteristics , Adult , Aged , COVID-19/pathology , Female , Humans , Leukocytes, Mononuclear/pathology , Male , Middle Aged , Nasal Mucosa/pathology , Single-Cell Analysis
8.
Alzheimers Res Ther ; 13(1): 110, 2021 06 09.
Article in English | MEDLINE | ID: covidwho-1262514

ABSTRACT

BACKGROUND: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. METHODS: In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. RESULTS: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. CONCLUSION: Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.


Subject(s)
Alzheimer Disease , COVID-19 , Cognitive Dysfunction , Alzheimer Disease/genetics , Brain , Endothelial Cells , Humans , Membrane Proteins , RNA-Binding Proteins , SARS-CoV-2
10.
Mayo Clin Proc Innov Qual Outcomes ; 5(4): 795-801, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1225334

ABSTRACT

Objective: To develop predictive models for in-hospital mortality and length of stay (LOS) for coronavirus disease 2019 (COVID-19)-positive patients. Patients and Methods: We performed a multicenter retrospective cohort study of hospitalized COVID-19-positive patients. A total of 764 patients admitted to 14 different hospitals within the Cleveland Clinic from March 9, 2020, to May 20, 2020, who had reverse transcriptase-polymerase chain reaction-proven coronavirus infection were included. We used LightGBM, a machine learning algorithm, to predict in-hospital mortality at different time points (after 7, 14, and 30 days of hospitalization) and in-hospital LOS. Our final cohort was composed of 764 patients admitted to 14 different hospitals within our system. Results: The median LOS was 5 (range, 1-44) days for patients admitted to the regular nursing floor and 10 (range, 1-38) days for patients admitted to the intensive care unit. Patients who died during hospitalization were older, initially admitted to the intensive care unit, and more likely to be white and have worse organ dysfunction compared with patients who survived their hospitalization. Using the 10 most important variables only, the final model's area under the receiver operating characteristics curve was 0.86 for 7-day, 0.88 for 14-day, and 0.85 for 30-day mortality in the validation cohort. Conclusion: We developed a decision tool that can provide explainable and patient-specific prediction of in-hospital mortality and LOS for COVID-19-positive patients. The model can aid health care systems in bed allocation and distribution of vital resources.

11.
JAMA Netw Open ; 4(4): e217746, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1201599

ABSTRACT

Importance: Understanding of SARS-CoV-2 variants that alter disease outcomes are important for clinical risk stratification and may provide important clues to the complex virus-host relationship. Objective: To examine the association of identified SARS-CoV-2 variants, virus clades, and clade groups with disease severity and patient outcomes. Design, Setting, and Participants: In this cross-sectional study, viral genome analysis of clinical specimens obtained from patients at the Cleveland Clinic infected with SARS-CoV-2 during the initial wave of infection (March 11 to April 22, 2020) was performed. Identified variants were matched with clinical outcomes. Data analysis was performed from April to July 2020. Main Outcomes and Measures: Hospitalization, intensive care unit (ICU) admission, mortality, and laboratory outcomes were matched with SARS-CoV-2 variants. Results: Specimens sent for viral genome sequencing originated from 302 patients with SARS-CoV-2 infection (median [interquartile range] age, 52.6 [22.8 to 82.5] years), of whom 126 (41.7%) were male, 195 (64.6%) were White, 91 (30.1%) required hospitalization, 35 (11.6%) needed ICU admission, and 17 (5.6%) died. From these specimens, 2531 variants (484 of which were unique) were identified. Six different SARS-CoV-2 clades initially circulated followed by a rapid reduction in clade diversity. Several variants were associated with lower hospitalization rate, and those containing 23403A>G (D614G Spike) were associated with increased survival when the patient was hospitalized (64 of 74 patients [86.5%] vs 10 of 17 patients [58.8%]; χ21 = 6.907; P = .009). Hospitalization and ICU admission were similar regardless of clade. Infection with Clade V variants demonstrated higher creatinine levels (median [interquartile range], 2.6 [-0.4 to 5.5] mg/dL vs 1.0 [0.2 to 2.2] mg/dL; mean creatinine difference, 2.9 mg/dL [95% CI, 0.8 to 5.0 mg/dL]; Kruskal-Wallis P = .005) and higher overall mortality rates (3 of 14 patients [21.4%] vs 17 of 302 patients [5.6%]; χ21 = 5.640; P = .02) compared with other variants. Infection by strains lacking the 23403A>G variant showed higher mortality in multivariable analysis (odds ratio [OR], 22.4; 95% CI, 0.6 to 5.6; P = .01). Increased variants of open reading frame (ORF) 3a were associated with decreased hospitalization frequency (OR, 0.4; 95% CI, 0.2 to 0.96; P = .04), whereas increased variants of Spike (OR, 0.01; 95% CI, <0.01 to 0.3; P = .01) and ORF8 (OR, 0.03; 95% CI, <0.01 to 0.6; P = .03) were associated with increased survival. Conclusions and Relevance: Within weeks of SARS-CoV-2 circulation, a profound shift toward 23403A>G (D614G) specific genotypes occurred. Replaced clades were associated with worse clinical outcomes, including mortality. These findings help explain persistent hospitalization yet decreasing mortality as the pandemic progresses. SARS-CoV-2 clade assignment is an important factor that may aid in estimating patient outcomes.


