Inflammatory Pathways Associated with Covid-19 Severity Differ Based on Obesity Status

Background: Severe COVID-19 and obesity are characterized by higher inflammation. We aimed to examine early inflammatory patterns in people with (Ob) and without (NOb) obesity and COVID-19 and how they relate to COVID-19 disease severity Methods: Ob (BMI >30 Kg/m2) and NOb with COVID-19 matched for age, sex and WHO disease severity provided blood early after diagnosis. Immunoassays measured 57 plasma biomarkers reflecting innate immune and endothelial activation, systemic inflammation, coagulation, metabolism and microbial translocation (Fig 1). Between-group differences were assessed by Mann- Whitney. Associations between subsequent maximal COVID-19 severity (mild vs moderate/severe/critical) and biomarkers were explored by logistic regression adjusted for age, sex, hypertension (HTN) and diabetes (DM). Data are median pg/mL [IQR] or n [%] unless stated Results: Of 100 subjects (50 Ob and 50 Nob) presenting between April 2020 and March 2021, characteristics (Ob vs Nob) included: age 65 [23-91] vs 65 [21-95];female sex 27 (48%) vs 28 (56%);BMI 33.7 [30.0-71.8] vs 23.3 [15.3-25.9];disease severity mild 22 [48%] vs 23 [46%], moderate 15 [30%] vs 13 [26%], severe 6 [12%] vs 7 [14%];HTN 30 (60%) vs 17 (34%);DM 19 [38%] vs 6 [12%];days from symptom onset 7 [2-17] vs 8 [1-15];vaccinated 3 (6%) vs 0 (0%). Compared to NOb, Ob had higher IFN-alpha (1.8 [0.6;11] vs 0.9 [0.1;4.7]), CRP (10 mAU/mL [9.6;10.2] vs 9.7 [7.2;10]), IL-1RA (197 [122;399] vs 138 [88;253]), IL-4 (288 AU/mL [161;424] vs 205 [82;333]), vWF (252 [166;383] vs 163 [96;318]), Zonulin (114 ng/mL [77;131] vs 57 [18;106]), Resistin (956 [569;1153] vs 727 [712;1525]), Leptin (3482 [1513;5738] vs 848 [249;2114]), and lower Adiponectin (1.12 mg/L [0.09;1.5] vs 1.5 [1.18;1.93]), all p< 0.05. In both groups higher, proinflammatory IL-18 and lower levels of antiinflammatory CCL22 and IL-5 were associated with higher odds of disease severity, and lower E-selectin with higher disease severity only in Ob. However, in NOb higher type 3 interferons (IL-28A), macrophage activation (sCD163, CCL3) and vascular inflammation markers (ICAM-1, VCAM-1), along with higher S100B, GM-CSF and leptin were also associated with disease severity, a pattern not observed in Ob (Fig 1) Conclusion(s): Although Ob had higher overall levels of inflammation than NOb, few biomarkers predicted subsequent COVID-19 severity in Ob. These differential inflammatory patterns suggest dysregulated immune responses in Ob with COVID-19. (Figure Presented).

Cellular and humoral immunogenicity of the COVID-19 vaccine and COVID-19 disease severity in individuals with immunodeficiency.

