June 29, 2023

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Clinical Reports

Intrinsic and effective severity of COVID-19 cases infected with the ancestral strain and Omicron BA.2 variant in Hong Kong
- Understanding severity of infections with SARS-CoV-2 and its variants is crucial to inform public health measures. Here researchers used COVID-19 patient data from Hong Kong to characterize the severity profile of COVID-19. Time-varying and age-specific effective severity measured by case-hospitalization risk and hospitalization-fatality risk was estimated with all individual COVID-19 case data collected in Hong Kong from 23 January 2020 through to 26 October 2022 over six epidemic waves. The intrinsic severity of Omicron BA.2 was compared with the estimate for the ancestral strain with the data from unvaccinated patients without previous infections. With 32,222 COVID-19 hospitalizations and 9,669 deaths confirmed over 6 epidemic waves, the time-varying hospitalization fatality risk dramatically increased from below 10% before the largest fifth wave of Omicron BA.2, to 41% during the peak of the fifth wave when hospital resources were severely constrained. The age-specific fatality risk in unvaccinated hospitalized Omicron cases was comparable to the estimates for unvaccinated cases with the ancestral strain. During epidemics predominated by Omicron BA.2, fatality risk was highest amongst older unvaccinated patients. Omicron has comparable intrinsic severity to the ancestral Wuhan strain although the effective severity is substantially lower in Omicron cases due to vaccination.
Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review
- Long COVID disproportionately affects premenopausal women, but relatively few studies have examined Long COVID's impact on female reproductive health. Researchers conducted a review of the literature documenting the female reproductive health impacts of Long COVID which may include disruptions to the menstrual cycle, gonadal function, ovarian sufficiency, menopause, and fertility, as well as symptom exacerbation around menstruation. Given limited research, researchers also reviewed the reproductive health impacts of overlapping and associated illnesses including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), connective tissue disorders like Ehlers-Danlos syndrome (EDS), and endometriosis, as these illnesses may help to elucidate reproductive health conditions in Long COVID. These associated illnesses, whose patients are 70%–80% women, have increased rates of dysmenorrhea, amenorrhea, oligomenorrhea, dyspareunia, endometriosis, infertility, vulvodynia, intermenstrual bleeding, ovarian cysts, uterine fibroids and bleeding, pelvic congestion syndrome, gynecological surgeries, and adverse pregnancy complications such as preeclampsia, maternal mortality, and premature birth. Additionally, in Long COVID and associated illnesses, symptoms can be impacted by the menstrual cycle, pregnancy, and menopause. Researchers proposed priorities for future research and reproductive healthcare in Long COVID based on a review of the literature. These include screening Long COVID patients for comorbid and associated conditions; studying the impacts of the menstrual cycle, pregnancy, and menopause on symptoms and illness progression; uncovering the role of sex differences and sex hormones in Long COVID and associated illnesses; and addressing historical research and healthcare inequities that have contributed to detrimental knowledge gaps for this patient population.
Melatonin effects on sleep quality of COVID-19 patients: a protocol for systematic review and meta-analysis of randomized controlled trials with trial sequential analysis
- Sleep disturbance is one of the common complaints of patients with COVID-19 infection. Melatonin is a physiological indoleamine involved in circadian rhythm regulation and it is currently used for secondary sleep disorders caused by various diseases. Some clinical randomized controlled trials (RCTs) have obtained a small amount of evidence and controversial results in support of their therapeutic effect on sleep disorders, but no studies have summarized and evaluated RCTs in all current databases to obtain conclusive results. Therefore, the aim of this systematic review and meta-analysis was to determine the efficacy and safety of melatonin in the treatment of sleep disturbances in patients with COVID-19. Researchers will search for RCT-type studies of melatonin in the treatment of sleep disturbances in patients with COVID-19. From inception to October 2022 will be available on PubMed/MEDLINE, Web of Science, Embase, CINAHL, PsycINFO, LILACS, SCOPUS, Cochrane Central Register of Controlled Trials, ICTRP, Wanfang Data, VIP database and CNKI, VIP database, China Biomedical Literature Database to search for eligible studies. There are no language and geographical restrictions. Two authors will independently screen and select eligible studies, assess methodological quality and perform data extraction. Two additional authors will independently extract data from each study. Then, meta-analysis will then be carried out using a fixed-effects or random-effects model, using the mean difference for continuous outcomes and the relative risk for dichotomous outcomes. Risk of bias assessment will be assessed using the Cochrane risk-of-bias tool. Heterogeneity between studies was assessed by Cochrane Q-test and I2. The quality of evidence for each outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Funnel plots, Begg's test and Egger's test will be used to assess the risk of publication bias. Subgroup analysis, data synthesis, meta-analysis and overall incidence of adverse events will be performed using Review Manager V.5.4 software and Stata software. Trial sequential analysis will be performed if appropriate. This study is an extraction review of data from existing studies, and thus it is unnecessary to obtain ethical approval. The results of this systematic review will be published in a peer-reviewed journal.
Awake prone positioning for non-intubated patients with COVID-19-related acute hypoxic respiratory failure: a systematic review based on eight high-quality randomized controlled trials
- Awake prone positioning has been widely used in non-intubated patients with acute hypoxic respiratory failure (AHRF) due to COVID-19, but the evidence is mostly from observational studies and low-quality randomized controlled trials (RCTs), with conflicting results from published studies. A systematic review of published high-quality RCTs to resolve the controversy over the efficacy and safety of awake prone positioning in non-intubated patients with AHRF due to COVID-19. Candidate studies were identified through searches of PubMed, Web of Science, Cochrane, Embase, Scopus databases from December 1, 2019 to November 1, 2022. Literature screening, data extraction and risk of bias assessment were independently conducted by two researchers. Eight RCTs involving 2657 patients were included. Meta-analysis of fixed effects models showed that awake prone positioning did not increase mortality, length of stay in ICU, total length of stay, or incidence of adverse events compared with usual care, but significantly reduced the intubation rate. Similar results were found in a subgroup analysis of patients who received only high flow nasal cannula; Intubation rate: OR = 0.69, 95%CI [0.58, 0.83]). All eight RCTs had high quality of evidence, which ensured the reliability of the meta-analysis results. Awake prone positioning is safe and feasible in non-intubated patients with AHRF caused by COVID-19, and can significantly reduce the intubation rate. More studies are needed to explore standardized implementation strategies for the awake prone positioning.

