Summary of Critical Articles August 13, 2020

Summary of Critical Articles August 13, 2020 Nuvance Health/UVMLCOM Global Health Program

Cumulative Number of Reviewed Articles Since Inception: 915

COVID-19 Statistics: Connecticut as of August 13, 2020

Fairfield Statistics:

Cases per 100,000 population: 1,920
Total Cases: 18126
Current number of patients in hospitals: 21
Deaths: 1,410
Death Rate: 7.77%

Editorials, Perspectives, Commentaries and Reflections

From the Heart, Having Coronavirus Disease 2019 (COVID-19), JAMA Cardiology, August 12, 2020
K-12 Virtual Schooling, COVID-19, and Student Success, JAMA Pediatrics, August 11, 2020
Operational Considerations on the American Academy of Pediatrics Guidance for K-12 School Reentry, JAMA Pediatrics, August 11, 2020
Cascading Risks of COVID-19 Resurgence During an Active 2020 Atlantic Hurricane Season, JAMA Network, August 12, 2020
Racial Disproportionality in Covid Clinical Trials, NEJM August 11, 2020

Public Health

Precision Public Health as a Key Tool in the COVID-19 Response, JAMA Network, August 12, 2020

Planetary Health

COVID-19 and the future of food systems at the UNFCCC, Lancet Planetary Health August 2020
Nested ecology and emergence in pandemics, Lancet Planetary Health August 2020
In sight but out of mind, Lancet Planetary Health August 2020
Forward planning for disaster-related mass gatherings amid COVID-19, Lancet Planetary Health August 11, 2020

Pathophysiology

COVID-19 pandemic more than a century after the Spanish flu, Lancet Infectious Diseases, August 11, 2020

Pathology

Ultrastructural Evidence of Direct Viral Damage to the Olfactory Complex in Patients Testing Positive for SARS-CoV-2, JAMA Otolaryngology - Head & Neck Surgery, August 13, 2020

Epidemiology

Applications of predictive modelling early in the COVID-19 epidemic, Lancet Digital Health, August 10, 2020
Sex differential in COVID-19 mortality varies markedly by age, Lancet August 13, 2020
Characteristics and Outcomes of COVID-19 Patients During Initial Peak and Resurgence in the Houston Metropolitan Area, JAMA Network, August 13, 2020

Clinical Practice and Innovations in Care Delivery

Covid-19 and the Mandate to Redefine Preventive Care, NEJM, August 12, 2020 Page 23

Clinical Manifestations

Multisystem inflammatory syndrome associated with COVID-19 in children in Pakistan, Lancet Child Adolesc Health, August 10, 2020
Pseudotumor cerebri syndrome associated with MIS-C: a case report, Lancet August 11, 2020

Diagnosis

SARS-CoV-2 PCR testing of skin for COVID-19 diagnostics: a case report, Lancet, August 13, 2020

Prevention

An Inactivated Virus Candidate Vaccine to Prevent COVID-19, JAMA August 13, 2020
Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes Interim Analysis of 2 Randomized Clinical Trials, JAMA August 13, 2020
Filtration Efficiency, Effectiveness, and Availability of N95 Face Masks for COVID-19 Prevention, JAMA Internal Medicine, August 11, 2020
Filtration Efficiency of Hospital Face Mask Alternatives Available for Use During the COVID-19 Pandemic, JAMA Internal Medicine, August 11, 2020

Treatment

Regulatory T Cells Tested in Patients With COVID-19 ARDS; JAMA Network, August 11, 2020
Extracorporeal Membrane Oxygenation for Patients With COVID-19 in Severe Respiratory Failure, JAMA Surgery, August 11, 2020
ECMO for severe ARDS associated with COVID-19: now we know we can, but should we?, Lancet Respiratory Medicine, August 13, 2020
Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study, Lancet Respiratory Medicine, August 13, 2020

Special Groups

Prevalence of SARS-CoV-2 Infection Among Health Care Workers in a Tertiary Community Hospital, JAMA Internal Medicine, August 11, 2020

Special Countries

Biomedical waste amid COVID-19: perspectives from Bangladesh, Lancet Global Health, August 13, 2020

Miscellaneous

Researchers Strive to Recruit Hard-Hit Minorities Into COVID-19 Vaccine Trials, JAMA Network, August 13, 2020

Editorials, Perspectives, Commentaries and Reflections

JAMA Cardiology, August 12, 2020

From the Heart, Having Coronavirus Disease 2019 (COVID-19)

Janet M. Shapiro

I could not endure hearing the television news about what COVID-19 was doing to the people of the city, the daily death toll, the overworked health care workers, and the stories of families grieving. I listened to the daily 7 pm cheers from New York City neighbors. As a lifelong New Yorker, the daily cheering/honking/clapping in honor of health care workers was a surprise and a true lift to the spirits. Someone was writing loving messages on the hospital sidewalk to the health care workers.

I direct an ICU in New York City, New York, a center of the COVID-19 pandemic. We treated a continuous wave of patients, tragic situations of young and old, patients with respiratory failure, shock, strokes, pulmonary embolism, and kidney failure. Before COVID-19 arrived, I felt invulnerable, not yet aware of the power of this virus. We would be okay because we were protected by our personal protective equipment. I was also protected by my white coat. When I started medical school at Columbia University in 1981, all physicians and students wore white coats and I have worn a white coat every day since. Although current generations have discarded the white coat, the white coat is defining for me as a physician and as the person who is not a patient. So I was less afraid for myself, but I was terribly afraid of bringing COVID-19 home.

COVID-19 is really, really tragic, worse than we could have ever expected. I experienced what it is to feel one’s body, the difficulty of a breath, a fast heartbeat, the vagueness of feeling unwell and the fear it brings. This is what patients experience on a daily basis. No one is safe from illness. COVID-19 reminded me of the miracle and fragility of a healthy body. Isolation of patients is painful to observe and to imagine for oneself. Our humanity is sustenance in this crisis: working together, caring for each other, hearing neighbors’ cheers, and providing kindness to patients and families even from a distance.

Of course, the magnitude of the losses continues to overwhelm: the sheer number of more than 100 000 deaths in this country, including so many health care workers.

JAMA Pediatrics, August 11, 2020

K-12 Virtual Schooling, COVID-19, and Student Success

Erik Black, et al

The pandemic has encouraged many parents to explore educational alternatives, particularly for students who may have health concerns such as those with respiratory disease or who are immunocompromised. With social distancing creating obstacles for traditional education, K-12 online learning may become more mainstream. For more information, consider the Michigan Virtual Learning Research Institute’s parent guide to online learning and the Universal Design for Learning. Future studies of the intersection of educational and health outcomes can clarify the effect of education on health and health on education. The COVID-19 pandemic offers a unique challenge for educators, policy makers, and health care professionals to partner with parents to make the best local and individual decisions for children.

Virtual schooling is the delivery of instruction through technology to students physically separated from their teachers. Formal virtual schools exist nationwide at all levels from kindergarten through 12th grade for both general and special education. At the elementary school level, online learning typically requires parental involvement and facilitation. Students at the middle school and high school levels often independently communicate via email, text, telephone, or video for group and individualized learning. Virtual schooling classes are frequently asynchronous, where students and teachers do not have to be online at the same time, allowing for learning anytime and any place. Unlike the rapid transfer of face-to-face curriculum into an online format in spring 2020, virtual schools use curriculum designed specifically for online instruction. These schools mostly employ teachers who are experienced online educators and often have online teaching certificates and graduate degrees that specifically include online education. Virtual schools also focus their ongoing professional development around online teaching and learning practices.

Many schools are still considering online or blended instruction as a necessary alternative or hybrid as this pandemic evolves. Also, many families may be considering whether some or all of their child’s current or future education could take place online. As such, parents should evaluate the unique strengths and needs of their children by considering the following questions:

Can their child maintain a study schedule and complete assignments with limited supervision?
Would their child be able to ask for help and effectively communicate with a teacher via telephone, text, email, or video?
Does their child have an intrinsic drive to learn skills, acquire knowledge, and complete assignments?
Does their child possess foundational reading, writing, math, and computer literacy skills?

Parents should also learn more about the virtual school options available to them. They should seek to understand the following:

How will student information be shared with their local school district?
Is the virtual school accredited?
How does the virtual school comply with state standards for K-12 educators (eg, licensure)?
Are Universal Design for Learning standards incorporated into instructional materials?
What support does the school provide for children with special needs?
What expectations does the school have for parents/caregivers?
What technology is necessary for participation? Who is responsible for providing it?
How will the virtual school facilitate communication about their child’s unique needs?

