COVID-19 Statistics: Connecticut

As of May 25, 2020

:

Fairfield Statistics:

• Cases per 100,000 population: 1,612
• Total Cases: 15,213
• Current number of patients in hospitals: 233
• Deaths: 1221
• Death Rate: 8.02%

The Arts and Medicine

JAMA, May 21, 2020

Oedipus and the Coronavirus Pandemic

Ryan M. Antiel

I feel defeated by death almost daily amidst the seemingly endless buzz of machines and procedures. Yet, as Berry reminds us, “the world of love includes death, suffers it, and triumphs over it…the world of love continues, and of this grief is the proof.”1 Perhaps one way to prevent medicine from becoming the enemy of its own kindred, as Oedipus inadvertently was to Thebes, is to ensure that love, which wills the good of the other, is present—even in a pandemic, even when supplies are short. Medicine is at its finest when it restores individual patients to the world of love. Seen from this perspective, the work of medicine itself can be an act of love.

Lancet, May 22, 2020

The Art of Medicine Compassion in a Time of COVID-19

Sandro Galea

It is worth reflecting on the extent to which our response to the COVID-19 pandemic has been informed by an understanding that we are all in this together, that the virus does not discriminate, and that as a result it benefits us all to comply with physical distancing guidelines to protect others and ourselves. Our empathy, our capacity to envision that we too could be affected, has been a powerful tool in the public health arsenal. But, in large part, it is hard not to notice that our empathy is informed here, as it often is, by an appreciation of our own personal risk. We feel regret and feel terrible about those who are suffering, in no small part because we can imagine that suffering being our own.

But is it true that this suffering is our own? Is it true that COVID-19 does not discriminate? Evidence is emerging that the effects of COVID-19, far from being indiscriminate, follow deeply entrenched patterns of health inequities, mirroring burdens of disease that are near universal. Those with resources, money, and power, often majority racial or ethnic groups, are better able to physically distance, work from home, and retain their employment. Those same groups then have lower risks of becoming infected or dying from COVID-19, probably reflecting a combination of factors, including better access to health care and a lower underlying burden of morbidity that predisposes to worse COVID-19 outcomes. It turns out that COVID-19 does discriminate, and that those who are already vulnerable—for example, the unstably housed, people on low income, those with poorer education, and individuals with less access to reliable nutritious food—are more likely to both become infected with the virus and die from COVID-19.

And this is where empathy fails. Empathy in the context of health is largely predicated on our appreciating the risks of a disease because we can imagine getting the disease ourselves. When we imagine we can also be infected, we are then willing to take the steps necessary to protect ourselves—and others—from the disease. And that force has been powerful and contributed to the dramatic change in how we live and in a shutdown of large parts of the world's economy, informed by fear of a novel disease and the need to protect ourselves and others around us.

Compassion extends beyond empathy. It does not motivate our action because we too may be harmed. Compassion motivates action because the phenomena we observe are unjust, not worthy of the world we would like to live in. Martin Luther King Jr spoke often of compassion, enjoining us to see that compassion ultimately motivates not to “[fling] a coin to a beggar” but to “see that the edifice which produces beggars needs restructuring”. Compassion pushes us to understand how we have structured the world, and to ask how we can structure it better, not because we may suffer but because others are suffering and that is not how the world should be.

Would our approach to COVID-19 have been different were we accustomed to seeing health through the lens of compassion? I would argue yes. First, we would have long invested in the conditions that make people healthy, aiming to remove the underlying disproportionate burden of preventable illness that accrues to vulnerable populations worldwide. Second, our response to COVID-19 would be informed in equal parts by efforts to contain the spread and to mitigate how the consequences of our efforts to do so can bring about disproportionate harm to those who are removed from the decision making around this pandemic. Third, our response would recognise the global differences that characterise a world that puts the burden of disease squarely on countries with fewer resources, often driven to that condition by centuries of cross-national injustice, and would push us to redouble our efforts to do everything in our power to help those countries, perhaps before our own.

Surely this moment calls for careful reflection and a reinvestment in compassion as a foundational approach to health. Calling attention to compassion in this way is not sentimental. It is pointing out a tangible good, without which health for all is impossible. In a sense, COVID-19 has shown us that a healthy person and a healthy world are the same. And healthy people and a healthy world are both strengthened immeasurably by having compassion at the heart of health.

Editorials, Perspectives, Commentaries and Reflections

JAMA, May 21, 2020

Building an “Army of Disease Detectives” to Trace COVID-19 Contacts

Rita Rubin

Health departments have used contact tracing—the practice of identifying and monitoring people who’ve had close contact with infected individuals—to control communicable diseases such as tuberculosis, syphilis, and HIV infection. But, in terms of the sheer number of cases and the ease with which it spreads, COVID-19 presents special challenges.

Estimates of the number of people needed to conduct COVID-19 contact tracing in the US range from 100 000 to more than 300 000. The higher estimate comes from ASTHO, which assumes that 1 contact tracer will be needed for every 1000 in the population. California is training 20 000 contact tracers over the following 2 months, while New York enlists 6400 to 17 000 contact tracers, depending on the projected number of cases.

Contact tracing involves helping people newly diagnosed with COVID-19 recall everyone with whom they came in close contact (having been within 6 feet of an individual for at least 15 minutes) when they might have been infectious, a period beginning 48 hours before symptoms appear.

Wuhan, with a population of about 11 million, had 1800 teams of epidemiologists, each with at least 5 members, tracing tens of thousands of contacts a day. Obviously tracers need at least a week of training and contacts need social and financial support during 2 weeks of quarantine and isolation.

JAMA, May 21, 2020

Prescribing Paid Sick Leave—An Important Tool for Primary Care During the Pandemic

Benjamin D. Sommers

It is a simple prescription: “Stay home. Tell your boss I told you to, so you can get paid. And get better soon.”

Congress has stepped in to help address this aspect of the pandemic by requiring many employers to provide paid sick leave for any person given medical advice to stay home related to COVID-19 as of April 1, 2020. But this policy only works if patients know about it.

The new federal law, the Families First Coronavirus Response Act, applies to private employers with fewer than 500 workers, as well as most public employers (without regard to employee count). The essence of the law is fairly simple. The employers who are covered by the law must continue to pay employees who (1) have been told by a physician to self-quarantine because they are sick with COVID-19, are suspected of having it, or have a high-risk medical condition, and (2) if they cannot work from home.

Under this new law, employees can obtain paid leave for up to 80 hours, with a maximum of $511 per day, and the federal government will fully pay the employer back with a tax credit. Firms with fewer than 50 workers are also subject to the law, though they can apply for an exemption if providing the leave would threaten the viability of the business. Employees are also eligible for up to 80 hours of paid leave at two-thirds of their pay rate if they are caring for another quarantined individual.

Unfortunately, many individuals, including those working for large employers as well as those working in the healthcare industry, are not eligible for leave under the law. In addition to employees of large companies who do not get paid sick leave under company policy or the new law, some employees of small companies (with fewer than 50 workers) may also be excluded from coverage under the law’s viability exemption.

JAMA, May 22, 2020

Translating Science on COVID-19 to Improve Clinical Care and Support the Public Health Response

Carlos del Rio, et al

Despite enormous progress in understanding COVID-19, there is little evidence that a solution, therapeutic or preventive, is close to being achieved. During the next phase of the pandemic, robust containment strategies will be vital to enter “the new normal” but even then, it may be too risky for some populations such as nursing home residents and other vulnerable groups.

Treatment and Chemoprevention

Currently only remdesivir has received EUA, but several strategies are being used or studied through either clinical trials, expanded access, or single patient emergency investigational new drug application.

Vaccine Development

At this time, more than 100 vaccine candidates are in development and 8 have entered clinical trials in humans. In the US, an mRNA vaccine developed by Moderna through funding from Biomedical Advanced Research and Development Authority (BARDA) has completed phase 1 trials and shown to be safe and immunogenic (NCT04283461). Even if the early candidate vaccines prove immunogenic and safe, it is unlikely that a vaccine will be widely available in less than 24 months.

Antibody Testing

It would be extremely unusual if individuals who recover from COVID-19 do not develop protective antibodies for some time. But current antibody tests should not be used as a sole diagnostic test. Use of serology for public health surveillance has begun with results suggesting variations in seroprevalence depending on geographic location. For example, a recent study in New York City suggested that approximately 20% of the population had been infected with SARS-CoV-2, whereas another study in Santa Clara, California, demonstrated a lower prevalence of between 2.5% and 4.2%.

Herd Immunity

The term herd immunity is often used when considering vaccine preventable infections. Vaccines protect in 2 ways. First, they induce an active immune response in the individual receiving the vaccine to directly protect against exposure to the pathogen. Second, vaccines indirectly prevent transmission of the pathogen to susceptible individuals because the potential for transmission is decreased with the higher the level of vaccine coverage in a population.

Estimates suggested that 60% or more of the population would need to be immune to herd immunity for COVID-19, approximately 200 million individuals in the US. Even at the current pace of new COVID-19 infections in the US. with more than 25 000 confirmed cases a day, it would be well into 2021 before the herd immunity threshold would be reached. If current daily death rates continue, more than half a million US residents would have died from COVID-19 by then. Thus, a strategy relying on herd immunity in absence of a vaccine carries an enormous potential human toll.

Second Wave

The public health landscape of the US is less like a single nation and more like 50 separate countries. The criteria proposed by the White House including a downward trajectory of documented cases within a 14-day period in the setting of a robust testing program has not been met by most states. Thus another wave or waves will be happening except adequate testing capacity will be available in all communities along with resources to safely isolate those who become ill.

NEJM, May 22, 2020

Surgery Scheduling in a Crisis

Michael Argenziano, et al

During the surge and peak phases of the pandemic, a hospital-appointed review committee was formed. Patients whose cases were classified as emergencies or urgent went directly to the OR, but semiurgent cases were evaluated by the committee, which then approved patients for surgery. The committee considered relative clinical urgency and Resource Intensity Classification (RIC)-estimated resource demands. Thus, during resource shortages, certain “high RIC” operations, such as a major hepatectomy, might receive lower priority than operations expected to require fewer resources, such as a colon resection. By mid-April, we were able to simplify the RIC by eliminating resources that were no longer in short supply, such as PPE and ventilators, from assessments.

Our flexible triage system remains relevant as we enter the recovery phase. For the foreseeable future, our rate-limiting resources will be ORs and beds, and the massive backlog of elective cases will pose an even greater challenge. We have therefore relied on a modification to the triage system that involves evaluating cases with a 3×3 matrix, with relative urgency plotted against the indicated procedure’s degree of resource intensity. Each surgical service categorizes its proposed cases on this grid weekly, a protocol that has helped us allocate available resources equitably.

JAMA, May 22, 2020

Nursing Home Care in Crisis in the Wake of COVID-19

David C. Grabowski, et al

Although less than 0.5% of the total US population (approximately 1.5 million people) live in nursing homes, nursing home residents have accounted for approximately 25% of the documented deaths due to COVID-19. Some states (such as Massachusetts and Pennsylvania) and some European countries (such as France and Ireland) have reported that residents of nursing homes account for 50% of the deaths.

Nursing homes are in crisis because of the COVID-19 pandemic. These facilities need immediate support from policy makers and clinicians including testing, PPE, and support for staff. When nursing homes are able to reopen, this need for clinical support will not end. Value-based payment models that meaningfully engage clinicians in both postacute care and long-term nursing home care should help nursing homes provide safe and appropriate care for patients recovering from COVID-19 and for other patients who require short-term or long-term nursing home care.

Viral Dynamics

Science, May 22, 2020

Projecting the Transmission Dynamics of SARS-CoV-2 Through the Postpandemic Period

Stephen M. Kissler, et al

Regardless of any projection model, more than 90% of people in any given country are still susceptible to SARS-CoV2. If the daily numbers of COVID19 is decreasing in some places, it is due to radical public health measurements. In other words, the virus retreat is due to successful public health measurements. It is under pressure. Removal of public health measures without establishing successful and efficient testing, tracing, isolating, quarantining, and treating, the virus will find the opportunity to spread and kill. So we are not talking about a wave or waves. We are talking about resurgence.

It is urgent to understand the future of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) transmission. Authors used estimates of seasonality, immunity, and cross-immunity for human coronavirus OC43 (HCoV-OC43) and HCoV-HKU1 using time-series data from the United States to inform a model of SARS-CoV-2 transmission. They projected that recurrent wintertime outbreaks of SARS-CoV-2 will probably occur after the initial, most severe pandemic wave. Absent other interventions, a key metric for the success of social distancing is whether critical care capacities are exceeded. To avoid this, prolonged or intermittent social distancing may be necessary into 2022. Additional interventions, including expanded critical care capacity and an effective therapeutic, would improve the success of intermittent distancing and hasten the acquisition of herd immunity. Longitudinal serological studies are urgently needed to determine the extent and duration of immunity to SARS-CoV-2. Even in the event of apparent elimination, SARS-CoV-2 surveillance should be maintained because a resurgence in contagion could be possible as late as 2024.

The total incidence of COVID-19 illness over the next 5 years will depend critically upon whether it enters into regular circulation after the initial pandemic wave, which in turn depends primarily upon the duration of immunity that SARS-CoV-2 infection imparts. The intensity and timing of pandemic and postpandemic outbreaks will depend on the time of year when widespread SARS-CoV-2 infection becomes established and, to a lesser degree, upon the magnitude of seasonal variation in transmissibility and the level of cross-immunity that exists between the betacoronaviruses. Social distancing strategies could reduce the extent to which SARS-CoV-2 infections strain health care systems. Highly effective distancing could reduce SARS-CoV-2 incidence enough to make a strategy that is based on contact tracing and quarantine feasible, as in South Korea and Singapore. Less effective one-time distancing efforts may result in a prolonged single-peak pandemic, with the extent of strain on the healthcare system and the required duration of distancing depending on the effectiveness. Intermittent distancing may be required into 2022 unless critical care capacity is increased substantially or a treatment or vaccine becomes available. The authors are aware that prolonged distancing, even if intermittent, is likely to have profoundly negative economic, social, and educational consequences. Their goal in modeling such policies is not to endorse them, but rather to identify likely trajectories of the pandemic under alternative approaches, to identify complementary interventions such as expanding ICU capacity and identifying treatments to reduce ICU demand, and to spur innovative ideas to expand the list of options to bring the pandemic under long-term control. Our model presents a variety of scenarios intended to anticipate possible SARS-CoV-2 transmission dynamics under specific assumptions. Authors do not take a position on the advisability of these scenarios given the economic burden that sustained distancing may impose, but we note the potentially catastrophic burden on the healthcare system that is predicted if distancing is poorly effective and/or not sustained for long enough.

The model will have to be tailored to local conditions and updated as more accurate data become available. Longitudinal serological studies are urgently required to determine the extent and duration of immunity to SARS-CoV-2, and epidemiological surveillance should be maintained in the coming years to anticipate the possibility of resurgence.

PNAS, May 13, 2020

The Airborne Lifetime of Small Speech Droplets and Their Potential Importance in SARS-CoV-2 Transmission

Valentyn Stadnytskyi, et al

Speech droplets generated by asymptomatic carriers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly considered to be a likely mode of disease transmission. Highly sensitive laser light scattering observations have revealed that loud speech can emit thousands of oral fluid droplets per second. In a closed, stagnant air environment, they disappear from the window of view with time constants in the range of 8 to 14 min, which corresponds to droplet nuclei of ca. 4 μm diameter, or 12- to 21-μm droplets prior to dehydration. These observations confirm that there is a substantial probability that normal speaking causes airborne virus transmission in confined environments.

Light scattering observation of airborne speech droplet nuclei, generated by a 25-s burst of repeatedly speaking the phrase “stay healthy” in a loud voice (maximum 85 dBB at a distance of 30 cm; average 59 dBB). (A) Chart of particle count per frame versus time (smoothed with a 24-s moving average), with the red curve representing the top 25% in scattering brightness and the green curve representing the rest. The bright fraction (red) decays with a time constant of 8 min, and the dimmer fraction (green) decays with a time constant of 14 min. Both exponential decay curves return to their respective background level of ca. 0 (red horizontal dashed line) and 0.4 (green dashed line) counts per frame. Time “0” corresponds to the time the stirring fan was turned off. The 25-s burst of speaking started 36 s before time 0. The black arrow (at 0.5 min) marks the start of the exponential fits. (B) Image of the sum of 144 consecutive frames (spanning 6 s) extracted shortly after the end of the 25-s burst of speaking. The dashed circle marks the needle tip used for focusing the camera. The full movie recording is available in ref. 17, with time “0” in the graph at time point 3:38 in the movie.

Lancet, May 21, 2020

Detection of SARS-CoV-2 in Human Breast Milk

Rüdiger Groß, et al

Authors examined milk from two nursing mothers infected with SARS-CoV-2.

Following admission and delivery (day 0), four samples from Mother 1 tested negative (figure 2). By contrast, SARS-CoV-2 RNA was detected in milk from Mother 2 at days 10 (left and right breast), 12, and 13. Samples taken subsequently were negative (figure 2). Ct values for SARS-CoV-2 N peaked at 29·8 and 30·4 in whole milk and skimmed milk, respectively, corresponding to 1·32 × 105 copies per mL and 9·48 × 104 copies per mL (mean of both isolations). Since milk components might affect RNA isolation and quantification, viral RNA recovery rates in milk spiked with serial dilutions of a SARS-CoV-2 stock were determined. We observed up to 89·2% reduced recovery rate in whole milk and 51·5% in skimmed milk, suggesting that the actual viral loads in whole milk of Mother 2 could be even higher than detected.

Authors detected SARS-CoV-2 RNA in milk samples from Mother 2 for 4 consecutive days. Detection of viral RNA in milk from Mother 2 coincided with mild COVID-19 symptoms and a SARS-CoV-2 positive diagnostic test of the newborn (Newborn 2). Mother 2 had been wearing a surgical mask since the onset of symptoms and followed safety precautions when handling or feeding the neonate (including proper hand and breast disinfection, strict washing, and sterilisation of milk pumps and tubes). However, whether Newborn 2 was infected by breastfeeding or other modes of transmission remains unclear. Further studies of milk samples from lactating women and possible virus transmission via breastfeeding are needed to develop recommendations on whether mothers with COVID-19 should breastfeed.

Epidemiology

JAMA, May 22, 2020

Coronavirus Disease 2019 Test Results After Clinical Recovery and Hospital Discharge Among Patients in China

Jinru Wu, et al

This study has used PCR not viral culture, Thus the infectivity remains unclear, as infectious viruses have not been isolated from stool or any other sample after full recovery.

The overall prognosis of patients with COVID-19 after meeting the criteria for hospital discharge has not been reported.

Among the 60 discharged patients enrolled in this study a total of 10 patients (16.7%) had RT-PCR results positive for SARS-CoV-2, including 5 patients (8.3%) with positive nasopharyngeal swab results and 6 patients (10.0%) with positive anal swab results (1 patient had positive results in both swab samples).

None of the patients with RT-PCR results positive for SARS-CoV-2 had clinical symptoms of COVID-19 after hospital readmission, except for occasional cough in 2 old patients with multiple comorbidities. In one of them developed a cough with sputum 5 days after hospital discharge and had RT-PCR results positive for SARS-CoV-2 on March 27, indicating a viral shedding duration of 56 days from illness onset.

JAMA, May 21, 2020

Outbreak Investigation of COVID-19 Among Residents and Staff of an Independent and Assisted Living Community for Older Adults in Seattle, Washington

Alison C. Roxby, et al

In independent/assisted living facilities, testing was a better strategy for identifying staff and older adults with COVID-19 than symptom screening. Adherence to social distancing and preventive guidelines may contribute to interruption of COVID-19 transmission. If logistically feasible, active surveillance paired with infection control measures can be vital to preventing COVID-19 in settings with high potential for person-to-person transmission.

Testing was performed on 80 residents; 62 were women (77%), with mean age of 86 (range, 69-102) years. SARS-CoV-2 was detected in 3 of 80 residents (3.8%); none felt ill, 1 male resident reported resolved cough and 1 loose stool during the preceding 14 days. Virus was also detected in 2 of 62 staff (3.2%); both were symptomatic. One week later, resident SARS-CoV-2 testing was repeated and 1 new infection detected (asymptomatic). All residents remained in isolation and were clinically stable 14 days after the second test.

In this study, symptom screening failed to identify residents with infections and all 4 residents with SARS-CoV-2 remained asymptomatic after 14 days. Although 1 asymptomatic infection was found on retesting, a widespread facility outbreak was avoided. Compared with skilled nursing settings, in assisted/independent living communities, early surveillance to identify asymptomatic persons among residents and staff, in combination with adherence to recommended preventive strategies, may reduce viral spread.

JAMA, May 21, 2020

Preventing COVID-19 in Assisted Living Facilities—A Balancing Act

Grace Y. Jenq, et al

The pandemic will undoubtedly add to loneliness and social isolation that already plagues many older adults.

As testing becomes more prevalent, accurate, and efficient, one might envision a system of point-of-care COVID-19 testing for visitors. In the end, COVID-19–associated deaths will not just be related to infection but falls, chronic conditions, and worsening emotional health.

As the name implies, assisted living facilities provide older adults with a range of assistance for activities of daily living. Nearly 1 million older adults live in an estimated 25 000 assisted living facilities in the US, most with impairments in cognition or mobility.

After 2 residents were hospitalized with confirmed COVID-19, universal testing of all residents and staff using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time polymerase chain reaction was performed.

Three of 80 residents had positive test results; 2 were fully asymptomatic and 1 experienced mild symptoms (resolved cough and a single loose stool) prior to testing.

Two of 62 staff also had positive test results, both of whom were symptomatic. One additional resident, also asymptomatic, had a positive test result during follow-up testing a week later. Staff only had baseline testing.

The results demonstrate that symptom screening alone had low specificity and positive predictive value among a group of older adults. For example, 41% of residents reported symptoms potentially compatible with viral illness, but only 4% had positive test results. These findings illustrate the myriad challenges of symptom-based testing for an infection that has nonspecific protean manifestations and a wide range of clinical severity.

JAMA, Infectious Diseases, May 21, 2020

Prevalence and Clinical Presentation of Health Care Workers With Symptoms of Coronavirus Disease 2019 in 2 Dutch Hospitals During an Early Phase of the Pandemic

Marjolein F. Q. et al

The high prevalence of mild clinical presentations, frequently not including fever, suggests that the currently recommended case definition for suspected COVID-19 should be used less stringently.

This cross-sectional study was performed in 2 teaching hospitals in the southern part of the Netherlands in March 2020, during the early phase of the COVID-19 pandemic. Health care workers employed in the participating hospitals who experienced fever or respiratory symptoms were asked to voluntarily participate in a screening for infection with the severe acute respiratory syndrome coronavirus 2.

Of 9705 HCWs employed (1722 male [18%]), 1353 (14%) reported fever or respiratory symptoms and were tested. Of those, 86 HCWs (6%) were infected with severe acute respiratory syndrome coronavirus 2 (median age, 49 years [range, 22-66 years]; 15 [17%] male), representing 1% of all HCWs employed. Most HCWs experienced mild disease, and only 46 (53%) reported fever. Eighty HCWs (93%) met a case definition of fever and/or coughing and/or shortness of breath. Only 3 (3%) of the HCWs identified through the screening had a history of travel to China or northern Italy, and 3 (3%) reported having been exposed to an inpatient with a known diagnosis of COVID-19 before the onset of symptoms.

Almost one-quarter (24%) of SARS-CoV-2-infected HCWs had no patient contact at all, and only 3 mentioned exposure to an inpatient known with COVID-19. Although we cannot exclude acquisition from known or unknown SARS-CoV-2–infected patients or HCWs to have occurred in some instances, hospital acquisition is unlikely to explain the vast majority of cases coming from more than 50 different departments in 2 hospitals.

Within the limited resolution in time since the onset of symptoms, cycle threshold values tended to be higher in HCWs who were tested later in the course of the disease and probably the chance of transmission higher during the first 5-6 days after the onset of symptoms.

JAMA Infectious Diseases, May 21, 2020

Coronavirus Disease 2019 (COVID-2019) Infection Among Health Care Workers and Implications for Prevention Measures in a Tertiary Hospital in Wuhan, China

Xiaoquan Lai, et al

The non–first-line HCWs had a higher infection rate than first-line HCWs differed from observation of previous viral disease epidemics. Rapid identification of staff with potential infection and routine screening among asymptomatic staff could help protect HCWs.

In this single-center case series including 9684 health care workers, 110 of whom had COVID-19, a higher rate of infection was found among those working in the low-contagion area during the early stage of the disease outbreak, especially among nurses younger than 45 years. Most health care workers with COVID-19 had nonsevere disease, with an asymptomatic carrier prevalence of 0.9% and a mortality rate of 0.9%.

A total of 335 medical staff were randomly sampled to estimate the prevalence of subclinical infection among a high-risk, asymptomatic population. Samples from surfaces in health care settings were also collected.

Overall, 110 of 9684 HCWs in Tongji Hospital (7000 beds) tested positive for COVID-19, with an infection rate of 1.1%. Of them, 70 (71.8%) were women, and they had a median (interquartile range) age of 36.5 (30.0-47.0) years. Seventeen (15.5%) worked in fever clinics or wards, indicating an infection rate of 0.5% (17 of 3110) among first-line HCWs. A total of 93 of 6574 non–first-line HCWs (1.4%) were infected. Non–first-line nurses younger than 45 years were more likely to be infected compared with first-line physicians aged 45 years or older (incident rate ratio, 16.1; 95% CI, 7.1-36.3; P < .001).

The prevalence of subclinical infection was 0.74% (1 of 135) among asymptomatic first-line HCWs and 1.0% (2 of 200) among non–first-line HCWs. No environmental surfaces tested positive. Overall, 93 of 110 HCWs (84.5%) with COVID-19 had nonsevere disease, while 1 (0.9%) died. The 5 most common symptoms were fever (67 [60.9%]), myalgia or fatigue (66 [60.0%]), cough (62 [56.4%]), sore throat (55 [50.0%]), and muscle ache (50 [45.5%]). Contact with indexed patients (65 [59.1%]) and colleagues with infection (12 [10.9%]) as well as community-acquired infection (14 [12.7%]) were the main routes of exposure for HCWs.

JAMA Infectious Diseases, May 21, 2020

Estimating Coronavirus Disease 2019 Infection Risk in Health Care Workers

Vincent Chi-Chung Cheng, et al

The prevalence of SARS-CoV2 among HCW is low and often has been acquired in community, not at work place. Infection control measures are effective and should be escalated in response to the rapidly evolving epidemic to provide maximal protection to our HCWs and patients.

Lai et al described a cohort of 110 HCWs with symptomatic COVID-19 in a tertiary hospital in Wuhan, China, with more than 7000 beds that was designated to care for patients with COVID-19 in both outpatient and inpatient settings during the early phase of the epidemic. From January 1 to February 9, 2020, one-third of HCWs were deployed to high-risk areas, including fever clinics and wards, to care for 10 830 patients with confirmed or suspected COVID-19, and 17 of 3110 frontline HCWs (0.55%) were infected with SARS-CoV-2. This relatively low infection rate is reassuring, as it suggests that personal protective equipment, if available, can protect frontline HCWs directly caring for patients with COVID-19. However, the infection rate was higher, at 73 of 4433 HCWs (1.65%), among non-frontline HCWs who only cared for patients who did not fulfill the clinical and epidemiological criteria of COVID-19. Another 20 of 2012 HCWs without direct patient contact (0.99%) were also confirmed to be infected, which suggests a community source of infection.

Kluytmans-van den Bergh at el assessed the prevalence and clinical manifestations of COVID-19 among HCWs in 2 hospitals in the Netherlands in the early phase of the pandemic. In their cross-sectional study, 86 of 1353 HCWs who reported fever or respiratory symptoms in the last 10 days (6.36%) had positive reverse transcriptase–polymerase chain reaction test results for SARS-CoV-2, resulting in an overall infection rate of 86 of 9705 HCWs (0.89%). Overall, health care workers in the Netherlands who were found to be infected were employed in 52 different hospital departments. The diversity of working locations among them suggests that hospital outbreak was unlikely; instead, the HCWs most likely acquired SARS-CoV-2 in the community.

Pathophysiology

NEJM, 21 May 2020

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Maximilian Ackermann, et al

Vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from influenza virus infection

There were three distinctive angiocentric features of Covid-19. The first feature was severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes. Second, the lungs from patients with Covid-19 had widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries.12,19Third, the lungs from patients with Covid-19 had significant new vessel growth through a mechanism of intussusceptive angiogenesis.

Authors examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs.

In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza. In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza.

ANGIOCENTRIC INFLAMMATION

ACE2-positive cells per field of view in uninfected control lungs showed scarce expression of ACE2 in alveolar epithelial cells and capillary endothelial cells. In lungs from patients with Covid-19 and lungs from patients with influenza, the relative counts of ACE2-positive cells per field of view were 0.25±0.14 and 0.35±0.15, respectively, for alveolar epithelial cells and 0.49±0.28 and 0.55±0.11, respectively, for endothelial cells. Furthermore, ACE2-positive lymphocytes were not seen in perivascular tissue or in the alveoli of the control lungs but were present in the lungs in the Covid-19 group and the influenza group (relative counts of 0.22±0.18 and 0.15±0.09, respectively).

THROMBOSIS AND MICROANGIOPATHY

Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza.

ANGIOGENESIS

In the lungs from patients with Covid-19, the density of intussusceptive angiogenic features was significantly higher than that in lungs from patients with influenza or in uninfected control lungs.

Angiogenic features of sprouting and intussusceptive angiogenesis were counted per field of view in microvascular corrosion casts of lungs from patients with Covid-19 (red), lungs from patients with influenza A(H1N1) (blue), and control lungs (white). In Panels A and B, the numeric densities of angiogenic features are summarized as box plots for intussusceptive and sprouting angiogenesis. The boxes reflect the interquartile range, and the whiskers indicate the range (up to 1.5 times the interquartile range). Outliers are denoted by singular points. Panels C and D show a chronological comparison of intussusceptive and sprouting angiogenesis in lungs from patients with Covid-19 and lungs from patients with influenza A(H1N1) plotted as a function of the duration of hospitalization. The median angiogenic feature count for each patient is displayed as one dot. The shaded areas encompassing the dotted linear regression lines are smoothed 95% confidence intervals. As a reference for increased blood-vessel formation in lung diseases, intussusceptive and sprouting angiogenesis as found in end-stage nonspecific interstitial pneumonia (NSIP), a chronic interstitial lung disease, at the time of lung transplantation (a mean of 1650 days from first consultation to lung transplantation) are shown (purple box plots). Findings in healthy control lungs are also indicated (white box plots). The white and purple box plots are displayed in relation to the y axis but not the x axis (as indicated by vertical dashed lines).

A total of 69 angiogenesis-related genes were differentially regulated only in the Covid-19 group, as compared with 26 genes differentially regulated only in the influenza group; 45 genes had shared changes in expression.

ACE2 is an integral membrane protein that appears to be the host-cell receptor for SARS-CoV-2.Our data showed significantly greater numbers of ACE2-positive cells in the lungs from patients with Covid-19 and from patients with influenza than in those from uninfected controls. We found greater numbers of ACE2-positive endothelial cells and significant changes in endothelial morphology, a finding consistent with a central role of endothelial cells in the vascular phase of Covid-19. Endothelial cells in the specimens from patients with Covid-19 showed disruption of intercellular junctions, cell swelling, and a loss of contact with the basal membrane. The presence of SARS-CoV-2 virus within the endothelial cells, a finding consistent with other studies, suggests that direct viral effects as well as perivascular inflammation may contribute to the endothelial injury.

Pathology

JAMA, May 21, 2020

Postmortem Examination of Patients With COVID-19

Tina Schaller, et al

In this postmortem evaluation of 10 patients with COVID-19, acute and organizing diffuse alveolar damage and SARS-CoV-2 persistence in the respiratory tract were the predominant histopathologic findings and constituted the leading cause of death in patients with and without invasive ventilation. Periportal liver lymphocyte infiltration was considered unspecific inflammation. Whether myoepicardial alterations represented systemic inflammation or early myocarditis is unclear; criteria for true myocarditis were not met. Central nervous system involvement by COVID-19 could not be detected.

Between April 4 and April 19, 2020, authors conducted serial postmortem examinations in patients with proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who died at the University Medical Center Augsburg (Germany).

Signs of exudative early-phase acute diffuse alveolar damage with hyaline membrane formation, intra-alveolar edema, and thickened alveolar septa with perivascular lymphocyte-plasmocytic infiltration were consistently found. Organizing-stage diffuse alveolar damage with pronounced fibroblastic proliferation, partial fibrosis, pneumocyte hyperplasia leading to interstitial thickening and collapsed alveoles, and patchy lymphocyte infiltration was the predominant finding.

Fully established fibrosis was most prominent in one patient, ultimately leading to almost complete destruction of pulmonary parenchyma. In 5 patients, minor neutrophil infiltration was indicative of secondary infection and/or aspiration.

Mild lymphocytic myocarditis and signs of epicarditis were detectable in 4 and 2 cases, respectively. Liver histology showed minimal periportal lymphoplasmacellular infiltration and signs of fibrosis. There was no morphologically detectable pathology in other organs. Specifically, no signs of encephalitis or central nervous system vasculitis were found.

At time of autopsy, SARS-CoV-2 was still detectable in the respiratory tracts of all patients. Polymerase chain reaction testing was positive in pleural effusion but negative in all CSF samples.

Prevention

Unpublished

Hong Kong University Hamster Research Shows Masks Effective in Preventing Covid-19 Transmission

Yuen Kwok-Yung, et al

Researchers used 52 hamsters in the experiment, which saw the presence of surgical mask-like barriers greatly lower the rate of infection.

The same research group previously established the world’s first golden Syrian hamster model for Covid-19 in February, showing hamsters – which have enzyme receptors very similar to those in humans – could transmit the virus from one to another through direct or indirect contact.

In this experiment, partitions made of surgical masks were set up between cages in an isolated facility, with an infected hamster on one side, and three healthy hamsters on the other. A fan was then placed in between to make sure the virus would “transmit” between cages. Fifty-two hamsters were used in the tests, which were carried out under three scenarios designed to replicate real-life situations: with mask barriers placed only on cages that held infected subjects; with partitions placed only on the uninfected side; and with no partition at all.

After seven days, 10 out of 15 healthy hamsters, or 66.7 percent, placed in cages with no partition had become infected.

But when surgical mask barriers were placed on the infected hamsters’ side, only two of 12 subjects in the adjoining cage, or 16.7 per cent, tested positive for the coronavirus.

That number rose to four of 12 when the partition was placed only on the cage with healthy subjects.

The study also found that hamsters infected with Covid-19 via direct injection had more severe symptoms than those that contracted it through the mask partitions. The latter group experienced lower clinical scores, milder histopathological changes, and lower viral loads in respiratory tract tissues.

Lancet, May 22, 2020

Safety, Tolerability, and Immunogenicity of a Recombinant Adenovirus Type-5 Vectored COVID-19 Vaccine: A Dose-Escalation, Open-Label, Non-Randomised, First-in-Human Trial

Feng-Cai Zhu, et al

The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation.

Authors aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain.

Authors did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. 108 Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays.

At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination.

Treatment

Lancet Respiratory Medicine, May 21, 2020

Novel Viruses, Old Data, and Basic Principles: How to Save Lives and Avoid Harm Amid the Unknown

Michael R Rose, et al

The 2013–16 west African Ebola epidemic had a staggering case fatality rate of 30–70%, yet surprisingly few of the dozens of Americans and Europeans medically evacuated from the region died, with the case fatality rate in Europe and the USA estimated at a mere 10%. Every American received experimental antiviral medications or convalescent plasma, and the efficacy and ethics of these therapies occupied both our national headlines and headspace. However, randomised clinical trials for both therapies have since failed to show benefit. Why, then, did so many more Americans survive if not due to preferential access to experimental therapies? The likely answer is the Americans survived not due to preferential access to unproven therapies but to proven ones.

5 years later, the world is facing another, much larger, pandemic, and we worry the medical community has not learned from this recent experience.

To be clear, searching for effective new therapies against COVID-19 is highly important. At the same time, we must remain cognisant that the odds are stacked against the candidates. Medications that decrease mortality are difficult to come by, leaving numerous diseases without direct remedies. Influenza provides an important perspective. Scientists have been searching for a cure since before the 1918 influenza pandemic, and more than 100 years later our best medicines for influenza merely shorten the duration of symptoms by a day at best. None has been shown to reduce mortality.

Of course, a lack of targeted therapies does not mean a patient with the 1918 influenza would not fare better today,

As with influenza, Ebola, and sepsis, the timely delivery of standard and supportive care will probably save more patients from COVID-19 in the months ahead than any of the unproven, and potentially dangerous, pharmacological therapies being both formally trialled and individually tried today. Hydroxychloroquine, for example, was widely used early in the pandemic on the basis of reports of a potential benefit. More recent assessment has called its use into question and even suggested harm. Rather than ruminating about which innovative therapeutic might help a given patient, our collective mental energy is better spent on guaranteeing the delivery of evidence-based care against COVID-19's main killers.

As clinicians caring for patients dying from COVID-19, we too yearn for a novel therapy for this novel disease. We also recognise and appreciate the scientific value of expert observations. Indeed, they are crucial to identify aspects of management where there truly is equipoise and thus indication for rigorous study. Prompt collection of such data must be prioritised so we will be armed with appropriate evidence to fight the inevitable second surge when it arrives. History tells us a pandemic is not a justification to abandon the basic principles of evidence-based medicine. In fact, adhering to these values has never been more important.

Lancet Diabetes and Endocrinology, May 20, 2020

Vitamin-D and COVID-19: Do Deficient Risk a Poorer Outcome?

Fiona Mitchell

A 2017 meta-analysis of individual patient data from 11 321 participants in 25 randomised controlled trials showed that vitamin D supplementation protected against acute respiratory tract infections and that patients with very low (<25 nmol/L) serum 25-hydroxyvitamin D concentrations (a marker of vitamin D status) gained the most benefit.

A growing body of circumstantial evidence now also specifically links outcomes of COVID-19 and vitamin D status. SARS-CoV-2, the virus responsible for COVID-19, emerged and started its spread in the Northern hemisphere at the end of 2019 (winter), when levels of 25-hydroxyvitamin D are at their nadir. Also, nations in the northern hemisphere have borne much of the burden of cases and mortality. In a cross-sectional analysis across Europe, COVID-19 mortality was significantly associated with vitamin D status in different populations. The low mortality rates in Nordic countries are exceptions to the trend towards poorer outcomes in more northerly latitudes, but populations in these countries are relatively vitamin D sufficient owing to widespread fortification of foods. Italy and Spain are also exceptions, but prevalence of vitamin D deficiency in these populations is surprisingly common. Additionally, black and minority ethnic people—who are more likely to have vitamin D deficiency because they have darker skin—seem to be worse affected than white people by COVID-19. For example, data from the UK Office for National Statistics shows that black people in England and Wales are more than four times more likely to die from COVID-19 than are white people.

A role for vitamin D in the response to COVID-19 infection could be twofold. First, vitamin D supports production of antimicrobial peptides in the respiratory epithelium, thus making infection with the virus and development of COVID-19 symptoms less likely. Second, vitamin D might help to reduce the inflammatory response to infection with SARS-CoV-2. Deregulation of this response, especially of the renin–angiotensin system, is characteristic of COVID-19 and degree of overactivation is associated with poorer prognosis. Vitamin D is known to interact with a protein in this pathway—angiotensin-converting enzyme 2 (ACE2)—which is also exploited by SARS-CoV-2 as an entry receptor. While SARS-CoV-2 downregulates expression of ACE2, vitamin D promotes expression of this gene.

NEJM, May 22,2020

Remdesivir for the Treatment of Covid-19 — Preliminary Report

John H. Beigel, et al

These preliminary findings support the use of remdesivir for patients who are hospitalized with Covid-19 and require supplemental oxygen therapy. However, given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient. Future strategies should evaluate antiviral agents in combination with other therapeutic approaches or combinations of antiviral agents to continue to improve patient outcomes in Covid-19.

The major consideration is the wide heterogeneity in baseline treatment which may have significant impact on outcome. More importantly the overall mortality on the remdesivir arm was high and similar to placebo except in sub group 5.

Remdesivir, an inhibitor of the viral RNA-dependent, RNA polymerase with inhibitory activity against SARS-CoV and the Middle East respiratory syndrome (MERS-CoV), was identified early as a promising therapeutic candidate for Covid-19 because of its ability to inhibit SARS-CoV-2 in vitro. In addition, in nonhuman primate studies, remdesivir initiated 12 hours after inoculation with MERS-CoV reduced lung virus levels and lung damage.

Enrollment for ACTT-1 began on February 21, 2020, and ended on April 19, 2020. There were 60 trial sites and 13 subsites in the United States (45 sites), Denmark (8), the United Kingdom (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1), and Singapore (1). Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir or placebo.

Remdesivir was administered intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death.

All patients received supportive care according to the standard of care for the trial site hospital. If a hospital had a written policy or guideline for use of other treatments for Covid-19, patients could receive those treatments. In the absence of a written policy or guideline, other experimental treatment or off-label use of marketed medications intended as specific treatment for Covid-19 were prohibited from day 1 through day 29 (though such medications could have been used before enrollment in this trial).

The primary outcome measure was the time to recovery, defined as the first day, during the 28 days after enrollment, on which a patient satisfied categories 1, 2, or 3 on the eight-category ordinal scale. The categories are as follows: 1, not hospitalized, no limitations of activities; 2, not hospitalized, limitation of activities, home oxygen requirement, or both; 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control reasons); 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (Covid-19–related or other medical conditions); 5, hospitalized, requiring any supplemental oxygen; 6, hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices; 7, hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); and 8, death.

Other outcomes included mortality at 14 and 28 days after enrollment and grade 3 and 4 adverse events and serious adverse events that occurred during the trial.

The primary outcome was initially defined as the difference in clinical status, defined by the eight-category ordinal scale, among patients treated with remdesivir as compared with placebo at day 15. This initial primary outcome became the key secondary outcome after the change in primary outcome. When this change was proposed, 72 patients had been enrolled and no interim data were available.

The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group); acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]); pyrexia (27 events [5.0%], as compared with 17 [3.3%]); hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]); and increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]). Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.

BMJ, May 14, 2020

Clinical Efficacy of Hydroxychloroquine in Patients with Covid-19 Pneumonia Who Require Oxygen: Observational Comparative Study Using Routine Care Data

Matthieu Mahévas, et al

In patients admitted to hospital with covid-19 pneumonia who require oxygen, hydroxychloroquine treatment seemed to have no effect on reducing admissions to intensive care or deaths at day 21 after hospital admission. Additionally, hydroxychloroquine treatment did not have any effect on survival without acute respiratory distress syndrome at day 21 after hospital admission. These results do not support the use of hydroxychloroquine in these patients.

Hydroxychloroquine has received worldwide attention after an in vitro study reported its potential activity against SARS-CoV-2, and small studies have released promising results. However, the effectiveness of hydroxychloroquine for treating covid-19 is the subject of serious debate. One uncontrolled French study included 26 hospital inpatients who were positive for SARS-CoV-2 PCR (polymerase chain reaction) on a nasopharyngeal swab. The study suggested that 600 mg/day of hydroxychloroquine was associated with a decrease in SARS-CoV-2 shedding and when combined with azithromycin it was more efficacious. However, another uncontrolled French study found no evidence of antiviral clearance with hydroxychloroquine and azithromycin in 11 patients admitted to hospital. A recent study randomised 62 patients into two parallel groups: a control group and a group receiving hydroxychloroquine (400 mg/day for five days). The study reported a shorter time to clinical recovery in the hydroxychloroquine group. However, these patients were not severely ill, the clinical endpoints were not clearly defined, and there was no stratification for comorbidities known to be associated with a poor outcome.

In this comparative observational study using data collected from routine care, 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care in four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020.

Hydroxychloroquine was given at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group).

The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting.

In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment.

Lancet, May 22, 2020

Hydroxychloroquine or Chloroquine With or Without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis

Mandeep R Mehra, et al

Authors were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

Authors did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation).

96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality.

Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.

Authors noted that higher BMI emerged as a risk marker for worse in-hospital survival. Obesity is a known risk factor for cardiac arrhythmias and sudden cardiac death. The most commonly reported arrhythmias are atrial fibrillation and ventricular tachycardia. Although age, race, and BMI were predictive of an increased risk for death with COVID-19 in this analysis, they were not found to be associated with an increased risk of ventricular arrhythmias on our multivariable regression analysis. The only variables found to be independently predictive of ventricular arrhythmias were the four treatment regimens, along with underlying cardiovascular disease and COPD.

Findings in this study suggest not only an absence of therapeutic benefit but also potential harm with the use of hydroxychloroquine or chloroquine drug regimens (with or without a macrolide) in hospitalised patients with COVID-19.

Lancet, May 22, 2020

Chloroquine or Hydroxychloroquine for COVID-19: Why Might They Be Hazardous?

Christian Funck-Brentano, et al

Despite limitations inherent to the observational nature of this study, Mehra and colleagues should be commended for providing results from a well designed and controlled study of the effects of chloroquine or hydroxychloroquine, with or without a macrolide, in a very large sample of hospitalised patients with COVID-19. Their results indicate an absence of benefit of 4-aminoquinoline-based treatments in this population and suggest that they could even be harmful. The incidence of repetitive ventricular arrhythmias ranged from 4·3% to 8·1% in patients treated with a 4-aminoquinoline, compared with 0·3% in the control group (p<0·0001). It is tempting to attribute the increased risk of in-hospital deaths to the higher observed incidence of drug-induced ventricular arrhythmias, given that these drugs are known to prolong QTc and provoke torsade de pointes. However, the relationship between death and ventricular tachycardia was not studied and causes of deaths (ie, arrhythmic vs non-arrhythmic) were not adjudicated. Although not all ventricular arrhythmias might have been detected, the number of deaths in the treatment groups was much greater than the number of patients who had ventricular arrhythmias. The risk of death associated with 4-aminoquinolines alone or combined with a macrolide was similar, whereas it would be expected that the combination of two QTc-prolonging drugs would increase their proarrhythmic potential. The HRs for death were similar in men and women, whereas women have a higher sensitivity to drug-induced QTc prolongation and a higher risk of drug-induced torsade de pointes3 than men. The study therefore does not suggest that the increased risk of death with 4-aminoquinolines was due to a proarrhythmic mechanism. Another hypothesis to explain the increased risk of death with 4-aminoquinolines is that their antiviral and immunomodulatory properties could worsen COVID-19 severity in some patients. Nevertheless, the increased incidence of ventricular arrhythmias is intriguing. Chloroquine, hydroxychloroquine, and azithromycin have sodium channel blocking properties that might contribute to proarrhythmia and heart failure in the context of myocardial injury and hypoxia present in COVID-19.12 This hypothesis remains to be tested.

Special Groups

JAMA, May 22, 2020

Labor and Delivery Visitor Policies During the COVID-19 Pandemic, Balancing Risks and Benefits

Kavita Shah Arora, et al

Implementing a labor and delivery unit visitor policy necessitates balancing risks and benefits in the face of uncertain and evolving information. Ideally, such policy making balances the benefits and risks to the patient, the visitor, the community, the health care team, and perhaps above all, to the infant, in an evidence-based, nonreactionary, and compassionate manner.