Subject(s)
COVID-19/genetics , Pandemics/statistics & numerical data , SARS-CoV-2 , Adult , COVID-19/epidemiology , COVID-19/virology , Cross-Sectional Studies , Female , Genome, Viral/genetics , Humans , Male , Middle Aged , Pandemics/prevention & control , Severity of Illness Index
12.
Chest ; 159(6): 2191-2204, 2021 06.
Article in English | MEDLINE | ID: covidwho-1149108

ABSTRACT

BACKGROUND: Since COVID-19 was identified, its clinical and biological heterogeneity has been recognized. Identifying COVID-19 phenotypes might help guide basic, clinical, and translational research efforts. RESEARCH QUESTION: Does the clinical spectrum of patients with COVID-19 contain distinct phenotypes and subphenotypes? STUDY DESIGN AND METHODS: We included adult patients (≥ 18 years) positive for laboratory-confirmed SARS-CoV-2 infection from a prospective COVID-19 registry database in the Cleveland Clinic Health System in Ohio and Florida. The patients were split into training and testing sets. Using latent class analysis (LCA), we first identified phenotypic clusters of patients with COVID-19 based on demographics, comorbidities, and presenting symptoms. We then identified subphenotypes of hospitalized patients with additional blood biomarker data measured on hospital admission. The associations of phenotypes/subphenotypes and clinical outcomes were investigated. Multivariable prediction models were established to predict assignment to the LCA-defined phenotypes and subphenotypes and then evaluated on an independent testing set. RESULTS: We analyzed data for 20,572 patients. Seven phenotypes were identified on the basis of different profiles of presenting COVID-19 symptoms and existing comorbidities, including the following groups: young, no symptoms; young, symptoms; middle-aged, no symptoms; middle-aged, symptoms; middle-aged, comorbidities; old, no symptoms; and old, symptoms. The rates of inpatient hospitalization for the phenotypes were significantly different (P < .001). Five subphenotypes were identified for the subgroup of hospitalized patients, including the following subgroups: young, elevated WBC and platelet counts; middle-aged, lymphopenic with elevated C-reactive protein; middle-aged, hyperinflammatory; old, leukopenic with comorbidities; and old, hyperinflammatory with kidney dysfunction. The hospital mortality and the times from hospitalization to ICU transfer or death were significantly different (P < .001). The models for predicting the LCA-defined phenotypes and subphenotypes showed high discrimination (concordance index, 0.92 and 0.91). INTERPRETATION: Hypothesis-free LCA-defined phenotypes and subphenotypes of patients with COVID-19 can be identified. These may help clinical investigators conduct stratified analyses in clinical trials and assist basic science researchers in characterizing the pathobiology of the spectrum of COVID-19 presentations.