JAMA Pediatrics, August 11, 2020

Operational Considerations on the American Academy of Pediatrics Guidance for K-12 School Reentry

C. Jason Wang, et al

To maximize health and educational outcomes, school districts should adopt some or all of the measures on the AAP guidance and prioritize them after considering local COVID-19 incidence, key stakeholder input, and budgetary constraints. Given the increased costs of preparing and operating schools, public schools will require additional funding from the state or the federal government, whereas private schools may need to temporarily increase tuition or seek some assistance from the government. If these are not attainable, schools will need more time to prepare to ensure the safety of students and staff.

Authors suggest that school districts engage key stakeholders to establish a COVID-19 task force, composed of the superintendent, members of the school board, teachers, parents, and health care professionals to develop policies and procedures.

In respect to physical distancing, If existing indoor spaces are inadequate, temporary modular buildings may be needed. Costs of these structures range from $40 to $100 per square foot. Physical distancing measures apply to school buses as well. Students should be assigned seats on buses, and school districts will need to assess the need to expand their fleet of buses or develop different pickup schedules. Students taking public transportation should use face coverings.

In terms of protective equipment, as the AAP guidance suggests, teachers who must work closely with students with special needs or with students who are unable to wear masks should wear N95 masks if possible or wear face shields in addition to surgical masks. Schools will also need to consider the expenditure of increasing disinfection efforts of all teaching spaces, common areas, and high-touch surfaces such as doorknobs, computers, and desks.

The AAP also recommends creating fixed cohorts of students and teachers to limit exposure of students to teachers and students to each other.

The AAP guidance states the importance of identifying symptoms and signs concerning for COVID-19 but does not discuss operational approaches in depth. To address this, we recommend that schools implement multilevel screening for students and staff.

Schools should consider hiring additional nurses, psychologists, or social workers (or sourcing them through partnerships with local health care facilities) not only to assist with screening and managing potential COVID-19 cases but also to provide more support for students and any staff members with emotional or psychiatric concerns.

Even with all the precautions in place, COVID-19 outbreaks within schools are still likely. Therefore, schools will need to remain flexible and consider temporary closures if there is an outbreak involving multiple students and/or staff and be ready to transition to online education. As such, school districts need to invest in developing or acquiring online education platforms and train teaching staff in switching seamlessly from in-person teaching to online education platforms.

JAMA Network, August 12, 2020

Cascading Risks of COVID-19 Resurgence During an Active 2020 Atlantic Hurricane Season

James M. Shultz, et al

The US has never experienced the twin risks of the COVID-19 pandemic overlaid upon climate-intensified hurricane threats. As such, much remains unknown. Emergency, public health, and health care professionals need to rapidly distill lessons learned from affected communities during Hurricane Hanna and with each 2020 storm and transmit best practices to their counterparts. This could be helpful to iteratively refine preparedness and response for storms arriving later in the season.

During the summer of 2020, resurging coronavirus disease 2019 (COVID-19) and climate-driven hurricanes are on a collision course, potentially creating double jeopardy for US coastal residents in the 8 contiguous hurricane coastal states from Texas to the Carolinas and for those who live in Puerto Rico and the US Virgin Islands. Hurricane coastal states generally remained open throughout the spring break weeks in March, imposed moderate mitigation restrictions during April and early May, and then moved early and aggressively to reopen. These same states are now on alert as an early developing active 2020 Atlantic hurricane season has already produced an unprecedented 9 named storms before the end of July.

A compelling cautionary tale for what to anticipate was provided in May 2020 when Cyclone Amphan strengthened to super cyclone status while moving northward along the funneling coastline of the Bay of Bengal that separates India from Bangladesh. Although both nations were strictly enforcing COVID-19 lockdowns at that time, they reportedly rapidly mobilized and evacuated more than 2.2 million citizens in Bangladesh and 4.3 million in the West Bengal and Odisha states of India from low-lying delta areas, and distributed these people to more than 15 000 shelters in the region, far more than ever before to allow shelter residents a degree of physical distancing. Although Bay of Bengal storms have accounted for 8 of the 10 deadliest tropical cyclones in history, timely mitigation limited Amphan-associated mortality to 80 deaths. However, the mass evacuation and sheltering process appears to have produced a spike in new COVID-19 cases in Kolkata, India, and other storm-affected regions, underscoring the near impossibility of neutralizing both the COVID-19 pandemic and natural hazard risks.

Best projections suggest that in the likely scenario that powerful Atlantic hurricanes make landfall along the hurricane coast during the months of August through November 2020, COVID-19 will still be actively circulating. This suggests that there is substantial risk for both serious injury and drowning during exposure to hurricane hazards among persons who refuse to evacuate, and COVID-19 transmission occurring due to exposure to infectious persons during evacuation and sheltering in public venues and households.

Three steps could be taken to help diminish combined hurricane and COVID-19 pandemic risks during the coming months. First, reestablish the COVID-19 prevention lifestyle. Second, improve communications to shape safer evacuation and sheltering.Third, learn from each 2020 storm and refine operations.

NEJM August 11, 2020

Racial Disproportionality in Covid Clinical Trials

Daniel B. Chastain, et al

Authors believe that sponsors, regulatory agencies, research funders, medical journals, and peer reviewers have a responsibility to ensure that clinical trials satisfy the requirements of the aforementioned federal law and NIH policy and present all demographic data. These groups can deem it unacceptable for proposals or manuscripts to fail to justify the demographic makeup of a study population. Researchers will have to consider strategies for recruiting participants from underserved groups by proactively addressing the possibility or fear of exploitation. To improve the response to Covid-19 and allocate resources appropriately, states and municipalities will need to report race and ethnicity data on cases and deaths promptly, while Covid-19 clinical trials incorporate marginalized communities by targeting populations at greatest risk — most notably, Black, Latinx, and Native American.

Despite disproportionately higher rates of Covid-19 infection, hospitalization, and death in racial and ethnic minority groups, the direct effects of genetic or biologic host factors remain unknown.

As we strive to overcome the social and structural causes of health care disparities, we must recognize the underrepresentation of minority groups in Covid-19 clinical trials.

Black Americans accounted for only about 20% of the 1063 patients in the placebo-controlled Adaptive Covid-19 Treatment Trial (ACTT-1) funded by the National Institute of Allergy and Infectious Diseases (NIAID) and 11% of the 397 patients randomly assigned to 5 or 10 days of remdesivir in the Gilead-funded study (GS-U.S.-540-5773). The proportions of Latinx and Native American patients were provided only for ACTT-1 and were 23% and 0.7%, respectively.

Covid-19 Cases and Deaths, According to Black or White Race and Latinx Ethnicity

Lack of diversity in these clinical trials may stem from long-standing medical distrust on the part of minority communities, but the problem may be compounded by cost (in particular hidden costs for such requirements as fuel, parking, meals, and lodging), poor health literacy, lack of information, language barriers, limited accessibility, and implicit biases against minorities. Another possible explanation is the lack of diversity among principal investigators who can obtain funding, since such diversity might curtail bias in recruitment of participants from underrepresented populations.

Public Health

JAMA Network, August 12, 2020

Precision Public Health as a Key Tool in the COVID-19 Response

Sonja A. Rasmussen, et al

The COVID-19 pandemic provides an opportunity for further evolution of the field of precision public health, as new tools and technologies begin to complement traditional medical and public health approaches to prevention and control. Just like precision medicine, precision public health will still need a strong evidentiary foundation. Careful evaluation of the validity and utility of these new technologies as applied to precision public health and their effectiveness in reducing COVID-19 cases and decreasing morbidity and mortality will be essential, along with consideration of the ethical, legal, and social implications. These applications will require a strong collaboration among the health care sector, individual clinicians and health centers, private sector, governments, and communities. Despite these challenges, at no time has precision public health been needed more than now.

Precision public health is an emerging discipline that uses extensive population-specific data to provide the right intervention to the right population at the right time. Precision public health uses data from traditional and emerging sources to target interventions for populations by person, place, and time, in part with a focus on reducing health disparities. Analogous to the use of genomic information in precision medicine, pathogen genomics has become the leading prototype of precision public health, with numerous applications in tracking and control of infectious disease outbreaks, most notably for foodborne diseases.

Beyond genomics, granular data from public health surveillance are essential to target public health interventions. Data on levels of COVID-19 infection and disease in a community need to be available so clinicians and public health professionals can provide the best guidance to communities about optimal interventions to prevent illness and death and to target public health interventions to regions of most need. Geographic information and other technologies can be integrated to identify hot spots to allow targeting of interventions. Measures such as number of daily cases per 100 000 (low <1, moderate 1-10, high 10-25, and critical >25) and percent positive rate on polymerase chain reaction testing (low <3%, moderate 3%-6%, high 6%-10%, and critical >10%) could be used to determine phases of reopening of communities.

Although traditional public health data are useful, the use of emerging digital data should also be explored. Some of these data are derived from nontraditional data sources and are included under the rubric of “big data” and associated predictive analytics including cell phone mobility data, information from wearable fitness trackers, and geographic information systems.

