Conserved longitudinal alterations of anti-S-protein IgG subclasses in disease progression in initial ancestral Wuhan and vaccine breakthrough Delta infections.

Introduction: COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Methods: Plasma samples were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. Results: We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected individuals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. Discussion: While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.

Prolonged inflammation in patients hospitalized for coronavirus disease 2019 (COVID-19) resolves 2 years after infection.

Long-term complications from coronavirus disease 2019 (COVID-19) are concerning, as survivors can develop subclinical multiorgan dysfunction. It is unknown if such complications are due to prolonged inflammation, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination may reduce sequela. We conducted a prospective longitudinal study on hospitalized patients over 24 months. Clinical symptoms were collected by self-reporting during follow-up, along with blood samples for quantification of inflammatory markers and immune cell frequencies. All patients were given one dose of mRNA vaccine at 12-16 months. Their immune profiles at 12 and 24 months were compared. Approximately 37% and 39% of our patients reported post-COVID-19 symptoms at 12 and 24 months, respectively. The proportion of symptomatic patients with more than one symptom decreased from 69% at 12 months to 56% at 24 months. Longitudinal cytokine profiling revealed a cluster of individuals with persistently high inflammatory cytokine levels 12 months after infection. Patients with prolonged inflammation showed elevated terminally differentiated memory T cells in their blood; 54% had symptoms at 12 months. The majority of inflammatory markers and dysregulated immune cells in vaccinated patients recovered to a healthy baseline at 24 months, even though symptoms persisted. Post-COVID-19 symptoms can linger for 2 years after the initial infection and are associated with prolonged inflammation. Prolonged inflammation in hospitalized patients resolves after 2 years. We define a set of analytes associated with persistent inflammation and presence of symptoms, which could be useful biomarkers for identifying and monitoring high-risk survivors.

Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals.

The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 - 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2.

Myeloperoxidase inhibition may protect against endothelial glycocalyx shedding induced by COVID-19 plasma.

BACKGROUND: SARS-CoV-2, the causative agent of COVID-19, is a threat to public health. Evidence suggests increased neutrophil activation and endothelial glycocalyx (EG) damage are independently associated with severe COVID-19. Here, we hypothesised that an increased level of blood neutrophil myeloperoxidase (MPO) is associated with soluble EG breakdown, and inhibiting MPO activity may reduce EG damage. METHODS: Analysing a subset of acute and convalescent COVID-19 plasma, 10 from severe and 15 from non-severe COVID-19 cases, and 9 from pre-COVID-19 controls, we determined MPO levels, MPO activity and soluble EG proteins (syndecan-1 and glypican-1) levels by enzyme-linked immunosorbent assay. In vitro primary human aortic endothelial cells were cultured with plasma untreated or treated with specific MPO inhibitors (MPO-IN-28, AZD5904) to determine EG shedding. We then investigated whether inhibiting MPO activity decreased EG degradation. RESULTS: In COVID-19 plasma, MPO levels, MPO activity and levels of soluble EG proteins are significantly raised compared to controls, and concentrations increase in proportion to disease severity. Despite clinical recovery, protein concentrations remain significantly elevated. Interestingly, there is a trend of increasing MPO activity in convalescent plasma in both severe and non-severe groups. MPO levels and MPO activity correlate significantly with soluble EG levels and inhibiting MPO activity leads to reduced syndecan-1 shedding, in vitro. CONCLUSIONS: Neutrophil MPO may increase EG shedding in COVID-19, and inhibiting MPO activity may protect against EG degradation. Further research is needed to evaluate the utility of MPO inhibitors as potential therapeutics against severe COVID-19.

COVID-19 can result in severe disease and is potentially fatal. Neutrophils, the most abundant white blood cells in circulation, secrete antimicrobials that have been linked to severe COVID-19 development. The endothelial glycocalyx (EG) is a carbohydrate rich layer that coats the inner surface of the vasculature and damage to the EG is observed in severe COVID-19. Here, we investigate whether myeloperoxidase, an antimicrobial released by neutrophils, is associated with EG damage in COVID-19 patients. We also determine whether reducing myeloperoxidase activity prevents damage to the EG. Our results suggest myeloperoxidase is associated with EG damage and severe COVID-19. We also demonstrated that a reduction in myeloperoxidase activity may protect against EG degradation. Further studies to evaluate the utility of MPO inhibitors as a therapy against severe COVID-19 are warranted.

Immune and coagulation profiles in 3 adults with multisystem inflammatory syndrome.

INTRODUCTION: There is a paucity of information on the cytokine, complement, endothelial activation, and coagulation profiles of multisystem inflammatory syndrome in adults (MIS-A), a rare but serious complication following recovery from SARS-CoV-2 infection. We aim to examine the immune biomarker and coagulation profiles in association with the clinical presentation and course of MIS-A. METHOD: The clinical features of MIS-A patients admitted to our tertiary hospital were documented. Their levels of interleukin (IL)-1ß, IL-6, IL-10, IL-17, IL-18, interferon-α (IFN-α), IFN-γ, interferon gamma-induced protein 10 (IP-10), tumour necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, complement activation product (complement 5a [C5a]), and endothelial biomarker intercellular adhesion molecule-1 (ICAM-1) levels were assayed. The haemostatic profile was assessed with standard coagulation testing and thromboelastography. RESULTS: Three male patients were diagnosed with MIS-A at our centre from January to June 2022 with a median age of 55 years. All had tested positive for SARS-CoV-2 12-62 days prior to MIS-A presentation, with gastrointestinal and cardiovascular systems as the most commonly involved. Levels of IL-6, IL-10, IL-18, IP-10 and MCP-1 were raised whereas IL-1ß, IFN-α, IFN-γ, IL-17 and TNF-α remained normal. Markedly elevated levels of C-reactive protein (CRP), ferritin and ICAM-1 were present in all. C5a was elevated in 2 patients. A hypercoagulable state was demonstrated by raised levels of D-dimer, factor VIII, von Willebrand factor antigen, and ristocetin cofactor with corresponding raised parameters in thromboelastography in the 2 patients who had their coagulation profile assessed. CONCLUSION: MIS-A patients demonstrate activation of pro-inflammatory cytokines, endotheliopathy, complement hyperactivation and hypercoagulability.

Clinical trials on the pharmacological treatment of long COVID: A systematic review.

The postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), also known as post-acute coronavirus disease 19 (COVID-19) or the long COVID syndrome (long COVID) is an emerging public health concern. A substantial proportion of individuals may remain symptomatic months after initial recovery. An updated review of published and ongoing trials focusing on managing long COVID will help identify gaps and address the unmet needs of patients suffering from this potentially debilitating syndrome. A comprehensive literature search was conducted on the international databases and clinical trial registries from inception to 31 July 2022. This review included 6 published trials and 54 trial registration records. There is significant heterogeneity in the characterization of long COVID and ascertainment of primary outcomes. Most of the trials are focused on individual symptoms of long COVID or isolated organ dysfunction, classified according to cardiovascular, respiratory and functional capacity, neurological and psychological, fatigue, and olfactory dysfunction. Most of the interventions are related to the mechanisms causing the individual symptoms. Although the six published trials showed significant improvement in the symptoms or organ dysfunction studied, these initial studies lack internal and external validity limiting the generalizability. This review provides an update of the pharmacological agents that could be used to treat long COVID. Further standardization of the diagnostic criteria, inclusion of participants with concomitant chronic cardiometabolic diseases and standardization of outcomes will be essential in future clinical trials.

Real-world effectiveness of sotrovimab and remdesivir for early treatment of high-risk hospitalized COVID-19 patients: A propensity score adjusted retrospective cohort study.

Early treatment of high-risk COVID-19 patients may prevent disease progression. However, there are limited data to support treatment of hospitalized or fully vaccinated patients with mild-to-moderate disease. In this retrospective cohort study, we studied the effect of early use of sotrovimab and remdesivir in high-risk hospitalized COVID-19 patients. We included PCR-confirmed COVID-19 patients admitted to the National Centre for Infectious Diseases who presented within the first 5 days of illness, and who were not requiring oxygen or ICU care at presentation. Sotrovimab- and remdesivir-treated groups were compared with control (no early treatment). A multiple propensity-score adjusted multivariable regression analysis was conducted with a composite primary endpoint of in-hospital deterioration (oxygen requirement, ICU admission, or mortality). Of 1118 patients, 841 were in the control group, 106 in the sotrovimab group and 169 in the remdesivir group. The median age was 63 years (IQR 46-74 years) and 505 (45.2%) were female. In unvaccinated patients, both remdesivir and sotrovimab treatment were protective (adjusted odds ratio [aOR] 0.19, 95% CI 0.064-0.60 and 0.18 [95% CI 0.066-0.47]), respectively. Contrarily, among the vaccinated patients there was no significant treatment effect with early remdesivir treatment (aOR 2.51, 95% CI 0.83-7.57, p = 0.10). Remdesivir and sotrovimab treatment, given early in the disease course to unvaccinated high-risk patients, was effective in reducing the risk of in-hospital deterioration and severe disease. This effect was not seen in fully vaccinated patients, which may be due to a small sample size or residual confounding.

Conserved longitudinal alterations of anti-S-protein IgG subclasses in disease progression in initial ancestral Wuhan and vaccine breakthrough Delta infections

Introduction COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Methods Plasma samples were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. Results We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected individuals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. Discussion While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.

Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals

The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 – 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2.

The Omicron-transformer: Rise of the subvariants in the age of vaccines.

INTRODUCTION: Omicron is the latest SARS-CoV-2 variant of concern, the pathogen that causes COVID-19. Since its emergence in late 2021, Omicron has displaced other circulating variants and caused successive waves of infection worldwide throughout 2022. Omicron is characterised by the rapid emergence of many subvariants and high rates of infection in people with vaccine- and/or infection induced immunity. This review article will consolidate current knowledge regarding Omicron subvariants, the role of boosters, and future vaccine development. METHOD: This narrative review is based on a literature search using PubMed. Search terms related to Omicron were used and priority was given to published peer-reviewed articles over pre-prints. RESULTS: Studies indicate that vaccinations and boosters are important to reduce disease severity, hospitalisation, and death from Omicron. A variety of factors, such as differing host factors, circulating variants, and forces of infection, can influence the benefit of repeated booster administration. Next-generation bivalent vaccines have now been approved in some countries including Singapore and have demonstrated the ability to induce broad variant protection. Future third-generation vaccines involving mucosal vaccines and/or pan-sarbecovirus vaccines may provide broader and longer-lasting protection. CONCLUSION: Due to current high levels of vaccine- and infection-induced immunity, it is likely that rates of severe illness, hospitalisation, and death due to Omicron will continue to moderate. Nevertheless, the virus is ever-changing, and public health policies, especially those related to vaccinations, will also have to continually evolve and adapt as COVID-19 transitions to endemicity.

Lower vaccine-acquired immunity in the elderly population following two-dose BNT162b2 vaccination is alleviated by a third vaccine dose.

Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where individuals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while individuals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older individuals against the ancestral Wuhan strain, Delta and Omicron variants.

