Worse Arterial Stiffness, and Not Endothelial Dysfunction, Is Associated with Pasc

Background: COVID-19 survivors can experience lingering symptoms known as PASC that appear in different phenotypes. The etiology remains elusive and endothelial dysfunction has been postulated as a main driver of PASC. Method(s): Prospective cohort including COVID- and COVID+ with (COVID+PASC+) or without (COVID+PASC-) PASC. We measured endothelial function using Endopat, an FDA approved test, with derived reactive hyperemic index RHI (endothelial dysfunction<=1.67) and arterial elasticity (augmentation index standardized at 75 bpm or AI@75;(lower =better). PASC symptoms were categorized into three non-exclusive phenotypes: Cardiopulmonary CP (postexertional malaise, shortness of breath, cough, palpitations), Neurocognitive N (change in smell/taste, neuropathy, 'brain fog', headache), and General G (fatigue, gastrointestinal or bladder problems). Result(s): We included 491 participants with 109 of the 186 with confirmed COVID+ experiencing PASC. Median number of days between COVID diagnosis and study visit was 249 days (IQR: 144, 510). Among COVID+PASC+, the median number of symptoms was 7.0 (IQR: 3.0,13.0);97 experienced symptoms categorized as G, 90 as N, and 87 as CP. COVID+ PASC+ had the lowest RHI (1.77+/-0.47) and the largest proportion [46.79% (n=51)] with RHI<=1.67 (Figure). AI@75 was the lowest in COVID- (3.11+/-15.97) followed by COVID+PASC- (3.57 +/- 16.34). Within COVID+PASC+, the mean AI@75 among G was 10.11+/-14.85, 11.36+/-14.67 with N, and highest (12.01 +/- 14.48) with CP. Symptoms' number was positively associated with AI@75 (p=0.01). The estimated mean difference in AI@75 between COVID+ PASC+ with CP and COVID+ PASC- was 8.44+/-2.46 (p=0.001), between COVID+ PASC+ with CP phenotype and COVID- was 8.9+/-1.91 (p< .0001), and between COVID+ PASC+ with CP phenotype and COVID+ PASC without CP phenotype was 7.51+/-3.75 (p=0.04) Conclusion(s): PASC was associated with worse arterial elasticity and within PASC, the cardiopulmonary phenotype had the highest arterial stiffness. (Figure Presented).

Incident New Onset Diabetes after Covid-19 Infection: A National Multicenter Cohort

Background: It is known that survivors of acute SARS-CoV-2 infection can experience a complex disease known as post-acute sequelae of COVID-19 (PASC). The clinical manifestations of acute COVID-19 have been well characterized however less is known about the risk of new onset diabetes mellitus (DM) in the post-acute phase of COVID-19. Method(s): An adult cohort with confirmed COVID-19 (by diagnosis or positive test) and without COVID-19 was sampled from a large national health research network between January 1st, 2020 and July 8th, 2022. We investigated the outcomes of a new diagnosis of DM (type I or II) occurring after COVID-19 through 12 months after infection. Risk estimates [incidence, relative risk (RR), attributable risk] were used to describe the probability of incident post-COVID diabetes. Hazard ratios and 95% confidence intervals were used to describe risk factors associated with new diabetes. Result(s): The 3-month probability of new diabetes was 2.48/1,000 among COVID+ and the relative risk (RR) of new diabetes was highest at 12 months [8.94 (8.54, 9.36)]. Vitamin D deficiency [HR: 1.52 (95% CI: 1.42, 1.63)] was associated with increased risk of T2DM and having vitamin D deficiency with either obesity (BMI > 30 kg/m2) or kidney dysfunction (GFR < 60) was associated with more than five times increased risk of T1DM. Conclusion(s): We observed a large proportion of excess diabetes starting at 3 months post COVID infection. Traditional risk factors for diabetes, omicron variant, and vitamin D deficiency are associated with increased risk of new diabetes outcome. PASC care should involve identification and management of diabetes. (Figure Presented).

