US Pharm. 2021;46(4):8-12.

COVID-19 Pandemic Impacting Global Mental Health

A study conducted at Columbia University Mailman School of Public Health in New York City reports a high global prevalence of both depression and anxiety during the COVID-19 pandemic and shows how implementation of mitigation strategies, including public transportation and school closures and stay-at-home orders impacted such disorders. The results are published in Psychological Medicine.

“Our research found an elevated global prevalence of these mental health issues during COVID-19 and also revealed there was a wide variance in each at the region- and country-level,” said João Castaldelli-Maia, MD, PhD, NIDA-INVEST postdoctoral fellow in the Department of Epidemiology and lead author. “In particular, Asia (most studies came from China) presented lower levels of both anxiety and depression compared with the other regions of the world. Closure of public transportation increased levels of anxiety, whether it was 2 weeks or 4 weeks past the passage of closure enactment, especially in Europe.”

Using an end date of July 29, 2020, the researchers analyzed data from Pubmed, MEDLINE, Web of Science, and medRxiv, among other databases, for depression and anxiety prevalence. They also reviewed the Oxford COVID-19 Government Response Tracker for the containment and closure policies indexes, and the Global Burden of Disease Study for previous levels of depression and anxiety. The World Health Organization database, which includes COVID literature for studies published by the same date, was also used.

In total, 226,638 individuals were assessed within 60 included studies. Global prevalence of both depression and anxiety during the COVID-19 pandemic were 24% and 2%, respectively. Asia, with rates of 18% for each, and China, especially, had the lowest prevalence of both disorders. Regarding the impact of mitigation strategies on mental health—whether it was public transportation closures, school closings, workplace closures, cancellation of public events, or restrictions on gathering—only public transportation closures increased prevalence of anxiety, especially in Europe.

Dr. Castaldelli-Maia and colleagues found a 21% global prevalence of anxiety. A subgroup analysis at the country level showed that China had a lower prevalence of anxiety at 15.5% compared with all other countries at 26%.

“Our study confirms how critical it is to investigate levels of mental health disorders and the possible impacts of social distancing measures on mental health outcomes,” according to Silvia Martins, MD, PhD, associate professor of epidemiology at Columbia Mailman School and senior author. “Mental health concerns should not be viewed only as a delayed consequence of the COVID-19 pandemic but also as a concurrent epidemic.”

Within the subgroup of Asian countries, estimates of depression prevalence ranged from 15% to 20%. When comparing the prevalence of depression in the pre– and post–COVID-19 eras, the estimates ranging from 1.3% to 3.4% are demonstrably larger after the initiation of COVID-19.

Depression was observed among 26% of the population in Europe and among 39% in other non-Asia regions of the world. A further analysis showed that China had a lower prevalence of depression, 16% compared with 29% in other countries.

Novel Coronavirus Circulated Undetected for Months

Using molecular dating tools and epidemiologic simulations, researchers at University of California (UC) San Diego School of Medicine, with colleagues at the University of Arizona and Illumina, Inc., estimate that the SARS-CoV-2 virus was likely circulating undetected for at most 2 months before the first human cases of COVID-19 were described in Wuhan, China, in late December 2019.

Writing in the March 18, 2021, online issue of Science, they also note that their simulations suggest that the mutating virus dies out naturally more than three-quarters of the time without causing an epidemic.

“Our study was designed to answer the question of how long could SARS-CoV-2 have circulated in China before it was discovered,” said senior author Joel O. Wertheim, PhD, associate professor in the Division of Infectious Diseases and Global Public Health at UC San Diego School of Medicine.

“To answer this question, we combined three important pieces of information: a detailed understanding of how SARS-CoV-2 spread in Wuhan before the lockdown, the genetic diversity of the virus in China, and reports of the earliest cases of COVID-19 in China. By combining these disparate lines of evidence, we were able to put an upper limit of mid-October 2019 for when SARS-CoV-2 started circulating in Hubei province.”

