Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Serologic Testing.

BACKGROUND: The role of serologic testing for SARS-CoV-2 has evolved during the pandemic as seroprevalence in global populations has increased. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the coronavirus disease 2019 (COVID-19) serology literature and construct updated best practice guidance related to SARS-CoV-2 serologic testing. This guideline is an update to the fourth in a series of rapid, frequently updated COVID-19 guidelines developed by IDSA. OBJECTIVE: To develop evidence-based recommendations and identify unmet research needs pertaining to the use of anti-SARS-CoV-2 antibody tests for diagnosis, decisions related to vaccination and administration of monoclonal antibodies or convalescent plasma in immunocompromised patients, and identification of a serologic correlate of immunity. METHODS: A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists and experts in systematic literature reviewed, identified, and prioritized clinical questions related to the use of SARS-CoV-2 serologic tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. RESULTS: The panel recommends against serologic testing to diagnose SARS-CoV-2 infection in the first two weeks after symptom onset (strong recommendations, low certainty of evidence). Serologic testing should not be used to provide evidence of COVID-19 in symptomatic patients with a high clinical suspicion and repeatedly negative nucleic acid amplification test results (strong recommendation, very low certainty of evidence). Serologic testing may assist with the diagnosis of multisystem inflammatory syndrome in children (strong recommendation, very low certainty of evidence). To seek evidence for prior SARS-CoV-2 infection, the panel suggests testing for IgG, IgG/IgM, or total antibodies to nucleocapsid protein three to five weeks after symptom onset (conditional recommendation, low certainty of evidence). In individuals with previous SARS-CoV-2 infection or vaccination, we suggest against routine serologic testing given no demonstrated benefit to improving patient outcomes (conditional recommendation, very low certainty of evidence.) The panel acknowledges further that a negative spike antibody test may be a useful metric to identify immunocompromised patients who are candidates for immune therapy. CONCLUSIONS: The high seroprevalence of antibodies against SARS-CoV-2 worldwide limits the utility of detecting anti-SARS CoV-2 antibody. The certainty of available evidence supporting the use of serology for diagnosis was graded as very low to low. Future studies should use serologic assays calibrated to a common reference standard.

WHO's essential medicines and AWaRe: recommendations on first- and second-choice antibiotics for empiric treatment of clinical infections.

The WHO Model List of Essential Medicines (EML) prioritizes medicines that have significant global public health value. The EML can also deliver important messages on appropriate medicine use. Since 2017, in response to the growing challenge of antimicrobial resistance, antibiotics on the EML were reviewed and categorized into three groups: Access, Watch and Reserve, leading to a new categorization called AWaRe. These categories were developed taking into account the impact of different antibiotics and classes on antimicrobial resistance, and the implications for their appropriate use. The 2023 AWaRe classification provides empiric guidance on 41 essential antibiotics for over 30 clinical infections targeting both the primary health care and hospital facility setting. A further 257 antibiotics not included on the EML have been allocated an AWaRe group for stewardship and monitoring purposes. This article describes the development of AWaRe focussing on the clinical evidence base that guided the selection of Access, Watch or Reserve antibiotics as first and second choices for each infection. The overarching objective was to offer a tool for optimising the quality of global antibiotic prescribing and reduce inappropriate use by encouraging the use of Access antibiotics (or no antibiotics) where appropriate. This clinical evidence evaluation and subsequent EML recommendations are the basis for the AWaRe antibiotic book and related smartphone applications. By providing guidance on antibiotic prioritization, AWaRe aims to facilitate the revision of national lists of essential medicines, update of national prescribing guidelines and surveillance of antibiotic use. Adherence to AWaRe would extend the effectiveness of current antibiotics while helping countries to expand access to these life-saving medicines for the benefit of current and future patients, health professionals, and the environment.

Risk factors for recognized and unrecognized SARS-CoV-2 infection: a seroepidemiologic analysis of the Prospective Urban Rural Epidemiology (PURE) study.

