In September 1665, plague was inadvertently transported from London to Eyam in Derbyshire on a consignment of cloth. This small country village subsequently became famous for its decision to instate a 'cordon sanitaire', isolating itself to prevent the disease from spreading. Much of Eyam's population perished during that torrid period. Eyam: Plague Village follows the local rector, the Revd William Mompesson, as he tries to support his parishioners and contain the disease. Basing his account closely on the known facts, David Paul describes the events during this time in the village's history from the perspectives of the rector, his wife Catherine, and the fictional character of Beth Hounsfeild, Catherine's cousin.

On 1 November 1666 farm worker Abraham Morten gasped his final breath - the last of 260 people to die from bubonic plague in the remote Derbyshire village of Eyam. Their fate had been sealed four months earlier when the entire village made the remarkable decision to quarantine itself in an heroic attempt to halt the spread of the Great Plague. This is the story of the villagers who refused to run.

Viral Dynamics

NEJM Journal Watch September 11, 2020

More Evidence of Protective Immunity After COVID-19

Thomas Glück, MD reviewing Addetia A et al. J Clin Microbiol 2020 Aug 21

During a COVID-19 outbreak on a fishing vessel, individuals with neutralizing anti–SARS-CoV-2 antibodies prior to exposure did not get infected.

Most COVID-19 patients develop neutralizing antibodies against SARS-CoV-2. Whether such antibodies make them immune to SARS-CoV-2 infection is unclear, especially after reports of patients who appeared to have contracted SARS-CoV-2 twice within a few weeks. Now, an observational study of a COVID-19 outbreak on a fishing vessel with 122 crew members (113 men and 9 women) sheds some light on this issue.

Investigators took nasopharyngeal swabs for reverse transcription polymerase chain reaction (RT-PCR) testing and blood for serological testing from 120 of the 122 crew members ≤2 days before departure. All of these individuals had negative RT-PCR results, but the SARS-CoV-2 antibody screening test was reactive in six of them. On day 18 of the trip, the ship had to return to shore after one crew member developed RT-PCR–confirmed SARS-CoV-2 infection and required hospitalization. Subsequently, all other crew members underwent RT-PCR testing, and 114 provided samples for serology.

During a median follow-up of 32.5 days, 101 crew members tested positive for SARS-CoV-2 by RT-PCR. Most of these crew members also seroconverted, as did 3 of the 21 with negative RT-PCR results, resulting in an 85% attack rate on board. Sequencing of 39 samples confirmed that the outbreak stemmed from a single viral clade. Of the six crew members with predeparture reactive antibody screening tests, only three actually showed neutralizing antibodies with typical postinfection titers. None of these individuals tested positive for SARS-CoV-2, while the other three developed RT-PCR–confirmed infection, yielding an 88% infection rate in individuals without neutralizing antibodies (P<0.002).

COMMENT

These results add to the growing evidence that the presence of neutralizing antibodies is protective immunity against SARS-CoV-2 infection. This notion is of major importance for the evaluation of vaccine-induced immune responses. Furthermore, the high infection rate among individuals lacking neutralizing antibodies questions the hypothesis that cross-reactive immunity caused by prior infection with other coronaviruses might be protective.

Lancet Infectious Diseases, September 11, 2020

SARS-CoV-2 transmission via speech-generated respiratory droplets

Adriaan Bax, et al

Many of the claimed points in support of airborne transmission of SARS-CoV-2 by the authors have other explanations.

Speech-generated acoustic waves involve high-speed passage of air, pressurised by the lungs, past the mucosal epithelial layers of the vibrating vocal folds. The sounds generated are further modulated by travel of this air through narrow passages between the tongue, lips, and teeth, dislodging oral fluid at all of these locations. Emission of droplets is inextricably linked to the physics of speech generation and unlikely to differ much from one individual to another. All speakers spit. Fortunately, when exiting the mouth, such droplets are still fairly large and easily blocked from entering the atmosphere by a generic cloth mask. Even in a quiescent environment, droplet nuclei require many minutes to descend to the bottom of the box. The extent to which dehydrated speech droplets can travel before reaching the ground in real-life situations depends crucially on factors such as air convection and ventilation. Physics dictates that air movement will carry such particles over considerable distances, fully analogous to the dispersion of cigarette smoke throughout a room.

The medical community has long acknowledged infection via speech-generated respiratory droplets, including droplet nuclei that might stay airborne for an extended time. The importance of symptomless transmission of SARS-CoV-2 (ie, in the absence of coughing or sneezing), whether retrospectively identified as asymptomatic, presymptomatic, or even oligosymptomatic, has also been well established. With high viral titres in the oral fluid of such carriers well documented and a substantial proportion of speech droplets of oral fluid now shown to remain airborne for many minutes, inhalation of such particles represents a direct route to the nasopharynx. Retrospective analyses of indoor superspreader events further support the role of speech droplets in airborne transmission.

NEJM Journal Watch, September 9, 2020

Evidence for Recurrent SARS-CoV-2 Infection

Stephen G. Baum, MD reviewing To KK-W et al. Clin Infect Dis 2020 Aug 25

Isolation of a different strain of SARS-CoV-2 from a patient who recovered from COVID-19 4 months earlier indicates one can be infected at least twice.