Hiv Infection Increases Risk of Pasc While Covid-19 Vaccination Is Protective

Background: People with HIV (PWH) are at a higher risk of severe acute COVID-19;however, their risk of subsequently developing post-acute sequelae of SARS-CoV2 (PASC) remains unclear. Furthermore, although vaccination has been shown to be protective against PASC in the general population, few studies have evaluated its effectiveness in PWH. Method(s): We used the TriNetX health research database to source data from 69 healthcare organizations within the US. We included any adults aged >= 18 years with positive SARS-CoV-2 between January 1, 2020 and September 16, 2022 and categorized them based on their HIV status, baseline sociodemographic characteristics, comorbidities and COVID-19 vaccination status. The primary outcome was risk of PASC, compared by HIV and vaccination status after 1:1 propensity score matching. PASC was defined as either the persistence of COVID-attributable symptoms or the occurrence of new-onset health conditions at least 28 days following COVID-19 diagnosis. For all analysis, statistical significance was set at p < 0.05. Result(s): Of 3,048,792 people with confirmed SARS-CoV-2 infection, 1% (n=28,904) were PWH, with 9% of PWH (n=2592) vaccinated. At 28 days post-COVID-19 diagnosis, PWH had lower mortality compared with their non-HIV counterparts (OR 0.78, 95% CI 0.70-0.87), but higher risk of developing new-onset diabetes (DM) (OR 1.26, 95% CI 1.11-1.42), heart disease (OR 1.27, 95% 1.14-1.41), malignancy (OR 1.66, 95% CI 1.45-1.89), thrombosis (OR 1.25, 95% CI 1.12-1.39) and mental health disorders (OR 1.70 (95% CI 1.53-1.90). Furthermore, vaccinated PWH had significantly lower odds of death (OR 0.63, 95% CI 0.42- 0.93) and each new-onset PASC outcome, as follows: DM (OR 0.51, 95% CI 0.32- 0.82), heart disease (OR 0.44, 95% CI 0.29-0.67), malignancy (OR 0.43 (95% CI 0.25-0.74), thrombosis (OR 0.51, 95% CI 0.33-0.78) and mental health disorders (OR 0.49, 95% CI 0.30-0.79). The risk of PASC was higher during the pre-Delta variant period but did not vary based on CD4 count or HIV viremia. Conclusion(s): HIV infection confers a higher risk of PASC. Importantly, COVID-19 vaccination significantly lowered mortality and was protective against PASC among PWH. With the increase in the number of COVID-19 survivors, vaccination offers an effective preventive strategy to address a burgeoning public health problem. (Table Presented).

Increased Gut Permeability and Oxidized Lipids in Pasc

Background: Post-acute sequelae of COVID-19 (PASC) is marked by persistent or newly developing symptoms beyond 4 weeks of infection. Investigating gut integrity, oxidized lipids and inflammatory markers is important for understanding PASC pathogenesis. Method(s): A cross-sectional study including COVID+ with PASC, COVID+ without PASC, and COVID- participants. We measured plasma markers by enzyme-linked immunosorbent assay to assess gut-barrier integrity: zonulin for intestinal permeability, lipopolysaccharide-binding protein (LBP) for microbial translocation, and fatty acid binding protein I-FABP for intestinal integrity, and to assess inflammation: high-sensitivity C-reactive protein (hsCRP) and oxidized low-density lipoprotein (Ox-LDL) assays. Result(s): 415 participants were enrolled in our study. 62.17% (n=258) were COVID- and 20.48% (n=85) had PASC. COVID- participants had lower age (43.68+/-13.69 vs. 46.45+/-13.45 years;p=0.04), lower BMI (27.91+/-6.05 vs. 31.28+/-9.03;p< .0001), 39.15% (n=101) were female sex [vs. 54.14% (n=85);p=0.003], and 41.86% (n=108) were non-white race [vs. 32.48% (n=51);p=0.06] compared to COVID+. Zonulin (p< .0001), and Ox-LDL (p< .0001) were associated with COVID and PASC status. The mean Zonulin among COVID- was 3755960.41+/-2541177.0 ng/mL, 3912178.91+/-2649882.95 ng/mL among COVID+ without PASC, and the highest (5899694.16+/-4110456.4 ng/ mL) among PASC. The mean Ox-LDL was lowest (51845.21+/-24328.46 U/L) among COVID-, 60530.09+/-26497.47 U/L among COVID+ without PASC, and 81917.21+/-32148.59 U/L among PASC. The estimated mean difference in Zonulin among PASC compared to COVID- was 2143734+/-368522 ng/mL (p< .0001) and compared to COVID+ without PASC was 1987515+/-471965 ng/mL (p< .0001). The estimated mean difference in Ox-LDL among PASC compared to COVID- was 30072+/-3311.02 U/L (p<.0001) and compared to COVID+ without PASC was 21387+/-4240.41 (p<.0001). Zonulin was positively associated with hs-CRP and Ox-LDL. For every unit increase in Zonulin we would expect hsCRP to increase by 86.14+/-15.09/100000 ng/mL (p<.0001) and OX-LDL to increase by 22.2+/-4.05/10000 ng/mL (p<.0001). Conclusion(s): PASC is associated with increased gut permeability, which in turn is associated with oxidized LDL and hsCRP. (Figure Presented).

New Onset Autoimmune Disease More Common after Covid-19

Background: Viral infections including SARS-CoV-2 may trigger autoimmune disease through T-cell-mediated autoimmune response through molecular mimicry-cross-reactive T-cell recognition or bystander T-cell activation. Autoantibodies have been detected in patients with COVID-19 and some human proteins have homologous regions with SARS-CoV-2 peptides that could function as autoantigens. While there are scattered reports of various autoimmune diseases diagnosed after COVID-19, the risk is not known. Method(s): TriNetX (a global federated health research network providing access to electronic medical records across 72 large healthcare organizations) was utilized to define a cohort of adults 18 years or older seen on or after January 1, 2020 with at least one follow-up visit after an index date. Exposure was defined as COVID-19 diagnosis by ICD10 code or positive laboratory test. Controls did not have COVID-19 (by the same criteria) and were propensity score-matched to patients who had COVID-19 by age and female sex. Index date was the date of COVID-19 diagnosis or first provider visit for any reason during the study period for controls. Outcomes (see table) were assessed starting one month after index date (to exclude prior undiagnosed autoimmune disease) until one year after. Patients with a specific outcome prior to the index date or within one month after the index date were excluded from the analysis for that outcome. Incidence by COVID-19 exposure status and risk ratios for each outcome were assessed. Result(s): 4,016,472 patients were included (2,008,236 in both groups). Overall, mean (SD) age was 49.2 (17.9) and 57.7% were female. Patients who had COVID-19 were more likely to be white (63 vs 56.9%;p< 0.001). Rheumatoid arthritis, psoriasis and type 1 diabetes mellitus had the highest incidence after COVID-19 (0.24, 0.22 and 0.19%, respectively). While the incidence of most of the autoimmune diseases assessed were low in both groups, the risk ratios for all but one condition (Grave's) showed statistically significant higher risk in patients after COVID-19 than in those without COVID-19 (see table). Risk ratios were highest for polyarteritis nodosa (4.43, 3.27-6.01), reactive arthritis (3.56, 2.05-6.2) and ANCA-associated vasculitis (3.36, 2.6-4.34). Conclusion(s): Autoimmune diseases were more likely to be diagnosed within the first year after COVID-19 than in age-, sex-matched controls. Future work will assess the validity of autoantibodies in predicting autoimmune disease after COVID-19. (Table Presented).

Sex Modifies the Effect of Covid-19 and Pasc Status on Arterial Stiffness

Background: Sex differences in immunological responses to COVID-19 infection and mechanisms that may contribute towards post-acute sequelae of SARS-Co-V2 (PASC) have been reported. However, evidence on the effects of COVID infection on vascular dysfunction and PASC are limited. Method(s): FDA approved EndoPAT device was used to measure endothelial function [Reactive Hyperemia Index (RHI)] and arterial stiffness [Augmentation Index standardized at 75 beats/min (AI@75;higher AI = worse arterial elasticity)] in an adult cohort (age >=18 years) with a history of COVID-19 infection (COVID+) or confirmed SARS-CoV2 antibody negative (COVID-). Generalized linear regression was used to compute estimates of RHI and AI@75. Adjusted models included age, sex, race, blood pressure, lipids, body mass index (BMI), smoking status, and pre-existing comorbidities. Two-way interactions were used to determine if the effects of COVID or PASC status on endothelial function depends on age, sex, race, smoking status, or prevalent comorbidities. Result(s): 61.99% (n=305) of study participants were COVID- and 187 (38.01%) were COVID+. Among COVID+, 57.22% (n=107) were female, 31.72% (n=59) were non-white race, and the average age was 46.64+/-13.79 years. COVIDparticipants had a smaller proportion (38.03%) of female sex (p< .0001), lower BMI [COVID+ (30.79+/-8.95 kg/m2) vs. COVID- (27.76+/-5.89 kg/m2);p< .0001], and higher proportion of smokers [COVID+ (17.78%) vs. COVID- (58.22%);p< .0001]. The average follow-up was 349.68+/-276.76 days and 109 (22.15%) COVID+ experienced PASC. 42.48% (n=80) of COVID+ and 41.64% (n=127) of COVID- had RHI<= 1.67 (p=0.8). The average AI@75 among COVID+ without PASC was 3.63+/-16.24, with PASC was 10.5+/-14.72, and 3.11+/-15.97 among COVID- (p=0.0001). Male sex had the lowest AI@75 (-0.08+/-14.9) compared to female sex (10.75+/-15.3;< .0001). In adjusted models, PASC, female sex had 8.14+/-2.95 higher AI@75 compared to PASC, male sex (p=0.006), 18.58+/-2.99 higher AI@75 compared to COVID+ without PASC, male sex (p< .0001), 13.81+/-2.11 higher AI@75 compared to COVID-, male sex (p< .0001), and 4.97+/-2.28 higher AI@75 compared to COVID-, female sex (p=0.03). Sex was not associated with RHI or modified the effect of COVID or PASC status on endothelial function Conclusion(s): The effect of COVID and PASC status on arterial stiffness depends on sex. Female sex is associated with increased arterial stiffness (worse arterial elasticity) in the post-acute phase of COVID-19. (Figure Presented).