Antiviral Therapeutics and Vaccines

Guidance on Measles during the Summer Travel Season
- As the summer travel season begins, the Centers for Disease Control and Prevention (CDC) is issuing this Health Alert Network (HAN) Health Advisory to remind clinicians and public health officials to provide guidance for measles prevention to international travelers and to be on alert for cases of measles. Guidance is also provided for people planning international travel. Measles (rubeola) is extremely contagious; one person infected by measles can infect 9 out of 10 of their unvaccinated close contacts. As of June 8, 2023, CDC has been notified of 16 confirmed U.S. cases of measles across 11 jurisdictions, with 14 (88%) linked to international travel. Based on current estimates, twice as many Americans are planning to travel internationally in 2023 compared with 2022. Many countries and popular travel destinations, such as London, England, have experienced measles outbreaks in recent years. The United States has seen an increase in measles cases during the first 5 months of 2023, with 16 reported cases compared with 3 in 2022 during the same period. Most of these cases were among children who had not received measles-mumps-rubella (MMR) vaccine. To prevent measles infection and spread from importation, all U.S. residents should be up to date on their MMR vaccinations, especially prior to international travel regardless of the destination.
Safety, immunogenicity and protection of heterologous boost with an aerosolised Ad5-nCoV after two-dose inactivated COVID-19 vaccines in adults: a multicentre, open-label phase 3 trial
- Aerosolized Ad5-nCoV is one of the first licensed mucosal respiratory vaccine against SARS-CoV-2 in the world; however, the safety profile of this vaccine has not been reported in a large population yet. This multicenter, open-label phase 3 trial, done in 15 centers in six provinces (Jiangsu, Hunan, Anhui, Chongqing, Yunnan, Shandong) in China, aimed to evaluate the safety and immunogenicity of aerosolized Ad5-nCoV in healthy adults (members of the general population with no acute febrile disorders, infectious disease, serious cardiovascular diseases, serious chronic diseases or progressive diseases that cannot be controlled) at least 18 years old, who had received two doses of inactivated COVID-19 vaccine as their primary regimen. This study contained a non-randomly assigned safety cohort and a centrally randomly assigned (1:1) immunogenicity subcohort. The patients in the immunogenicity subcohort received aerosolized Ad5-nCov (aerosolized Ad5-nCoV group) or inactivated vaccine (inactivated COVID-19 group) The primary endpoints were the incidence of adverse reactions within 28 days following the booster vaccination with aerosolised Ad5-nCoV in the safety population (collected through a daily record of any solicited or unsolicited adverse events filled by each participant) and the geometric mean titre of neutralising antibodies at day 28 after the booster dose in the immunogenicity subcohort (measured with a pseudovirus neutralisation test). Between Jan 22, 2022, and March 12, 2022, researchers recruited 11 410 participants who were screened for eligibility, of whom 10 267 (99·8%) participants (5738 [55·9%] men, 4529 [44·1%] women; median age 53 years [18–92]) received the study drugs: 9847 (95·9%) participants in the open-label cohort to receive aerosolised Ad5-nCoV, and 420 (4·1%) in the immunogenicity subcohort (212 in the aerosolised Ad5-nCoV group and 208 in the inactivated vaccine group). Adverse reactions were reported by 1299 (13%) of 10 059 participants within 28 days after receiving the booster vaccination with aerosolised Ad5-nCoV, but most of the adverse reactions reported were mild to moderate in severity. Participants in the aerosolised Ad5-nCoV group had a significantly higher level of the neutralising antibodies against omicron BA.4/5 (GMT 107·7 [95% CI 88·8–130·7]) than did those in the inactivated vaccine group (17·2 [16·3–18·2]) at day 28. The heterologous booster regimen with aerosolised Ad5-nCoV is safe and highly immunogenic, boosting both systemic and mucosal immunity against omicron subvariants.