From the onset of this horrific coronavirus pandemic, questions have arisen about potential for reinfection. Now, investigators in Hong Kong report findings on a person with an apparent second SARS-CoV-2 infection.

The 33-year-old, ostensibly immunocompetent male, living in Hong Kong, had laboratory-confirmed COVID-19 in March 2020. Symptoms included productive cough, sore throat, fever, and headache. He was hospitalized, recovered, and was discharged 2 weeks later following two negative SARS-CoV-2 nasopharyngeal and throat swabs. Four and one half months later, entry screening upon his return to Hong Kong from Spain via the U.K. was positive for SARS-CoV-2. He was and remained asymptomatic but had slightly elevated C-reactive protein.

Laboratory testing of serum specimens collected 10 days after first-episode onset and 1 day after second-episode hospitalization were negative for SARS-CoV-2–specific immunoglobulin G, but testing from second-episode day 5 was positive for SARS-CoV-2 IgG. Whole-genome sequencing showed that the viruses belonged to different clades. Differences resided in areas coding for the spike protein and for some nonstructural and accessary proteins. The first viral genome was related to strains from the U.S. and England in March and April 2020, and the second genome to strains from Switzerland and England isolated in July and August.

COMMENT

This report — particularly the differing genetics of the virus isolates — provides the strongest evidence so far that one can be infected with SARS-CoV-2 more than once, within a relatively short timeframe. The development of antibodies after the second infection supports new infection rather than colonization. The first infection was mild, and other evidence has shown that antibody titers may be lower in these cases. These findings should not be surprising; no one would be shocked if a person recovering from an influenza was later infected with strain that underwent antigenic drift. As the authors point out, we should, when we have a vaccine, inoculate those who have recovered from mild SARS-CoV-2 infection.

Clinical Infectious Diseases (accepted for publication)

Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain

Jan Van Elslande, et al

In March 2020, a 51-year-old woman presented with symptoms of headache, fever, myalgia, coughing, chest pain and dyspnea. She also mentioned anosmia and a change in taste. She was not immunocompromised, but took a daily dose of inhaled corticosteroids for asthma. A nasopharyngeal swab tested positive with SARS-CoV-2 PCR. Oxygen saturation by capillary oximeter was 94%. Hospitalisation was not deemed necessary at the time and the patient was asked to self quarantine for 2 weeks. Because of persisting symptoms of tiredness, muscle pains and dyspnea, she stayed at home for 5 weeks before returning to work.

Three months after initial onset of symptoms, she experienced a relapse of symptoms with headache, cough and fatigue. Rhinitis was also present. There was no travel history. The patient’s symptoms were similar to the first episode in March, although milder. The nasopharyngeal swab was again positive for SARS-CoV-2, suggesting a reinfection. The symptoms resolved after one week. At that time, the patient tested positive for anti-SARS-CoV-2 nucleocapsid antibodies. Full-length genome sequencing revealed that the initial infection was caused by a lineage B.1.1 SARS-CoV-2 virus and the relapsing infection by a lineage A. Eleven mutations were identified across the genome of the two strains (11/29903 differences, 99.7% identity). This difference is in line with other circulating strains in Belgium.

The fact that a symptomatic reinfection with SARS-CoV-2 can occur already 3 months after the first infection is not unexpected. Symptomatic reinfections with human non-SARS coronaviruses are common and not atypical within 1 year after initial infection, despite the presence of antibodies. Reinfections with human non-SARS coronaviruses are, however, typically milder as was the case in our patient. The fact that clinical reinfection can occur shortly after the first infection further underlines the fact that both healthcare workers and patients who had a prior SARS-CoV-2 infection are not always protected against re-infection.

JAMA Pediatrics, September 14, 2020

Frequency of Children vs Adults Carrying Severe Acute Respiratory Syndrome Coronavirus 2 Asymptomatically

Gregorio P. Milani, et al

In this study conducted among individuals hospitalized in Milan, one of the cities with the highest SARS-CoV-2 burden in the world, about 1% of children and 9% of adults without any symptoms or signs of SARS-CoV-2 infection tested positive for the virus. It has been estimated that approximately 80% of adults with SARS-CoV-2 are asymptomatic. The few available reports on children are from China and suggest that children who are asymptomatic might be 15% of individuals positive for SARS-CoV-2. In this study, children without symptoms and signs of SARS-CoV-2 carried the virus less frequently than adults, suggesting that their role as facilitators of the spreading of SARS-CoV-2 infection could be reconsidered.

Pathophysiology

JAMA September 10, 2020

Racial/Ethnic Variation in Nasal Gene Expression of Transmembrane Serine Protease 2 (TMPRSS2)

Supinda Bunyavanich, et al

This study of nasal epithelial gene expression in a racially/ethnically diverse cohort showed significantly higher expression of TMPRSS2 in Black individuals compared with other self-identified races/ethnicities. Given the essential role of TMPRSS2 in SARS-CoV-2 entry, higher nasal expression of TMPRSS2 may contribute to the higher burden of COVID-19 among Black individuals. TMPRSS2 inhibitors such as camostat mesylate are undergoing clinical trials to test their utility for COVID-19 treatment. The finding of racial/ethnic variation in TMPRSS2 expression emphasizes that inclusion of diverse participants and analyses stratified by race/ethnicity should be incorporated into such trials.