Planetary Health

Lancet Planetary Health August 2020

COVID-19 and the future of food systems at the UNFCCC

Sylvia Gralak, et al

Not only do our food systems fail to sustain us nutritionally, but they are also the single greatest driver of environmental degradation, causing unprecedented biodiversity loss, environmental pollution, and water shortages.

The UN Framework Convention on Climate Change (UNFCCC) is the primary global forum dedicated to climate change. Despite increasing attention to food security in UNFCCC processes and outcomes over the past decade, including in the preamble of the Paris Agreement and Koronivia workshops, dietary practises have thus far been relatively neglected.

There is both a need and opportunity to pursue food systems change considering the threats to food security brought about by COVID-19. There is an imminent need to take planetary health into account and pave the way for a green post-pandemic recovery with clear commitments towards healthy, equitable, and sustainable food systems. We call on the UNFCCC to mobilise parties to face this challenge with a rational and collaborative approach. As such, we make the following recommendations.

To meet the Paris agreement, food systems, including dietary change, must be included in Nationally Determined Contributions (NDCs).

Evidence has shown that meeting the Paris Agreement is not possible without widespread dietary change; we therefore strongly encourage the inclusion of food production, food loss and waste, and dietary changes in negotiations related to Agriculture, Forestry and Other Land Use at the UNFCCC.

As the central forum for climate action, the UNFCCC must recognise the importance of dietary change as a mitigation strategy and reflect this in the food offered at their events.

Lancet Planetary Health August 2020

Nested ecology and emergence in pandemics

Aaron Jenkins, et al

Within our global ecosystems, biodiversity is declining faster than at any point in human history and habitat removal is causing wildlife to move closer to human settlements.

Global growth in trade and consumption is enabling the mixing of wildlife, domestic animals, and other marketable natural products, which is increasing the risk of disease transmission from animals to humans. COVID-19 is the latest dangerous infectious disease facilitated by human behaviours that provide transmission opportunities from animals into humans, other examples include Zika, Hendra, Ebola virus disease, SARS, Middle East respiratory syndrome, and avian influenza. Human-forced climate change exacerbates these risks. Shifting wildlife migration patterns can cause the emergence of novel diseases as new species-interactions occur. The increasing frequency of natural disasters, such as the 2019–20 Australian wildfires, increase respiratory vulnerability, and air pollution particles facilitate pathogen transport. Other climate-related events, such as Tropical Cyclone Harold in the Pacific Islands (April, 2020) and Amphan in south Asia (May, 2020), have caused widespread flooding, damage to infrastructure (including water and sanitation facilities), and distress to people and animals who are crowded into evacuation centres while governments try to enforce social distancing and hygiene. Vulnerable populations and places—eg, with elevated levels of poverty, high prevalence of non-communicable diseases, or degraded natural systems—are at high risk of having poor health outcomes and being epicentres for the emergence of pathogens with pandemic potential. The COVID-19 pandemic highlights our interdependence; however, it also highlights the consequences of widening social inequities and the misunderstood nature of disturbances in our natural systems.

Seeing ourselves as part of ecosystems, with mutual relationships with our surroundings, recognises interdependencies not adequately addressed by the way we treat where we live.

Lancet Planetary Health August 2020

In sight but out of mind

Editorial

The human impact of climatic extremes is however complicated and in general worsened by the ongoing COVID-19 pandemic. At the time of writing some 9·6 million people are swamped by monsoon floods in south Asia compounding the difficulties and human tragedy of COVID-19 in the region. As the season continues heat waves are likely to challenge pandemic prevention measures in many regions.

The first half of this year has been among the hottest on record. As we have noted before, record breaking climatic conditions are now so common that reporting on them risks sounding repetitive and mundane.

Of course, global average temperature is just one measure of the climate and regional temperatures differ from that mean state. This year Siberia has experienced exceptionally high temperatures, with a record-breaking 38°C in the Russian town of Verkhoyansk in mid-June—the highest temperature ever recorded in the Arctic Circle. This heatwave is causing severe impacts in the region, including extensive wildfires, loss of permafrost, and invasive insect pests.

The evidence of human induced climate heating has never been clearer or more tangible.

Lancet Planetary Health August 11, 2020

Forward planning for disaster-related mass gatherings amid COVID-19

Shahul H Ebrahim, et al

Occurrences of extreme humid heat, higher than the optimal human survivability limit of 35°C, have more than doubled in frequency since 1979, leading to an increased frequency of tropical cyclones (also known as hurricanes or typhoons; panel). These are formed when ocean temperatures increase to greater than 27°C, and can move at speeds greater than 322 km/h; at landfall, they cause tornadoes, torrential rains, high winds, and flooding. Additionally, climate change is increasing the risk of extreme and longer wildfire seasons. Floods and landslides related to seasonal monsoon rains in the Indian subcontinent (typically starting in mid-June each year) have become frequent. In east Africa, the path of the monsoons and the new vegetation they provide are followed by an ongoing outbreak of desert locust swarms, decimating crops and livestock that depend on the vegetation. Further distal effects of the weather extremes might be unpredictable, such as extreme rainfalls triggering volcano eruptions, landslides, or breakage of dams. El Niño Southern Oscillation, which affects countries in the Pacific Rim from Peru to Indonesia and Australia, can also bring heavy rainfall and long droughts.

Panel: Global hotspots for tropical cyclones and their timing

The Atlantic basin; cyclone season June–November; around six of 12 storms reach category 3–5 in strength (5 being the highest).
The Eastern Pacific basin (includes the Central Pacific); cyclone season May–November; around 13 of 16 storms reach category 3–5.
The Northwest Pacific basin; cyclones throughout the year; the most active region, between three and 28 named storms are of category 3–5.
The North Indian basin; cyclone season April–December; around four to six storms occur of category 3–5.
The Southwest Indian basin; cyclone season October–May; average of ten cyclones throughout the year; storm category 2–4.
The Australian and Southeast Indian basin; cyclone season October–May; five of nine cyclones reach category 3–5.
The Australian and Southwest Pacific basin; cyclone season November–April; average of 16 cyclones per year of storm category 3–4.

Congregate shelters and large-scale population movements—hallmarks of a natural disaster response—can determine the rate of COVID-19 transmission and challenge the physical distancing requirements of lockdowns.

An inventory of available dwellings (for example, school buildings, community halls, and places of worship) or temporary structures such as tents should be developed. Envisioning options for adequate portable water and sanitation infrastructure is also crucial. Distribution sites for basic necessities such as food and medicine can serve as venues for continued pandemic risk communication and distribution of face coverings and preventive care for common water-transmitted and soil-transmitted conditions. COVID-19 testing capacity would need to be augmented to help respond to outbreaks. Disaster preparedness and planning should include staff from the national communicable disease control units, and focus on diseases that are likely to spread the fastest in displaced congregations with inadequate water and sanitation resources. A natural disaster plan that includes the triaging of a volunteer work force, use of national defence forces for supply chain management, facilitations of domestic philanthropies to substitute social support needs, and rapid access to UN resources can all help to optimise the use of shrinking domestic and global assets during this ongoing pandemic.

Pathophysiology;

Lancet Infectious Diseases, August 11, 2020

COVID-19 pandemic more than a century after the Spanish flu

Emilie Javelle, et al

If introduced in our contemporary world, the influenza strain that caused the 1918 Spanish flu would probably not repeat the same scenario. Autopsy series have revealed that the majority of deaths at any age resulted from bacterial coinfections with common species of the upper respiratory tract, including Streptococcus pneumoniae. Thus, antibacterial interventions and pneumococcal immunisation have substantially reduced the morbimortality of flu and probably explain the attenuation of influenza pandemic excess mortality during the past century.

Severe acute respiratory syndrome coronaviruses (SARS-CoVs) have a different pattern of disease. Autopsies during the 2002–03 SARS-CoV outbreak showed desquamative viral bronchio-alveolitis, but also interlobular and alveolar capillaritis and multiorgan vasculitis with associated thrombotic phenomena mostly in venules. In patients who died from SARS-CoV-2, anatomopathological analyses have highlighted small and medium arterial endothelial lesions with cytoplasm vacuolisation, cell detachment, and platelet plus fibrin aggregates. It appears then that, unlike influenza, severe and fatal SARS-CoV infections do not result from the combined occurrence of viral and bacterial pneumonia but are due to a secondary vascular and inflammatory disease in which immune responses dysregulation and host factors have a role.

