Increased incidence of adult-onset Still's disease in association with COVID-19 vaccination and SARS-CoV-2 infection.

BACKGROUND: Adult-onset Still's disease (AOSD) is a multi-system, auto-inflammatory disease characterized by fever, arthralgia, typical rash, leukocytosis, sore throat, and liver dysfunction, among other symptoms. Retrospective studies about the frequencies of AOSD have shown that this disease is very rare. However, there has been an increased scientific interest in the last 2 years, as numerous case studies on AOSD have been published. These case studies describe the occurrence of AOSD after SARS-CoV-2 infection and/or COVID-19 vaccination. METHODS: We analyzed the incidence of AOSD to examine a potential association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. The TriNetX dataset consists of 90 million patients. We found 8474 AOSD cases, which we analyzed regarding SARS-CoV-2 infection and/or vaccination status. We also analyzed the cohorts considering demographic data, lab values, co-diagnoses and treatment pathways. RESULTS: We divided the AOSD cases into four cohorts: primary cohort (AOSD), Cov cohort (AOSD + SARS-CoV-2 infection), Vac cohort (AOSD + COVID-19 vaccination) and Vac + Cov cohort (AOSD + COVID-19 vaccination + SARS-CoV-2 infection). For the primary cohort, we found an annual incidence of 0.35 per 100.000. We found an association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. According to the numerical analysis, the incidence of AOSD doubled for the Cov cohort and Vac cohort. Moreover, the incidence of AOSD was 4.82 times higher for Vac + Cov cohort. The lab values for inflammatory markers were increased. Co-diagnoses such as rash, sore throat, and fever appeared in all AOSD cohorts, with the highest occurrences in the AOSD + COVID-19 vaccination + SARS-CoV-2 infection cohort. We identified several lines of treatments, mainly in association with adrenal corticosteroids. CONCLUSIONS: This research supports the assumption of an association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. However, AOSD remains a rare disease and the usage of vaccines to fight the COVID-19 pandemic should not be questioned because of the increased incidence of AOSD.

Onset of Oral Lichenoid Lesions and Oral Lichen Planus Following COVID-19 Vaccination: A Retrospective Analysis of about 300,000 Vaccinated Patients.

INTRODUCTION: Onset of oral lichenoid lesions (OLL) or oral lichen planus (OLP) can be rare adverse reactions to vaccines. Recently, the first solitary cases were reported after COVID-19 vaccination. The aim of the present study was to assess if an increased frequency of OLL/OLP can be found after COVID-19 vaccination within a large real-world cohort. It was assumed that the incidence of OLL/OLP was significantly higher in subjects who received COVID-19 vaccine (cohort I) compared to individuals who were not vaccinated (cohort II). PATIENTS AND METHODS: Initial cohorts of 274,481 vaccinated and 9,429,892 not vaccinated patients were retrieved from the TriNetX database (TriNetX, Cambridge, Massachusetts, USA), and matched for age, gender and the frequency of use of non-steroidal anti-inflammatory drugs, beta blockers, and angiotensin-converting enzyme inhibitors. RESULTS: After matching each cohort, we accounted for 217,863 patients. Among cohort I, 146 individuals had developed OLL/OLP within 6 days after COVID-19 vaccination (88 and 58 subjects had received mRNA- and adenovirus vector-based vaccines), whereas in cohort II, 59 patients were newly diagnosed with OLL/OLP within 6 days after having visited the clinic for any other reason. The risk of developing OLL/OLP was calculated as 0.067% vs. 0.027%, for cohorts I and II, whereby the risk difference was highly significant (p < 0.001; log-rank test). RR and OR were 2.475 (95% CI = 1.829; 3.348) and 2.476 (95% CI = 1.830; 3.350), respectively. DISCUSSION: The hypothesis was confirmed. Accordingly, the obtained results suggest that the onset of OLL/OLP is a rare adverse drug reaction to COVID-19 vaccines, especially to mRNA vaccines. Thus far, it remains unknown if specific components of the formulations cause a type IV hypersensitive reaction corresponding to OLL, or if the immune response post vaccination triggers a T cell-driven autoimmune reaction directed against the basal layer of keratinocytes of the oral mucosa in terms of OLP. Although OLL and OLP are both classified as premalignant lesions, spontaneous remission may be expected over time, at least in the case of OLL. Therefore, the presented findings should not place any limitation toward the use of COVID-19-vaccines in broad levels of the population.

A Comparative Analysis of COVID-19 Vaccines Based on over 580,000 Cases from the Vaccination Adverse Event Reporting System.

BACKGROUND: The COVID-19 pandemic is being battled via the largest vaccination campaign in history, with more than eight billion doses administered thus far. Therefore, discussions about potentially adverse reactions, and broader safety concerns, are critical. The U.S. Vaccination Adverse Event Reporting System (VAERS) has recorded vaccination side effects for over 30 years. About 580,000 events have been filed for COVID-19 thus far, primarily for the Johnson & Johnson (New Jersey, USA), Pfizer/BioNTech (Mainz, Germany), and Moderna (Cambridge, USA) vaccines. METHODS: Using available databases, we evaluated these three vaccines in terms of the occurrence of four generally-noticed adverse reactions-namely, cerebral venous sinus thrombosis, Guillain-Barré syndrome (a severe paralytic neuropathy), myocarditis, and pericarditis. Our statistical analysis also included a calculation of odds ratios (ORs) based on total vaccination numbers, accounting for incidence rates in the general population. RESULTS: ORs for a number of adverse events and patient groups were (largely) increased, most notably for the occurrence of cerebral venous sinus thrombosis after vaccination with the Johnson & Johnson vaccine. The overall population OR of 10 increases to 12.5 when limited to women, and further yet (to 14.4) among women below age 50 yrs. In addition, elevated risks were found (i) for Guillain-Barré syndrome (OR of 11.6) and (ii) for myocarditis/pericarditis (ORs of 5.3/4.1, respectively) among young men (<25 yrs) vaccinated with the Pfizer/BioNTech vaccine. CONCLUSIONS: Any conclusions from such a retrospective, real-world data analysis must be drawn cautiously, and should be confirmed by prospective double-blinded clinical trials. In addition, we emphasize that the adverse events reported here are not specific side effects of COVID vaccines, and the significant, well-established benefits of COVID-19 vaccination outweigh the potential complications surveyed here.