Although this study suggests one factor that may partially contribute to COVID-19 risk among New York–area Black individuals, many additional factors are likely, especially because gene expression and race/ethnicity reflect multiple social, environmental, and geographic factors.

The result of this study also does not explain the high mortality among old people and men compared to young individuals and women.

Coronavirus disease 2019 (COVID-19) has disproportionately affected communities of color. In many areas of the US, infection and death rates for COVID-19 are 2 to 3 times higher in Black individuals than their proportion of the population. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spread by airway contact and uses transmembrane serine protease 2 (TMPRSS2) to facilitate viral entry and spread. Host-expressed TMPRSS2 on nasal and bronchial epithelium activates the SARS-CoV-2 spike protein and cleaves the angiotensin-converting enzyme 2 receptor to which the virus binds, enabling SARS-CoV-2 to enter the body.

Racial/ethnic differences in TMPRSS2 gene–related activity in prostate tissue have been associated with disproportionately higher incidence of prostate cancer in Black men vs White men. Recognizing that many factors contribute to COVID-19 health disparities, we investigated TMPRSS2 nasal gene expression in a racially/ethnically diverse cohort.

This cross-sectional study used nasal epithelium collected during 2015-2018 from individuals within the Mount Sinai Health System (New York, New York). Healthy individuals and individuals with asthma aged 4 to 60 years underwent nasal brushing for research on asthma biomarkers.

The cohort (n = 305) was 8.2% Asian individuals, 15.4% Black individuals, 26.6% Latino individuals, 9.5% individuals of mixed race/ethnicity, and 40.3% White individuals. Of the participants, 48.9% were male and 49.8% had asthma.

There were no significant associations between TMPRSS2 expression and sex, age, or asthma.

Public Health

JAMA Network Open September 11, 2020

Assessment of Mental Health of Chinese Primary School Students Before and After School Closing and Opening During the COVID-19 Pandemic

Lei Zhang, et al

This longitudinal cohort study investigated psychological symptoms, nonsuicidal self-injury, and suicidal ideation, plans, and attempts among a cohort of children and adolescents before the outbreak started (wave 1, early November 2019) and 2 weeks after school reopening (wave 2, mid-May 2020) in an area of China with low risk of COVID-19.

A total of 1241 students participated in the 2 waves of the survey (mean [SD] age, 12.6 [1.4] years; age range, 9.3-15.9 years; 736 [59.3%] male). A total of 729 fathers (58.7%) had a lower secondary education level, and 325 (26.2%) and 187 (15.1%) had higher secondary and tertiary levels, respectively. A total of 102 children (8.2%) resided in households with a monthly disposable income of US $288 or fewer.

The preliminary findings were consistent with a recent systematic review suggesting the association between enforced social isolation imposed by disease containment measures with future mental health problems among children and adolescents.

Epidemiology

CEBM September 9, 2020

Declining COVID-19 Case Fatality Rates across all ages: analysis of German data

Jason Oke, et al

This analysis shows that the fatality rate from COVID-19 has declined in all age groups, and the older age groups drive the overall reduction.

Germany has experienced a lower CFR than other similar European countries, something which has been attributed to higher rates of testing and more confirmed cases.

The figure below shows the trend (log scale) in cases and deaths since week 10 (week commencing 3rd March) till week 35 (week ending 31st August). In the early phase of the pandemic, deaths in Germany mirrored cases, but the recent trend is for cases to increase whilst deaths continue to decline.

Crude estimates of the CFR over time show that for people aged 80 and over the average CFR was 29% up to week 18, fell to 17% in weeks 19 to 27, and for mid-July onwards the CFR was 11% – a decrease of 61%.

A larger decrease is seen in the ages 60-79 with average CFR ~ 9% in March/April falling to 2% in July August.

More granular estimates of CFR trends that take account of the lag between cases and deaths provide similar patterns with a steep decline from early April and levelling off in the summer months. This analysis shows that the fatality rate from COVID-19 has declined in all age groups, and the older age groups drive the overall reduction.

Given German CFRs were low to start within the older age groups, it is likely in countries with higher CFRs at the outset, the effect could be more extensive.

Future work will focus on whether this pattern continues as we go into the Autumn and Winter and seek to address these issues in other countries, and further understand the reasons for these patterns.

JAMA September 14, 2020

Change in Donor Characteristics and Antibodies to SARS-CoV-2 in Donated Blood in the US, June-August 2020

Roger Y. Dodd, et al

This study found that, after the introduction of antibody testing, the proportion of first-time donors increased, and donations from younger and racial and ethnic minority donors were more likely to be reactive. In addition, reactivity rates increased with time. This increase may be due to donors with higher rates of prior exposure donating to obtain antibody test results, particularly first-time donors, but may also reflect increased exposure in the general population or increased recognition of the need for convalescent plasma.

NEJM Journal Watch, September 9, 2020

Estimating Population SARS-CoV-2 Infection Rates Across the U.S.

Carlos del Rio, MD reviewing Havers FP et al. JAMA Intern Med 2020 Jul 21 Brown TS and Walensky RP. JAMA 2020 Jul 21

A seroprevalence study conducted between March and May 2020 suggests that less than 10% of the population had been infected; however, the study's estimated population prevalences were much greater than the number of cases reported at all sites.

Knowing what percentage of the population has been infected with SARS-CoV-2 is important during the pandemic, yet relying on only reported cases likely underestimates the true prevalence of infection. Using residual blood samples from two commercial laboratories, investigators from the Centers for Disease Control and Prevention studied the prevalence of antibodies to SARS-CoV-2 in 10 geographic regions of the U.S. with known community transmission to estimate the seroprevalence between March 23 and May 12, 2020.

Of 16,025 sera samples tested, 55.2% were from women and 36.5% from individuals 65 years and older. Seroprevalence ranged from 1% in the San Francisco Bay area in late April to 6.9% in New York City metro area in late March. Seroprevalence did not vary significantly by age or sex. The investigators conclude that the likely number of SARS-CoV-2 infections ranges from 6 times more than reported in Connecticut to 24 times more in the Minneapolis-St. Paul area.

COMMENT

Based on these findings and those from other studies, the true number of SARS-CoV-2 infections in the U.S. is likely at least 10 times the number reported. As much of the country experienced a substantial increase in infections after the study was done, a repeat study probably would find that a much higher percent of the population has been infected. However, as the authors of an accompanying editorial point out, even though this estimate is much higher than the formally reported infection rate, it still falls short of the estimated 60% to 70% rate required for herd immunity.

NEJM Journal Watch, September 10, 2020

Risk Factors for Return Visits After ED Discharge in Patients with COVID-19

Lauren M. Westafer, DO, MPH, MS reviewing Kilaru AS et al. Acad Emerg Med 2020 Aug 27

Age ≥60 years, abnormal chest radiograph, hypoxemia, and fever may portend higher risk for a return visit after emergency department discharge.

Many patients evaluated for suspected or confirmed COVID-19 can be discharged from the emergency department (ED). However, little is known about return visits following discharge. Researchers retrospectively evaluated return admissions within 72 hours among 1419 adult patients with confirmed COVID-19 who were discharged from five EDs in Pennsylvania and New Jersey between March 1 and May 28, 2020.

Overall 8.6% of patients returned to the ED within 72 hours. Nearly 5% of patients were admitted to the hospital within 72 hours of the index visit and 8.2% of patients were admitted within 7 days. In adjusted analyses, factors associated with increased odds of admission were age ≥60 years (compared with <40 years; odds ratio, 4.6), oxygen saturation <95% on ED arrival (OR, 2.9), fever (OR, 2.4), and abnormal chest radiograph (OR, 2.4). In an analysis of the 117 patients who returned to the ED within 7 days, age ≥40 years, history of hypertension, and obesity were also associated with increased odds of return admission.

COMMENT

In this study, 1 in 12 patients with COVID-19 required hospital admission within the week after an initial ED discharge. These results underscore the importance of risk stratifying patients for discharge (the threshold for which may change as healthcare systems become strained) and may help identify patients who should take extra precautions (e.g., measuring home pulse oximetry). Fortunately, many of the risk factors identified seem valid and are readily available: older age, hypoxemia, fever, and abnormal chest radiograph.

Annals of Internal Medicine September 2, 2020

Infection Fatality Ratios for COVID-19 Among Noninstitutionalized Persons 12 and Older: Results of a Random-Sample Prevalence Study

Justin Blackburn, et al

For seniors in Indiana, the COVID-19 infection fatality ratio was 2.5 times higher than the estimated fatality ratio for seasonal influenza, according to a study in the Annals of Internal Medicine. The 0.6% mortality rate calculated by others for SARS-CoV-2-exposed individuals is 6 times higher than the 0.1% usually cited for seasonal influenza. But given the overestimation of commonly accepted influenza mortality rates due to failure to take asymptomatic infections into account, SARS-CoV-2 can be seen to be not 6 times, or 2.5 times, but at least 10 times as lethal as seasonal flu.

Researchers estimated nearly 190,000 cumulative infections from a population-based statewide sample. They calculated a COVID-19 infection fatality ratio of 0.26% among noninstitutionalized residents aged 12 and older. Infection fatality ratios were higher among those aged 60 and older (1.71%) and non-whites (0.59%). The infection fatality ratio among those aged 65 and older for seasonal influenza, the authors report, is 0.8%.

The Authors calculated the IFR by age, race, sex, and ethnicity on the basis of the cumulative number of confirmed COVID-19 deaths as of 29 April 2020, divided by the number of infections. Although nursing home residents were not tested, they represented 54.9% of Indiana's deaths. Thus, they excluded nursing home residents from all calculations (that is, deaths and infections). To account for all infections, they added the number of patients hospitalized with COVID-19 during the testing period and noninstitutionalized COVID-19 deaths into the denominator.

As of 29 April 2020, Indiana had recorded 1099 COVID-19 deaths, 495 of which occurred in noninstitutionalized persons. This random-sample study estimated 187 802 cumulative infections, to which 180 hospitalizations were added. The average age among all COVID-19 decedents was 76.9 years (SD, 13.1). The overall noninstitutionalized IFR was 0.26%. In order of magnitude, the demographic-stratified IFR varied most by age, race, ethnicity, and sex. Persons younger than 40 years had an IFR of 0.01%; those aged 60 or older had an IFR of 1.71%. Whites had an IFR of 0.18%; non-Whites had an IFR of 0.59%.

Of note, the IFR for non-Whites is more than 3 times that for Whites, despite COVID-19 decedents in that group being 5.6 years younger on average.

Clinical Practice and Innovations in Care Delivery

NEJM Catalyst, September 11, 2020

Economic and Clinical Impact of Covid-19 on Provider Practices in Massachusetts

Zirui Song, et al

A survey of health care providers reveals significant adverse effects on the ability to serve patients and sustain the practice. Without policy solutions and financial support, practice sales and closures may be imminent.

“I have never until now feared for my practice’s viability. I don’t think any amount of financial assistance will get us to pre-Covid-19 operation levels. The amount of renovation needed to make the space safe for that volume is not possible.” — Family Medicine practice

“The pandemic was worse than tsunami. I lack words to describe how precariously my business has suffered since the Covid-19. I have lost my whole life savings and would need at least $350,000 to stand again.” — Home Care practice

“We are working twice as hard, for half the result. It is exhausting and disheartening. Everyone, providers and staff, is burning out.” — Endocrine practice

“I continue to pay for office space that I can’t use. Now I have to pay for a telemedicine service also, in order to provide video sessions for my patients. Because I’m simultaneously homeschooling my daughter, I can’t work as many hours. My husband was furloughed so we’re desperate financially. Without assistance from the PPP loan my practice would have to close.” — Clinical Psychology practice

“The advent of Covid-19 has decimated our practice as the majority of our behavioral health consultants to the nursing homes have been restricted from entry. Telehealth services are made difficult as the average age of our population is 85 and they reside in LTC facilities. Sadly, many of our patients have died from Covid, which will likely result in the loss of customers as nursing facilities close and consolidate.” — Geriatric Psychiatry practice

“The pandemic has caused tremendous uncertainty and threatened to end primary care as we know it. We are doing our part to take the best care of our patients that we can and keep sick patients out of ERs, hospitals, and other health care settings, but we are not being compensated enough to keep our practice open. Our patients would suffer tremendously if we cannot stay open.” — Family Medicine practice

“As ophthalmologists, this has been a disaster. Telehealth is not an option. Elective surgery is not permitted. We have very high fixed costs. Our income will be in negative numbers unless we close practice or file for bankruptcy. Even if we open fully, hard to know when patients will return. I am truly torn as to what to do. I love my patients, staff, and fellow doctors but can’t afford to take on more debt to continue. We are no different than the thousands of other businesses that have and will continue to fail as this pandemic plays out.” — Ophthalmology practice

“Covid has destroyed my practice. I used to think that healthcare was the safest field to be in as it would always be needed no matter how the rest of the economy was. This belief has been shattered. My practice has evaporated. Patients have been terrified and will not seek medical care unless they are dying.… Haircutters are reopened yet neurosurgery cannot do surgeries that are not life-threatening. Many other states are already allowing elective procedures but not Massachusetts. Medicare is also not supportive as I submitted an application for the accelerated payment program but it is in limbo as they stopped paying those for no obvious reason. My emergency disaster loan still never completed processing either. I used to feel important to the community and now I am superfluous.” — Neurosurgery practice

Summary of Key Findings

• Study population: Respondents included 398 practices across specialties in Massachusetts, from small independent private practices to large provider organizations, over 50 days from May 20 through July 9, 2020.
• Workforce: Cumulatively, 21% of nonclinical staff, 23% of nurses/other clinical staff, and 11% of nurse practitioners or physician assistants were reportedly furloughed or laid off due to Covid-19. Fewer physicians were out of practice.
• Patient visits: In-person visits declined by 44% after March 2020, driven by fewer visits to primary care and specialty practices, with less than half of this decline substituted by telehealth visits. Telehealth substitution for in-person visits was more complete in behavioral health. Health systems experienced less of a decline in in-person visits.
• Clinical activity: About 60%–80% of procedures, imaging, tests, and referrals were canceled or deferred in primary care, specialty practices, and those other than behavioral health.
• Telehealth capacity: Practices on average reported reaching about two-thirds of their full capacity for telehealth, led by behavioral health, health systems, and primary care.
• Revenues and expenses: Practice revenues declined more than did practice expenses after Covid-19. Independent practices reported larger percent reductions in revenues relative to expenses (42% reduction in revenues vs. 18% reduction in expenses among independent primary care practices) than did non-independent practices.
• Practice responses: More than 60% of practices reported they would cut salaries of providers or employees, cut services or other operating expenses, and furlough or lay off more employees without additional financial assistance, with a roughly 40% likelihood of following through. Consolidation, selling, or closing the practice were reported by 20%–40% of practices, driven by independent practices such as primary care (60% noted closure at 21% likelihood).
• Payment preferences: Going forward, smaller practices preferred pure fee-for-service to alternative payment models including global payment, while larger practices had a stronger preference for global payment. Independent behavioral health and specialist providers were more likely to clearly prefer pure fee-for-service, while primary care providers viewed global payment more favorably relative to pure fee-for-service than did other providers. Practices not infrequently reported a strong preference for pure fee-for-service over alternative models despite reporting economic peril caused by the decline in visits and utilization.
• Stories: Respondents offered anecdotes of patient impact, personal impact, practice impact, and more, such as the following: “We are working twice as hard, for half the result. It is exhausting and disheartening. Everyone, providers and staff, is burning out” and “I have never until now feared for my practice’s viability. I don’t think any amount of financial assistance will get us to pre-Covid-19 operation levels. The amount of renovation needed to make the space safe for that volume is not possible.”

NEJM Catalyst, September 11, 2020

The Covid-19 Pandemic Accelerates the Transition to Virtual Care

James Robinson, et al

Kaiser Permanente responded to the Covid-19 pandemic by expanding existing and developing new virtual care modalities. Prior to the pandemic, virtual care consisted primarily of secure e-mail messaging, e-visits, telephone calls, and video visits with the patient’s primary care physician, nurse practitioner, or specialty care physician, all linked to the patient’s electronic medical record. With the onset of the pandemic, Kaiser Permanente developed a Covid-19 landing page on its main website, launched a patient self-assessment tool, and expanded e-visits to give guidance on Covid-19–related symptoms. By the week of July 12, Kaiser Permanente in Southern California was experiencing 681,000 virtual encounters per week, of which 11% were related to Covid-19 infection. Virtual encounters increased from 38% of total ambulatory visits in February to a peak of 87% at the end of April and then settled to 77% in the middle of July.

The Covid-19 pandemic, which dissuaded caregivers from recommending — and patients from seeking — in-person visits, has caused an upsurge of interest in telemedicine and other forms of virtual care nationally. As an integrated health care system that encompasses a health plan, hospitals, and eight independent and physician-led Permanente Medical Groups, Kaiser Permanente has the economic incentive and the organizational capacity to promote virtual modalities for many forms of primary and specialty care. Already in February 2020, before the onset of the Covid-19 pandemic, virtual modalities accounted for 38% of total ambulatory care encounters in the Southern California region. In response to the pandemic, the organization expanded its virtual modalities from telephone visits, video visits, and secure email to include a specially designed e-visit for Covid-19 and the creation of a new Covid-19 online patient self-assessment.

The trends reported here are from a large integrated delivery system with its own payer arm; there may be variations in experiences at physician practices and provider organizations that are less integrated with health plans. Several studies and surveys from non-integrated physician practices report dramatic reductions in total ambulatory care and patient access, with only very modest increases in virtual visits.1-4

In marked contrast, during this difficult period at Kaiser Permanente in Southern California, while total weekly encounters reached a low of 591,000 in April, the July 12 level of 883,750 exceeds the number of pre–Covid-19 encounters, 829,362. The decline in in-person encounters has been mitigated by the near doubling in virtual care visits.

Virtual care modalities can both supplement and substitute for in-person care. Based on the experience of Kaiser Permanente in Southern California, the keys to physician acceptance and patient adoption include reliable technology platforms, integration points into other care channels and the electronic medical record, and multiple virtual modalities to address patient preference. Virtual care at Kaiser Permanente spanned telephone, video, email, e-visits, and the online self-assessment. All were secure and connected to the patient’s electronic medical record, with the exception of the self-assessment, which was designed to be accessible to nonmembers without electronic records. Covid-19 has accelerated the utilization of virtual modalities. KP SCAL is capitalizing on this momentum to broaden its virtual offerings, including expanding e-visits to include 27 new conditions, in addition to Covid-19.

Prevention

NEJM Journal Watch, September 10, 2020

Masks to Prevent Viral Respiratory Infections

Neil H. Winawer, MD, SFHM reviewing Chou R et al. Ann Intern Med 2020 Jun 24

A literature review sheds light on the paucity of scientifically rigorous studies.

We don't know much about the comparative effectiveness of respiratory protective devices in lowering risk for acquiring COVID-19 or other respiratory diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), influenza, or influenza-like illnesses. Researchers analyzed 39 studies (18 randomized control trials and 21 observational studies) that were conducted in both community and healthcare settings. The results are as follows:

• In no study was the effectiveness of masks for preventing SARS-CoV-2 infection evaluated in a community setting.
• Only two studies (both cohort studies) of masks to prevent SARS-CoV-2 were conducted in healthcare settings, and both had severe limitations.
• Community mask use possibly was associated with lower risk for SARS-CoV-1 infection in observational studies.
• In high- or moderate-risk healthcare settings, observational studies showed that risk for infection with SARS-CoV-1 and MERS-CoV probably was lower with mask use than with nonuse, and N95 masks probably were more effective than surgical masks.
• Randomized trials conducted in community settings to evaluate mask use for preventing influenza or influenza-like illness showed little or no difference between N95 and surgical masks and probably no difference between surgical masks and no masks, but adherence to mask use was low.
• In healthcare settings, N95 and surgical masks were associated with similar risks for acquiring influenza-like illness.
• In no study was reuse or extended use of N95 masks evaluated.

COMMENT

Unfortunately, direct evidence on the comparative effectiveness of masks for preventing SARS-CoV-2 infection is sparse. In healthcare settings, using N95 respirators versus surgical masks might lower risk for SARS-CoV-1 infection, so despite the lack of SARS-CoV-2 studies, continuing this practice makes sense. Universal mask-wearing might well be effective in helping to contain viral transmission (as is suggested by seemingly better control of viral infections in places where mask-wearing is nearly ubiquitous), but it's difficult to study this topic rigorously in a clinical setting. Interestingly, a recent analysis suggests that even when masking doesn't prevent SARS-CoV-2 infection fully, it can lower the viral inoculum and increase the likelihood that infection will be mild or asymptomatic.

Treatment

NEJM Journal Watch, September 9, 2020

Steroids for COVID-19: Debate Continues

Hana M. El Sahly, MD reviewing Jeronimo CMP et al. Clin Infect Dis 2020 Aug 12

A randomized clinical trial failed to demonstrate a clinical benefit of methylprednisolone in hospitalized COVID-19 patients.

The preliminary report from the randomized RECOVERY clinical trial (NEJM JW Infect Dis Sep 2020 and N Engl J Med 2020 Jul 17; [e-pub]) demonstrated that 10 days of dexamethasone resulted in a mortality benefit in hospitalized COVID-19 patients, especially those on mechanical ventilation. Investigators at a referral center in Brazil have now performed a double-blind, randomized, placebo-controlled clinical trial evaluating the efficacy of a 5-day course of methylprednisolone (MP) at reducing the mortality of patients hospitalized with COVID-19.

Of 416 patients randomized, 393 (mean age, 55 years) completed follow-up: 194 in the MP arm and 199 in the placebo arm. No patient received remdesivir, anti-IL-6, or anti-IL-1 agents. The most common comorbidities were diabetes, hypertension, and alcohol use disorder. One third of patients were mechanically ventilated. Mortality at day 28 was 37.1% in the MP group and 38.2% in the placebo group. No between-group differences were apparent in mortality at 7 days or 14 days, viral clearance in the upper airways, or need for mechanical ventilation at 7 days. In a subgroup analysis, day-28 mortality was significantly lower with MP versus placebo among patients older than 60 years of age (46.6% vs. 61.9%).

COMMENT

The findings from this trial stand in contrast to those from RECOVERY. The two trials had several methodologic differences including the corticosteroid agent, the duration of treatment, and study design, with this trial being placebo-controlled and double blinded whereas RECOVERY was open-label and had no matching placebo. Mortality rates in both trials were much higher than have been observed in many U.S. hospitals. Clinicians ideally need a third large clinical trial to help address the dilemma. In the absence of additional data, dexamethasone remains indicated for the management of mechanically ventilated patients with COVID-19.

September 11, 2020

Cardiovascular Magnetic Resonance Findings in Competitive Athletes Recovering From COVID-19 Infection

Saurabh Rajpal, et al

Of 26 competitive athletes, 4 (15%) had CMR findings suggestive of myocarditis and 8 additional athletes (30.8%) exhibited LGE without T2 elevation suggestive of prior myocardial injury. COVID-19–related myocardial injury in competitive athletes and sports participation remains unclear. Cardiac magnetic resonance imaging has the potential to identify a high-risk cohort for adverse outcomes and may, importantly, risk stratify athletes for safe participation because CMR mapping techniques have a high negative predictive value to rule out myocarditis. A recent study by Puntmann et al demonstrated cardiac involvement in a significant number of patients who had recovered from COVID-19. A recent expert consensus article recommended 2-week convalescence followed by no diagnostic cardiac testing if asymptomatic and an electrocardiogram and transthoracic echocardiogram in mildly symptomatic athletes with COVID-19 to return to play for competitive sports. However, emerging knowledge and CMR observations question this recommendation. Cardiac magnetic resonance imaging evidence of myocardial inflammation has been associated with poor outcomes, including myocardial dysfunction and mortality.

Miscellaneous

NEJM Journal Watch, September 9, 2020

COVID-19: AstraZeneca Vaccine Trials Halted / Outcomes in Young Adults / Nosocomial Infection / Childhood Cases Pass Half Million

By Amy Orciari Herman, Edited by Susan Sadoughi, MD

Here are some of the latest developments in COVID-19:

AstraZeneca vaccine trials halted: AstraZeneca has halted all trials of its experimental SARS-CoV-2 vaccine after a participant experienced "an unexplained illness" in a U.K.-based, phase 3 trial, the company has announced. The trials will be paused while an independent panel assesses the vaccine's safety. The New York Times reports that a trial participant developed transverse myelitis, which can be triggered by viruses, but "the timing of this diagnosis, and whether it was directly linked to AstraZeneca's vaccine, is still unknown." The vaccine is a chimpanzee adenovirus-vectored vaccine that expresses SARS-CoV-2 spike protein.

Outcomes in young adults: Of some 3200 U.S. adults aged 18 to 34 hospitalized with COVID-19, 21% required ICU admission, 10% required mechanical ventilation, and 3% died. Over one third of all patients were obese (and 25% overall were morbidly obese), 18% had diabetes, and 16% had hypertension. Morbid obesity, hypertension, and male sex were independent predictors of death or need for mechanical ventilation. Writing in JAMA Internal Medicine, the researchers note that young adults with multiple risk factors for adverse outcomes faced risks similar to middle-aged adults without such risk factors.

Nosocomial infection: Nosocomial infection with SARS-CoV-2 was rare at a Boston hospital during the height of the COVID-19 outbreak in that region, according to a study in JAMA Network Open. The hospital enacted an extensive infection control program that included dedicated COVID-19 units, use of personal protective equipment according to CDC guidance, universal masking, and restricted visitors. Of some 700 COVID-19 cases diagnosed in patients on day 3 or later of hospitalization, just one was considered acquired in the hospital (likely from a presymptomatic visitor). Additionally, among roughly 8400 patients with hospitalizations unrelated to COVID-19 who were tested for SARS-CoV-2 within 14 days after discharge, just one positive case was considered hospital acquired.

Childhood cases pass half million: As of Sept. 3, over 513,000 cases of COVID-19 had been reported in U.S. children, accounting for nearly 10% of all U.S. cases, the American Academy of Pediatrics reported on Tuesday. The hospitalization rate varied widely across locations, from 0.3% in North Dakota to 8.3% in New York City.

NEJM Journal Watch, September 4, 2020

Preventing Problematic Internet Use During the COVID-19 Pandemic

Matthew E. Peters, MD reviewing Király O et al. Compr Psychiatry 2020 Jul

Consensus guidance and practical recommendations for preventing unhealthy use of the Internet and other communication technologies.

Sponsors and Authors: A multinational group of experts in the problematic use of information and communications technology (ICT), who were supported by COST (European Cooperation in Science and Technology)

Background and Objective

Spatial/social distancing, strongly promoted during the COVID-19 pandemic, has led to school closures, work-from-home policies, and legal mandates — resulting in millions of people in isolation. ICT (e.g., computers, smartphones, television) has allowed the dissemination of knowledge and remote social contact. However, this period of heightened ICT use might also encourage out-of-control levels of gambling, viewing pornography, social media use, and shopping. To highlight ways to counteract the risks associated with heightened ICT use, a multinational group of experts has issued consensus guidance.

Key Points

• General recommendations include making an activity schedule, sleeping regularly, being physically active, using relaxation techniques, maintaining relationships, finding ways to be alone if isolated with family or others, and staying knowledgeable about the status of the pandemic.

Guidance specific to ICT use:

• Self-monitoring and regulating one's screen time
• Acting as good role models for children
• Using digital well-being apps, relying on tools other than ICT when possible (e.g., wall clocks)
• Seeking help when needed

COMMENT

Although some of the guidance issued by this consensus panel may feel like simple common sense, it is critical for such recommendations to be as concrete as possible. Although some clinicians routinely ask about ICT use, many do not. During the COVID-19 pandemic, much has been removed from daily life (e.g., job and school attendance, in-person social activities). For many, the time previously spent on these routine activities is now spent using ICT. Prudent clinicians should begin asking about ICT use.

Neuromodulation 27 April 2020

The Use of Non‐invasive Vagus Nerve Stimulation to Treat Respiratory Symptoms Associated With COVID‐19: A Theoretical Hypothesis and Early Clinical Experience

Peter Staats, et al

The gammaCore stimulator is a multiuse, handheld device that delivers electrical stimulation when applied to the skin of the neck. It comes with a control switch that activates low-voltage stimulation at two-minute intervals, with a maximum of 30 stimulations per 24-hour period.

Vagus nerve stimulation has been demonstrated to block production of cytokines in sepsis and other medical conditions. The authors hypothesize that non‐invasive vagus nerve stimulation (nVNS) might provide clinical benefits in patients with respiratory symptoms similar to those associated with COVID‐19.

Information on two case reports was obtained via email correspondence and phone interviews with the patients.

Both patients reported clinically meaningful benefits from nVNS therapy. In case 1, the patient used nVNS to expedite symptomatic recovery at home after hospital discharge and was able to discontinue use of opioid and cough suppressant medications. In case 2, the patient experienced immediate and consistent relief from symptoms of chest tightness and shortness of breath, as well as an improved ability to clear his lungs.

Preliminary observations and a strong scientific foundation suggest that nVNS might provide clinical benefits in patients with COVID‐19 via multiple mechanisms.

There are two presumed mechanisms by which VNS may help patients with respiratory distress due to COVID‐19. First, the smooth muscles found in the walls of bronchi and bronchioles regulate the flow of air into the lungs. Under normal conditions, when greater volumes of air are required by the body, smooth muscle relaxes to dilate the bronchi and bronchioles. When the inflammatory response is dysregulated, bronchoconstriction results, limiting the flow of air to and from the lungs. VNS may inhibit this airway constriction through a parasympathetic‐sympathetic reflex arc, whereby stimulation of an afferent vagal nerve causes an efferent sympathetically mediated release of catecholamines that results in smooth muscle relaxation. This represents an additional benefit of VNS, considering the potential for viruses to induce asthmatic reactions.

The potential for nVNS to decrease cough may be of particular benefit for patients with COVID‐19, as mitigating cough at any stage of the disease is likely to curb transmission.

Evidence indicates that stimulation of the CAP leads to acetylcholine (ACh) binding to α‐7‐nicotinic ACh receptors (α7nAChRs), resulting in reduced production of the inflammatory cytokines tumor necrosis factor (TNF), IL‐1β, and IL‐6.

Multiple studies also demonstrate the ability of nVNS to decrease the level of inflammatory cytokines.