Likewise, the age-specific patterns during influenza epidemics have been hypothesised to be driven by the immune history of the hosts, with a kind of imprinting induced by the influenza viruses encountered in life. Thus, the highest fatality rate in 1918 could have occurred in young adults because individuals older than 40 years had probably acquired a relative pre-immunity to influenza strains circulating before 1878. In 1977–78, the low proportion of influenza-related deaths among the group aged 20–65 years was linked with antibodies previously acquired against H1N1 viruses circulating before 1957. Similarly, this event might have thereafter reduced the attack rates of the 2009 H1N1 influenza virus in elderly people. To date, whether relative pre-immunity against SARS-CoVs exists is unknown. SARS-CoV-2 affects mainly older people, and access to high-quality health care probably explains in part disparities in SARS-CoV-2 mortality rates in people younger than 65 years. Partial protection against, or on the contrary antibody-dependent enhancement of, coronavirus disease could be conferred by previous exposure to antigenically related strains. However, specific antibodies against endemic coronaviruses are inconstantly acquired and of short duration.

Pathology

JAMA Otolaryngology - Head & Neck Surgery, August 13, 2020

Ultrastructural Evidence of Direct Viral Damage to the Olfactory Complex in Patients Testing Positive for SARS-CoV-2

Patrizia Morbini, et al

Authors report the clinicopathologic and ultrastructural postmortem findings observed in the olfactory system of 2 patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–positive nasal swabs who underwent minimally invasive autopsy, including nasal endoscopic dissection of the olfactory complex.

The first patient had anosmia and died of COVID-19 pneumonia in the intensive care unit; the second patient had ill-defined olfactory dysfunction and died of cardiopulmonary transthyretin amyloidosis. Transmission electron microscopy results revealed the presence of 80-nm to 100-nm viral particles on the cell membrane of ciliated respiratory cells in the olfactory mucosa of patient 2 (Figure 1, A). In the olfactory bulb (OB) samples of patient 1, transmission electron microscopy showed intracytoplasmic viral inclusion bodies (Figure 1, B) and interstitial viral particles (Figure 1, C). On light microscopy, the OB sections of patient 1 showed marked CD163-positive/CD68-negative microglial cell infiltration (Figure 2) that was associated with sparse CD3-positive lymphocytes, mostly of the CD8-positive cytotoxic subset.

Transmission electron microscopy micrographs showing viral particles (arrowhead) on the cytoplasmic surface (A) in the olfactory epithelium of patient 2, a viral cytoplasmic inclusion body (arrowhead) in the cytoplasm of a cell of the olfactory bulb of patient 1 (B), and viral particles in the interstitial space of the same sample from patient 1 (C).

Light micrographs of the olfactory bulb sample of patient 1 showing marked hypercellularity on hematoxylin-eosin (original magnification, ×10) (A), mostly composed of CD163–positive (B)/CD68-negative (C) macrophages on immunohistochemical stains (original magnification, ×20).

The recent finding of SARS-CoV-2 receptor angiotensin-converting enzyme 2 and TMPRSS2 transcripts in olfactory horizontal basal cells, microvillar cells, Bowman glands, and olfactory sustentacular cells, but not in olfactory neuron sensors, provided a proof of concept of the susceptibility of the olfactory organ to SARS-CoV-2 infection. We were able to identify SARS-CoV-2 particles in the OB of a patient with severe COVID-19 that were associated with a diffuse infiltration of CD163-positive macrophages and cytotoxic T lymphocytes.

Epidemiology

Lancet Digital Health, August 10, 2020

Applications of predictive modelling early in the COVID-19 epidemic

Chiara Poletto, et al

Regarding the most important application of these models, there has been notable success: predictive modelling correctly predicted that a global pandemic was probable and that there would be severe consequences for human health in the absence of strong public health measures to restrict human contact.

Predictive modelling is valuable when assumptions are related, the variables to be estimated are clearly defined, and researchers or policy makers who use the model outputs have a clear understanding of what can and cannot be achieved by this method. Indeed, calls for national disease-forecasting centres have arisen from the crucial need to educate policy makers at all levels on how to integrate predictive modelling into decision-making processes.

Deriving insights with predictive modelling requires diverse datasets, which are often imperfect, particularly in the crucial period of epidemic emergence when surveillance is imprecise and little is known about the epidemiology or the clinical features of the disease. For example, extensive clinical case counts and genomic data were combined with large-scale records of human mobility and behaviour using predictive modelling, owing in part to the massive deployment of digital information sources. In this Comment, we highlight several important discoveries resulting from the application of predictive modelling to diverse data sources that affected clinical and policy decisions.

In the weeks following the first report of COVID-19, predictive models anticipated the pattern of international spread but also quantified the extent of the epidemic in China. Specifically, a predictive model by Imai and colleagues used travel volumes from Wuhan and the dates when imported cases first arrived in cities within China and globally to forecast the size of the epidemic in Wuhan. The results of this study suggested that substantially more cases were present in Wuhan than were reported in the official statistics. Identifying the potential discrepancy between reported cases and true disease burden provided a crucial early warning to the international community. Next, statistical modelling and data-driven computer simulations provided accurate projections of global epidemic dispersal, quantifying the role of physical distancing in China and reductions in international travel on the spatiotemporal pattern of spread of COVID-19. These predictive models showed that the cordon sanitaire around Wuhan reduced the growth rate of exported cases but came too late to prevent national and international seeding. Control of the epidemic in countries outside China failed because of the difficulty in detecting and isolating infected travellers. Mechanistic modelling of the natural history and transmission of COVID-19 anticipated this difficulty. A predictive model provided the first evidence for the hypothesis, now widely accepted, that presymptomatic and asymptomatic infected individuals fuel local epidemics. Consequently, the majority of imported cases went undetected, generating extensive chains of local transmission. Owing to the difficulties of syndromic surveillance and incomplete testing, COVID-19 mortality has often been the most easily measured, widely available, and easily compared metric for epidemic progression. Estimates of infection fatality rates generated by early studies of expatriated travellers paved the way for later efforts to characterise unknown epidemic burden using various modelling approaches that relate mortality to unknown epidemic prevalence.

Lancet August 13, 2020

Sex differential in COVID-19 mortality varies markedly by age

Sunil S Bhopal, et al

Authors examined the sex ratio through the life course to see if the COVID-19 mortality sex-differential was the same at every age. They analysed data across England and Wales, France, Germany, Italy, Netherlands, Portugal, Korea, and Spain, covering an estimated population of 194 349 591 men and 201 715 364 women from the beginning of the pandemic until June 21, 2020. Belgium and the USA were not included due to presentation of data in different age categories.

These data alter our understanding of male–female differences; the relationship is not straightforward, and efforts should now be made to understand risk based on the interaction of sex and age, along with other factors.

Hypotheses based on risk factors that are known to change with both sex and age seem to be the most probable explanations for the differences observed. These include differences in occupation, lifestyle (including smoking and alcohol use), medical comorbidities, or use of medications. These explanations reflect social and cultural factors related to gender rather than the biology of sex. Genetic explanations will need to consider the interaction of age, sex, and the risk factors previously mentioned through the life course, including gene expression and epigenetics.

JAMA Network, August 13, 2020

Characteristics and Outcomes of COVID-19 Patients During Initial Peak and Resurgence in the Houston Metropolitan Area

Farhaan S. Vahidy, et al

An increase in COVID-19 hospitalizations was observed across a major health care system in the greater Houston area, which was temporally related to phased reopening. Throughout the reporting period, hospital admission guidelines were consistently based on risk stratification by evaluation of severity of symptoms, comorbidities, diagnostic findings, and pulse oximetry. During surge 2, the absolute number of RT-PCR tests performed increased, as did the proportion of positive results. Therefore, higher hospital census likely reflects higher rates of community COVID-19 prevalence. Surge 2 data indicated a demographic shift of the pandemic toward a younger, predominantly Hispanic, and lower socioeconomic patient population with an overall lower comorbidity burden, ICU admission rate, and in-hospital mortality. The demographic and socioeconomic shift may reflect return to work and relaxation of COVID-19 transmission mitigation practices. Additionally, in-hospital mortality among ICU-treated surge 2 patients was 4.6% lower than that in surge 1. The overall better outcomes during surge 2 may be explained by a combination of lower comorbidity burden, lesser disease severity, and better medical management.

Texas is experiencing resurgence of coronavirus disease 2019 (COVID-19). Authors report sociodemographic, clinical, and outcome differences across the first and second surges of COVID-19 hospitalizations at Houston Methodist, an 8-hospital health care system in Houston, Texas.

As of July 7, 2020, 2904 unique COVID-19 patients had been hospitalized, representing 774 and 2130 patients during surge 1 and 2, respectively. The Figure presents total, ICU, and non-ICU daily hospital census along with a 7-day mean across the study period. Dates corresponding to various phases of statewide reopening are also highlighted. Patients in surge 2 (vs surge 1) were younger (mean age, 57.3 vs 59.9 years; difference, −2.62 years; 95% CI, −4.04 to −1.20 years), the proportion identifying as Hispanic was higher (43.3% vs 25.7%; difference, 17.64%; 95% CI, 13.89%-28.79%), and the median zip code–based income was lower ($60 765 vs $65 805; difference, −$5040; 95% CI, −$7641 to −$2439). Surge 2 patients had a significantly lower burden of overall and specific comorbidities such as diabetes, hypertension, and obesity.