Sensitive to Infection but Strong in Defense-Female Sex and the Power of Oestradiol in the COVID-19 Pandemic.

The incidence of SARS-CoV2 infections is around 15% higher in premenopausal women compared to age matched men, yet the fatality rate from COVID-19 is significantly higher in men than women for all age strata. Sex differences have also been observed in recent epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), with SARS-CoV 2 virus infection sex differences appear more dramatic. The regulation and expression of the angiotensin converting enzyme 2 (ACE2) is the key for this special coronavirus SARS-CoV-2 to enter the cell. 17ß-oestradiol increases expression level and activity of angiotensin converting enzyme-2 (ACE2) and the alternative signaling pathway of Ang II via the angiotensin II receptor type II (AT2R) and the Mas receptor is more dominant in female sex than in male sex. Maybe a hint to explain the higher infection risk in women. The same hormonal milieu plays a major role in protecting women where morbidity and mortality are concerned, since the dominant female hormone, oestradiol, has immune-modulatory properties that are likely to be protective against virus infections. It is also known that the X chromosome contains the largest number of immune-related genes, potentially conferring an advantage to women in efficient immune responsiveness. Lifestyle factors are also likely to be contributory. Premenopausal women could possibly face higher exposure to infection (hence higher infection rates) because economic conditions are often less favorable for them with less opportunity for home office work because of jobs requiring mandatory attendance. Due to the additional task of childcare, it is likely that contact times with other people will be longer. Women generally make healthier lifestyle choices, thus reducing the disease burden that confers high risk of mortality in COVID-19 infected men. This narrative review aims to present key concepts and knowledge gaps on the effects of oestrogen associated with SARS-CoV2 infection and COVID-19 disease.

A Birds-Eye (Re)View of Acid-Suppression Drugs, COVID-19, and the Highly Variable Literature.

This Perspective examines a recent surge of information regarding the potential benefits of acid-suppression drugs in the context of COVID-19, with a particular eye on the great variability (and, thus, confusion) that has arisen across the reported findings, at least as regards the popular antacid famotidine. The degree of inconsistency and discordance reflects contradictory conclusions from independent, clinical-based studies that took roughly similar approaches, in terms of both experimental design (retrospective, observational, cohort-based, etc.) and statistical analysis workflows (propensity-score matching and stratification into sub-cohorts, etc.). The contradictions and potential confusion have ramifications for clinicians faced with choosing therapeutically optimal courses of intervention: e.g., do any potential benefits of famotidine suggest its use in a particular COVID-19 case? (If so, what administration route, dosage regimen, duration, etc. are likely optimal?) As succinctly put this March in Freedberg et al. (2021), "…several retrospective studies show relationships between famotidine and outcomes in COVID-19 and several do not." Beyond the pressing issue of possible therapeutic indications, the conflicting data and conclusions related to famotidine must be resolved before its inclusion/integration in ontological and knowledge graph (KG)-based frameworks, which in turn are useful for drug discovery and repurposing. As a broader methodological issue, note that reconciling inconsistencies would bolster the validity of meta-analyses which draw upon the relevant data-sources. And, perhaps most broadly, developing a system for treating inconsistencies would stand to improve the qualities of both 1) real world evidence-based studies (retrospective), on the one hand, and 2) placebo-controlled, randomized multi-center clinical trials (prospective), on the other hand. In other words, a systematic approach to reconciling the two types of studies would inherently improve the quality and utility of each type of study individually.

IL-13 is a driver of COVID-19 severity.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2-infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13-induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13-mediated HA synthesis in pulmonary pathology.

Evidence for treatment with estradiol for women with SARS-CoV-2 infection.

BACKGROUND: Given that an individual's age and gender are strongly predictive of coronavirus disease 2019 (COVID-19) outcomes, do such factors imply anything about preferable therapeutic options? METHODS: An analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in 5-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and peri-/post-menopausal (> 50 years). RESULTS: The incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is higher in women than men (by about + 15%) and, in contrast, the fatality rate is higher in men (about + 50%). Interestingly, the relationships between these quantities are linked to age: pre-adolescent girls and boys had the same risk of infection and fatality rate, while adult premenopausal women had a significantly higher risk of infection than men in the same 5-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in peri- and postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years, there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17ß-estradiol influences expression of the human angiotensin-converting enzyme 2 (ACE2) protein, which plays a role in SARS-CoV-2 cellular entry, propensity score matching was performed for the women's sub-cohort, comparing users vs. non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women > 50 years receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95% CI [0.18, 0.62] and the hazard ratio (HR) was 0.29, 95% CI [0.11,0.76]. For younger, pre-menopausal women (15-49 years), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels. CONCLUSIONS: As of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.