Background: A well-coordinated adaptive immune response is crucial for limiting COVID-19 disease. Some individuals with immunodeficiency are at a high risk of developing severe COVID-19. Therefore, the development of standardized methods for measuring different arms of the vaccine response in the setting of immunodeficiency is of particular interest. In this study, we compared the vaccine response of individuals living with immunodeficiency with healthy controls in terms of interferon gamma (IFN-γ) production and spike protein-specific antibody level post primary COVID-19 vaccination and booster vaccines. Additionally, the disease severity of those individuals who contracted COVID-19 was assessed. Methods: Whole blood was stimulated overnight from 71 participants and 99 healthy controls. Commercially available PepTivator® peptide pool and trimeric spike protein stimulation were used. ELISA was used to analyze IFN-γ levels. The total SARS-CoV-2 spike protein antibody titre was measured using a Roche Elecsys® S total antibody assay. Patient characteristics, COVID-19 infection status and IDDA 2.1 'Kaleidoscope' scores were recorded. Vaccine responses were scored from zero to three. Results: 99% of healthy controls, 89% of individuals with IEI and 76% with secondary immunodeficiency (SID) had an IFN-γ level above the validated reference range after peptide mix stimulation following primary vaccination. There was an increase in IFN-γ levels in patients with inborn errors of immunity (IEI) following the booster vaccine (p = 0.0156). 100% of healthy controls, 70% of individuals living with IEI and 64% of individuals living with SID had detectable spike protein-specific antibody levels following the primary vaccination. 55% of immunodeficiency patients who had mild COVID-19 and 10% with moderate/severe COVID-19 had detectable antibody and IFN-γ levels post vaccine. The mean pre-infection IDDA 2.1 scores were higher in individuals who developed moderate/severe COVID-19 (25.2 compared to 9.41). Conclusions: Covid whole-blood IGRA is a highly accurate, straightforward and robust assay and can be easily adapted to measure cellular response to COVID-19. A complete evaluation of the vaccine response may be particularly important for individuals living with immunodeficiency. A clinical immunodeficiency score and a validated vaccine response score may be valuable tools in estimating COVID-19 disease risk and identifying individuals living with immunodeficiency who may benefit from enhanced vaccination schedules.

Myocardial Injury Is Not Associated with Mortality in Severe Covid-19

Background Biochemical markers of cardiac injury and strain are proven indicators of severe COVID-19. Whether enzyme elevation is a product of cardiopulmonary strain versus myocardial viral injury is not well defined. CARDIO-COVID is a registry designed to study COVID-19 patients admitted to ICUs with evidence of cardiac injury. Methods Inclusion criteria for the CARDIO-COVID registry are PCR positive test for SARS-CoV2, ICU admission and either elevated troponin, elevated NT-proBNP/BNP, or new onset heart failure. Registry contains 1328 cases from 16 centers in the US, Canada, and Europe. 838 cases were included for analysis. Cases were collected between March 2020 - May 2021. Multivariate regression analyses were performed. Results Patients were 51.3% male, average age of 67.4 years and 32% Caucasian. 63% had pre-existing cardiovascular disease. Morbidity and mortality were common: 40% died, 50% underwent intubation, 20% required renal replacement therapy, and 5% had cardiac arrest requiring CPR. New onset arrhythmias were common (26%), but VT/VF was rare (4.8%). Cardiovascular complications were minor drivers of morbidity: 4.8% had ACS requiring catheterization, 8.0% had new onset heart failure (median EF 43% (IQR 31 - 47.75%), 4.4% had a CVA, and 6.7% had PE. Of patients who died, 65% died from hypoxemic respiratory failure, 10.5% from septic shock, 9.3% from PEA, and 3.1% from cardiogenic shock. Modeling showed insignificant increased odds of death in patients with MACE (p-value 0.22, OR 1.94 CI 0.67 - 5.82). Age (p-value 0.005) and intubation (p-value 0.001, OR 5.8 CI 2.1 - 18) were strongest predictors of death. Every increase in age by one year was associated with 5% increase in odds of death. Degree of cardiac enzyme elevation was not associated with MACE, death, or intubation. Conclusion While elevated cardiac enzymes are common in severe COVID-19, cardiac complications are not common drivers of mortality. Respiratory failure and septic shock are leading causes of death. These findings suggest that in severe COVID-19 cardiac enzyme elevation usually reflects cardiopulmonary strain from respiratory distress rather than myocardial injury portending cardiac failure or death.Copyright © 2023 American College of Cardiology Foundation