Daily Hospital Census of Total, Intensive Care Unit, and Non–Intensive Care Unit COVID-19 Patients Across Houston Methodist: Daily hospital census of coronavirus disease 2019 patients across all Houston Methodist hospitals is provided for total, intensive care unit (ICU), and medical/surgical (non-ICU) units. The dashed gray line represents a running 7-day mean total hospital census. SAHO indicates stay-at-home order. Various timeline markers correspond to statewide gubernatorial reopening plan: phase 1, opening of retail stores, malls, restaurants, and nail salons at 25% capacity; phase 2, opening of child care centers, massage parlors, youth clubs, bars, and nightclubs, with phase 1 reopening expanded to 50%; and phase 3, bars allowed to operate at 50% capacity.aMemorial Day holiday weekend, bLarge public rallies in Houston.

A greater proportion of surge 2 patients received remdesivir and enoxaparin. A smaller proportion of surge 2 patients were admitted to the ICU (20.1% vs 38.1%; difference, −18.07%; 95% CI, −21.89% to −14.25%). Length of hospital stay was less (4.8 vs 7.1 days; difference, −2.31 days; 95% CI, −2.78 to −1.84 days). Among dead or discharged patients (n = 2252 [77.5%] overall; n = 774 in surge 1 and n = 1478 in surge 2), surge 2 in-hospital mortality was significantly lower compared with that for surge 1 (5.1% vs 12.1%; difference, −7.07%; 95% CI, −9.63% to −4.51%). In-hospital mortality among discharged and deceased ICU-treated patients during surge 2 was not significantly lower than that during surge 1 (49/214 [22.9%] vs 81/295 [27.5%]; difference, −4.56%; 95% CI, −12.15% to 3.03%). The mean daily proportion of individuals with positive RT-PCR results during surge 1 was 13%, whereas it was 25% during surge 2.

Clinical Practice and Innovations in Care Delivery

NEJM, August 12, 2020

Covid-19 and the Mandate to Redefine Preventive Care

Daniel M. Horn, et al

A large-scale shift to a population-based prevention strategy is long overdue. The Covid-19 pandemic is delaying life-saving preventive screening for millions of patients, and our health system will struggle to catch up. Perhaps this crisis will be the impetus for change.

Authors believe the U.S. health care system should embrace this moment as an opportunity to shift the focus of preventive care from face-to-face annual exams to a strategy that focuses on population health: clinical registries that readily identify all preventive services for which a patient is due; annual prevention kits for patients that facilitate widespread deployment of home-based testing, shared decision making, and self-scheduling of preventive screening tests and procedures in more convenient and approachable community settings; and robust community-based strategies involving navigators to overcome health disparities in underserved populations.

The primary hurdles for implementation of this plan are payment reform and provider and patient acceptance.

Clinical Manifestations

Lancet Child Adolescent Health, August 10, 2020

Multisystem inflammatory syndrome associated with COVID-19 in children in Pakistan

Masood Sadiq, et al

Authors report the initial experience from The Children's Hospital Lahore, Pakistan—the first report of this new inflammatory syndrome from south Asia.

There are eight children so far who fulfil both the WHO criteria of Multisystem inflammatory syndrome in children (MIS-C), and paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS). All the children were male, except one, and the age range was 5–15 (median 9·5) years. Three patients had a positive PCR for SARS CoV-2 but none of the patients had been symptomatic with classic COVID-19 respiratory symptoms in the 6 weeks prior to admission. No comorbid condition was present in any of the children. SARS-CoV-2 antibodies were positive for all eight of the patients. Despite being clinically unwell, with laboratory evidence of elevated C-reactive protein, ferritin, and D-dimers, no pathological organism was isolated in any of the eight children.

There were two major presentations: one as atypical or typical Kawasaki disease (6 of 8, 75%) and a more severe second one with shock or low cardiac output (2 of 8, 25%). Common presenting features were fever, body aches, and abdominal pain. Patient 2 presented with altered consciousness and signs of meningism, and an initial diagnosis of meningoencephalitis was made. He had cardiopulmonary resuscitation for 10 min and was intubated and ventilated before the diagnosis of MIS-C could be made. This child had acute myocardial dysfunction, became hypotensive and showed clinical signs of vasoplegia. He went into multiorgan failure and died on day 10 of ventilation. Patient 6 also presented with high-grade fever and signs of meningism. He needed inotropic support and volume resuscitation but did not need ventilation and recovered.

The other six children (patients 1, 3, 4, 5, 7, and 8) presented more subacutely with presentation resembling Kawasaki disease; all had at least two features of classic Kawasaki disease. Two of these six patients (patients 7 and 8) had sufficient criteria for typical Kawasaki disease. None of these six children showed evidence of myocardial dysfunction, although pericardial effusion was observed in 3 of 6 children.

Coronary artery dilatation was seen in five (62·5%) patients. Both children with shock-like presentation had coronary artery involvement, but two patients who fulfilled the Kawasaki disease criteria showed healthy coronary arteries. All children except one (7 of 8, 87·5%) received intravenous immunoglobulin (2 g/kg bodyweight) within the first 2 days of their stay. Three patients received therapeutic anticoagulation (enoxaparin) on the basis of the high risk of thromboembolism and amount of D-dimers. With the exception of the one death discussed already, the other seven children have been discharged home.

Children and adolescents younger than 20 years of age constitute 10·6% (24 625 of 231 818) of the total reported confirmed cases of COVID-19 in Pakistan as of July 8, 2020, with a mortality of 0·3% for those aged 10 years or younger and 0·5% for those aged 11–20 years. With the ongoing spread of this virus in countries such as Pakistan, the paediatric and cardiology communities should be mindful of this emerging disease.

Lancet August 11, 2020

Pseudotumor cerebri syndrome associated with MIS-C: a case report

Lana D Verkuil, et al

A previously healthy 14-year-old girl with diffuse dilation of the right coronary artery. Presumed atypical Kawasaki shock syndrome was treated with intravenous immunoglobulin and intravenous methylprednisolone. During hospitalization she developed pseudotumor cerebri for which Acetazolamide 250 mg twice daily and an oral prednisone taper were prescribed. She recovered fully.

Multisystem inflammatory syndrome in children (MIS-C) is a recently reported paediatric syndrome associated with SARS-CoV-2 infection. Based on this patient's papilloedema, abducens palsy, normal brain parenchyma, and increased cerebrospinal fluid opening pressure with normal constituents, in the setting of MIS-C, she meets criteria for secondary pseudotumor cerebri syndrome (PTCS). PTCS might be primary (idiopathic intracranial hypertension); however, inflammatory and infectious conditions have been implicated as secondary causes.

Although cerebrospinal fluid dynamics were altered in our patient with MIS-C, the mechanism remains unclear. Doxycycline was thought to be non-contributory because doxycycline-related PTCS typically occurs after 1–2 months of use. As our understanding of MIS-C evolves, an ocular fundus examination might be required as part of a multi-system approach to assess patients with suspected MIS-C. PTCS is a potentially vision-threatening condition and should be considered in this clinical setting.

Diagnosis

Lancet, August 13, 2020

SARS-CoV-2 PCR testing of skin for COVID-19 diagnostics: a case report

Dagmar Jamiolkowski, et al

This case emphasises the use of SARS-CoV-2 PCR testing of skin biopsy samples as an additional diagnostic tool, helping to shed light on the actual prevalence of COVID-19 in the general population.

Colmenero and colleagues detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in endothelial cells of cutaneous chilblain lesions via immunohistochemistry methods in seven paediatric patients with negative nasopharyngeal swabs.

Here, we report the case of an 81-year-old woman who presented with a temperature of up to 39°C and a generalised macular eruption with partial vasculitis-like patterns and palmoplantar accentuation.

A SARS-CoV-2 PCR (nasopharyngeal swab, Cobas SARS-CoV-2 Test, Roche Diagnostics, Rotkreuz, Switzerland) was negative. 6 weeks later, serology tests against anti-SARS-CoV-2 antibodies (Elecsys Anti-SARS-CoV-2, Roche Diagnostics, Rotkreuz, Switzerland) were negative.

Figure: SARS-CoV2 in human skin. (A) Clinical images of the back, (B) thighs and (C) palms showing a generalized macular eruption. (D) Whole skin biopsy with subacute lichenoid interface dermatitis and perivascular lymphohistiocytic infiltration in the upper dermis (H&E, 400x).