Subject(s)
COVID-19/epidemiology , Adult , Aged , Blood Cell Count , C-Reactive Protein , COVID-19/blood , COVID-19/complications , Cohort Studies , Critical Care , Female , Florida , Hospital Mortality , Hospitalization , Humans , Latent Class Analysis , Male , Middle Aged , Ohio , Phenotype , Young Adult
13.
Front Neurosci ; 15: 606926, 2021.
Article in English | MEDLINE | ID: covidwho-1102486

ABSTRACT

The clinical characteristics and biological effects on the nervous system of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain poorly understood. The aim of this study is to advance epidemiological and mechanistic understanding of the neurological manifestations of coronavirus disease 2019 (COVID-19) using stroke as a case study. In this study, we performed a meta-analysis of clinical studies reporting stroke history, intensive inflammatory response, and procoagulant state C-reactive protein (CRP), Procalcitonin (PCT), and coagulation indicator (D-dimer) in patients with COVID-19. Via network-based analysis of SARS-CoV-2 host genes and stroke-associated genes in the human protein-protein interactome, we inspected the underlying inflammatory mechanisms between COVID-19 and stroke. Finally, we further verified the network-based findings using three RNA-sequencing datasets generated from SARS-CoV-2 infected populations. We found that the overall pooled prevalence of stroke history was 2.98% (95% CI, 1.89-4.68; I 2=69.2%) in the COVID-19 population. Notably, the severe group had a higher prevalence of stroke (6.06%; 95% CI 3.80-9.52; I 2 = 42.6%) compare to the non-severe group (1.1%, 95% CI 0.72-1.71; I 2 = 0.0%). There were increased levels of CRP, PCT, and D-dimer in severe illness, and the pooled mean difference was 40.7 mg/L (95% CI, 24.3-57.1), 0.07 µg/L (95% CI, 0.04-0.10) and 0.63 mg/L (95% CI, 0.28-0.97), respectively. Vascular cell adhesion molecule 1 (VCAM-1), one of the leukocyte adhesion molecules, is suspected to play a vital role of SARS-CoV-2 mediated inflammatory responses. RNA-sequencing data analyses of the SARS-CoV-2 infected patients further revealed the relative importance of inflammatory responses in COVID-19-associated neurological manifestations. In summary, we identified an elevated vulnerability of those with a history of stroke to severe COVID-19 underlying inflammatory responses (i.e., VCAM-1) and procoagulant pathways, suggesting monotonic relationships, thus implicating causality.

14.
JMIR Public Health Surveill ; 6(4): e25174, 2020 12 23.
Article in English | MEDLINE | ID: covidwho-1067574

ABSTRACT

BACKGROUND: Different states in the United States had different nonpharmaceutical public health interventions during the COVID-19 pandemic. The effects of those interventions on hospital use have not been systematically evaluated. The investigation could provide data-driven evidence to potentially improve the implementation of public health interventions in the future. OBJECTIVE: We aim to study two representative areas in the United States and one area in China (New York State, Ohio State, and Hubei Province), and investigate the effects of their public health interventions by time periods according to key interventions. METHODS: This observational study evaluated the numbers of infected, hospitalized, and death cases in New York and Ohio from March 16 through September 14, 2020, and Hubei from January 26 to March 31, 2020. We developed novel Bayesian generalized compartmental models. The clinical stages of COVID-19 were stratified in the models, and the effects of public health interventions were modeled through piecewise exponential functions. Time-dependent transmission rates and effective reproduction numbers were estimated. The associations of interventions and the numbers of required hospital and intensive care unit beds were studied. RESULTS: The interventions of social distancing, home confinement, and wearing masks significantly decreased (in a Bayesian sense) the case incidence and reduced the demand for beds in all areas. Ohio's transmission rates declined before the state's "stay at home" order, which provided evidence that early intervention is important. Wearing masks was significantly associated with reducing the transmission rates after reopening, when comparing New York and Ohio. The centralized quarantine intervention in Hubei played a significant role in further preventing and controlling the disease in that area. The estimated rates that cured patients become susceptible in all areas were small (<0.0001), which indicates that they have little chance to get the infection again. CONCLUSIONS: The series of public health interventions in three areas were temporally associated with the burden of COVID-19-attributed hospital use. Social distancing and the use of face masks should continue to prevent the next peak of the pandemic.