Cases of COVID-19 were first reported in late-December 2019 in Wuhan, located in the Hubei Province of central China. The virus quickly spread beyond Hubei. Chinese authorities cordoned off the region and implemented mitigation measures nationwide. By April 2020, local transmission of the virus was under control, but by then, COVID-19 was pandemic, with more than 100 countries reporting cases.

SARS-CoV-2 is a zoonotic coronavirus, believed to have jumped from an unknown animal host to humans. Numerous efforts have been made to identify when the virus first began spreading among humans, based on investigations of early diagnosed cases of COVID-19. The first cluster of cases—and the earliest sequenced SARS-CoV-2 genomes—were associated with the Huanan Seafood Wholesale Market, but study authors say the market cluster is unlikely to have marked the beginning of the pandemic because the earliest documented COVID-19 cases had no connection to the market.

Regional newspaper reports suggest COVID-19 diagnoses in Hubei date back to at least November 17, 2019, suggesting the virus was already actively circulating when Chinese authorities enacted public-health measures.

In the new study, researchers used molecular clock evolutionary analyses to try to home in on when the first, or index, case of SARS-CoV-2 occurred. Molecular clock is a term for a technique that uses the mutation rate of genes to deduce when two or more life forms diverged—in this case, when the common ancestor of all variants of SARS-CoV-2 existed, estimated in this study to as early as mid-November 2019.

Molecular dating of the most recent common ancestor is often interpreted to be synonymous with the index case of an emerging disease. However, said coauthor Michael Worobey, PhD, professor of ecology and evolutionary biology at the University of Arizona, “The index case can conceivably predate the common ancestor—the actual first case of this outbreak may have occurred days, weeks, or even many months before the estimated common ancestor. Determining the length of that ‘phylogenetic fuse’ was at the heart of our investigation.”

Based on this work, the researchers estimate that the median number of persons infected with SARS-CoV-2 in China was less than one until November 4, 2019. Thirteen days later, it was four individuals, and just nine on December 1, 2019. The first hospitalizations in Wuhan with a condition later identified as COVID-19 occurred in mid-December.

The original strain of SARS-CoV-2 became epidemic, the authors write, because it was widely dispersed, which favors persistence, and because it thrived in urban areas where transmission was easier. In simulated epidemics involving less dense rural communities, epidemics went extinct 94.5% to 99.6% of the time.

The COVID-19 virus has since mutated multiple times, with a number of variants becoming more transmissible.

“Pandemic surveillance wasn’t prepared for a virus like SARS-CoV-2,” Dr. Wertheim said. “We were looking for the next SARS or MERS, something that killed people at a high rate, but in hindsight, we see how a highly transmissible virus with a modest mortality rate can also lay the world low.”

Noninvasive Skin Swab Samples Quickly Detect COVID-19

Researchers at the University of Surrey in England have found that noninvasive skin swab samples may be enough to detect COVID-19.

The most widely used approach to testing for COVID-19 requires a polymerase chain reaction (PCR) test, which involves taking a swab of the back of the throat and far inside the nose.

In a paper published by Lancet EClinicalMedicine, chemists from Surrey teamed up with Frimley NHS Trust and the universities of Manchester and Leicester to collect sebum samples from 67 hospitalized patients—30 of whom had tested positive for COVID-19 and 37 who had tested negative. The samples were collected by gently swabbing a skin area rich in sebum—an oily, waxy substance produced by the body’s sebaceous glands—such as the face, neck, or back.

The researchers analyzed the samples by using liquid chromatography mass spectrometry and a statistical modeling technique called partial least-squares discriminate analysis to differentiate between the COVID-19 positive and negative samples.

The Surrey team then found that patients with a positive COVID-19 test had lower lipid levels—or dyslipidemia—than their counterparts with a negative test. The accuracy of the study’s results increased further when medication and additional health conditions were controlled.