A lesional whole skin 4 mm punch biopsy sample was taken from the left flank, which showed a subacute lichenoid interface dermatitis with vacuolisation of the basal epidermal keratinocytes and scant lymphohistiocytic perivascular infiltration in the upper dermis. No leukocytoclastic vasculitis or microthrombosis was present. Over the next 2 weeks, the patient's rash gradually improved.

PCR testing of the skin using established methods1 detected SARS-CoV-2 at low copy numbers (37 per 1 × 106 human RPPH1 copies).

Prevention

JAMA August 13, 2020

An Inactivated Virus Candidate Vaccine to Prevent COVID-19

Mark J. Mulligan

This preliminary report by Xia et al provides important interim safety, tolerability, and immune response results for a β-propiolactone–inactivated whole-virus vaccine against COVID-19. These interim data are of interest given the urgent global need for protective COVID-19 vaccines. With 7.8 billion individuals worldwide at risk for SARS-CoV-2 infection and COVID-19 morbidity and mortality, humanity needs as many safe and protective COVID-19 vaccines as possible.

In this issue of JAMA, Xia and colleagues report results from an interim analysis of data for a SARS-CoV-2–inactivated virus vaccine plus adjuvant, the first protein immunogen COVID-19 vaccine candidate to be reported. The authors report preliminary findings from phase 1 and 2 randomized, active-controlled (aluminum hydroxide [alum]), double-blind, clinical trials of a β-propiolactone–inactivated SARS-CoV-2 vaccine adjuvanted in 0.5 mg of aluminum hydroxide. Healthy participants aged 18 to 59 years were enrolled and the trials were conducted in Henan Province, China. In phase 1, which included 96 healthy adults, 3 immunogen (inactivated virus) dose levels were studied (2.5, 5, and 10 µg, and an alum adjuvant–only dose; 24 participants in each group) and 3 vaccinations were administered on days 0, 28, and 56. For phase 2, which included 224 healthy adults, the middle dose (5 µg) was selected and administered twice at intervals shorter than in phase 1, either days 0 and 14 or days 0 and 21 (n = 84 in each group; plus 28 alum-only participants for each schedule).

Tolerability was assessed with a diary card, which participants completed for 7 days after each vaccination and recorded the presence, severity, and duration of solicited local reactions (eg, injection site pain, redness, swelling) and solicited systemic reactions (eg, fever, headache, fatigue). Safety was assessed by analysis of blood chemistry and hematology at 4 days after each injection and by collection of unsolicited adverse events and serious adverse events occurring during the 28-day period after vaccinations. The primary immunogenicity end point was SARS-CoV-2 neutralization measured as a 50% plaque reduction neutralization test (PRNT50) of serum samples collected 14 days after final vaccination.

This preliminary report indicates that the inactivated whole-virus vaccine candidate was tolerated, safe, and produced neutralizing antibodies at 14 days after booster vaccination. The primary safety outcome, 7-day postinjection adverse reactions, occurred in the phase 1 trial in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum-only, low-dose, medium-dose, and high-dose groups, respectively, and in the phase 2 trial occurred in 5 (6.0%), 4 (14.3%), 16 (19.0%), and 5 (17.9%) patients in the days 0 and 14 vaccine, days 0 and 14 alum-only, days 0 and 21 vaccine, and days 0 and 21 alum-only groups, respectively. The most common adverse events were injection site pain, followed by fever, both of which were self-limited and mild. For the primary immunogenicity outcome, neutralizing antibody response at 14 days after the final booster vaccination, the geometric mean titers of neutralizing antibodies in the phase 1 trial in the low-, medium-, and high-dose groups were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, and in the phase 2 trial were 121 (95% CI, 95-154) and 247 (95% CI, 176-345), respectively, in the days 0 and 14 and days 0 and 21 vaccine groups.

JAMA August 13, 2020

Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes

Interim Analysis of 2 Randomized Clinical Trials

Shengli Xia; et al

This inactivated COVID-19 vaccine had a low rate of adverse reactions and demonstrated immunogenicity, but longer-term assessment of safety and efficacy will require phase 3 trials.

This is the first report of phase 1 and 2 clinical trials of a whole-virus inactivated COVID-19 vaccine among healthy adults. The inactivated vaccine was well tolerated in all dose groups under different injection procedures with no vaccine-related serious adverse events. The most common adverse reaction was injection site pain, which was mild and self-limiting. The incidence rate of adverse reactions in the current study (15.0% among all participants) was lower compared with results of other candidate vaccines. Although all these studies reported that the adverse reactions were mostly mild and moderate in severity and self-limiting, the incidence rates in the vaccine groups (mostly >60% and in some studies 100%) were higher compared with the control group. Therefore, the inactivated vaccine in the current study suggests a relatively better safety profile compared with vaccines using other platforms.

Screening, Randomization, and Inclusion in Safety and Immunogenicity Analyses of Inactivated Vaccine for SARS-CoV-2: Laboratory tests included routine blood tests, liver enzymes, total bilirubin, creatinine, urea nitrogen, urine protein, urine sugar, and urinary occult blood. bThe comorbidities in the exclusion criteria included cardiovascular disease, cancer, respiratory disease, autoimmune disease, tuberculosis, severe liver disease, congenital malformation, mental illness, nervous system diseases, uncontrolled hypertension and diabetes, severe malnutrition, fever within 14 days, and other diseases that could affect participation and compliance in the trial as judged by the investigators. cThe low, medium, and high doses represent 2.5, 5, and 10 μg/dose, respectively.

Antibody Responses at Different Time Points in the Phase 1 Trial: The dots represent individual participant values. Boxplots show the 25th, 50th (median), and 75th percentiles. Whiskers extend to the upper and lower adjacent values, the farthest values within 1.5 × the interquartile range beyond the 25th and 75th percentiles. The numbers below the boxes indicate the number of participants at the lowest measurable value. Alum indicates aluminum hydroxide; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Antibody Responses 14 Days After the Second Dose in the Phase 2 Trial: Prevaccination is not shown; there were 14 participants in both aluminum hydroxide (alum)–only groups and 42 in both of the medium-dose vaccine groups. No measurable antibody responses could be detected at baseline, and thus, the baseline values were all imputed by the lower limit of detection of the assays, which was 5 for the neutralizing antibody measurement and 10 for the specific IgG-binding antibody measurement. The dots represent individual participant values. Boxplots show the 25th, 50th (median), and 75th percentiles. Whiskers extend to the upper and lower adjacent values, the farthest values within 1.5 × the interquartile range beyond the 25th and 75th percentiles. The numbers below the boxes indicate the number of participants at the lowest measurable value. Only half of the participants in the phase 2 trial were scheduled for the hormoral immunogenicity measurement at day 14 after the second injection. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2.

JAMA Internal Medicine, August 11, 2020

Filtration Efficiency, Effectiveness, and Availability of N95 Face Masks for COVID-19 Prevention

Caitlin M. Dugdale, et al

We endorse the health care community’s cry for the best possible protection for all frontline clinicians and essential health care workers. We are further reassured by the cross-sectional study from Long Island, New York, also in this issue of JAMA Internal Medicine, demonstrating that the effectiveness of PPE; the frequency of SARS-CoV-2 antibody positivity among hospital employees required to use PPE was no higher than that of the general population in that area. Taken together, these and other emerging data suggest that surgical masks and N95 alternatives will continue to keep clinicians and health care workers safe.

Results of the following study demonstrated that N95 masks reprocessed using ethylene oxide sterilization, as well as masks that are up to 11 years past expiration, maintain very high filtration efficiency under laboratory conditions. N95 masks with suboptimal fit still had comparable filtration efficiency of more than 90%. Their KN95 counterparts, millions of which have been purchased by or donated to US hospitals, performed less well, with filtration efficiency ranging from 53% to 85%. Surgical masks secured with either ties or ear loops also had much lower filtration efficiency of 37% to 69%, as might be expected by their more comfortable, thinner filter and looser fit.

Although surgical masks have lower filtration efficiency than N95 respirators, observational studies have shown no significant benefit of N95 masks over surgical masks for prevention of severe acute respiratory syndrome coronavirus (odds ratio, 0.86; 95% CI, 0.22-3.33) or other respiratory viruses (odds ratio, 0.96; 95% CI, 0.85-1.08). For health care workers, routine care for a patient with COVID-19 if both are wearing surgical masks is not considered to be a high-risk occupational exposure. Yet, SARS-CoV-2 viral particles have been identified in the air for several hours after an aerosolizing event simulated in a laboratory and near air vents in a clinical setting. There has been concern for the possibility of SARS-CoV-2 airborne transmission; however, the viability and infectiousness of SARS-CoV-2 viral particles in aerosol form remains unknown. Importantly, no documented SARS-CoV-2 outbreaks have been linked to settings in which surgical masks were assiduously used in lieu of N95 masks, which suggests that even if airborne transmission is a considerable contributor to SARS-CoV-2 transmission, surgical masks are likely sufficient to prevent it. Because the infectious dose of virus required to cause clinical infection also remains unknown, it is possible that blocking most, even if not all, viral particles through masks with lower filtration efficiencies of submicron particles is sufficient to prevent disease in the vast majority of cases.

Beyond N95 laboratory-based efficacy and ensuring proper fit-tested use, costs have been a major challenge in procurement of adequate mask supply, with prices increasing in some cases up to 30- to 100-fold. Outside of pandemic conditions, surgical and N95 masks generally cost approximately $0.08 and $0.50 each, respectively. Standard pricing for KN95 masks, which are generally not sold in the United States, is unavailable, but they have been sold during the crisis from $2 to $4 per mask. Expired masks, which would otherwise be discarded, should be cost free. While competition and price gouging for masks has certainly hindered access, supply has been the biggest problem. Reprocessed masks, which can cost up to 6 times the original price of the mask itself, are among the few solutions to continued inadequate supply. Until we have a better understanding of how filtration efficacy translates to improved protection against SARS-CoV-2 transmission, health care systems are left to pay top dollar to keep their most valuable resources—clinicians and health care workers—safe.

In the following article, Sickbert-Bennett and colleagues demonstrate that reprocessed use and expired supply of N95 masks are safe and offer excellent alternatives to standard single-use N95 masks. Despite lower filtration efficiencies of submicron particles, surgical masks and other N95 alternatives likely provide adequate protection against transmission for routine care.

JAMA Internal Medicine, August 11, 2020

Filtration Efficiency of Hospital Face Mask Alternatives Available for Use During the COVID-19 Pandemic

Emily E. Sickbert-Bennett, et al

Evidence from previous studies suggests that even face masks with less than 95% FFE (eg, surgical masks) are effective in preventing acquisition of epidemic coronaviruses (ie, severe acute respiratory syndrome coronavirus 1, SARS-CoV-2) by clinicians and other health care workers except possibly during aerosol-generating procedures. For prevention of a related coronavirus, severe acute respiratory syndrome coronavirus 1, N95 respirators had no increased prevention benefit over surgical masks. However, the CDC and Infectious Diseases Society of America has recommended the use of N95 respirators especially during aerosol-generating procedures as long as the supplies are available. This evaluation provides quantitative results on which health care administrators, supply chain leaders, and hospital epidemiologists can make evidence-based decisions to protect clinicians and other health care workers during a pandemic or long-term mask shortage.

Of the 29 different fitted face mask alternatives tested on 1 man and 1 woman, expired N95 respirators with intact elastic straps and respirators subjected to ethylene oxide and hydrogen peroxide sterilization had unchanged Comparative fitted filtration efficiencies (FFE) (>95%). The performance of N95 respirators in the wrong size had slightly decreased performance (90%-95% FFE). All of the respirators not listed as approved in this evaluation (n = 6) failed to achieve 95% FFE. Neither of the 2 imported respirators authorized for use by the Centers for Disease Control and Prevention that were not NIOSH-approved tested in this study achieved 95% FFE, and the more effective of the 2 functioned at approximately 80% FFE. Surgical and procedural face masks had filtering performance that was lower relative to that of N95 respirators (98.5% overall FFE), with procedural face masks secured with elastic ear loops showing the lowest efficiency (38.1% overall FFE).

Evaluation of Fitted Filtration Efficiency (FFE) Using the Occupational Safety and Health Administration Modified Ambient Aerosol CNC Quantitative Fit Testing

Protocol for Filtering Facepiece: When used on a man, the overall FFE for a National Institute for Occupational Safety and Health–approved N95 respirator was 98.5% (A), the overall FFE of a surgical mask with ties was 71.5% (B), and the overall FFE of a procedural mask with elastic ear loops was 38.1% (C). Data correspond to particle penetration into the face mask as expressed as the percentage of total particle/cc measured simultaneously outside of the face mask.

Treatment

JAMA Network, August 11, 2020

Regulatory T Cells Tested in Patients With COVID-19 ARDS

Jennifer Abbasi

Two men with coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) survived after treatment with off-the-shelf regulatory T cells, also known as Tregs, Johns Hopkins physicians recently reported. The investigational allogenic Tregs with lung-homing markers were derived from cord blood.

The critically ill patients, aged 69 years and 47 years, had multiorgan failure and had been treated with therapies including tocilizumab, hydroxychloroquine, broad-spectrum antibiotics, vasopressors, and inhaled nitric oxide. The men were intubated in prone positions and the 47-year-old received extracorporeal membrane oxygenation (ECMO) support.

The men eventually were extubated and needed tracheostomies. When the study was written, the patient who had undergone ECMO was discharged home and the other was at a ventilator weaning facility.

JAMA Surgery, August 11, 2020

Extracorporeal Membrane Oxygenation for Patients With COVID-19 in Severe Respiratory Failure

Asif K. Mustafa, et al

This study demonstrates promising outcomes, with most patients alive and no longer receiving ventilator care and ECMO support and 73% discharged and no longer receiving oxygen. Complications have been minimal; there were no ischemic strokes, inotropic support, and tracheostomy requirements because of the early extubation strategy. Mortality was 15%.

Authors present the experience in using single-access, dual-stage venovenous ECMO, with an emphasis on early extubation of patients while they received ECMO support.

Care with ECMO was performed in 40 consecutive patients between the ages of 22 and 64 years (mean [SE] age, 48.4 [1.5] years); 30 (75%) were men, 16 (40%) were African American individuals, and 14 (35%) were Hispanic individuals. The mean (SE) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 34.2 (1.1). Obesity was the primary preexisting condition (28 patients [70%]). All patients reached maximum ventilator support, with 90% placed in a prone position (29 patients [73%]), paralyzed (31 patients [78%]), or both, pre-ECMO; 24 patients (60%) required vasopressors. Eleven patients could not be placed in a prone position because of increasing hemodynamic instability and/or worsening oxygenation or ventilation with pronation. All patients demonstrated considerably elevated levels of inflammatory markers, such as D-dimer and ferritin, prior to ECMO use. The mean (SE) time from intubation to ECMO was 4.0 (0.5) days.

As of July 17, ventilator support has been successfully discontinued in all patients, resulting in a mean (SE) time of 13.0 (2.6) days from ECMO initiation to extubation, while 32 (80%) were no longer receiving ECMO care. Twenty-nine (73%) have been discharged from the hospital while no longer receiving oxygen. Complications have been minimal, with no ischemic strokes, inotropic support, or tracheostomies. Ten patients required reintubation; however, they have all since been extubated. Mortality was 15% (6 patients). All patients were treated with systemic anticoagulation.

A, Timeline with detailed mean (SE) durations of the various treatment phases. Percentages of patients who have been extubated, decannulated from extracorporeal membrane oxygenation (ECMO), and discharged from the hospital are also stated. All data points include 40 patients unless otherwise indicated. B, Cumulative number of events are plotted by date. ICU indicates intensive care unit.

Lancet Respiratory Medicine, August 13, 2020

ECMO for severe ARDS associated with COVID-19: now we know we can, but should we?

Kiran Shekar, et al

The scale and quality of ECMO care, if replicated in other jurisdictions, might potentially save lives; however, clearly at a cost in terms of resources and potential complications. Any decisions on whether and when to use ECMO for very severe COVID-19 would have to be made locally with a clear recognition of the extensive resources required (mainly human resources), the expected caseload, and the potential implications for other patients.

Early reports also suggested that patients with severe ARDS associated with COVID-19 should not receive venovenous extracorporeal membrane oxygenation (ECMO) because mortality ranged from 84–100% in patients treated with ECMO. In The Lancet Respiratory Medicine, Matthieu Schmidt and colleagues present a cohort study of 83 patients (median age 49 [IQR 41–56] years; 61 [73%] men) who received ECMO for severe ARDS associated with COVID-19 in the Paris–Sorbonne University Hospital Network intensive care units (ICUs). Their results showed an estimated 31% (95% CI 22–42) probability of death at 60 days, which is similar to that seen in studies of ECMO for severe ARDS outside the pandemic. However, 24% of patients were still in the ICU on day 60. Notably, patients received outstanding pre-ECMO management with high adherence to evidence-based ARDS practices, including prone-positioning in 78 (94%) patients.

It is difficult to draw valid conclusions from comparisons with historical data, especially given that these patients were substantially younger than previously reported patients with severe ARDS associated with COVID-19, and increased age is a well supported risk factor for mortality. Furthermore, although the data are encouraging, the results might not be generalisable, as they come primarily from one highly experienced ECMO centre, and there is a known relationship between hospital-level volume of ECMO cases and patient outcomes when using ECMO.