There are limited data on individual risk factors for SARS-CoV-2 infection (including unrecognized infection). In this seroepidemiologic substudy of an ongoing prospective cohort study of community-dwelling adults, participants were thoroughly characterized pre-pandemic. The SARS-CoV-2 infection was ascertained by serology. Among 8,719 participants from 11 high-, middle-, and low-income countries, 3,009 (35%) were seropositive for SARS-CoV-2. Characteristics independently associated with seropositivity were younger age (odds ratio, OR; 95% confidence interval, CI, per five-year increase: 0.95; 0.91-0.98) and body mass index >25 kg/m2 (OR, 95% CI: 1.16, 1.01-1.34). Smoking (as compared with never smoking, OR, 95% CI: 0.83, 0.70-0.97) and COVID-19 vaccination (OR, 95% CI: 0.70, 0.60-0.82) were associated with a reduced risk of seropositivity. Among seropositive participants, 83% were unaware of having been infected with SARS-CoV-2. Seropositivity and a lack of awareness of infection were more common in lower-income countries. The COVID-19 vaccination reduces the risk of SARS-CoV-2 infection (including recognized and unrecognized infections). Overweight or obesity is an independent risk factor for SARS-CoV-2 infection. Infection and lack of infection awareness are more common in lower-income countries.IMPORTANCEIn this large, international study, evidence of SARS-CoV-2 infection was obtained by testing blood specimens from 8,719 community-dwelling adults from 11 countries. The key findings are that (i) the large majority (83%) of community-dwelling adults from several high-, middle-, and low-income countries with blood test evidence of SARS-CoV-2 infection were unaware of this infection-especially in lower-income countries; and (ii) overweight/obesity predisposes to SARS-CoV-2 infection, while COVID-19 vaccination is associated with a reduced risk of SARS-CoV-2 infection. These observations are not attributable to other individual characteristics, highlighting the importance of the COVID-19 vaccination to prevent not only severe infection but possibly any infection. Further research is needed to understand the mechanisms by which overweight/obesity might increase the risk of SARS-CoV-2 infection.

More Than a Decade Since the Latest CONSORT Non-inferiority Trials Extension: Do Infectious Diseases Trials Do Enough?

More than a decade after the Consolidated Standards of Reporting Trials group released a reporting items checklist for non-inferiority randomized controlled trials, the infectious diseases literature continues to underreport these items. Trialists, journals, and peer reviewers should redouble their efforts to ensure infectious diseases studies meet these minimum reporting standards.

Conduct and reporting of multivariate network meta-analyses: a scoping review.

OBJECTIVES: Combining multivariate and network meta-analysis methods simultaneously in a multivariate network meta-analysis (MVNMA) provides the methodological framework to analyze the largest amount of evidence relevant to decision-makers (i.e., from indirect evidence and correlated outcomes). The objectives of this scoping review were to summarize the characteristics of MVNMAs published in the health sciences literature and map the methodological guidance available for MVNMA. STUDY DESIGN AND SETTING: We searched MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature from inception to 28 August 2023, along with citations of included studies, for quantitative evidence syntheses that applied MVNMA and articles addressing MVNMA methods. Pairs of reviewers independently screened potentially eligible studies. Collected data included bibliographic, methodological, and analytical characteristics of included studies. We reported results as total numbers, frequencies, and percentages for categorical variables and medians and interquartile ranges for continuous variables that were not normally distributed. RESULTS: After screening 1,075 titles and abstracts, and 112 full texts, we included 38 unique studies, of which, 10 were quantitative evidence syntheses that applied MVNMA and 28 were articles addressing MVNMA methods. Among the 10 MVNMAs, the first was published in 2013, four used studies identified from already published systematic reviews, and eight addressed pharmacological interventions, which were the most common interventions. They evaluated interventions for metastatic melanoma, colorectal cancer, prostate cancer, oral hygiene, disruptive behavior disorders, rheumatoid arthritis, narcolepsy, type 2 diabetes, and overactive bladder syndrome. Five MVNMAs analyzed two outcomes simultaneously, and four MVNMAs analyzed three outcomes simultaneously. Among the articles addressing MVNMA methods, the first was published in 2007 and the majority provided methodological frameworks for conducting MVNMAs (26/28, 93%). One study proposed criteria to standardize reporting of MVNMAs and two proposed items relevant to the quality assessment of MVNMAs. Study authors used data from 18 different illnesses to provide illustrative examples within their methodological guidance. CONCLUSIONS: The application of MVNMA in the health sciences literature is uncommon. Many methodological frameworks are published; however, standardization and specific criteria to guide reporting and quality assessment are lacking. This overview of the current landscape may help inform future conduct of MVNMAs and research on MVNMA methods.

The Infectious Diseases Society of America Guidelines on the Diagnosis of Coronavirus Disease 2019 (COVID-19): Molecular Diagnostic Testing.

Accurate molecular diagnostic tests are necessary for confirming a diagnosis of coronavirus disease 2019 (COVID-19) and for identifying asymptomatic carriage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The number of available SARS-CoV-2 nucleic acid detection tests continues to increase as does the COVID-19 diagnostic literature. Thus, the Infectious Diseases Society of America (IDSA) developed an evidence-based diagnostic guideline to assist clinicians, clinical laboratorians, patients, and policymakers in decisions related to the optimal use of SARS-CoV-2 nucleic acid amplification tests. In addition, we provide a conceptual framework for understanding molecular diagnostic test performance, discuss nuances of test result interpretation in a variety of practice settings, and highlight important unmet research needs related to COVID-19 diagnostic testing. IDSA convened a multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review to identify and prioritize clinical questions and outcomes related to the use of SARS-CoV-2 molecular diagnostics. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. The panel agreed on 12 diagnostic recommendations. Access to accurate SARS-CoV-2 nucleic acid testing is critical for patient care, hospital infection prevention, and the public health response to COVID-19 infection. Information on the clinical performance of available tests continues to grow, but the quality of evidence of the current literature to support this updated molecular diagnostic guideline remains moderate to very low. Recognizing these limitations, the IDSA panel weighed available diagnostic evidence and recommends nucleic acid testing for all symptomatic individuals suspected of having COVID-19. In addition, testing is suggested for asymptomatic individuals with known or suspected contact with a COVID-19 case when the results will impact isolation/quarantine/personal protective equipment (PPE) usage decisions. Evidence in support of rapid testing and testing of upper respiratory specimens other than nasopharyngeal swabs, which offer logistical advantages, is sufficient to warrant conditional recommendations in favor of these approaches.

Protocol for a longitudinal cohort study of Lyme disease with physical, mental and immunological assessment.

INTRODUCTION: There are limited data on the longitudinal impact of Lyme disease. Predictors of recovery have not been fully established using validated data collection instruments. There are sparse data on the immunological response to infection over time. METHODS AND ANALYSIS: This study is a longitudinal cohort study that will recruit 120 participants with Lyme disease in Ontario and Nova Scotia, Canada, with follow-up for up to 24 months. Data will be collected using the Short-Form 36 physical and mental component summaries, Depression and Anxiety Severity Scale Questionnaire, Fatigue Severity Scale and a battery of neuropsychological tests. Mononuclear cells, gene expression and cytokine profiling from blood samples will be used to assess immunological response. Analyses will include the use of non-linear mixed-effects modelling and proportional hazards models. ETHICS AND DISSEMINATION: Ethics approval has been obtained from ethics boards at McMaster University (Hamilton Integrated Research Ethics Board) (7564), Queens University (EMD 315-20) and Nova Scotia Health Research Ethics Board (1027173), and the study is enrolling participants. Written informed consent is obtained from all participants. The results will be disseminated by publication in a peer-reviewed journal and presented at a relevant conference. A brief report will be provided to decision-makers and patient groups.

The impact of respiratory infections and probiotic use on the nasal microbiota of frail residents in long-term care homes.

Background: Residents in long-term care homes, who tend to be of advanced age and frail, are at increased risk of respiratory infections. The respiratory microbiota is known to change with age, but whether these changes contribute to the risk of infection is not known. Our goal was to determine how the nasal microbiota of frail older adults changes during symptoms of influenza-like illness (ILI) and how this may be impacted by enrolment in a placebo-controlled trial testing the feasibility of administering a Lactobacillus rhamnosus GG probiotic to prevent respiratory infection (2014-2017). Methods: The microbiome of the nasal (mid-turbinate) of 150 residents of long-term care homes was interrogated using 16S rRNA gene sequencing. Results: We identified a diverse and individualised microbiota which could be separated into nine distinct clusters based on Bray-Curtis distances. Samples collected during symptoms of ILI differed statistically from those collected pre- and post-cold and influenza season, and we observed decreased temporal stability (as measured by movement between clusters) in individuals who experienced ILI compared to those who did not. Conclusions: The use of probiotics decreased ILI-induced changes to the microbiota; however, it is not clear whether this decrease is sufficient to prevent respiratory illness.

Vaccine Effectiveness of non-adjuvanted and adjuvanted trivalent inactivated influenza vaccines in the prevention of influenza-related hospitalization in older adults: A pooled analysis from the Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN).

BACKGROUND: Influenza vaccines prevent influenza-related morbidity and mortality; however, suboptimal vaccine effectiveness (VE) of non-adjuvanted trivalent inactivated influenza vaccine (naTIV) or quadrivalent formulations in older adults prompted the use of enhanced products such as adjuvanted TIV (aTIV). Here, the VE of aTIV is compared to naTIV for preventing influenza-associated hospitalization among older adults. METHODS: A test-negative design study was used with pooled data from the 2012 to 2015 influenza seasons. An inverse probability of treatment (IPT)-weighted logistic regression estimated the Odds Ratio (OR) for laboratory-confirmed influenza-associated hospitalization. VE was calculated as (1-OR)*100% with accompanying 95% confidence intervals (CI). RESULTS: Of 7,101 adults aged ≥ 65, 3,364 received naTIV and 526 received aTIV. The overall VE against influenza hospitalization was 45.9% (95% CI: 40.2%-51.1%) for naTIV and 53.5% (42.8%-62.3%) for aTIV. No statistically significant differences in VE were found between aTIV and naTIV by age group or influenza season, though a trend favoring aTIV over naTIV was noted. Frailty may have impacted VE in aTIV recipients compared to those receiving naTIV, according to an exploratory analysis; VE adjusted by frailty was 59.1% (49.6%-66.8%) for aTIV and 44.8% (39.1%-50.0%) for naTIV. The overall relative VE of aTIV to naTIV against laboratory-confirmed influenza hospital admission was 25% (OR 0.75; 0.61-0.92), demonstrating statistically significant benefit favoring aTIV. CONCLUSIONS: Adjusting for frailty, aTIV showed statistically significantly better protection than naTIV against influenza-associated hospitalizations in older adults. In future studies, it is important to consider frailty as a significant confounder of VE.

Equity issues rarely addressed in the development of COVID-19 formal recommendations and good practice statements: a cross-sectional study.

BACKGROUND AND OBJECTIVE: To identify COVID-19 actionable statements (e.g., recommendations) focused on specific disadvantaged populations in the living map of COVID-19 recommendations (eCOVIDRecMap) and describe how health equity was assessed in the development of the formal recommendations. METHODS: We employed the place of residence, race or ethnicity or culture, occupation, gender or sex, religion, education, socio-economic status, and social capital-Plus framework to identify statements focused on specific disadvantaged populations. We assessed health equity considerations in the evidence to decision frameworks (EtD) of formal recommendations for certainty of evidence and impact on health equity criteria according to the Grading of Recommendations, Assessment, Development, and Evaluations criteria. RESULTS: We identified 16% (124/758) formal recommendations and 24% (186/819) good practice statements (GPS) that were focused on specific disadvantaged populations. Formal recommendations (40%, 50/124) and GPS (25%, 47/186) most frequently focused on children. Seventy-six percent (94/124) of the recommendations were accompanied with EtDs. Over half (55%, 52/94) of those considered indirectness of the evidence for disadvantaged populations. Considerations in impact on health equity criterion most frequently involved implementation of the recommendation for disadvantaged populations (17%, 16/94). CONCLUSION: Equity issues were rarely explicitly considered in the development COVID-19 formal recommendations focused on specific disadvantaged populations. Guidance is needed to support the consideration of health equity in guideline development during health emergencies.

Examining the effect of the COVID-19 pandemic on community virus prevalence and healthcare utilisation reveals that peaks in asthma, COPD and respiratory tract infection occur with the re-emergence of rhino/enterovirus.

INTRODUCTION: Airway disease exacerbations are cyclical related to respiratory virus prevalence. The COVID-19 pandemic has been associated with reduced exacerbations possibly related to public health measures and their impact on non-COVID-19 respiratory viruses. We aimed to investigate the prevalence of non-COVID-19 respiratory viruses during the pandemic compared with prior in Ontario, Canada and healthcare utilisation related to asthma, chronic obstructive pulmonary disease (COPD) and respiratory tract infection. METHODS: This is a population-based retrospective analysis of respiratory virus tests, emergency department (ED) visits and hospitalisations between 2015 and 2021 in Ontario. Weekly virus testing data were used to estimate viral prevalence for all non-COVID-19 respiratory viruses. We plotted the %positivity and observed and expected counts of each virus to visualise the impact of the pandemic. We used Poisson and binomial logistic regression models to estimate the change in %positivity, count of positive viral cases and count of healthcare utilisation during the pandemic. RESULTS: The prevalence of all non-COVID-19 respiratory viruses decreased dramatically during the pandemic compared with prior. Comparing periods, the incidence rate ratio (IRR) for positive cases corresponded to a >90% reduction for non-COVID-19 respiratory viruses except adenovirus and rhino/enterovirus. Asthma-related ED visits and hospital admissions fell by 57% (IRR 0.43 (95% CI 0.37 to 0.48)) and 61% (IRR 0.39 (95% CI 0.33 to 0.46)). COPD-related ED visits and admissions fell by 63% (IRR 0.37 (95% CI 0.30 to 0.45)) and 45% (IRR 0.55 (95% CI 0.48 to 0.62)). Respiratory tract infection ED visits and admissions fell by 85% (IRR 0.15 (95% CI 0.10 to 0.22)), and 85% (IRR 0.15 (95% CI 0.09 to 0.24)). Rather than the usual peaks in disease condition, during the pandemic, healthcare utilisation peaked in October when rhino/enterovirus peaked. CONCLUSIONS: The prevalence of nearly all non-COVID-19 respiratory viruses decreased during the pandemic and was associated with marked reductions in ED visits and hospitalisations. The re-emergence of rhino/enterovirus was associated with increased healthcare utilisation.

Leveraging Influenza Virus Surveillance From 2012 to 2015 to Characterize the Burden of Respiratory Syncytial Virus Disease in Canadian Adults ≥50 Years of Age Hospitalized With Acute Respiratory Illness.

Background: Respiratory syncytial virus (RSV) disease in older adults is undercharacterized. To help inform future immunization policies, this study aimed to describe the disease burden in Canadian adults aged ≥50 years hospitalized with RSV. Methods: Using administrative data and nasopharyngeal swabs collected from active surveillance among adults aged ≥50 years hospitalized with an acute respiratory illness (ARI) during the 2012-2013, 2013-2014, and 2014-2015 influenza seasons, RSV was identified using a respiratory virus multiplex polymerase chain reaction test to describe the associated disease burden, incidence, and healthcare costs. Results: Of 7797 patients tested, 371 (4.8%) were RSV positive (2.2% RSV-A and 2.6% RSV-B). RSV prevalence varied by season from 4.2% to 6.2%. Respiratory virus coinfection was observed in 11.6% (43/371) of RSV cases, with influenza A being the most common. RSV hospitalization rates varied between seasons and increased with age, from 8-12 per 100 000 population in adults aged 50-59 years to 174-487 per 100 000 in adults aged ≥80 years. The median age of RSV cases was 74.9 years, 63.7% were female, and 98.1% of cases had ≥1 comorbidity. Among RSV cases, the mean length of hospital stay was 10.6 days, 13.7% were admitted to the intensive care unit, 6.4% required mechanical ventilation, and 6.1% died. The mean cost per RSV case was $13 602 (Canadian dollars) but varied by age and Canadian province. Conclusions: This study adds to the growing literature on adult RSV burden by showing considerable morbidity, mortality, and healthcare costs in hospitalized adults aged ≥50 years with ARIs such as influenza.

Respiratory protection: what SARS-CoV-2 has taught us.

PURPOSE OF REVIEW: This review summarizes the epidemiological evidence for respiratory personal protective equipment for SARA-CoV-2, a topic of considerable controversy. RECENT FINDINGS: The main findings are that the observational studies and non-coronavirus disease 2019 (COVID-19) randomized trials do not provide clear evidence that the N95 respirators offer superior protection over surgical masks. A randomized controlled trial on COVID-19 provides evidence that the absolute risk to healthcare workers over time using surgical masks is similar to N95 respirators. SUMMARY: The implications of the findings are that surgical masks and N95 respirators can be considered for respiratory protection in healthcare workers.

GloveCare: a pilot study in preparation for a cluster crossover randomized controlled trial of non-sterile glove-based care in preventing late-onset infection in the NICU.

BACKGROUND: Late-onset infections (LOI) are a major cause of morbidity and mortality among patients in the neonatal intensive care unit (NICU). Gloving after hand hygiene may be a pragmatic approach to prevent infections that arise when healthcare workers' hands transmit pathogens to neonates. OBJECTIVE: To determine the feasibility of conducting a multicenter, open-labeled randomized controlled trial (RCT) to determine whether a protocol that requires healthcare workers (HCWs) in a level 3 NICU to wear non-sterile gloves plus hand hygiene reduces the occurrence of a late-onset infection, compared to hand hygiene alone. METHODS: In this single-center pilot study, we recruited neonates admitted to the McMaster Children's Hospital NICU from June 2017 to May 2018. The NICU was randomized to begin with the standard (control) arm for 6 months (June 2017 to Dec 2017), followed by the gloving (GloveCare) arm for 6 months (Jan 2018 to July 2018), with a 2-week washout period in-between to educate healthcare workers about gloving. We measured numerous feasibility outcomes including enrollment, event rate, and compliance with hand hygiene (Moment 1: before patient contact, Moment 2: before clean procedure, Moment 3: after body fluid contact, Moment 4: after patient contact) and gloving compliance. RESULTS: We enrolled 750 neonates (390 Standard care, 360 GloveCare) and achieved 100% enrollment. We found higher hand hygiene compliance during the standard care arm compared to the GloveCare for all four moments of hand hygiene (Moment 1: 87% vs 79%, OR=1.86 (1.34, 2.59); Moment 2: OR=1.73 (1.00, 3.01); Moment 3: OR=1.11 (0.62, 1.98); Moment 4: OR=1.65 (1.27, 2.14)). We developed and validated a method to calculate glove compliance, which ranged from 48 to 85%, and was highest for moment 3 (doffing after a procedure or body fluid exposure risk). No adverse events were documented for patients or staff. DISCUSSION: Reduction in hand hygiene compliance in the GloveCare arm presents a pragmatic challenge in ascertaining the effectiveness of gloving to prevent LOI. Most LOIs were non-sterile-site infections, which is considered a less patient-important or clinically relevant outcome compared to sterile-site LOI. Ensuring efficient collection and validation of hand hygiene and gloving data is imperative. CONCLUSION: The pilot study demonstrated the feasibility of this intervention though modifications to improve hand hygiene compliance during GloveCare will be important prior to a multicenter cluster RCT to assess the efficacy of non-sterile glove-based care in preventing LOI in the NICU. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03078335.

Comparison of three dosing intervals for the primary vaccination of the SARS-CoV-2 mRNA Vaccine (BNT162b2) on magnitude, neutralization capacity and durability of the humoral immune response in health care workers: A prospective cohort study.

OBJECTIVES: The dosing interval of a primary vaccination series can significantly impact on vaccine immunogenicity and efficacy. The current study compared 3 dosing intervals for the primary vaccination series of the BNT162b2 mRNA COVID-19 vaccine, on humoral immune response and durability against SARS-CoV-2 ancestral and Beta variants up to 9 months post immunization. METHODS: Three groups of age- and sex-matched healthcare workers (HCW) who received 2 primary doses of BNT162b2 separated by 35-days, 35-42 days or >42-days were enrolled. Vaccine induced antibody titers at 3 weeks, 3 and 6-9 months post-second dose were assessed. RESULTS: There were 309 age- and sex-matched HCW (mean age 43 [sd 13], 58% females) enrolled. Anti-SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibody titers showed significant waning in levels beyond 35 days post first dose. The second dose induced a significant rise in antibody titers, which peaked at 3 weeks and then declined at variable rates across groups. The magnitude, consistency and durability of response was greater for anti-Spike than anti-RBD antibodies; and for IgG than IgA or IgM. Compared to the shorter schedules, a longer interval of >42 days offered the highest binding and neutralizing antibody titers against SARS-CoV-2 ancestral and Beta (B1.351) variants beyond 3 months post-vaccination. CONCLUSIONS: This is the first comprehensive study to compare 3 dosing intervals for the primary vaccination of BNT162b2 mRNA COVID-19 vaccine implemented in the real world. These findings suggest that delaying the second dose beyond 42 days can potentiate and prolong the humoral response against ancestral and Beta variants of SARS-CoV-2 up to 9 months post-vaccination.

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles: A Systematic Review.

Importance: Randomized clinical trials (RCTs) on COVID-19 are increasingly being posted as preprints before publication in a scientific, peer-reviewed journal. Objective: To assess time to journal publication for COVID-19 RCT preprints and to compare differences between pairs of preprints and corresponding journal articles. Evidence Review: This systematic review used a meta-epidemiologic approach to conduct a literature search using the World Health Organization COVID-19 database and Embase to identify preprints published between January 1 and December 31, 2021. This review included RCTs with human participants and research questions regarding the treatment or prevention of COVID-19. For each preprint, a literature search was done to locate the corresponding journal article. Two independent reviewers read the full text, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2 tool. Time to publication was analyzed using a Cox proportional hazards regression model. Differences between preprint and journal article pairs in terms of outcomes, analyses, results, or conclusions were described. Statistical analysis was performed on October 17, 2022. Findings: This study included 152 preprints. As of October 1, 2022, 119 of 152 preprints (78.3%) had been published in journals. The median time to publication was 186 days (range, 17-407 days). In a multivariable model, larger sample size and low risk of bias were associated with journal publication. With a sample size of less than 200 as the reference, sample sizes of 201 to 1000 and greater than 1000 had hazard ratios (HRs) of 1.23 (95% CI, 0.80-1.91) and 2.19 (95% CI, 1.36-3.53) for publication, respectively. With high risk of bias as the reference, medium-risk articles with some concerns for bias had an HR of 1.77 (95% CI, 1.02-3.09); those with a low risk of bias had an HR of 3.01 (95% CI, 1.71-5.30). Of the 119 published preprints, there were differences in terms of outcomes, analyses, results, or conclusions in 65 studies (54.6%). The main conclusion in the preprint contradicted the conclusion in the journal article for 2 studies (1.7%). Conclusions and Relevance: These findings suggest that there is a substantial time lag from preprint posting to journal publication. Preprints with smaller sample sizes and high risk of bias were less likely to be published. Finally, although differences in terms of outcomes, analyses, results, or conclusions were observed for preprint and journal article pairs in most studies, the main conclusion remained consistent for the majority of studies.

The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Antigen Testing.

BACKGROUND: 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. OBJECTIVE: The 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 non-medical settings. METHODS: 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 April 1, 2022. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. RESULTS: The panel made ten diagnostic recommendations. These recommendations address Ag testing in symptomatic and asymptomatic individuals and assess single versus repeat testing strategies. CONCLUSIONS: U.S. Food and Drug Administration (FDA) SARS-CoV-2 Ag tests with Emergency Use Authorization (EUA) have high specificity and low to moderate sensitivity compared to 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 contrast, Ag tests have high specificity, and, 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 to testing once, but no empirical data were available to inform this question. Based on these observations, rapid RT-PCR or laboratory-based NAAT remains the testing method 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.

Prognostic factors for streptococcal toxic shock syndrome: systematic review and meta-analysis.

OBJECTIVES: To quantify the prognostic effects of demographic and modifiable factors in streptococcal toxic shock syndrome (STSS). DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE and CINAHL from inception to 19 September 2022, along with citations of included studies. ELIGIBILITY CRITERIA: Pairs of reviewers independently screened potentially eligible studies of patients with Group A Streptococcus-induced STSS that quantified the association between at least one prognostic factor and outcome of interest. DATA EXTRACTION AND SYNTHESIS: We performed random-effects meta-analysis after duplicate data extraction and risk of bias assessments. We rated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: One randomised trial and 40 observational studies were eligible (n=1918 patients). We found a statistically significant association between clindamycin treatment and mortality (n=144; OR 0.14, 95% CI 0.06 to 0.37), but the certainty of evidence was low. Within clindamycin-treated STSS patients, we found a statistically significant association between intravenous Ig treatment and mortality (n=188; OR 0.34, 95% CI 0.15 to 0.75), but the certainty of evidence was also low. The odds of mortality may increase in patients ≥65 years when compared with patients 18-64 years (n=396; OR 2.37, 95% CI 1.47 to 3.84), but the certainty of evidence was low. We are uncertain whether non-steroidal anti-inflammatory drugs increase the odds of mortality (n=50; OR 4.14, 95% CI 1.13 to 15.14; very low certainty). Results failed to show a significant association between any other prognostic factor and outcome combination (very low to low certainty evidence) and no studies quantified the association between a prognostic factor and morbidity post-infection in STSS survivors. CONCLUSIONS: Treatment with clindamycin and within clindamycin-treated patients, IVIG, was each significantly associated with mortality, but the certainty of evidence was low. Future research should focus on morbidity post-infection in STSS survivors. PROSPERO REGISTRATION NUMBER: CRD42020166961.