Hypoxia and R-factor: predictors of abnormal lft in covid-19

IDDF2022-ABS-0170 Table 1Demographics, comorbidities, laboratory investigations and clinical outcomes of COVID-19 patients stratified by ALT All (n=163) Status of ALT P-value¶ Characteristics Abnormal (n=50) Normal (n=113) Age in years, median (IQR) 56 (43–65) 60 (50–67) 55 (37–64) 0.022 Gender, n (%) 0.124 Male 96 (58.9) 34 (68.0) 62 (54.9) Female 67 (41.1) 16 (32.0) 51 (45.1) Ethnic group, n (%) 0.520 Chinese 98 (60.1) 34 (68.0) 64 (56.6) Malay 18 (11.0) 4 (8.0) 14 (12.4) Indian 20 (12.3) 6 (12.0) 14 (12.4) Others 27 (16.6) 6 (12.0) 21 (18.6) Comorbidities, n (%) Diabetes 32 (19.6) 13 (26.0) 19 (16.8) 0.201 Hyperlipidemia 57 (35.0) 24 (48.0) 33 (29.2) 0.032 Hypertension 61 (37.4) 26 (52.0) 35 (31.0) 0.014 Ischemic heart disease 15 (9.2) 7 (14.0) 8 (7.1) 0.238 Chronic liver disease 4 (2.5) 1 (2.0) 3 (2.7) 1.000 Charlson Comorbidity Index, median (IQR) 0 (0–1) 0 (0–1) 0 (0–1) 0.400 BMI, kg/m2, median (IQR), n=46 24.3 (23.2–27.9) 22.9 (22.1–24.2) 24.6 (23.6–28.7) 0.011 GI symptoms, n (%) Diarrhoea 29 (17.8) 12 (24.0) 17 (15.0) 0.186 Abdominal pain 4 (2.5) 0 (0.0) 4 (3.5) 0.313 Nausea/vomiting 10 (6.1) 0 (0.0) 10 (8.8) 0.032 Abnormal chest radiography on admission 55 (33.7) 22 (44.0) 33 (29.2) 0.074 Laboratory investigations on admission, median (IQR) ALT, U/L 23 (18–31) 29 (22–33) 21 (17–26) <0.0005 ALT/LDH ratio, n=162 0.05 (0.04–0.07) 0.06 (0.04–0.07) 0.05 (0.03–0.06) 0.039 ALP 72 (60–89) 72 (61–90) 72 (60–89) 0.700 R factor 0.94 (0.70–1.26) 1.15 (0.86–1.49) 0.87 (0.63–1.19) <0.0005 WBC, x109/L 4.70 (3.80–5.70) 4.75 (3.80–5.83) 4.70 (3.85–5.70) 0.844 Lymphocyte, x109/L 1.11 (0.84–1.49) 0.99 (0.74–1.23) 1.20 (0.87–1.65) 0.002 PLT, x 109/L 188 (150–225) 177 (142–223) 193 (155–226) 0.306 CRP, mg/L, n=162 10.75 (3.15–39.40) 30.10 (11.28–50.65) 6.85 (1.95–23.88) <0.0005 LDH, U/L, n=162 420 (350–547) 482 (378–572) 408 (342–525) 0.033 Creatinine, μmol/L 72 (61–87) 76 (65–88) 71 (59–87) 0.288 Albumin, g/L, n=156 39 (37–42) 39 (37–41) 40 (37–43) 0.044 BIL, μmol/L, n=152 11 (9–14) 11 (9–14) 12 (9–15) 0.555 Medication used, n (%) NSAIDs 22 (13.5) 4 (8.0) 18 (15.9) 0.218 β-lactam 47 (28.8) 22 (44.0) 25 (22.1) 0.008 Hydroxychloroquine 7 (4.3) 1 (2.0) 6 (5.3) 0.677 Lopinavir/Ritonavir (Kaletra) 25 (15.3) 16 (32.0) 9 (8.0) <0.0005 Remdesivir 12 (7.4) 5 (10.0) 7 (6.2) 0.516 Interferon 9 (5.5) 6(12.0) 3 (2.7) 0.025 Days of symptoms before admission, median (IQR) 4 (3–7) 4 (2–7) 5 (3–7) 0.396 Length of stay in days, median (range) 13(8–17) 16(13–24) 11 (7–16) <0.0005 Clinical severity HDU/ICU, n (%) 29 (17.8) 16 (32.0) 13 (11.5) 0.003 Required supplementary oxygen, n (%) 50 (30.7) 29 (58.0) 21 (18.6) <0.0005 Days on supplementary oxygen, median (IQR), n=50 11 (6–18) 12 (6–21) 8 (5–15) 0.15 Intubated, n (%) 13 (8.0) 10 (20.0) 3 (2.7) <0.0005 Death, n (%) 5 (3.1) 3 (6.0) 2 (1.8) 0.169 Sample size, n=163, except where indicated.¶ P values are from Fisher’s exact test or chi-square test for categorical variables and Mann-Whitney U test for continuous variables. P values< 0.05 are in bold.ALP, alkaline phosphatase;ALT, alanine aminotransferase;AST, aspartate aminotransferase;BIL, bilirubin;BMI, body mass index;CRP, c-reactive protein;GI, gastrointestinal;ICU, intensive care unit;IQR, interquartile range;LDH, lactate dehydrogenase;HDU, high dependency unit;PLT, platelet count;WBC, white blood cell.Results30.7% of patients developed abnormal ALT: they were more likely to be older and had comorbidities of hyperlipidaemia and hypertension. Multivariate logistic regression (IDDF2022-ABS-0170 Table 2) showed that R-factor ≥1 on admission (aOR 3.13, 95%CI 1.41–6.95) and hypoxia (aOR3.54, 95%CI 1.29–9.69) were independent risk factors for developing abnormal ALT, but not medications or comorbidities. The R-factor on admission trended higher for patients who developed abnormal LFT as compared to those who didn’t, regardless of the day of illness (IDDF2022-ABS-0170 Figure 1. R-factor). The patients who developed abnormal ALT also ran a more severe course of illness with a greater proportion needing supplementary oxygen (58%vs18.6%, p <0.0005), admission to Intensive Care/High Dependency Unit (32%vs11.5%, p=0.003) and intubation (20%vs2.7%, p<0.0005). The death rate between the 2 groups was similar. IDDF2022-ABS-0170 Table 2Odds ratio of risk factors for development of abnormal ALTVariable Univariable model Multivariable model ‡ cOR (95% CI) P value aOR (95% CI) P value Age in years <45 1.00 Referent 1.00 Referent 45–64 3.42 (1.28–9.11) 0.014 2.69 (0.84–8.47) 0.096 65+ 4.31 (1.49–12.42) 0.007 2.84 (0.66–12.19) 0.160 Gender Male 1.00 Referent Female 0.57 (0.28–1.15) 0.118 Diabetes 1.74 (0.78–3.87) 0.176 Hyperlipidemia 2.24 (1.13–4.45) 0.022 1.14 (0.43–3.00) 0.796 Hypertension 2.41 (122–4.78) 0.0110.89 (0.31–2.58) 0.835 Ischemic heart disease 2.14 (0.73–6.26) 0.166 Presence of GI symptom(s) on admission 1.17 (0.53–2.58) 0.695 Abnormal chest x-ray on admission 1.90 (0.96–3.80) 0.067 0.91 (0.36–2.25) 0.833 R factor on admission <1 1.00 Referent 1.00 Referent ≥1 3.12 (1.56–6.24) 0.001 3.13 (1.41–6.95) 0.005 Use of acetaminophen No 1.00 Referent Yes, <2 g/day 1.48 (0.39–5.65) 0.567 Yes, ≥2 g/day 2.86 (0.71–11.46) 0.139 Use of β-lactam 2.77 (1.35–5.65) 0.005 1.12 (0.38–3.24) 0.840 Use of Hydroxychloroquine 0.36 (0.04–3.11) 0.355 Use of Lopinavir/Ritonavir (Kaletra) 5.44 (2.20–13.43) <0.0005 2.20 (0.57–8.45) 0.252 Use of Remdesivir 1.68 (0.51–5.58) 0.395 Use of interferon 5.00 (1.20–20.88) 0.027 0.80 (0.12–5.22) 0.813 Hypoxia 6.05 (2.9–12.62) <0.0005 3.54 (1.29–9.69) 0.014 ‡ Variables in the multivariable logistic regression model were age group, hyperlipidemia, hypertension, whether there was abnormal chest x-ray on admission, R factor on admission, use of β-lactam, use of LPV/r, use of interferon, and hypoxia, P values<0.05 are in bold, aOR, adjusted odds ratio, cOR, crude odds ratio IDDF2022-ABS-0170 Figure 1ConclusionsLiver injury is associated with poorer clinical outcomes in COVID-19 patients. R-factor ≥1 on admission and hypoxia are independent risk factors for developing abnormal ALT in COVID-19. More studies are required to see if the incorporation of the R-factor into conventional clinical risk scores can improve the performance in predicting disease progression/discriminating disease severity and applicability in emerging virus variants.