Demonstration of stable clusters of symptoms in long COVID

Background. Long COVID is a heterogenous condition. We previously demonstrated distinct phenotypes of long COVID, but the impact of later waves caused by SARS-CoV-2 variants on long COVID presentations has not been described. Methods. We selected individuals with ongoing symptoms > 4 weeks from PCR-confirmed COVID-19 in a multicentre, prospective cohort study. We used multiple correspondence analysis and hierarchical clustering on self-reported symptoms to identify symptom clusters, in individuals recruited during two periods;cohort 1 from March 2020 to April 2021, and cohort 2 from April 2021 to March 2022. We explored differences in symptoms by mapping acute infection to one of four COVID-19 waves in Ireland (table 1) as well as vaccination status, and used Chi2 test to compare symptoms frequencies. Results. Demographics are shown in Table 2. Cluster analysis of each cohort demonstrated 3 distinct clusters in both cohorts, which shared similar clinical characteristics;a musculoskeletal/pain symptom cluster, a cardiorespiratory cluster and a third less symptomatic cluster (Figure 1). While symptoms within clusters were similar across both periods, in the cardiorespiratory cluster, the frequency of palpitations decreased (56% vs 16%) and cough increased (14% vs 45%) between reporting periods (both P< 0.01). Furthermore, a greater proportion of palpitations were reported in those with COVID-19 from waves 1 and 2 (35% and 28%) compared to 3 and 4 (both 12%, P< 0.001), and a greater proportion of chest pain in waves 1, 2 and 4 compared to wave 3. There were no differences in other symptoms (Table 3). Additionally there were significantly less palpitations reported in those vaccinated at the time of review (17% vs 31% P=0.002), but not chest pain (30% vs 39% P=0.13). In multivariate analysis, infection in wave 3 and 4 but not vaccination status remained significantly associated with lower reported palpitations (OR (95% CI) 0.28 (0.13-0.97) and 0.5 (0.06-0.87) for waves 3 and 4, both P< 0.05), and wave 3 infection remained independently associated with lower reported chest pain (OR 0.3 (0.25-0.7)). Conclusion. Three symptom clusters define long COVID across the two cohorts, but characteristics of the cardiorespiratory phenotype have evolved over time with evolution of SARS-CoV-2 variants. (Table Presented).

Broad and Potent Activity Against Sars-Like Viruses by an Engineered Human Monoclonal Antibody

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.

Comparison between SARS-Cov-2, non-SARS-Cov-2 Coronavirus, Influenza and RSV Infections among Solid Organ Transplant Recipients

Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been raging since the end of 2019 and has shown worse outcomes in solid organ transplant recipients (SOTR). The clinical differences as well as outcomes between these respiratory viruses have not been well defined in SOTR. Methods. This is a retrospective cohort study of adult SOTR with nasopharyngeal swab or bronchoalveolar lavage PCR positive for either SARS-CoV-2, non-SARSCoV-2 coronavirus, influenza, or respiratory syncytial virus (RSV) from January 2017 to October 2020;both inpatient and outpatient. The follow up period was up to three months. Clinical characteristics and outcomes were evaluated. Development of lower respiratory tract infection (LRTI) was defined as new pulmonary infiltrates with or without symptoms. For statistical analysis, Fischer's exact test and log rank test were performed. Results. During study period, 157 SARS-CoV-2, 72 non-SARS-CoV-2 coronavirus, 100 influenza, 50 RSV infections were identified. Patient characteristics and outcomes are shown in tables 1 and 2, respectively. Secondary infections were not statistically significantly different between SARS-CoV-2 vs. non-SARS-CoV-2 coronavirus and influenza (p=0.25, 0.56) respectively, while it was statistically significant between SARS-CoV-2 and RSV (p=0.0009). Development of LRTI was higher in SARS-CoV-2 when compared to non-SARS-CoV-2 coronavirus (p=0.03), influenza (p=0.0001) and RSV (p=0.003). Admission to ICU was higher with SARS-CoV-2 compared to non-SARS-CoV-2 coronavirus (p=0.01), influenza (p=0.0001) and RSV (p=0.007). SARS-CoV-2 also had higher rates of mechanical ventilation when compared to non-SARS-CoV-2 coronavirus (p=0.01), influenza (p=0.01) and RSV (p=0.03). With time to event analysis, higher mortality with SARS-CoV-2 as compared to non-SARSCoV-2 coronavirus, influenza, and RSV (p=0.01) was shown (Figure 1). Conclusion. We found higher incidence of ICU admission, mechanical ventilation, and mortality among SARS-CoV-2 SOTR vs other respiratory viruses. To validate these results, multicenter study is warranted.

Unusual presentation of paraneoplastic myopathy and non-bacterial thrombotic endocarditis due to metastatic gastrointestinal malignancy

Introduction: Gastrointestinal (GI) malignancies are associated with paraneoplastic sequelae such as non-bacterial thrombotic endocarditis (NBTE) and inflammatory myopathy. We describe a unique case in which a metastatic gastric malignancy presented without typical GI symptoms and instead was discovered after pursuing a unifying diagnosis for a constellation of cardiac, neurologic, and musculoskeletal manifestations. Case Description/Methods: A 61-year-old woman presented to a tertiary medical center with shoulder and thigh soreness and weakness with functional decline in the 3 months prior to presentation. Her medical history included morbid obesity, atrial fibrillation (AF), diabetes mellitus, and resolved COVID-19 pneumonia. Her physical exam was notable for proximal muscle weakness and tenderness, bilateral ptosis, vertical gaze deficit, and 4/6 diastolic murmur. Laboratory values included CRP 3.2 mg/dL (normal range <0.8 mg/dL), ESR 51 mm/hour (, 30 mm/hour), creatine kinase 822 IU/L (25-185 IU/L), and aldolase 24.3 U/L (<8.1 U/L). A muscle biopsy was performed revealing an equivocal inflammatory myopathy process. The gaze deficit prompted an MRI of the brain, revealing multiple thromboembolic strokes. COVID related hypercoagulability and AF were considered, however given the murmur on exam, a transesophageal echocardiogram was performed which showed large mobile echodensities on the aortic valve. She was empirically treated for infectious endocarditis, though with concern for NBTE and occult malignancy. CT scan of the abdomen and pelvis with IV contrast was then performed, demonstrating metastatic liver lesions and enlarged gastrohepatic and cardiophrenic lymph nodes. In discussion with radiology, it was suggestive of a gastric primary malignancy. Carcinoembryonic antigen and carbohydrate antigen 19-9 returned at 4965 ng/mL (<3 ng/mL) and 1878 U/mL (<35 U/mL), respectively. The patient ultimately decided to pursue hospice care. Discussion: In this unusual case, a gastric malignancy presented with paraneoplastic phenomena in multiple systems, but without GI symptoms. Physical exam findings led to critical diagnostic steps. NBTE is associated with malignancy, commonly carcinomas of the stomach, biliary system, pancreas, ovaries, or lung. Inflammatory myopathy can also share strong associations with cancer. Our report highlights a unique diagnostic journey and should alert physicians to include GI malignancy on the differential when presented with NBTE and myopathy..

Sars-cov-2 versus non-sars-cov-2 infection among solid organ transplant recipients: Case control study

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been raging since the end of 2019. The clinical differences between non-SARSCoV-2 coronavirus and SARS-CoV-2 in solid organ transplant recipients (SOTR) are not well defined. Methods: This is a case control study of adult SOTR with PCR positive nasopharyngeal sample or bronchoalveolar lavage, for either SARS-CoV-2 or non-SARS-CoV-2 coronavirus, from 1/2017 to 10/2020. Follow up period was up to three months. Secondary infections were diagnosed by culture or viral PCR from a sterile specimen. Clinical outcomes were compared amongst both groups. Results: Seventy-two non-SARS-CoV-2 coronavirus and 129 SARS-CoV-2 infections were identified. Patient's demographic information and outcomes are shown in table 1 and 2 respectively. Secondary infections and ICU admissions were statistically significantly different between both groups, and higher mortality was observed in the SARS-CoV-2 group. With time to event analysis, there was trend to higher mortality with SARS-CoV-2 infection as compared to non-SARS-CoV-2 (p=0.06)(figure). Conclusions: Our study shows SOTR with SARS-CoV-2 infection may have a significant worse outcome as compared to non-SARS-CoV-2. Secondary infection was also common after this respiratory viral infection in both groups.

Clinical outcomes of solid organ transplant recipients treated with REMDESIVIR and convalescent plasma for COVID-19 at the largest transplant center in The United States

Purpose: Solid organ transplant recipients (SOTr) are at high risk for severe disease with SARS-CoV-2. Data on efficacy of potential treatment options and long-term outcomes are lacking. We describe our experience with use of remdesivir and convalescent plasma in SOTr with COVID-19. Methods: Single-center, retrospective cohort study of SOTr diagnosed with SARSCoV- 2 infection by PCR from March 1st to September 30th, 2020. Multivariate logistic regression analysis was performed based on univariate analysis to identify the risk factors for higher mortality. Results: 129 SOTr were identified (Table. 1). Median time from transplant to diagnosis of infection was 27 (IQR, 8-73) months. 48 (37.2%) and 27 (21%) patients received remdesivir and convalescent plasma, respectively (Table 2). 5/48 (10.4%) patients developed mild transaminitis that did not warrant discontinuation of therapy. No adverse effects were seen with convalescent plasma. Anti-metabolite agents were decreased or stopped in majority of the patients (81%). During follow-up, 12 (9%) patients developed clinically suspected acute rejection. Death, graft loss, and secondary infection occurred in 15 (12%), 20 (16%), and 20 (16%) recipients, respectively. RT-PCR negativity was achieved at a median of 37 (IQR, 25-41) days. Risk factors identified for high mortality were elevated creatinine (p=0.029, Odds ratio[OR] 1.5, 95% Confidence Interval[CI] 1.0- 2.1) and older age (p=0.003, OR 1.1, 95% CI 1.0 - 1.2) at the time of diagnosis. Conclusions: SARS-CoV-2 RT-PCR positive SOT recipients in our cohort had favorable outcomes. Use of remdesivir and convalescent plasma was found to be safe. Older age and elevated creatinine at the time of diagnosis were found to be risk factors for higher mortality.

A Comparison of the Performance of SARS-CoV-2 Antibody Assays in Healthcare Workers with COVID-19

Aims Since its emergence, significant interest surrounds the use of SARS-CoV-2 serological tests as an alternative or as an adjunct to molecular testing. However, given the speed of this pandemic, paralleled with the pressure to develop and provide serological tests in an expediated manner, not every assay has undergone the rigorous evaluation that is usually associated with medical diagnostic assays. We aimed to examine the performance of several commercially available SARS-CoV-2 IgG antibody assays among participants with confirmed COVID-19 disease and negative controls. Methods Serum taken between day 17 and day 40 post onset of symptoms from 41 healthcare workers with RT-PCR confirmed COVID-19 disease, and pre-pandemic serum from 20 negative controls, were tested for the presence of SARS-CoV-2 IgG using 7 different assays including point-of-care (POC) and laboratory-based assays. Results Assay performance varied. The lab-based Abbott diagnostics SARS-CoV-2 IgG assay proved to be the assay with the best positive and negative predictive value, and overall accuracy. The POC Nal von Minden GmbH and Biozek assays also performed well. Conclusion Our research demonstrates the variations in performance of several commercially available SARS-CoV-2 antibody assays. These findings identify the limitations of some serological tests for SARS-CoV-2. This information will help inform test selection and may have particular relevance to providers operating beyond accredited laboratories.