Dr. Melanie Bailey, coauthor of the study from the University of Surrey, said, “Unfortunately, the specter of future pandemics is firmly on the top of the agenda for the scientific community. Our study suggests that we may be able to use noninvasive means to test for diseases such as COVID-19 in the future—a development which I am sure will be welcomed by all.”

Matt Spick, coauthor of the study from the University of Surrey, added, “COVID-19 damages many areas of metabolism. In this work, we show that the skin lipidome can be added to the list, which could have implications for the skin’s barrier function, as well as being a detectable symptom of the disease itself.”

Progesterone Therapy May Improve COVID-19 Outcomes in Men

COVID-19 disproportionately affects men compared with women, raising the possibility that a hormone like progesterone may improve clinical outcomes for certain hospitalized men with the disease. New research from Cedars-Sinai in Los Angeles published online in the journal Chest supports this hypothesis.

The pilot clinical trial, involving 40 men, is believed to be the first published study to use progesterone to treat male COVID-19 patients whose lung functions have been compromised by the coronavirus. While the findings are promising, larger clinical trials are needed to establish the potential of this experimental therapy, the investigators said.

The study was prompted by multiple reports that men are at higher risk of mortality and severe illness from COVID-19 than are women, according to Sara Ghandehari, MD, director of Pulmonary Rehabilitation in the Women’s Guild Lung Institute at Cedars-Sinai and principal investigator for the trial.

“As an ICU doctor, I was struck by the gender disparity among COVID-19 patients who were very sick, remained in the hospital, and needed ventilators,” she said. In addition, some published research had indicated that premenopausal women, who generally have higher progesterone levels, had less severe COVID-19 disease than did postmenopausal women, who have lower progesterone levels. While the bodies of both men and women naturally produce progesterone, women produce much more of the hormone during their reproductive years.

Dr. Ghandehari hypothesized that the gender differences in disease outcomes might be due, in part, to a protective effect from female hormones. In particular, preclinical studies elsewhere had pointed to progesterone as having certain anti-inflammatory properties. This finding suggested progesterone might be useful in dampening a sometimes-fatal immune response, known as a cytokine storm, that can worsen lung damage and attack other organs in COVID-19 patients.

For the Cedars-Sinai clinical trial, conducted from April through August 2020, 40 male patients who were hospitalized with moderate-to-severe COVID-19 were randomly assigned to one of two groups. Patients in the control group received the standard medical care at the time for the disease. Patients in the experimental group received standard care plus twice-daily injections of 100 mg of progesterone for 5 days while they were hospitalized. Both groups were assessed daily for 15 days or until they were discharged from the hospital.

The study showed that compared with the control group, patients in the group treated with progesterone scored a median 1.5 points higher on a standard 7-point scale of clinical status after 7 days. The scale ranged from a high of 7 (“not hospitalized, no limitations on activities”) to 1 (“death”). Although the progesterone group overall also had fewer days of hospitalization and a lower need for supplemental oxygen and mechanical ventilation, the differences between the two groups in those specific categories were not statistically significant.

There were no serious adverse events, including life-threatening events, attributable to progesterone administration. There were two deaths, one in each group, during the 15-day study period, neither of which was attributable to progesterone.

“While our findings are encouraging for the potential of using progesterone to treat men with COVID-19, our study had significant limitations,” Dr. Ghandehari said.

She noted the sample size was relatively small and involved mainly white, Hispanic, and obese patients with a moderate burden of comorbidities, which increase the risk for worse outcomes. Further, although the clinical trial was randomized and controlled, it was unblinded—meaning that the investigators, the patients, and the treating physicians knew who received the experimental treatment.

“Further research is necessary in larger, more heterogeneous populations, including postmenopausal women and at other treatment centers, to establish the degree of clinical efficacy and to assess any other potential safety concerns of this treatment approach,” said Dr. Ghandehari, who also is assistant director of the Lung Transplant Program at Cedars-Sinai.

