Pressured cytotoxic T cell epitope strength among SARS-CoV-2 variants correlates with COVID-19 severity.

Heterogeneity in susceptibility among individuals to COVID-19 has been evident through the pandemic worldwide. Cytotoxic T lymphocyte (CTL) responses generated against pathogens in certain individuals are known to impose selection pressure on the pathogen, thus driving emergence of new variants. In this study, we probe the role played by host genetic heterogeneity in terms of HLA-genotypes in determining differential COVID-19 severity in patients. We use bioinformatic tools for CTL epitope prediction to identify epitopes under immune pressure. Using HLA-genotype data of COVID-19 patients from a local cohort, we observe that the recognition of pressured epitopes from the parent strain Wuhan-Hu-1 correlates with COVID-19 severity. We also identify and rank list HLA-alleles and epitopes that offer protectivity against severe disease in infected individuals. Finally, we shortlist a set of 6 pressured and protective epitopes that represent regions in the viral proteome that are under high immune pressure across SARS-CoV-2 variants. Identification of such epitopes, defined by the distribution of HLA-genotypes among members of a population, could potentially aid in prediction of indigenous variants of SARS-CoV-2 and other pathogens.

In-Hospital Virtual Peer-to-Peer Consultation to Increase Guideline-Directed Medical Therapy for Heart Failure: A Pilot Randomized Trial.

Background: Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) improves clinical outcomes and quality of life. Optimizing GDMT in the hospital is associated with greater long-term use in HFrEF. This study aimed to describe the efficacy of a multidisciplinary virtual HF intervention on GDMT optimization among patients with HFrEF admitted for any cause. Methods: In this pilot randomized, controlled study, consecutive patients with HFrEF admitted to non-cardiology medicine services for any cause were identified at a large academic tertiary care hospital between May to September 2021. Major exclusions were end-stage renal disease, hemodynamic instability, concurrent COVID-19 infection, and current enrollment in hospice care. Patients were randomized to a clinician-level virtual peer-to-peer consult intervention providing GDMT recommendations and information on medication costs vs. usual care. Primary endpoints included 1) proportion of patients with new GDMT initiation or use, and 2) changes to HF optimal medical therapy (OMT) scores which included target dosing (range 0-9). Results: Of 242 patients identified, 91 (38%) were eligible and randomized to intervention (N=52) or usual care (N=39). Baseline characteristics were similar between intervention and usual care (mean age 63 vs. 67 years, 23% vs. 26% female, 46% vs. 49% Black, mean EF 33% vs. 31%). GDMT use on admission was also similar. There were greater proportions of patients with GDMT initiation or continuation with the intervention compared with usual care. After adjusting for OMT score on admission, changes to OMT score at discharge were higher for the intervention group compared with usual care (+0.44 vs. -0.31, absolute difference +0.75, adjusted estimate 0.86 ± 0.42; p=0.041). Conclusions: Among eligible patients with HFrEF hospitalized for any cause on non-cardiology services, a multidisciplinary pilot virtual HF consultation increased new GDMT initiation and dose optimization at discharge.

In-silico study of influence of HLA heterogeneity on CTL responses across ethnicities to SARS-CoV-2.

Differences in outcome to COVID-19 infection in different individuals is largely attributed to genetic heterogeneity leading to differential immune responses across individuals and populations. HLA is one such genetic factor that varies across individuals leading to differences in how T-cell responses are triggered against SARS-CoV-2, directly influencing disease susceptibility. HLA alleles that influence COVID-19 outcome, by virtue of epitope binding and presentation, have been identified in cohorts worldwide. However, the heterogeneity in HLA distribution across ethnic groups limits the generality of such association. In this study, we address this limitation by comparing the recognition of CTL epitopes across HLA genotypes and ethnic groups. Using HLA allele frequency data for ethnic groups from Allele Frequency Net Database (AFND), we construct synthetic populations for each ethnic group and show that CTL epitope strength varies across HLA genotypes and populations. We also observe that HLA genotypes, in certain cases, can have high CTL epitope strengths in the absence of top-responsive HLA alleles. Finally, we show that the theoretical estimate of responsiveness and hence protection offered by a HLA allele is bound to vary across ethnic groups, due to the influence of other HLA alleles within the HLA genotype on CTL epitope recognition. This emphasizes the need for studying HLA-disease associations at the genotype level rather than at a single allele level.

COVID-19 associated mucormycosis (CAM) in India: a formidable challenge.

Together with the ongoing serious COVID-19 second wave in India, a serious fungal infection, mucormycosis has been increasingly found in COVID-19-recovered patients. Colloquially known as 'black fungus', mucormycosis commonly causes necrosis in the head and neck including the nose, paranasal sinuses, orbits, and facial bones, with possible intracranial spread. The disease causes high morbidity and mortality given that it progresses rapidly and diagnosis is often delayed. Given the sheer magnitude of the outbreak, the Indian Health Ministry has advised all states to declare mucormycosis an epidemic. Typically, the disease has been found to be linked to COVID-19 infections caused by the B.1.617.2 (Delta) variant, which has spread rapidly throughout the country. This variant has already become a cause for global concern, having spread to at least 40 countries, including the USA and UK. We present the findings of a study conducted on COVID-19 associated mucormycosis (CAM) patients, and discuss the associated risk factors to raise awareness for OMFS colleagues.

Acute cardiovascular hospitalizations and illness severity before and during the COVID-19 pandemic.

BACKGROUND: Cardiovascular disease (CVD) hospitalizations declined worldwide during the COVID-19 pandemic. It is unclear how shelter-in-place orders affected acute CVD hospitalizations, illness severity, and outcomes. HYPOTHESIS: COVID-19 pandemic was associated with reduced acute CVD hospitalizations (heart failure [HF], acute coronary syndrome [ACS], and stroke [CVA]), and worse HF illness severity. METHODS: We compared acute CVD hospitalizations at Duke University Health System before and after North Carolina's shelter-in-place order (January 1-March 29 vs. March 30-August 31), and used parallel comparison cohorts from 2019. We explored illness severity among admitted HF patients using ADHERE ("high risk": >2 points) and GWTG-HF (">10%": >57 points) in-hospital mortality risk scores, as well as echocardiography-derived parameters. RESULTS: Comparing hospitalizations during January 1-March 29 (N = 1618) vs. March 30-August 31 (N = 2501) in 2020, mean daily CVD hospitalizations decreased (18.2 vs. 16.1 per day, p = .0036), with decreased length of stay (8.4 vs. 7.5 days, p = .0081) and no change in in-hospital mortality (4.7 vs. 5.3%, p = .41). HF hospitalizations decreased (9.0 vs. 7.7 per day, p = .0019), with higher ADHERE ("high risk": 2.5 vs. 4.5%; p = .030), but unchanged GWTG-HF (">10%": 5.3 vs. 4.6%; p = .45), risk groups. Mean LVEF was lower (39.0 vs. 37.2%, p = .034), with higher mean LV mass (262.4 vs. 276.6 g, p = .014). CONCLUSIONS: CVD hospitalizations, HF illness severity, and echocardiography measures did not change between admission periods in 2019. Evaluating short-term data, the COVID-19 shelter-in-place order was associated with reductions in acute CVD hospitalizations, particularly HF, with no significant increase in in-hospital mortality and only minor differences in HF illness severity.

COVID-19: Loss of bridging between innate and adaptive immunity?

COVID-19 has spread to most countries in the world. However, there are some striking differences in how COVID-19 is behaving in different age groups. While data on COVID-19 is limited, children appear to be less susceptible to severe disease. These unique characteristics may be considered as a potential link to understanding the immune system and response in COVID-19 and lead to an effective cure to the disease. We suggest a possible role of loss of bridging between innate and adaptive immunity in COVID-19 and a potential treatment modality also discussed.