Diagnostics

The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Antigen Testing
- Immunoassays designed to detect SARS-CoV-2 protein antigens (Ag) are commonly used to diagnose COVID-19. The most widely used tests are lateral flow assays that generate results in approximately 15 minutes for diagnosis at the point-of-care. Higher throughput, laboratory-based SARS-CoV-2 Ag assays have also been developed. The number of commercially available SARS-CoV-2 Ag detection tests has increased rapidly, as has the COVID-19 diagnostic literature. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the literature and develop best-practice guidance related to SARS-CoV-2 Ag testing. This guideline is an update to the third in a series of frequently updated COVID-19 diagnostic guidelines developed by the IDSA. IDSA's goal was to develop evidence-based recommendations or suggestions that assist clinicians, clinical laboratories, patients, public health authorities, administrators, and policymakers in decisions related to the optimal use of SARS-CoV-2 Ag tests in both medical and nonmedical settings. A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review identified and prioritized clinical questions related to the use of SARS-CoV-2 Ag tests. A review of relevant, peer-reviewed published literature was conducted through 1 April 2022. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. The panel made 10 diagnostic recommendations that address Ag testing in symptomatic and asymptomatic individuals and assess single versus repeat testing strategies. US Food and Drug Administration (FDA) SARS-CoV-2 Ag tests with Emergency Use Authorization (EUA) have high specificity and low to moderate sensitivity compared with nucleic acid amplification testing (NAAT). Ag test sensitivity is dependent on the presence or absence of symptoms and, in symptomatic patients, on timing of testing after symptom onset. In most cases, positive Ag results can be acted upon without confirmation. Results of point-of-care testing are comparable to those of laboratory-based testing, and observed or unobserved self-collection of specimens for testing yields similar results. Modeling suggests that repeat Ag testing increases sensitivity compared with testing once, but no empirical data were available to inform this question. Based on these observations, rapid RT-PCR or laboratory-based NAAT remain the testing methods of choice for diagnosing SARS-CoV-2 infection. However, when timely molecular testing is not readily available or is logistically infeasible, Ag testing helps identify individuals with SARS-CoV-2 infection. Data were insufficient to make a recommendation about the utility of Ag testing to guide release of patients with COVID-19 from isolation. The overall quality of available evidence supporting use of Ag testing was graded as very low to moderate.