Subject(s)
COVID-19/prevention & control , COVID-19/therapy , Hospitalization/statistics & numerical data , Public Health Practice/statistics & numerical data , Bayes Theorem , COVID-19/epidemiology , China/epidemiology , Humans , Masks/statistics & numerical data , Models, Statistical , Physical Distancing , Quarantine/statistics & numerical data , United States/epidemiology
15.
ChemRxiv ; 2020 Jul 02.
Article in English | MEDLINE | ID: covidwho-1027422

ABSTRACT

The global Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of co-existing medical conditions while the underlying mechanisms remain unclear. Furthermore, there are no proven effective therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, diseases manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measure revealed underlying pathogenesis for broad COVID-19-associated manifestations. Multi-modal analyses of single-cell RNA-sequencing data showed that co-expression of ACE2 and TMPRSS2 was elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn's disease patients compared to uninflamed tissues, revealing shared pathobiology by COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicated that COVID-19 shared intermediate inflammatory endophenotypes with asthma (including IRAK3 and ADRB2). To prioritize potential treatment, we combined network-based prediction and propensity score (PS) matching observational study of 18,118 patients from a COVID-19 registry. We identified that melatonin (odds ratio (OR) = 0.36, 95% confidence interval (CI) 0.22-0.59) was associated with 64% reduced likelihood of a positive laboratory test result for SARS-CoV-2. Using PS-matching user active comparator design, melatonin was associated with 54% reduced likelihood of SARS-CoV-2 positive test result compared to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (OR = 0.46, 95% CI 0.24-0.86).

16.
Crit Care Explor ; 2(12): e0300, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-998494

ABSTRACT

Objectives: To develop an algorithm that predicts an individualized risk of severe coronavirus disease 2019 illness (i.e., ICU admission or death) upon testing positive for coronavirus disease 2019. Design: A retrospective cohort study. Setting: Cleveland Clinic Health System. Patients: Those hospitalized with coronavirus disease 2019 between March 8, 2020, and July 13, 2020. Interventions: A temporal coronavirus disease 2019 test positive cut point of June 1 was used to separate the development from validation cohorts. Fine and Gray competing risk regression modeling was performed. Measurements and Main Results: The development set contained 4,520 patients who tested positive for coronavirus disease 2019 between March 8, 2020, and May 31, 2020. The validation set contained 3,150 patients who tested positive between June 1 and July 13. Approximately 9% of patients were admitted to the ICU or died of coronavirus disease 2019 within 2 weeks of testing positive. A prediction cut point of 15% was proposed. Those who exceed the cutoff have a 21% chance of future severe coronavirus disease 2019, whereas those who do not have a 96% chance of avoiding the severe coronavirus disease 2019. In addition, application of this decision rule identifies 89% of the population at the very low risk of severe coronavirus disease 2019 (< 4%). Conclusions: We have developed and internally validated an algorithm to assess whether someone is at high risk of admission to the ICU or dying from coronavirus disease 2019, should he or she test positive for coronavirus disease 2019. This risk should be a factor in determining resource allocation, protection from less safe working conditions, and prioritization for vaccination.