Heterologous booster vaccination with CoronaVac following prime vaccination with mRNA vaccine.

Objective: Despite the high vaccine efficacy of mRNA COVID-19 vaccines, there are individuals who developed excessive reactogenic and/or allergic responses after the first mRNA dose and were considered ineligible for further mRNA doses. CoronaVac, an inactivated SARS-CoV-2 vaccine, is recommended in Singapore as an alternative. Methods: Individuals, ineligible for further mRNA vaccines (BNT162b2 or mRNA-1273) because of excessive reactive responses to prime mRNA vaccination, were recruited and offered two doses of CoronaVac as booster vaccination 38-224 days post their mRNA vaccine dose. Individuals who did not develop any excessive reactive responses after the prime mRNA vaccination were also recruited and given another mRNA vaccine as booster vaccination. Blood samples were collected at days 0, 21 and 90 post first CoronaVac dose and mRNA dose, respectively, for analysis. Results: We showed that two CoronaVac booster doses induced specific immunity in these mRNA vaccine-primed individuals. Although the spike-specific antibody response was lower, their memory B cell response against the receptor-binding domain (RBD) of the spike protein was similar, compared with individuals who received two BNT162b2 injections. The spike-specific memory T cell response also increased following CoronaVac booster doses. However, specific immunity against the Omicron variant was low, similar to individuals with two BNT162b2 doses. Conclusion: Our findings showed that while mRNA vaccine-primed individuals can opt for two subsequent doses of CoronaVac, an additional dose may be necessary to achieve protection, especially against newly emerging immune escape variants such as Omicron.

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia.

Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.

Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients.

Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU µg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42-2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.