COVID-19 Transmission Rare in Schools With Masking, Distancing, Contact Tracing

Wearing masks, social distancing, and frequent hand-washing have kept in-school COVID-19 transmission low, according to results of a pilot study in Missouri aimed at identifying ways to keep elementary and secondary schools open and safe during the pandemic.

In-school COVID-19 transmission is rare, even among close school contacts of those who test positive for the virus, when schools heed public-health precautions such as mandatory masking, social distancing, and frequent hand-washing, according to results of the pilot study. A close contact is anyone who has been within 6 feet for more than 15 minutes in a 24-hour period with someone infected with COVID-19.

The study is part of a larger, ongoing collaboration involving the CDC, Washington University School of Medicine in St. Louis, the Missouri Department of Health and Senior Services, the Missouri Department of Elementary and Secondary Education, Saint Louis University, the Springfield-Greene and St. Louis counties health departments, and school districts in the St. Louis and Springfield, Missouri, areas.

The findings were published March 19 in the CDC’s journal, Morbidity and Mortality Weekly Report. The Missouri school findings mirror those of schools in other states, demonstrating that COVID-19 prevention efforts can significantly curb the spread of SARS-CoV-2 among students, teachers, and staff.

“This work is imperative because keeping kids in school provides not only educational enrichment but also social, psychological, and emotional health benefits, particularly for students who rely on school-based services for nutritional, physical, and mental health support,” said senior author Johanna S. Salzer, DVM, PhD, a veterinary medical officer with the CDC’s National Center for Emerging and Zoonotic Infectious Diseases.

The pilot study involved 57 schools in the Pattonville School District in St. Louis County and the Springfield Public School District in Greene County in southwest Missouri, as well as two private schools in St. Louis County. All schools in the pilot study required students, teachers, staff, and visitors to wear masks while on campus or buses.

Other safety measures to prevent transmission included a focus on hand hygiene, deep cleaning of facilities, physical distancing in classrooms, daily symptom screenings for COVID-19, installing physical barriers between teachers and students, offering virtual learning options, and increasing ventilation.

For 2 weeks in December, the schools involved in the pilot project notified the research team of students, teachers, and staff who were either infected with COVID-19 or quarantined due to being considered a close contact of someone who had tested positive. In St. Louis, close contacts of students or teachers who had tested positive were placed in quarantine, meaning they were not to leave their homes for 14 days from when last exposed to a positive case. In Springfield, however, some of the close contacts of those who had tested positive were placed in modified quarantine, meaning they could stay in school if they and the infected person were wearing masks when in close contact; in this scenario, the infected person still isolated at home.

Participants in the pilot study included 193 persons across 22 of the 57 schools—37 who tested positive for COVID-19 and 156 of their close contacts. Among participants who were COVID-19 positive, 24 (65%) were students, and 13 (35%) were teachers or staff members. Of the close contacts, 137 (88%) were students, and 19 (12%) were teachers or staff members.

Among the 102 close contacts who agreed to testing for COVID-19 using saliva tests, only two people received positive test results indicating probable school-based SARS-CoV-2 secondary transmission. Further, no outbreaks were identified in participating schools despite the high rates of community spread in December, even among the Springfield schools that followed modified quarantine protocols allowing some close contacts of positive individuals to remain in school.

“Schools can operate safely during a pandemic when prevention strategies are followed,” said one of the study’s leading researchers, Jason Newland, MD, a Washington University professor of pediatrics, who treats patients at St. Louis Children’s Hospital. Dr. Newland led the pilot program with the CDC and has advised multiple school districts in Missouri on plans for reopening schools. “The pilot study demonstrates low transmission in schools and no student-to-teacher transmission—and this was during the height of the pandemic in December, with high rates of community spread,” he said.

Added Randall Williams, MD, director of the Missouri Department of Health and Senior Services, “Schools with proper prevention strategies remain a safe environment for students and teachers during the pandemic.”

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