Mitochondrial Dysfunction Is Associated with Post-Acute Sequelae of Covid-19

Background: Mitochondrial (mt) dysfunction has been described in acute severe SARS-CoV2 infection. It remains unclear whether the disturbances in mt are also present in post-acute sequelae of COVID-19 (PASC). Method(s): We analyzed cross-sectional data from participants without history of COVID and SARS-CoV2 antibody negative (COVID-), with documented prior COVID and full recovery (COVID+ PASC-), and with prior COVID with PASC as defined by the CDC (COVID+PASC+). Mt respiration was measured from peripheral blood mononuclear cells utilizing the Seahorse XFe96 analyzer. Generalized linear regression was used to compare estimates of mt and non-mt respirations, and unadjusted odds ratios using multinomial logistic regression to assess if mt respiration were associated with PASC. Result(s): For this analysis, 59 participants were enrolled, 71.19% (n=42) had a confirmed COVID-19 diagnosis. The overall mean age was 47.47 +/- 14.86 years, 69.49% (n=41) were females and 33.90% (n=20) were non-white race. There was no difference in demographics between participants with and without COVID (p>=0.72). Amongst all COVID+ participants, 19% (n=11) had hypertension and 8% (n=5) had diabetes. Among all COVID+, the median time between COVID diagnosis and study evaluation was 210 (IQR: 119, 453) days, and 50% (n=21) of COVID+ experienced persistent symptoms consistent with PASC. PASC participants had the highest observed values in non-mt respiration (21.57 +/- 10.77 pmol/min), basal respiration (38.95 +/- 17.58 pmol/min), proton leak (10.41 +/- 3.1), maximal respiration (103.91 +/- 58.63 pmol/min), spare respiratory capacity (64.96 +/- 41.82 pmol/min), and ATP production (28.55 +/-14.85 pmol/min). Basal respiration, ATP production, maximal respiration, and non-mt respiration were highest in PASC compared to COVID- (p<=0.02). There was marginal evidence (p=0.05) of a mean difference (8.09 pmol/min) in ATP production between COVID+PASC+ and COVID+PASC-, without differences in proton leak (p=0.23) or spare respiration capacity (p=0.07). Every unit increase in non-mt respiration, basal respiration, maximal respiration, and ATP production increased the predicted odds of PASC by 10.99, 5.6, 1.6 and 6.2%, respectively (Figure). Conclusion(s): Individuals with PASC are consuming more oxygen and producing more ATP in the PBMCs compared to controls. There also appears to be increased PBMC ATP production between PASC and COVID+. We hypothesize that this may reflect a crucial pathogenic mechanism in PASC that may be associated with ongoing inflammation. (Figure Presented).

ZINC DEFICIENCY IS INDEPENDENTLY ASSOCIATED with INCREASED COVID-19 DISEASE SEVERITY

Background: COVID-19 has the most impact on people with comorbidities likely due to a higher inflammatory state. Zinc (Zn) is known for its substantial involvement in immune response as an antioxidant and anti-inflammatory agent. Zn plasma levels' clinical significance at COVID diagnosis is not yet established. We investigated the effects of Zn deficiency and inflammation on COVID-19 outcomes. Methods: Plasma Zn levels were collected from patients during the acute phase of a confirmed COVID-19 diagnosis. Data was dichotomized into Zn deficient (Zn<75 μ g/dL) and Zn sufficient (Zn ≥75 μ g/dL). Soluble tumor necrosis factor alpha receptor II (sTNF-RII) and intestinal fatty-acid binding protein (I-FABP) were also measured. COVID-19 outcomes were classified according to the WHO clinical progression scale (0-10), then stratified into 3 groups [grp 1= (WHO score 0-4) asymptomatic or mild disease;moderate grp 2= (WHO 5-6), and severe grp 3= (7-10)]. Hazard ratios (AHRs) and 95% Confidence Intervals (CIs) were computed using cumulative logit regression and adjusted for demographics, BMI, comorbidities, inflammation markers, and laboratory data. Results: We included 149 patients with a confirmed COVID-19 diagnosis. The median age (interquartile range [IQR]) was 53 years (38.0, 63.0);42% of the patients were female, 52% non-white, and 86% had at least one comorbidity. Overall, 50% of patients were in grp 1= asymptomatic or mild, whereas 8.5% had the worse outcome (grp 3). More than half of the participants (54%) had sufficient zinc levels. There was not enough evidence to suggest any differences regarding age, gender, body mass index (BMI), hemoglobin, white blood cells, transaminases enzymes, I-FABP, and sTNF-RII between the Zn-sufficient and deficient arms (p>0.05). However, 21% of the Zn sufficient arm were non-White compared to 31% in the deficient arm (p= 0.0004). Patients with zinc deficiency had a median BMI of 31.96 kg/m2 (IQR: 26.69, 36.44) and a median sTNF-RII of 3027.00 (IQR: 2446.00, 4468.00). In adjusted models, as zinc levels decreased, the risk of severe COVID-19 outcomes increased [AHR: 0.24 (95% CI: 0.06, 0.93)]. As sTNF-RII increases, but not I-FABP, the risk of severe COVID-19 outcomes rises two-fold [AHR: 2.17 (95% CI: 1.10, 4.31)]. Conclusion: Zinc deficiency and higher levels of sTNF-RII during acute COVID-19 presentation are independently associated with worse outcomes, suggesting a potential relationship between these 2 variables in COVID-19 progression.

Characterizing COVID-19 presentation and clinical outcomes in HIV patients in the US

Background: HIV infection is considered a risk factor for severe SARS-CoV-2 (COVID-19) infection;however, there are limited studies assessing the impact of HIV on COVID-19 presentation and clinical outcomes. Methods: We used TriNetX (a large global health research network) to compare adult HIV and non-HIV patients with confirmed SARS-CoV-2 infection who sought care across 44 healthcare facilities in the US January to December 2020. We assessed demographic characteristics, comorbidities, presenting symptoms, laboratory parameters, rate of hospitalization, rate of intensive care service utilization requiring mechanical ventilation and mortality at 30 days after diagnosis. Continuous data were compared using independent t-tests and categorical data were compared using Chi-square or Fishers exact test, as appropriate. Potential confounders were addressed using 1:1 greedy nearest-neighbor propensity score matching based on demographics and key comorbidities. For outcomes of interest, we calculated odds ratios (OR) and 95% confidence intervals (CI), with p < 0.05 considered statistically significant in all analyses. Results: Of 297194 confirmed COVID-19 cases, 1638 (0.6%) were HIV-infected, with > 83% on antiretroviral therapy (ART) and 48% virally suppressed (HIV-1 RNA < 20 copies/μL). Compared with their non-HIV counterparts, HIV patients were more commonly younger (p < 0.001), male (p < 0.001), African American or Hispanic (p < 0.001), had more cardiovascular disease (p < 0.001) and other comorbidities, were more symptomatic at presentation and had higher utilization of all healthcare services (Table 1). On laboratory parameters, HIV patients were more anemic (p < 0.001), thrombocytopenic (p < 0.001) and had elevated serum creatinine (p < 0.001), procalcitonin (p=0.042) and interleukin-6 (p=0.010) levels. In propensity score-matched analysis by demographics and relevant comorbidities, HIV patients had significantly higher odds of hospitalization [OR 1.26, 95% CI (1.04-1.53);p=0.023] and severe illness requiring intensive care stay and mechanical ventilation [OR 1.32, 95% CI (1.10-1.58);p=0.003]. Mortality at 30 days was higher among HIV patients but did not attain statistical significance (2.9% vs 2.3%;p=0.123). Conclusion: In one the largest studies to date, HIV patients had more underlying risk factors, symptom severity and higher odds of hospitalizationand mechanical ventilation but were not significantly more at risk of death at 30 days after COVID-19 diagnosis compared to non-HIV controls. (Figure Presented).