Diagnosis and treatment of may-thurner syndrome in a geriatric patient

INTRODUCTION: May-Thurner Syndrome (MTS) is the extrinsic compression of the left common iliac vein by the right common iliac artery against the lumbar vertebrae. While most MTS patients are asymptomatic, some develop deep vein thrombosis (DVT) from venous flow obstruction. Incidence and prevalence are unknown but estimated to occur in 2-5% of patients with lower extremity venous disease. Symptomatic MTS commonly presents in patients 20-40 years-old and rarely occurs in geriatric patients. CASE: An 82-year-old female with past medical history of hypertension, former smoker (quit 50 years prior) presented with acute left lower extremity (LLE) swelling and pain. No prior history of thrombosis, recent travel or surgery, hormone use, trauma or malignancy. Patient lived alone and was functionally independent. Upon admission, patient was afebrile and in no respiratory distress. COVID-19 testing negative. Physical exam notable for unilateral LLE 2+ pitting edema with erythema and mild tenderness. LLE ultrasound revealed extensive femoropopliteal, peroneal and posterior tibial DVT extending into the external iliac vein. CT chest, abdomen and pelvis with contrast showed compression of the proximal left common iliac vein by the right common iliac artery. Initially treated with heparin drip. Later underwent left iliofemoral pharmacomechanical thrombectomy with placement of bare metal stents resulting in successful restoration of blood flow. Patient was discharged on dual antiplatelet therapy and enoxaparin with plan to transition to rivaroxaban. DISCUSSION: Symptomatic MTS commonly presents in women and risk factors include hypercoagulable states, scoliosis, dehydration, cancer and radiation exposure. MTS can be treated with catheter-directed thrombolysis, venoplasty and/or stent placement. Post-thrombotic syndrome develops in 60% of iliofemoral DVTs within the first 5 years. While the decision to pursue thrombolysis and stenting is straight-forward in the typical MTS patient, this was not as obvious in our patient due to her geriatric age and uncertainty of benefit. Given her independence and few comorbidities, intervention was elected. Our case demonstrates that symptomatic MTS can present for the first time in a geriatric patient and that careful consideration is warranted in developing a treatment plan.

A modified early warning score predicts decompensation in COVID-19 patients

Background: The novel coronavirus disease (COVID-19) results in severe illness in a significant proportion of patients, necessitating a way to discern which patients will become critically ill and which will not. In one large case series, 5.0% of patients required an intensive care unit (ICU) and 1.4% died. Several models have been developed to assess decompensating patients. However, research examining their applicability to COVID-19 patients is limited. An accurate predictive model for patients at risk of decompensation is critical for health systems to optimally triage emergencies, care for patients, and allocate resources. Methods: An early warning score (EWS) algorithm created within a large academic medical center, with methodology previously described, was applied to COVID-19 patients admitted to this institution. 122 COVID-19 patients were included. A decompensation event was defined as inpatient mortality or an unanticipated transfer to an ICU from an intermediate medical ward. The EWS was calculated at 12-hour and 24-hour intervals. Results: Of 122 patients admitted with COVID-19, 28 had a decompensation event, yielding an event rate of 23.0%. 8 patients died, 13 transferred to the ICU, and 6 both transferred to the ICU and died. Decompensation within 12 and 24 hours were predicted with areas under the curve (AUC) of 0.850 and 0.817, respectively. Using a three-tiered risk model, use of the customized EWS score for patients identified as high risk of decompensation had a positive predictive value of 44.4% and 11.1% and specificity of 99.3% and 99.6% and 12- and 24-hour intervals. Amongst medium-risk patients, the score had a specificity of 85.0% and 85.4%, respectively. Conclusion: This EWS allows for prediction of decompensation, defined as transfer to an ICU or death, in COVID-19 patients with excellent specificity and a high positive predictive value. Clinically, implementation of this score can help to identify patients before they decompensate in order to triage at time of presentation and allocate step-down beds, ICU beds, and treatments such as remdesivir.

Antidemocratic and Exclusionary Practices: COVID-19 and the Continuum of Violence

The global coronavirus pandemic has reified divisions, inequity, and injustices rooted in systems of domination such as racism, sexism, neoliberal capitalism, and ableism. Feminist scholars have theorized these interlocking systems of domination as the "continuum of violence." Building on this scholarship, we conceptualize the U.S. response to and the consequences of the COVID-19 pandemic as reflective of the continuum of violence. We argue that crises like pandemics expose the antidemocratic and exclusionary practices inherent in this continuum, which is especially racialized and gendered. To support our argument, we provide empirical evidence of the continuum of violence in relation to COVID-19 vis-a-vis the interrelated issues of militarization and what feminists call "everyday security," such as public health and gender-based violence. The continuum of violence contributes theoretically and practically to our understanding of how violence that the pandemic illuminates is embedded in broader systems of domination and exclusion.