Epidemiology

SARS-CoV-2 Variants and Age-Dependent Infection Rates among Household and Nonhousehold Contacts
- To determine the effects of age and variants of concern on transmission of SARS-CoV-2, researchers analyzed infection rates among close contacts over 4 periods in Toyama Prefecture, Japan. Among household contacts, odds of infection were 6.2 times higher during the period of the Omicron variant than during previous periods, particularly among children and adolescents.
Effect of COVID-19 Vaccination on Household Transmission of SARS-CoV-2 in the Omicron Era: The Vaccine Effectiveness, Networking, and Universal Safety (VENUS) study
- This retrospective study was conducted using vaccination records, COVID-19 infection data, and resident registry data from two Japanese municipalities. Households that experienced their first COVID-19 case between January and April 2022 were categorized into two groups according to the presence/absence of children aged ≤11 years. Researchers constructed multivariable logistic regression models with generalized estimating equations to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for household transmission according to the vaccination statuses of primary cases and household contacts. Researchers analyzed 7,326 households with 17,586 contacts. In all households, the OR for household transmission was <0.6 (P<0.001) when the primary case and/or contact were vaccinated. In households with children aged ≤11 years, the OR was 0.71 (P<0.001) when only the contact was vaccinated. In households with all members aged ≥12 years, the OR was <0.5 (P<0.001) when the primary case and/or contact were vaccinated. COVID-19 vaccination effectively reduced household transmission in Japan during the Omicron variant wave.
Incidence of myopericarditis after mRNA COVID-19 vaccination: A meta-analysis with focus on adolescents aged 12–17 years
- The incidence of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12–17 years remains unknown. Therefore, researchers conducted a study to pool the incidence of myopericarditis following COVID-19 vaccination in this age group. Researchers did a meta-analysis by searching 4 electronic databases until February 6, 2023. The following main keywords were used: “COVID-19”, “vaccines”, “myocarditis”, “pericarditis”, and “myopericarditis”. Observational studies reporting on adolescents aged 12–17 years who had myopericarditis in temporal relation to receiving mRNA COVID-19 vaccines were included. The pooled incidence of myopericarditis and 95 % confidence interval (CI) were calculated using a single-group meta-analysis. Fifteen studies were included. The pooled incidences of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12–17 years were 43.5 (95 % CI, 30.8–61.6) cases per million vaccine doses for both BNT162b2 and mRNA-1273 (39 628 242 doses; 14 studies), and 41.8 (29.4–59.4) cases for BNT162b2 alone (38 756 553 doses; 13 studies). Myopericarditis was more common among males (66.0 [40.5–107.7] cases) than females (10.1 [6.0–17.0] cases) and among those receiving the second dose (60.4 [37.6–96.9] cases) than those receiving the first dose (16.6 [8.7–31.9] cases). The incidences of myopericarditis did not differ significantly when grouped by age, type of myopericarditis, country, and World Health Organization region. None of the incidences of myopericarditis pooled in the current study were higher than those after smallpox vaccinations and non-COVID-19 vaccinations, and all of them were significantly lower than those in adolescents aged 12–17 years after COVID-19 infection. The incidences of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12–17 years were very rare; they were not higher than other important reference incidences. These findings provide an important context for health policy makers and parents with vaccination hesitancy to weight the risks and benefits of mRNA COVID-19 vaccination among adolescents aged 12–17 years.
Incident autoimmune diseases in association with SARS-CoV-2 infection: a matched cohort study
- To investigate whether the risk of developing an incident autoimmune disease is increased in patients with prior COVID-19 disease compared to those without COVID-19, a large cohort study was conducted. A cohort was selected from German routine health care data. Based on documented diagnoses, researchers identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through December 31, 2020. Patients were matched 1:3 to control patients without COVID-19. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyze the onset of autoimmune diseases during the post-acute period. Incidence rates (IR) per 1000 person-years were calculated for each outcome and patient group. Poisson models were deployed to estimate the incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding diagnosis of COVID-19. In total, 641,704 patients with COVID-19 were included. Comparing the incidence rates in the COVID-19 (IR=15.05, 95% CI: 14.69–15.42) and matched control groups (IR=10.55, 95% CI: 10.25–10.86), we found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID-19. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune diseases of the vasculitis group. Patients with a more severe course of COVID-19 were at a greater risk for incident autoimmune disease. SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection.