Naval Medical Center Portsmouth (NMCP) COVID-19 Literature Report #100: Friday, 19 August 2022

Prepared By: Tracy C. Shields, MSIS, AHIP (Ms.; she/her) <tracy.c.shields2.civ@ mail.mil> Naval Medical Center Portsmouth; Library Services, Reference Medical Librarian

Purpose: These reports, which were published twice a week then biweekly from March 2020 until August 2022, were curated collections of current research, special reports, and news regarding the COVID-19 pandemic that may be of interest to medical providers, leadership, and decision makers. All reports are available online at https://nmcp.libguides.com/covidreport. Archived reports are also available through the Medical Heritage Library and BUMED's Office of

Medical History collection at archive.org.

Disclaimer: | am not a medical professional. This document is current as of the date noted above. While | make every effort to find and summarize available data, | cannot cover everything in the literature on COVID-19. Due to the rapid evolution of the literature, | will not update past reports when new information arises; for retracted papers specific to COVID-19,

see the list of retracted papers from Retraction Watch.

TABLE OF CONTENTS An End Has a Start..... 2 Pregnancy and Postpartum Period..... 14 The Big Picture..... 3 Pediatric Population..... 17 COVID-19 Vaccines..... 4 Other Infectious Diseases and Public a8 . Health Threats ..... 23

Transmission, Exposure, and Surveillance . — es

.6 Special Topic: Monkeypox..... 25 Treatments and Management..... 8 References..... 29

Long COVID and Other Post-Infectious Findings..... 11

NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

An End Has a Start Reflecting on the NMCP COVID-19 Literature Reports

The novel coronavirus cases caught my attention early. On 21 January 2020, | asked my fellow medical librarian colleagues on social media about it: "#medlibs: Do you pull together resources (articles, websites, etc) for your patrons on emerging or newsworthy medical topics? For example, new coronovirus [sic] outbreak in China, major new studies. Do you have demand for that sort of thing?"

Only a few people responded and no one really discussed it. Still, my gut told me there was something there, so | set up some literature alerts and kept an eye out for notable news items. In my role as a medical librarian, | had done something similar for 2009 H1N1 pandemic, the 2015 Zika virus outbreak, and other health threats. | assumed it would be more for my personal interest and maybe a few providers might ask for information.

Soon after the World Health Organization declared the novel coronavirus outbreak a pandemic on 11 March 2020, the library's immediate leadership approached me about putting together something that could be disseminated to leaders and decision makers. My initial interest and monitoring morphed into these reports; it was a relatively easy transition.

The first report went out on Tuesday, 31 March 2020 and was only 8 pages (which seemed ridiculously long at the time). Already there were over 165,000 cases of COVID-19 in the United States and the pandemic was barely underway. | thought | would do these reports for a short time — maybe a few months at best — and we would adjust to a new "normal". | was too optimistic by far, even in my pessimism. The reports would span weeks, then months, then years.

Now, two and half years later, this is the last NUCP COVID-19 Literature Report. | compiled the reports, sent to my leadership, and really never knew if anyone read them, if they mattered or made a difference. | kept at it though, and in doing so became an "expert" at covid literature. There are things | wish | didn't know about this disease and pandemic, things | wish | had never seen or read, and so many things | wish had been done differently.

In many ways ending this project is a relief, but it is also bittersweet. This project has consumed untold hours of my professional life and given me a front-row seat to documenting the covid pandemic. It has been a depressing yet invigorating learning experience. It's time | focused on other efforts.

The covid pandemic continues as there are new, emerging, and ongoing threats to public health: monkeypox; polio; Langya virus; climate change and its impact on human health and infectious diseases. | will monitor those events as well — and hope there will not be a need for another set of reports like these.

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

The Big Picture

News in Brief

"CDC unveils streamlined COVID-19 guidance" (CIDRAP).

"A 'staggering' number of people couldn't get care during the pandemic, poll finds" (NPR). CDC

"In an effort to address its missteps during Covid, CDC plans an 'ambitious' agency overhaul" (STAT).

"CDC, under fire, lays out plan to become more nimble and accountable" (WP). Beyond COVID

"Abortion bans complicate access to drugs for cancer, arthritis, even ulcers" (WP).

Journal Articles

MMWR: Summary of Guidance for Minimizing the Impact of COVID-19 on Individual Persons, Communities, and Health Care Systems — United States, August 2022 (19 August 2022)

"What is already known about this topic? High levels of immunity and availability of effective COVID-19 prevention and management tools have reduced the risk for medically significant illness and death.

What is added by this report? To prevent medically significant COVID-19 illness and death, persons must understand their risk, take steps to protect themselves and others with vaccines, therapeutics, and nonpharmaceutical interventions when needed, receive testing and wear masks when exposed, receive testing if symptomatic, and isolate for 25 days if infected.

What are the implications for public health practice? Medically significant illness, death, and health care system strain can be reduced through vaccination and therapeutics to prevent severe illness, complemented by use of multiple prevention methods to reduce exposure risk and an emphasis on protecting persons at high risk for severe illness."

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

COVID-19 Vaccines News in Brief

"Pending regulatory approval, Pfizer/BioNTech's Omicron-specific COVID vaccine could be ready to roll out as soon as October, BioNTech announced" (Medpage; see also: BioNTech press release).

"What's behind the FDA's controversial strategy for evaluating new COVID boosters" (NPR).

"A complicated fall vaccine campaign: Updated Covid boosters, flu shots, and how to time the jabs" (STAT).

Journal Articles

Cell Rep Med: Multiple BCG vaccinations for prevention of COVID-19 and other infectious diseases in Type 1 diabetes (15 August 2022)

"There is a need for safe and effective platform vaccines to protect against COVID-19 and other infectious diseases. In this randomized, double-blinded, placebo-controlled Phase 2/3 trial, we evaluate the safety and efficacy of multi-dose Bacillus Calmette-Guerin (BCG) vaccine for prevention of COVID-19 and other infectious disease in a COVID-19- unvaccinated, at-risk-community-based cohort. The at-risk population are adults with type 1 diabetes. We enrolled 144 subjects and randomized 96 to BCG and 48 to placebo. There were no drop-outs over the 15-month trial. A cumulative incidence of 12.5% of placebo- treated and 1% of BCG-treated participants meets criteria for confirmed COVID-19, yielding an efficacy of 92%. The BCG group also displays fewer infectious disease symptoms and lesser severity, and fewer infectious disease events per patient, including COVID-19. There were no BCG-related systemic adverse events. BCG’s broad-based infection protection suggests that it may provide platform protection against new SARS-CoV-2 variants and other pathogens."

JAMA Netw Open: Health Care Utilization in the 6 Months Following SARS-CoV-2 Infection (12 August 2022)

"Question: Is SARS-CoV-2 associated with health care utilization 6 months after the acute stage of infection?

Findings: In this cohort study of 127 859 patients with positive SARS-CoV-2 test results matched to 127 859 patients with negative SARS-CoV-2 test results, health care utilization was elevated in patients with positive SARS-CoV-2 results 6 months after the acute infection. Other than COVID-19 and infectious disease sequelae, the most notable post—

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

COVID-19 conditions associated with elevated health care utilization over 6 months included alopecia (hair loss), bronchitis, pulmonary embolism or deep vein thrombosis, and dyspnea.

Meaning: These findings suggest that health care systems should consider long-term strategic resource allocation in response to the expected elevated health care utilization experienced by patients with SARS-CoV-2 infection for at least 6 months following the acute stage of infection."

JAMA Ophthalmol: COVID-19 Vaccination Rates Among US Adults With Vision or Hearing Disabilities (11 August 2022)

"Question: What is the prevalence of COVID-19 vaccination among US adults with vision or hearing disabilities?

Findings: In this cross-sectional study of 916 085 participants, adults with blindness were less likely to initiate COVID-19 vaccination compared with adults with little to no vision impairment. Adults with deafness were also less likely to initiate the COVID-19 vaccination compared with adults with little to no hearing impairment.

Meaning: The findings suggest that, compared with adults without vision or hearing impairment, COVID-19 vaccination rates were lower among adults with vision or hearing disabilities, and additional research may be needed to monitor COVID-19 vaccination disparities among this population."

JAMA Netw Open: Durability of Heterologous and Homologous COVID-19 Vaccine Boosts (10 August 2022)

"Question: What is the durability of humoral and cellular immune responses in individuals who originally received the BNT162b2 vaccine and were boosted with Ad26.COV2.S or BNT162b2?

Findings: In this cohort study of 68 adults, both Ad26.COV2.S and BNT162b2 were associated with increased humoral and cellular immune responses. Boosting with Ad26.COV2.S was associated with durable antibody and T-cell responses for at least 4 months.

Meaning: A heterologous mix-and-match vaccine strategy was associated with durable antibody and T-cell responses against the SARS-CoV-2 Omicron variant."

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

Vaccine: COVID-19 vaccine hesitancy cannot fully explain disparities in vaccination coverage across the contiguous United States (08 August 2022)

"Vaccine hesitancy has been identified as a major obstacle preventing comprehensive coverage against the COVID-19 pandemic. However, few studies have analyzed the association between ex-ante vaccine hesitancy and ex-post vaccination coverage.

This study leveraged one-year county-level data across the contiguous United States to examine whether the prospective vaccine hesitancy eventually translates into differential vaccination rates, and whether vaccine hesitancy can explain socioeconomic, racial, and partisan disparities in vaccine uptake. A set of structural equation modeling was fitted with vaccine hesitancy and vaccination rate as endogenous variables, controlling for various potential confounders.

The results demonstrated a significant negative link between vaccine hesitancy and vaccination rate, with the difference between the two continuously widening over time. Counties with higher socioeconomic statuses, more Asian and Hispanic populations, more elderly residents, greater health insurance coverage, and more Democrats presented lower vaccine hesitancy and higher vaccination rates. However, underlying determinants of vaccination coverage and vaccine hesitancy were divergent regarding their different associations with exogenous variables. Mediation analysis further demonstrated that indirect effects from exogenous variables to vaccination coverage via vaccine hesitancy only partially explained corresponding total effects, challenging the popular narrative that portrays vaccine hesitancy as a root cause of disparities in vaccination.

Our study highlights the need of well-funded, targeted, and ongoing initiatives to reduce persisting vaccination inequities."

Transmission, Exposure, and Surveillance

News in Brief

"How much virus does a person with COVID exhale? New research has answers" (Nature). Opinion: "PCR testing can help clarify confusion over Covid-19 rebound and isolation" (STAT). "When you have covid, here's how you know you are no longer contagious" (WP).

"Tens of thousands of people exposed to bat coronaviruses each year" (Nature).

"How many animal species have caught COVID? First global tracker has (partial) answers" (NPR).

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

Journal Articles

JAMA Netw Open: Awareness of SARS-CoV-2 Omicron Variant Infection Among Adults With Recent COVID-19 Seropositivity (17 August 2022)

"Question: What proportion of individuals who recently contracted the SARS-CoV-2 Omicron variant were aware of their infectious status?

Findings: In this cohort study of 210 adults with evidence of seroconversion during a regional Omicron variant surge, 56% reported being unaware of any recent Omicron variant infection.

Meaning: Findings of this study suggest that low rates of Omicron variant infection awareness may be a key contributor to rapid transmission of the virus within communities."

JAMA Netw Open: Risk of SARS-CoV-2 Acquisition in Health Care Workers According to Cumulative Patient Exposure and Preferred Mask Type (15 August 2022)

"In this follow-up study, we analyzed the SARS-CoV-2 risk for HCWs depending on cumulative exposure to patients with COVID-19 and assessed whether this risk can be modulated by the use of respirator compared with surgical masks....

In this study, SARS-CoV-2 positivity in HCWs was associated with cumulative COVID-19 patient exposure. The odds of being SARS-CoV-2—positive were reduced by more than 40% in individuals using respirators irrespective of cumulative exposure, even after adjusting for multiple work- and nonwork-related covariables."

MMWR: COVID-19 Self-Test Data: Challenges and Opportunities — United States, October 31, 2021—June 11, 2022 (12 August 2022)

"What is already known about this topic? COVID-19 self-test use has increased but reporting of results is not required.

What is added by this report? During October 31, 2021—June 11, 2022, 10.7 million test results were voluntarily reported by users of four manufacturers’ self-tests; during that period, 361.9 million laboratory-based and point-of-care test results were reported. Completeness of reporting demographic variables and trends in percent positivity were similar across test types.

What are the implications for public health practice? Self-tests are a valuable risk-reduction tool that can guide individual actions, but they currently offer limited utility in enhancing public health surveillance. Laboratory-based and point-of-care test result data, in combination with other COVID-19 surveillance information, continue to provide strong situational awareness."

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

Treatments and Management News in Brief

"COVID rebound is surprisingly common — even without Paxlovid" (Nature).

Journal Articles

JAMA Intern Med: Clinical and Genetic Risk Factors for Acute Incident Venous Thromboembolism in Ambulatory Patients With COVID-19 (18 August 2022)

"Question: What is the 30-day acute risk of venous thromboembolism (VTE) among ambulatory patients with COVID-19, and what are the clinical and genetic risk factors predisposing them to developing post—COVID-19 VTE?

Findings: In this retrospective cohort study of 18 818 outpatients with COVID-19 and 93 179 propensity score—matched noninfected participants, a higher VTE incidence was observed in the former (hazard ratio, 21.42); however, this risk was considerably attenuated among the fully vaccinated, after breakthrough infection. Older age, male sex, obesity, no vaccination or partial vaccination, and inherited thrombophilia were independent risk factors for COVID-19-—associated VTE.

Meaning: The results of this study suggest that ambulatory patients with COVID-19, either vaccinated or not, present a clinically relevant increased risk of incident VTE during the acute phase, with the risk pronounced by factors of older age, male sex, obesity, incomplete vaccination, and factor V Leiden thrombophilia."

JAMA Netw Open: Institutional Surgical Response and Associated Volume Trends Throughout the COVID-19 Pandemic and Postvaccination Recovery Period (18 August 2022)

"Question: How did surgical volumes change with respect to subspecialty and patient acuity during the COVID-19 pandemic, and did they recover after the peak and vaccine release periods?

Findings: In this cohort study, a retrospective analysis of 129 956 records of weekly surgical procedures from January 6, 2019, to December 31, 2021, revealed that the overall volume did not fully recover to pre—COVID-19 levels well into 2021. Recovery rates were inconsistent across surgical subspecialties and case classes.

Meaning: Further research and hospital-level changes are needed to address the backlog of surgical services and muted recovery of surgical procedures to pre—COVID-19 volumes."

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

NEJM: Randomized Trial of Metformin, lvermectin, and Fluvoxamine for Covid-19 (18 August 2022)

"BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.

METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2- by-3 factorial design to test the effectiveness of three repurposed drugs — metformin, ivermectin, and fluvoxamine — in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (<93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications.

RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [Cl], 0.66 to 1.09; P=0.19) with metformin, 1.05 (95% Cl, 0.76 to 1.45; P=0.78) with ivermectin, and 0.94 (95% Cl, 0.66 to 1.36; P=0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% Cl, 0.35 to 0.94) with metformin, 1.39 (95% Cl, 0.72 to 2.69) with ivermectin, and 1.17 (95% Cl, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% Cl, 0.20 to 1.11) with metformin, 0.73 (95% Cl, 0.19 to 2.77) with ivermectin, and 1.11 (95% Cl, 0.33 to 3.76) with fluvoxamine.

CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19."

JAMA: Association of COVID-19 vs Influenza With Risk of Arterial and Venous Thrombotic Events Among Hospitalized Patients (16 August 2022)

"Question: Is the 90-day incidence of arterial thromboembolism and venous thromboembolism higher in patients hospitalized with COVID-19 vs in patients hospitalized with influenza?

Findings: In this retrospective cohort study that included 93 906 patients, hospitalization with COVID-19 before vaccine availability and during vaccine availability was significantly

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

associated with higher 90-day risk of venous thromboembolism (adjusted hazard ratios, 1.60 and 1.89, respectively) vs hospitalization with influenza in 2018-2019, but there was no significant difference in the risk of arterial thromboembolism among those hospitalized with COVID-19 during either period (adjusted hazard ratios, 1.04 and 1.07) vs those hospitalized with influenza.

Meaning: Hospitalization with COVID-19 both before and during vaccine availability was significantly associated with a higher risk of venous thromboembolism, but not arterial thromboembolism, vs hospitalization with influenza in 2018-2019."

Emerg infect Dis: Rapid Increase in Suspected SARS-CoV-2 Reinfections, Clark County, Nevada, USA, December 2021 (15 August 2022)

"Genetic differences between SARS-CoV-2 variants raise concerns about reinfection. Public health authorities monitored the incidence of suspected reinfection in Clark County, Nevada, USA, during March 2020-March 2022. Suspected reinfections, defined as a second positive PCR test collected >90 days after an initial positive test, were monitored through an electronic disease surveillance system.

We calculated the proportion of all new cases per week that were suspected reinfections and rates per 1,000 previously infected persons by demographic groups. The rate of suspected reinfection remained <2.7% until December 2021, then increased to =11%, corresponding with local Omicron variant detection. Reinfection rates were higher among adults 18-50 years of age, women, and minority groups, especially persons identifying as American Indian/Alaska Native. Suspected reinfection became more common in Clark County after introduction of the Omicron variant, and some demographic groups are disproportionately affected. Public health surveillance could clarify the SARS-CoV-2 reinfection burden in communities."

JAMA Netw Open: Virologic Efficacy of Casirivimab and Imdevimab COVID-19 Antibody

Combination in Outpatients With SARS-CoV-2 Infection: A Phase 2 Dose-Ranging Randomized Clinical Trial (15 August 2022)

"Question: Can casirivimab and imdevimab effectively reduce the viral load of SARS-CoV-2 with lower doses and a subcutaneous route of administration?

Findings: In this phase 2 randomized clinical trial of outpatients with SARS-CoV-2, all casirivimab and imdevimab doses and routes of administration showed statistically significant and comparable reductions in viral load through day 7 vs placebo in those who were seronegative at baseline.

Meaning: These findings, combined with the results from additional studies examining clinical efficacy, justify lowering the dose of casirivimab and imdevimab from 2400 mg to

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

1200 mg and suggest that subcutaneous administration is a viable alternative to intravenous administration."

Clin Infect Dis: Readmissions, post-discharge mortality and sustained recovery among patients admitted to hospital with COVID-19 (08 August 2022)

"Background: Many interventional in-patient COVID-19 trials assess primary outcomes through day 28 post-randomization. Since a proportion of patients experience protracted disease or relapse, such follow-up period may not fully capture the course of the disease, even when randomization occurs a few days after hospitalization.

Methods: Among adults hospitalized with COVID-19 in Eastern Denmark from March 18, 2020 - January 12, 2021 we assessed: all-cause mortality, recovery and sustained recovery 90 days after admission, and readmission and all-cause mortality 90 days after discharge. Recovery was defined as hospital discharge and sustained recovery as recovery and alive without readmissions for 14 consecutive days.

Results: Among 3,386 patients included in the study 2,796 (82.6%) reached recovery and 2,600 (77.0%) achieved sustained recovery. Of those discharged from hospital, 556 (19.9%) were readmitted, and 289 (10.3%) died. Overall, the median time to recovery was 6 days (Interquartile range (IQR), 3-10), and 19 days (IQR, 11-33) among patients in intensive care in the first two days of admission.

Conclusions: Post-discharge readmission and mortality rates were substantial. Therefore, sustained recovery should be favored to recovery outcomes in clinical COVID-19 trials. A 28- day follow-up period may be too short the critically ill."

Long COVID and Other Post-Infectious Findings News in Brief "Long-COVID treatments: why the world is still waiting" (Nature).

"It's not just long COVID — Society has been underestimating the long-term consequences of viruses, bacterial infections, and parasites for ages" (Atlantic).

"Risk of 'brain fog' and other conditions persists up to two years after Covid infection" (STAT).

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

Journal Articles

Lancet Psychiatry: Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients (17 August 2022)

"Background: COVID-19 is associated with increased risks of neurological and psychiatric sequelae in the weeks and months thereafter. How long these risks remain, whether they affect children and adults similarly, and whether SARS-CoV-2 variants differ in their risk profiles remains unclear.

Methods: In this analysis of 2-year retrospective cohort studies, we extracted data from the TriNetX electronic health records network, an international network of de-identified data from health-care records of approximately 89 million patients collected from hospital, primary care, and specialist providers (mostly from the USA, but also from Australia, the UK, Spain, Bulgaria, India, Malaysia, and Taiwan). A cohort of patients of any age with COVID-19 diagnosed between Jan 20, 2020, and April 13, 2022, was identified and propensity-score matched (1:1) to a contemporaneous cohort of patients with any other respiratory infection. Matching was done on the basis of demographic factors, risk factors for COVID-19 and severe COVID-19 illness, and vaccination status. Analyses were stratified by age group (age <18 years [children], 18-64 years [adults], and 265 years [older adults]) and date of diagnosis. We assessed the risks of 14 neurological and psychiatric diagnoses after SARS- CoV-2 infection and compared these risks with the matched comparator cohort. The 2-year risk trajectories were represented by time-varying hazard ratios (HRs) and summarised using the 6-month constant HRs (representing the risks in the earlier phase of follow-up, which have not yet been well characterised in children), the risk horizon for each outcome (ie, the time at which the HR returns to 1), and the time to equal incidence in the two cohorts. We also estimated how many people died after a neurological or psychiatric diagnosis during follow-up in each age group. Finally, we compared matched cohorts of patients diagnosed with COVID-19 directly before and after the emergence of the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529) variants.

Findings: We identified 1 487 712 patients with a recorded diagnosis of COVID-19 during the study period, of whom 1 284 437 (185 748 children, 856 588 adults, and 242 101 older adults; overall mean age 42-5 years [SD 21-9]; 741 806 [57-8%] were female and 542 192 [42:2%] were male) were adequately matched with an equal number of patients with another respiratory infection. The risk trajectories of outcomes after SARS-CoV-2 infection in the whole cohort differed substantially. While most outcomes had HRs significantly greater than 1 after 6 months (with the exception of encephalitis; Guillain-Barré syndrome; nerve, nerve root, and plexus disorder; and parkinsonism), their risk horizons and time to equal incidence varied greatly. Risks of the common psychiatric disorders returned to baseline after 1-2 months (mood disorders at 43 days, anxiety disorders at 58 days) and subsequently reached an equal overall incidence to the matched comparison group (mood

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

disorders at 457 days, anxiety disorders at 417 days). By contrast, risks of cognitive deficit (known as brain fog), dementia, psychotic disorders, and epilepsy or seizures were still increased at the end of the 2-year follow-up period. Post-COVID-19 risk trajectories differed in children compared with adults: in the 6 months after SARS-CoV-2 infection, children were not at an increased risk of mood (HR 1:02 [95% Cl 0:94-1:10) or anxiety (1-00 [0-94—1-06]) disorders, but did have an increased risk of cognitive deficit, insomnia, intracranial haemorrhage, ischaemic stroke, nerve, nerve root, and plexus disorders, psychotic disorders, and epilepsy or seizures (HRs ranging from 1-20 [1:09-1:33] to 2:16 [1:46—3-19]). Unlike adults, cognitive deficit in children had a finite risk horizon (75 days) and a finite time to equal incidence (491 days). A sizeable proportion of older adults who received a neurological or psychiatric diagnosis, in either cohort, subsequently died, especially those diagnosed with dementia or epilepsy or seizures. Risk profiles were similar just before versus just after the emergence of the alpha variant (n=47 675 in each cohort). Just after (vs just before) the emergence of the delta variant (n=44 835 in each cohort), increased risks of ischaemic stroke, epilepsy or seizures, cognitive deficit, insomnia, and anxiety disorders were observed, compounded by an increased death rate. With omicron (n=39 845 in each cohort), there was a lower death rate than just before emergence of the variant, but the risks of neurological and psychiatric outcomes remained similar.

Interpretation: This analysis of 2-year retrospective cohort studies of individuals diagnosed with COVID-19 showed that the increased incidence of mood and anxiety disorders was transient, with no overall excess of these diagnoses compared with other respiratory infections. In contrast, the increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout. The differing trajectories suggest a different pathogenesis for these outcomes. Children have a more benign overall profile of psychiatric risk than do adults and older adults, but their sustained higher risk of some diagnoses is of concern. The fact that neurological and psychiatric outcomes were similar during the delta and omicron waves indicates that the burden on the health-care system might continue even with variants that are less severe in other respects. Our findings are relevant to understanding individual-level and population-level risks of neurological and psychiatric disorders after SARS-CoV-2 infection and can help inform our responses to them."

Clin Infect Dis: Symptom burden and immune dynamics 6 to 18 months following mild SARS- CoV-2 infection -a case-control study (12 August 2022)

"Background: The burden and duration of persistent symptoms after non-severe COVID-19

remains uncertain. This study aimed to assess post-infection symptom trajectories in home- isolated COVID-19 cases compared to age- and time-period matched seronegative controls, and investigate immunological correlates of long COVID.

Methods: A prospective case-control study conducted between February 28th and April 4th 2020 included home-isolated COVID-19 cases followed for 12 (n = 233) to 18 (n = 149)

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NMCP COVID-19 Literature Report #100: Friday, 19 August 2022 Tracy C. Shields, MSIS, AHIP (Reference Medical Librarian at Naval Medical Center Portsmouth, Library Services)

months, and 189 age-matched SARS-CoV-2 naive controls. We collected clinical data at baseline, 6, 12 and 18 months post-infection, and blood samples at 2, 4, 6 and 12 months for analysis of SARS-CoV-2 specific humoral and cellular responses.

Results: Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared to controls, adult cases had a high risk of fatigue (27% excess risk, gender and comorbidity adjusted odds ratio [aOR] 5.86, 95% confidence interval [Cl]3.27-10.5), memory problems (21% excess risk, aOR 7.42, Cl 3.51-15.67), concentration problems (20% excess risk, aOR 8.88, Cl 3.88-20.35), and dyspnea (10% excess risk, aOR 2.66, Cl 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%, Cl 1.5, 21.5, p = 0.024) and among women (excess risk 18.7%, Cl 4.4, 32.9, p = 0.010). Longitudinal spike IgG was significantly associated with dyspnea at 12 months. The spike- specific clonal CD4 + TCRB depth was significantly associated with both dyspnea and number of symptoms at 12 months.

Conclusions: This study documents a high burden of persisting symptoms after mild COVID- 19, and suggest that infection induced SARS-CoV-2 specific immune responses may influence long-term symptoms."

Pregnancy and Postpartum Period Journal Articles

Clin Infect Dis: SARS-CoV-2 testing and detection during peripartum hospitalizations among a multi-center cohort of pregnant persons, March 2020—February 2021 (12 August 2022)

"Background: Identifying SARS-CoV-2 infections during peripartum hospitalizations is important to guide care, implement prevention measures, and understand infection burden.

Methods: This cross-sectional analysis used electronic health record data from hospitalizations during which pregnancies ended (peripartum hospitalizations) among a cohort of pregnant persons at 3 U.S. integrated healthcare networks (Sites 1-3). Maternal demographic, medical encounter, SARS-CoV-2 testing, and pregnancy and neonatal outcome information was extracted for persons with estimated delivery and pregnancy end dates during March 2020-February 2021 and 21 prenatal care record. Site-stratified multivariable logistic regression was used to identify factors associated with testing and compare pregnancy and neonatal outcomes among persons tested.

Results: Among 17,858 pregnant persons, 10,863 (60.8%) had peripartum SARS-CoV-2 testing; 222/10,683 (2.0%) had positive results. Testing prevalence varied by site and was

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lower during March-May 2020. Factors associated with higher peripartum SARS-CoV-2 testing odds were Asian race (adjusted odds ratio [aOR]: 1.36; 95% Cl: 1.03-1.79; referent: White) (Site 1), Hispanic or Latina ethnicity (aOR: 1.33; 95% Cl: 1.08-1.64) (Site 2), peripartum Medicaid coverage (aOR: 1.33; 95% Cl: 1.06-1.66) (Site 1), and preterm hospitalization (aOR: 1.69; 95% Cl: 1.19-2.39 [Site 1]; aOR: 1.39; 95% Cl: 1.03-1.88 [Site 2]).

Conclusions: Findings highlight potential disparities in SARS-CoV-2 peripartum testing by demographic and pregnancy characteristics. Testing practice variations should be considered when interpreting studies relying on convenience samples of pregnant persons testing positive for SARS-CoV-2. Efforts to address testing differences between groups could improve equitable testing practices and care for pregnant persons with SARS-CoV-2 infections."

JAMA Netw Open: Comparison of Severe Maternal Morbidities Associated With Delivery During Periods of Circulation of Specific SARS-CoV-2 Variants (12 August 2022)

"Question: Does the association between SARS-CoV-2 infection and severe maternal morbidity (SMM), including nonrespiratory complications, vary by viral strain?

Findings: In this retrospective cohort study of 3129 patients with SARS-CoV-2 infection and 12 504 patients without infection giving birth in a large US health system between March 2020 and January 2022, the risk of SMM associated with SARS-CoV-2 infection was significantly higher during the phase of the pandemic when the Delta variant was predominant (July 2021-November 2021). This association was also noted specifically for both respiratory and nonrespiratory SMM.

Meaning: These findings highlight the importance of the prevention of SARS-CoV-2 infection in pregnant individuals and the consideration of infection as a risk factor for adverse peripartum maternal outcomes."

JAMA Netw Open: Comparison of Pregnancy and Birth Outcomes Before vs During the COVID- 19 Pandemic (12 August 2022)

"Question: Was the COVID-19 pandemic associated with changes in pregnancy-related outcomes?

Findings: In a cohort of more than 1.6 million pregnant patients across 463 US hospitals, the number of live births decreased by 5.2% during the COVID-19 pandemic (March 2020 to April 2021) compared with the 14 months prior. While live-birth outcomes and mode of delivery remained stable, small but significant increases in pregnancy-related complications and maternal death during delivery hospitalization were observed.

Meaning: In this study, the COVID-19 pandemic was associated with increases in pregnancy- related complications and maternal deaths during delivery hospitalization."

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Lancet Infect Dis: Safety of COVID-19 vaccines in pregnancy: a Canadian National Vaccine Safety (CANVAS) network cohort study (11 August 2022)

"Background: Pregnant individuals have been receiving COVID-19 vaccines following pre- authorisation clinical trials in non-pregnant people. This study aimed to determine the frequency and nature of significant health events among pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals.

Methods: We did an observational cohort study, set in seven Canadian provinces and territories including Ontario, Quebec, British Columbia, Alberta, Nova Scotia, Yukon, and Prince Edward Island. Eligibility criteria for vaccinated individuals were a first dose of a COVID-19 vaccine within the previous 7 days; an active email address and telephone number; ability to communicate in English or French; and residence in the aforementioned provinces or territories. Study participants were pregnant and non-pregnant females aged 15-49 years. Individuals were able to participate as controls if they were unvaccinated and fulfilled the other criteria. Data were collected primarily by self-reported survey after both vaccine doses, with telephone follow-up for those reporting any medically attended event. Participants reported significant health events (new or worsening of a health event sufficient to cause work or school absenteeism, medical consultation, or prevent daily activities) occurring within 7 days of vaccination or within the past 7 days for unvaccinated individuals. We employed multivariable logistic regression to examine significant health events associated with MRNA vaccines, adjusting for age group, previous SARS-CoV-2 infection, and trimester, as appropriate.

Findings: As of Nov 4, 2021, 191 360 women aged 15-49 years with known pregnancy status had completed the first vaccine dose survey and 94 937 had completed the second dose survey. 180 388 received one dose and 94 262 received a second dose of an mRNA vaccine, with 5597 pregnant participants receiving dose one and 3108 receiving dose two, and 174 765 non-pregnant participants receiving dose one and 91 131 receiving dose two. Of 6179 included unvaccinated control participants, 339 were pregnant and 5840 were not pregnant. Overall, 226 (4-0%) of 5597 vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227 (7:3%) of 3108 after dose two, compared with 11 (3-2%) of 339 pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event within 7 days of the vaccine after dose two of mRNA-1273 (adjusted odds ratio [aOR] 4-4 [95% Cl 2-4-8-3]) compared with pregnant unvaccinated controls within the past 7 days, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant vaccinated females had decreased odds of a significant health event compared with non-pregnant vaccinated females after both dose one (aOR 0:63 [95% Cl 0-55-0-72]) and dose two (aOR 0:62 [0:54-0-71]) of any MRNA

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vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention.

Interpretation: COVID-19 mRNA vaccines have a good safety profile in pregnancy. These data can be used to appropriately inform pregnant people regarding reactogenicity of COVID-19 vaccines during pregnancy, and should be considered alongside effectiveness and immunogenicity data to make appropriate recommendations about best use of COVID-19 vaccines in pregnancy."

Pediatric Population News in Brief

"Should parents delay kids' second COVID vaccine? Here's what the research says" (Nature).

Journal Articles

Vaccines and Boosters

MMWR: Safety Monitoring of Pfizer-BioNTech COVID-19 Vaccine Booster Doses Among Children Aged 5-11 Years — United States, May 17—July 31, 2022 (19 August 2022)

"What is already known about this topic? A Pfizer-BioNTech COVID-19 vaccine booster dose is recommended for children aged 5—11 years; approximately 657,302 third doses were administered to children in this age group during May—July 2022.

What is added by this report? Among children aged 5—11 years, local and systemic reactions were reported to v-safe with similar frequency after doses 2 and 3; specific reactions differed in severity. Vaccine administration errors were the most common events reported to the Vaccine Adverse Event Reporting System. No reports of myocarditis or death after receipt of dose 3 were received.

What are the implications for public health practice? Among children aged 5—11 years, serious adverse events after dose 3 are rare. Additional provider education might prevent vaccine administration errors."

JAMA Netw Open: Long-term Effectiveness Associated With the BNT162b2 Vaccine Against SARS-CoV-2 Infection Among Adolescents in South Korea (17 August 2022)

"Our results suggest that after vaccination with BNT162b2, the effectiveness of the vaccine against SARS-CoV-2 infection among adolescents waned over time, with limited protection

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observed 30 to 59 days after administration of a second dose of the vaccine. Regardless, our findings suggest an association between the BNT162b2 vaccine and sustained effectiveness against critical SARS-CoV-2 infection, as reported previously."

NEJM: Effectiveness of BNT162b2 Vaccine against Omicron in Children 5 to 11 Years of Age (11 August 2022)

"Background: Since it was first identified in early November 2021, the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread quickly and replaced the B.1.617.2 (delta) variant as the dominant variant in many countries. Data on the real-world effectiveness of vaccines against the omicron variant in children are lacking.

Methods: In a study conducted from January 21, 2022, through April 8, 2022, when the omicron variant was spreading rapidly, we analyzed data on children in Singapore who were 5 to 11 years of age. We assessed the incidences of all reported SARS-CoV-2 infections (confirmed on polymerase-chain-reaction [PCR] assay, rapid antigen testing, or both), SARS- CoV-2 infections confirmed on PCR assay, and coronavirus disease 2019 (Covid-19)-related hospitalizations among unvaccinated, partially vaccinated (21 day after the first dose of vaccine and up to 6 days after the second dose), and fully vaccinated children (27 days after the second dose). Poisson regression was used to estimate vaccine effectiveness from the incidence rate ratio of outcomes.

Results: A total of 255,936 children were included in the analysis. Among unvaccinated children, the crude incidence rates of all reported SARS-CoV-2 infections, PCR-confirmed SARS-CoV-2 infections, and Covid-19-related hospitalizations were 3303.5, 473.8, and 30.0 per 1 million person-days, respectively. Among partially vaccinated children, vaccine effectiveness was 13.6% (95% confidence interval [Cl], 11.7 to 15.5) against all SARS-CoV-2 infections, 24.3% (95% Cl, 19.5 to 28.9) against PCR-confirmed SARS-CoV-2 infection, and 42.3% (95% Cl, 24.9 to 55.7) against Covid-19-related hospitalization; in fully vaccinated children, vaccine effectiveness was 36.8% (95% Cl, 35.3 to 38.2), 65.3% (95% Cl, 62.0 to 68.3), and 82.7% (95% Cl, 74.8 to 88.2), respectively.

Conclusions: During a period when the omicron variant was predominant, BNT162b2 vaccination reduced the risks of SARS-CoV-2 infection and Covid-19-related hospitalization among children 5 to 11 years of age."

Lancet: Vaccine effectiveness of two-dose BNT162b2 against symptomatic and severe COVID-19

among adolescents in Brazil and Scotland over time: a test-negative case-control study (08 August 2022)

"Background: Little is known about vaccine effectiveness over time among adolescents, especially against the SARS-CoV-2 omicron (B.1.1.529) variant. This study assessed the

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associations between time since two-dose vaccination with BNT162b2 and the occurrence of symptomatic SARS-CoV-2 infection and severe COVID-19 among adolescents in Brazil and Scotland.

Methods: We did test-negative, case-control studies in adolescents aged 12-17 years with COVID-19-related symptoms in Brazil and Scotland. We linked records of SARS-CoV-2 RT- PCR and antigen tests to national vaccination and clinical records. We excluded tests from individuals who did not have symptoms, were vaccinated before the start of the national vaccination programme, received vaccines other than BNT162b2 or a SARS-CoV-2 booster dose of any kind, or had an interval between their first and second dose of fewer than 21 days. Additionally, we excluded negative SARS-CoV-2 tests recorded within 14 days of a previous negative test, negative tests recorded within 7 days after a positive test, any test done within 90 days after a positive test, and tests with missing sex and location information. Cases (SARS-CoV-2 test-positive adolescents) and controls (test-negative adolescents) were drawn from a sample of individuals in whom tests were collected within 10 days of symptom onset. We estimated the adjusted odds ratio and vaccine effectiveness against symptomatic COVID-19 for both countries and against severe COVID-19 (hospitalisation or death) for Brazil across fortnightly periods.

Findings: We analysed 503 776 tests from 2 948 538 adolescents in Brazil between Sept 2, 2021, and April 19, 2022, and 127 168 tests from 404 673 adolescents in Scotland between Aug 6, 2021, and April 19, 2022. Vaccine effectiveness peaked at 14-27 days after the second dose in both countries during both waves, and was significantly lower against symptomatic infection during the omicron-dominant period in Brazil (64-7% [95% Cl 63-0- 66-3]) and in Scotland (82:6% [80-6-84-5]), than it was in the delta-dominant period (80:7%