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1.
Topics in Antiviral Medicine ; 31(2):142, 2023.
Article in English | EMBASE | ID: covidwho-2320685

ABSTRACT

Background: High titer COVID-19 convalescent plasma (CCP) reduces hospitalizations among immunocompetent outpatients. This study evaluated recipient post-transfusion S receptor binding domain (S-RBD) IgG antibody levels and the association of progressing to hospitalization among unvaccinated outpatients with COVID-19 treated with CCP or control plasma. Method(s): This analysis focused on participants from a multicenter doubleblind, randomized, controlled trial comparing treatment of outpatients with COVID-19 convalescent plasma (CCP) or control plasma without SARS-CoV-2 antibodies. Participants with confirmed SARS-CoV-2 infection were transfused within 9-days of symptom onset between June 2020 and October 2021 (n=110 vaccinated control;n=105 vaccinated CCP;n=464 unvaccinated control;n=472 unvaccinated CCP;total n=574 control and n=577 CCP recipients). All subjects had specimens collected the day prior to transfusion (D-1), within 30 minutes after transfusion (D0), 14 (D14), 28 (D28), and 90 (D90) days post-transfusion. Ancestral SARS-CoV-2 S-RBD was measured by an in-house validated ELISA. All 54 COVID-19-related hospitalizations occurred within 2 weeks of transfusion. Result(s): Post-transfusion anti-S-RBD IgG levels on D0 were significantly greater for CCP (median=4 titer,log3) compared to control (median=2 titer,log3;p< 0.001) recipients. Neither sex nor age impacted antibody levels following CCP treatment at D14, D28, and D90. Vaccinated recipients had greater titers than unvaccinated recipients prior to transfusion with little change in titers post-transfusion. Unvaccinated recipients had low antibody titers on D-1 with CCP recipients exhibiting a significant increase in titer from D-1 to D0 compared to controls (mean fold change=1.89;p< 0.001). Among unvaccinated recipients, those who received CCP transfusion late ( >5 days after symptom onset) and had low D0 antibody levels (< 4.24 titer, log3) had the greatest proportion of hospitalizations (5.5%). In contrast, those who received CCP transfusion early (< 5 days after symptom onset) with high D0 antibody levels ( >4.24 titer, log3) had no hospitalizations. Unvaccinated CCP recipient anti-S-RBD IgG antibody levels on D0 correlated with donor anti-S-RBD IgG antibody levels (r=0.30, p< 0.001). Conclusion(s): Among unvaccinated outpatients with COVID-19, CCP recipient antibody dilutional titers after transfusion over 540 titer correlated with protection against hospitalization when transfusion occurred within 5 days of symptom onset. (Figure Presented).

3.
Circulation Conference: American Heart Association's ; 146(Supplement 1), 2022.
Article in English | EMBASE | ID: covidwho-2194403

ABSTRACT

Introduction: Cardiovascular disease patients with COVID-19 present prolonged hospitalization and increased mortality. Cardiovascular complications including myocarditis have been reported in association with COVID-19. We recently reported that levels of cardiac low-density lipoprotein receptor (LDLR) are elevated in patients with heart failure. We hypothesized that LDLR may play a role in COVID-19-induced myocarditis. Method(s): K18 hACE2tg mice were inoculated with SARS-CoV-2 Washington (WA-1) native strain, replication-competent chimeric (ch) SARS-CoV-2, or PBS and lung viral load and histopathology were compared (N=4). We interrogated the LDLR in 4-month-old K18 hACE2tg mice via intravenous injection of AAV9-cTnT-hLDLR (gain of function), AAV9-cTnT-hIDOL (Induced Degrader of LDLR, loss of function), or AAV9-cTnT-Luciferase (control). After 4 weeks, mice were inoculated intratracheally with chSARS-CoV-2. Five days after inoculation, mice were sacrificed, and blood and tissues collected for histopathological analysis and RNA/protein studies to evaluate myocarditis. Myocarditis was established by histological analysis according to the Dallas criteria. Result(s): Both native SARS-CoV-2 and chSARS-CoV-2 had ~60% infectivity as measured by qPCR and immunostaining. Over-expression (OE) of cardiomyocyte-specific hLDLR together with chSARS-CoV-2 induced myocarditis with prominent cardiomyocyte degeneration, necrosis, and immune cell infiltration: T cells (59 cells/mm ;p<0.05) and Macrophages (109 cells/mm ;p=0.0002) compared to the single control groups. In addition, hLDLR-OE increased heart expression of Osteopontin (12.6 vs 1.2%;p<0.05), pAKT(Ser473) (14.4 vs 3.5;p<0.05) and ICAM-1 (9.0 vs 3.3%;p<0.05). OE of cardiac-specific hIDOL mice infected with chSARS-CoV-2 reduced macrophage infiltration into the heart compared to hLDLR-OE myocarditis and control chSARS-CoV-2 groups (p<0.0001 and p<0.05), respectively. hIDOL-OE reduced cardiac ICAM-1 compared to myocarditis and control chSARS-CoV-2 groups (p<0.01 and p<0.05), respectively. Conclusion(s): Cardiac LDLR drives COVID-19-associated myocarditis in a new mouse model of SARS-CoV-2 infection.

6.
American Journal of Transplantation ; 22(Supplement 3):660, 2022.
Article in English | EMBASE | ID: covidwho-2063476

ABSTRACT

Purpose: Kidney transplantation (KT) from coronavirus disease 2019 (COVID-19) positive donors has been avoided due to concerns for donor-derived transmission and possibility of the kidney being a viral reservoir. There is no long-term safety data, and sensitive molecular testing for SARS-CoV-2 in donor kidney is not routinely performed. We report a case of successful KT from a deceased donor who died from severe COVID-19 respiratory illness whose donor kidney and aorta were probed for virus using in situ hybridization (ISH) and quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR). Method(s): A 30-year-old female was admitted to the hospital with severe COVID-19 pneumonia with a positive RT-PCR test for SARS-CoV-2 on nasopharyngeal swab. With clinical worsening, she was placed on extracorporeal membrane oxygenation, but developed hypoxic brain injury and progressed to brain death. Renal function was stable during her hospital course with serum creatinine concentration of 0.7 mg/dL. SARS-CoV-2 RT-PCR on bronchoalveolar lavage and nasopharyngeal samples tested again three days prior to donation was negative. A 55-year-old male recipient with an end-stage renal disease secondary to hypertension was transplanted with the left kidney from the above donor. The donor kidney was studied using pre-implantation surgical biopsy tissues to investigate the presence of SARS-CoV-2 RNA. Aorta tissue with the kidney was also studied given high expression of angiotensin-converting enzyme 2 receptors in vasculature. Result(s): ISH analyses did not show any positive signal for SARS-CoV-2 RNA in the donor kidney sample compared to a SARS-CoV-2 positive lung control. All samples tested by qRT-PCR were also negative for SARS-CoV-2. We found no evidence of SARS-CoV-2 mRNA in the donor kidney and aorta. The recipient has been free of COVID-19 related signs or symptoms and tested negative for SARSCoV- 2 by nasopharyngeal swab RT-PCR on days 20, 30, and 90 following KT. After an initial period of delayed graft function requiring hemodialysis, the recipient now has excellent renal recovery over 6 months following the transplant, and the most recent creatinine is 1.3 mg/dL. Conclusion(s): Taken together with recent observations of successful KT outcomes from mild or asymptomatic COVID-19 donors, we believe that the transmission risk of SARS-CoV-2 through KT is likely to be very low. Use of deceased donors who died after severe COVID-19 can be considered for KT. Larger scale studies are needed to confirm our findings.

7.
American Journal of Transplantation ; 22(Supplement 3):872-873, 2022.
Article in English | EMBASE | ID: covidwho-2063469

ABSTRACT

Purpose: Humoral response to COVID-19 vaccines is attenuated in many solid organ transplant recipients (SOTRs), necessitating additional primary and booster vaccinations. The omicron variant demonstrates substantial immune evasion, and it is not known if boosters increase neutralizing capacity versus omicron among SOTRs. We therefore investigated SOTR antibody response and neutralization versus variants of concern (VOC) including omicron to a 4th vaccine dose (D4). Method(s): Within a national, prospective observational cohort, 25 SOTRs underwent anti-SARS-CoV-2 spike and receptor binding domain (RBD) IgG testing using the Meso Scale Discovery platform before and 2-4 weeks after D4. Surrogate neutralization (%ACE2 inhibition [%ACE2i], range 0-100% with >20% correlating with live virus neutralization), was measured versus full spike proteins of the ancestral ("vaccine") strain and 5 VOCs including delta and omicron. Change in IgG level and %ACE2i were compared using paired Wilcoxon rank-sum testing. Result(s): Demographics are outlined in Table 1, including median (IQR) age 59 (45- 55) years, 64% kidney recipients, and D4 receipt (60% Moderna, 40% Pfizer) median (IQR) 93 days (28-134) post D3. Two participants had SARS-CoV-2 exposure per anti-nucleocapsid testing, including one incident infection. Overall, anti-RBD (92%- >100%) and anti-spike (84%->92%) seropositivity increased after D4, as did median (IQR) anti-spike IgG 42.3 (4.9-134.2)->228.9 (115.4-655.8) WHO binding antibody units (p<0.05). Median (IQR) %ACE2i significantly increased after D4 vs the vaccine strain 5.8% (0-16.8)->20.6% (5.8-45.9) and delta variant 9.1% (4.9-12.8)->17.1% (10.3-31.7) (both p<0.001). In contrast, no SOTR showed neutralization vs omicron before or after D4: median (IQR) %ACE2i 4.1% (0-6.9)->0.5% (0-5.7) (p=0.11). Conclusion(s): Although a 4th vaccine dose increased anti-spike IgG and neutralizing capacity vs some VOC, there was no omicron variant neutralization among SOTRs. SOTRs may remain at high risk for SARS-CoV-2 infection despite boosting, thus additional protective interventions should be urgently explored. (Figure Presented).

8.
Topics in Antiviral Medicine ; 30(1 SUPPL):330, 2022.
Article in English | EMBASE | ID: covidwho-1879967

ABSTRACT

Background: Live virus micro-neutralization (MN) is the gold standard for quantifying the neutralizing titer (NT) of antibodies to SARS-CoV-2. However, performing MN is labor intensive and requires a biosafety level 3 laboratory. We assessed the performance of 8 immunoassays which measure SARS-CoV-2 NT and compared them to gold standard MN results. Methods: Samples from 269 individuals known to previously be SARS-CoV-2 PCR+ (i.e., convalescent individuals, <10% hospitalized) and 200 pre-pandemic individuals were evaluated on 3 lateral flow immunoassays (LFAs;Wondfo Colloidal Gold, Wondfo Colored Microsphere, Wondfo Finecare) and 5 enzyme-linked immunoassays (ELISAs;ImmunoRank, GenScript, Cusabio, Euroimmun NeutraLISA, Euroimmun QuantiVac). MN was performed on all samples from convalescent individuals;results were classified as undetectable vs any detection of MN NT (NT<20 vs. NT>20), as well as high and low MN NT (NT>80 vs. NT<80). Receiver operating curve analysis was used to assess accuracy for detecting levels of NT. The area under the curve (AUC) was calculated for the manufacturer's cut off and empirically to identify the best discriminatory cut off value. Cohen's kappa statistics were calculated to assess categorical agreement and Spearman's rank statistics were calculated to assess correlations. Results: Of the 269 convalescent plasma samples, 89 (33%) had MN NT values <20 (undetectable) and 117 (43%) >80 (high NT). Using the manufacturer's cutoffs, sensitivity for detection of samples with any NT ranged from 79% to 100%, and the false-positive rate (ie, classifying samples with undetectable NT as positive) was highest for LFAs (72% to 84%) and ranged from 14% to 69% for the ELISAs. For all assays except the ImmunoRank and NeutraLISA ELISAs, discrimination to identify samples with any NT was improved by raising the cut off values (Table). AUCs of ∼0.94 to discriminate high NT samples could be achieved for all quantifiable assays using an adjusted cut off value. Cohen's kappa statistic ranged from 0.20 to 0.69. Spearman's rank correlation between each assay and NT value ranged from 0.73 to 0.86. Using the manufacturer's cutoffs, specificity on pre-pandemic samples was ≥98% for all assays except for Cusabio which was 86%. Conclusion: The performance of immunoassays using manufacturer's cutoff to discriminate samples with any NT was accurate (AUC>0.83 for all assays), but could be improved by changing the cutoff. Identifying samples with high NT could be achieved using an alternative cutoff.

10.
Toxicology Letters ; 350:S69, 2021.
Article in English | EMBASE | ID: covidwho-1598223

ABSTRACT

Early reports from Wuhan suggested that 36% of COVID-19 patients show neurological symptoms, later European studies showed as much as 60%;cases of viral encephalitis have been reported. This suggests that the virus might be neurotropic under unknown circumstances. This is well established for other coronaviruses. Many questions remain with regard to the current pandemic, including the influence of SARS-COV-2 on the developing brain. In order to understand why some patients develop such symptoms and others do not and whether developing brain might be more susceptible than adult counterpart, we addressed the infectability of the central nervous system (CNS). Reports that the ACE2 receptor - critical for virus entry into lung cells - is found in different neurons support this expectation. We employed a human induced pluripotent stem cell (iPSC)-derived BrainSphere model. A short-term infection of the BrainSpheres with SARS-CoV-2 led to infection of a fraction of neural cells with replication of the virus evident at 72 hpi. Virus particles were found in the neuronal cell bodies extending into apparent neurite structures. PCR measurements corroborated the replication of the virus, suggesting at least a tenfold increase in virus copies per total RNA. Immature and more mature cultures have been compared. 12week BrainSpheres were more sensitive to infection than 5-week ones, suggesting that maturation processes (such as synaptogenesis and network formation) might render more sensitive to the infection. These findings were supported by others in similar brain organoid models. These recent findings will be summarized to understand the advantages and limitations of brain organoids in infectious diseases in particular for the developing nervous system, as brain organoids mimic embryonic stages of development.

12.
Toxicology Letters ; 350:S69-S69, 2021.
Article in English | Web of Science | ID: covidwho-1519432
13.
Topics in Antiviral Medicine ; 29(1):68, 2021.
Article in English | EMBASE | ID: covidwho-1249890

ABSTRACT

Background: Sustained molecular detection of SARS-CoV-2 RNA in the upper respiratory tract (URT) is common and confounds infection control efforts in the community. The mean duration of viral RNA detection is ∼17 days, and ∼14% of people with mild or no symptoms have detectable viral RNA for > 4 weeks. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection in an intensively-sampled prospective observational cohort of outpatients with mild COVID-19 who had concomitant URT virus and mucosal IgG sampling. Methods: 95 participants ≥ 30 years old with known symptom onset date and at least two positive SARS-CoV-2 qRT-PCR results were enrolled. Participants self-collected mid-nasal, oropharyngeal, and oral crevicular fluid (OCF) samples 4-5 times within 3 weeks. 1-3 months after symptom onset, height and weight were measured and nasopharyngeal, salivary, OCF, and blood samples were collected. SARS-CoV-2 qRT-PCR was performed on samples, and positive samples were tested for propagation in virus culture. A multiplex mucosal IgG immunoassay with multiple SARS-CoV-2 antigens was performed on OCF. Plasma titers of neutralizing antibodies, SARS-CoV-2 spike (S) antibodies, and S-receptor binding domain (RBD) antibodies were obtained by microneutralization assay and indirect ELISA. Time to qRT-PCR clearance wasmeasured from symptom onset until the midpoint between the last positive qRT-PCR test and the next negative test. Associations were estimated using a Cox proportional hazard model. Hazards of viral RNA clearance were compared for different age, sex, race/ethnicity, and body mass index (BMI) groups and whether fever was one of the first three symptoms, adjusting for comorbidities and immunocompromised status. Results: See Table for participant characteristics. Of 56 participants with observed viral RNA clearance, mean time to clearance was 33.5 days. The hazard ratio for obesity vs overweight/normal weight was 0.37 (95% CI 0.18-0.78, p=0.009). Elevated mucosal SARS-CoV-2-specific IgG did not associate with faster viral RNA clearance. The maximum time from symptom onset to virus culture. positive sample was 12 days, which is just after the mean time of first positive mucosal SARS-CoV-2-specific IgG detection. Conclusion: Obesity is associated with prolonged SARS-CoV-2 RNA detection in outpatients. Mucosal SARS-CoV-2 IgG is not associated with faster clearance of viral RNA from the URT, suggesting that viral clearance is mediated by select host immune responses.

14.
Clinical Cancer Research ; 26(18 SUPPL), 2020.
Article in English | EMBASE | ID: covidwho-991988

ABSTRACT

Background: Death from COVID-19 disproportionately affects men, with up to 80% of deaths in severe COVID-19cases being in men. There are a number of potential differences that might contribute to these sex differences.TMPRSS2 is a serine protease that primes the spike protein of SARS-CoV-2, a critical step in viral entry. TMPRSS2is most highly expressed in the prostate where it is under androgen control, upregulated by testosterone anddownregulated by antiandrogens. ACE2, the receptor used for entry into the host cell, is located on the Xchromosome and may also have levels that are altered by hormones, with estradiol downregulating its expression.Previous research on acute lung injury demonstrated that estradiol seems to have beneficial effects on repair of lunginjury. Therefore, our central hypothesis is that hormones may partially contribute to the gender disparity seen inCOVID-19 patients, with high levels of testosterone being harmful and high levels of estrogen being helpful.Bicalutamide is a nonsteroidal antiandrogen that inhibits the action of androgens and, via feedback on thehypothalamic-pituitary axis, upregulates estradiol. We are conducting a phase II clinical trial to determine ifbicalutamide improves the percentage of COVID+ patients with clinical improvement by 7 days. Methods: We will enroll 40 patients who are hospitalized for COVID-19 with minimal respiratory symptoms(respiratory rate <30 and < 6L oxygen by nasal canula). Patients with more severe symptoms or oxygenrequirements, who have taken hormones within the past month, or have pre-existing liver or cardiac disease will beexcluded. Patients will be randomized 1:1 (20 in each arm) to bicalutamide or standard of care and will be stratifiedby gender. The primary outcome is comparing the percentage of patients with clinical improvement at day 7, compared to historical controls based on the World Health Organization categorical scale of clinical improvement.Key secondary clinical endpoints include all-cause mortality at 28 and 60 days, need for mechanical ventilation orICU care, and safety of bicalutamide in this population. We will also determine the impact of bicalutamide therapy onviral infectivity by studying the reduction in viral load, hormone modulation and engagement of the endocrine axis, and immune response modulation promoting pro-repair immune function in patients with COVID-19. Clinical trialregistration number: NCT04374279.

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