17.
J Urol ; 205(2): 441-443, 2021 02.
Article in English | MEDLINE | ID: covidwho-967503

ABSTRACT

PURPOSE: TMPRSS2 is a host co-receptor for cell entry of SARS-CoV-2. A prior report suggested that use of androgen deprivation therapy, which downregulates TMPRSS2, may protect men with prostate cancer from infection. MATERIALS AND METHODS: This is a cohort study of a prospective registry of all patients tested for SARS-CoV-2 between March 12 and June 10, 2020 with complete followup until disease recovery or death. The main exposure examined was the use of androgen deprivation therapy, and the outcome measures were the rate of SARS-CoV-2 positivity and disease severity as a function of androgen deprivation therapy use. RESULTS: The study cohort consisted of 1,779 men with prostate cancer from a total tested population of 74,787, of whom 4,885 (6.5%) were positive for SARS-CoV-2. Of those with prostate cancer 102 (5.7%) were SARS-CoV-2 positive and 304 (17.1%) were on androgen deprivation therapy. Among those on androgen deprivation therapy 5.6% were positive as compared to 5.8% not on androgen deprivation therapy. Men on androgen deprivation therapy were slightly older (75.5 vs 73.8 years, p=0.009), more likely to have smoked (68.1% vs 59.3%, p=0.005) and more likely to report taking steroids (43.8% vs 23.3%, p <0.001). Other factors known to increase risk of infection and disease severity were equally distributed (asthma, diabetes mellitus, hypertension, coronary artery disease, heart failure and immune suppressive disease). Multivariable analysis did not indicate a difference in infection risk for those with prostate cancer on androgen deprivation therapy (OR 0.93, 95% CI 0.54-1.61, p=0.8). CONCLUSIONS: Androgen deprivation therapy does not appear to be protective against SARS-CoV-2 infection.


Subject(s)
Androgen Antagonists/therapeutic use , COVID-19/epidemiology , Prostatic Neoplasms/drug therapy , Serine Endopeptidases/metabolism , Aged , Down-Regulation , Humans , Male , Prospective Studies , Registries , Risk Assessment , Risk Factors , SARS-CoV-2
18.
PLoS Biol ; 18(11): e3000970, 2020 11.
Article in English | MEDLINE | ID: covidwho-914191

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56-0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription-polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54-0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52-0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31-0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19.


Subject(s)
COVID-19/drug therapy , Drug Repositioning , Melatonin/administration & dosage , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Datasets as Topic , Host-Pathogen Interactions/genetics , Humans , Pandemics , Transcriptome
20.
Chest ; 158(4): 1364-1375, 2020 10.
Article in English | MEDLINE | ID: covidwho-805083

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is sweeping the globe. Despite multiple case-series, actionable knowledge to tailor decision-making proactively is missing. RESEARCH QUESTION: Can a statistical model accurately predict infection with COVID-19? STUDY DESIGN AND METHODS: We developed a prospective registry of all patients tested for COVID-19 in Cleveland Clinic to create individualized risk prediction models. We focus here on the likelihood of a positive nasal or oropharyngeal COVID-19 test. A least absolute shrinkage and selection operator logistic regression algorithm was constructed that removed variables that were not contributing to the model's cross-validated concordance index. After external validation in a temporally and geographically distinct cohort, the statistical prediction model was illustrated as a nomogram and deployed in an online risk calculator. RESULTS: In the development cohort, 11,672 patients fulfilled study criteria, including 818 patients (7.0%) who tested positive for COVID-19; in the validation cohort, 2295 patients fulfilled criteria, including 290 patients who tested positive for COVID-19. Male, African American, older patients, and those with known COVID-19 exposure were at higher risk of being positive for COVID-19. Risk was reduced in those who had pneumococcal polysaccharide or influenza vaccine or who were on melatonin, paroxetine, or carvedilol. Our model had favorable discrimination (c-statistic = 0.863 in the development cohort and 0.840 in the validation cohort) and calibration. We present sensitivity, specificity, negative predictive value, and positive predictive value at different prediction cutoff points. The calculator is freely available at https://riskcalc.org/COVID19. INTERPRETATION: Prediction of a COVID-19 positive test is possible and could help direct health-care resources. We demonstrate relevance of age, race, sex, and socioeconomic characteristics in COVID-19 susceptibility and suggest a potential modifying role of certain common vaccinations and drugs that have been identified in drug-repurposing studies.


Subject(s)
Betacoronavirus , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Adult , Aged , Algorithms , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Female , Humans , Logistic Models , Male , Middle Aged , Models, Statistical , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Predictive Value of Tests , Retrospective Studies , Risk Factors , SARS-CoV-2
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