Lancet Respiratory Medicine, August 13, 2020

Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study

Matthieu Schmidt, et al

The estimated 60-day survival of ECMO-rescued patients with COVID-19 was similar to that of studies published in the past 2 years on ECMO for severe ARDS. If another COVID-19 outbreak occurs, ECMO should be considered for patients developing refractory respiratory failure despite optimised care.

From March 8 to May 2, 2020, 492 patients with COVID-19 were treated in our ICUs. Complete day-60 follow-up was available for 83 patients (median age 49 [IQR 41–56] years and 61 [73%] men) who received ECMO. Pre-ECMO, 78 (94%) patients had been prone-positioned; their median driving pressure was 18 (IQR 16–21) cm H2O and PaO2/FiO2 was 60 (54–68) mm Hg. At 60 days post-ECMO initiation, the estimated probabilities of occupation in each state were 6% (95% CI 3–14) for state 1, 18% (11–28) for state 2, 45% (35–56) for state 3, and 31% (22–42) for state 4. 35 (42%) patients had major bleeding and four (5%) had a haemorrhagic stroke. 30 patients died.

Study profile for patients included in this study, and their outcomes on July 10, 2020. ICU=intensive care unit. ECMO=extracorporeal membrane oxygenation.

Stacked probability plot for the multi-state model, The plot illustrates the actual state occupation probabilities of being in each endpoint state—on ECMO, in ICU and weaned off ECMO, alive and out of ICU, or died—over the 90 days following ECMO implantation. The respective probabilities and mean lengths of stay (with 95% CI) in each of these four states are reported in table 4. See the appendix (p 15) for all possible transition probabilities from one state to another over time. ECMO=extracorporeal membrane oxygenation. ICU=intensive care unit.

An autopsy-based histological analysis of the pulmonary vessels of patients with COVID-19 showed widespread thrombosis with microangiopathy, with alveolar capillary microthrombi being nine times more frequent in patients with COVID-19 than in those with influenza. Consistent with other series, authors also observed an unusually high on-ECMO rate of proven pulmonary embolism (19%), an event not reported for the 156 patients treated with ECMO in the EOLIA trial. Those thromboembolic events occurred, despite an early increase of our anticoagulation target for patients with COVID-19 receiving venovenous ECMO support, suggesting that other strategies, beyond systemic anticoagulation, are warranted to care for SARS-CoV-2 induced lung endothelial injuries. It should also be noted that haemorrhagic stroke occurred in 5% of our patients, which was more frequent than in the EOLIA trial (2%).3 The higher anticoagulation regimen, and specific SARS CoV-2-associated vasculitis and critical illness associated microbleeds could explain this finding. However, the frequency of severe haemorrhagic events requiring transfusion in our study was similar to those of patients treated with ECMO in the EOLIA trial.

Compared with the EOLIA trial of patients with severe ARDS (44% bacterial and 21% viral pneumonia) treated with ECMO,3 in our study of patients with COVID-19, ECMO support (median 20 [IQR 10–40] days vs 11 [7–18] days) and ICU stay (36 [23–60] days vs 23 [13–34] days) lasted longer, highlighting the great severity of SARS-CoV-2 associated pulmonary damage and organ failure. Still, the needs for circuit changes were similar to those reported in a previous venovenous ECMO series. Septic shock was the primary cause of death in 10 (33%) of 30 patients but none of them were converted to venoarterial or venoarterial-venous ECMO for cardiovascular support. Indeed, the use of these types of ECMO has been proposed in patients with septic shock with severe myocardial dysfunction and decreased cardiac index, which was not the case in our patients. Lastly, our antibiotic-treated ventilator-associated pneumonia rate was higher (87%) than for patients in the EOLIA trial (39%), and might reflect the longer mechanical ventilation or specific SARS-CoV-2 induced immunoparalysis. It should also be noted that few of our patients received high-dose corticosteroids.

Special Groups

JAMA Internal Medicine, August 11, 2020

Prevalence of SARS-CoV-2 Infection Among Health Care Workers in a Tertiary Community Hospital

Allen Jeremias, et al

The findings of the present study indicate that the rate of SARS-CoV-2 infection among health care workers is lower than what has been reported for the general public in the surrounding region. Given that health care workers in hospitals are exposed to a much higher density of the virus, this is strong evidence that current PPE practices are protective, easing health care workers’ concern and psychological distress.

Employees were tested with a reverse transcriptase–polymerase chain reaction (RT-PCR) test and an antibody test from March 1 to April 30, 2020, at a large tertiary community hospital in Roslyn, New York. The health system began offering antibody testing (Anti-SARS-CoV-2 ELISA [IgG] [EUROIMMUN US]; SARS-CoV2-IgG [Abbott]) on April 16, 2020, and encouraged all employees to be tested. Antibody testing was performed in workers who were asymptomatic or were previously symptomatic with no symptoms for at least 14 days. Hospital employees who had symptoms of COVID-19 were offered the RT-PCR test (cobas SARS-CoV-2 [Roche] and Xpert Xpress SARS-CoV-2 [Cepheid]). All testing was on a voluntary basis. Personal protective equipment (PPE) policy was based on US Centers for Disease Control and Prevention guidelines and was dependent on risk of exposure. All employees caring for patients with COVID-19 were required to wear an N95 mask, isolation gown, and gloves. Health care workers involved with procedures that could generate aerosolized virus dispersal, such as mechanical intubation, required additional eye protection.

Among 3046 employees, 1699 (56%) underwent antibody testing, 617 (20%) underwent RT-PCR testing, and 359 (12%) underwent both. The average (SD) age among all employees was 42.8 (13.8) years and 2137 (70%) were women. When comparing employees who elected to undergo either form of testing vs those who did not, there were no meaningful differences with respect to age, job title, or work area.

There were 167 employees (9.8%) who tested positive for antibodies. There was no significant difference in antibody positive rates across job titles or work areas (Figure).

Health Care Workers Who Tested Positive for SARS-CoV-2 Antibodies by Job Title and Department: Percentage of employees who tested positive for antibodies based on job title (A) and department (B). The dotted line indicates the general population on Long Island. A total of 1699 employees were surveyed, including 322 in ancillary services, 100 in environmental health, 1043 nurses, 79 physicians, and 155 technologists. Of the 1699 employees, 88 worked in the emergency room (ER), 489 on the hospital floor, 321 in the intensive care unit (ICU), 400 in operational services (ie, employees who rotate through all areas of the hospital), 243 in procedural services (eg, operating room, cardiac procedures, diagnostic radiology procedures, endoscopy), and 158 in other services

When comparing the prevalence of antibodies among hospital employees with the rate reported by the State of New York for the general public on Long Island, hospital employees had a significantly lower positive rate (9.9% vs 16.7%, P < .001).

Employees with positive antibody test results were similar in age (41.5 [SD, 13.5] vs 43.4 [SD, 13.7] years, P = .09) and sex (women 9.4% vs men 11.1%, P = .31). There was no significant difference between race as a whole. There was no significant difference in infection rates among those working in high vs low exposure areas (10.9% vs 10.9%, P = .99).

Special Countries

Lancet Global Health, August 13, 2020

Biomedical waste amid COVID-19: perspectives from Bangladesh

Mostafizur Rahman, et al

Worldwide, it is estimated that at least 5·2 million people, including 4 million children, die each year because of diseases related to unmanaged medical waste.

Bangladesh, there are around 654 government hospitals and 5055 private hospitals and clinics with 141 903 beds in total, along with an additional 9061 diagnostic centre beds, all of which lead to the generation of huge amounts of biomedical waste. The average medical waste generation rate is 1·63–1·99 kg per bed per day in Dhaka, the capital of Bangladesh. In April 2020, at least 14 500 tonnes of waste from health care was generated across the country because of COVID-19, which has undoubtedly increased due to the increasing infection rate. Also, on average, 206 tonnes of medical waste are produced because of COVID-19 per day in Dhaka alone. This poorly managed waste poses a large environmental threat and might create a prolonged and unwanted public health hazard and be a potential source of re-emerging infection.

Approximately 40 000 informal waste collectors working across the country are at high risk of getting infected by SARS-CoV-2 because they work without adequate protection. There might be a serious risk of spreading SARS-CoV-2 if used masks, gloves, and other personal protective equipment are not managed and disposed of properly. Additionally, household waste (eg, tissues, masks, gloves) puts waste management workers at increased health risk.

Miscellaneous

JAMA Network, August 13, 2020

Researchers Strive to Recruit Hard-Hit Minorities Into COVID-19 Vaccine Trials

Mary Chris Jaklevic

Perhaps the biggest hurdle is that many people of color don’t believe the health care system will act in their interest. Memories of abusive research practices, including the government’s notorious Tuskegee syphilis study that ended in 1972, are “still alive and well in people’s memory.

Given the rate at which they are getting sick and dying, Brooks said people of color don’t have the luxury of time.

COVID-19’s startling toll on minorities has drawn widespread attention to the need for diversity in large-scale phase 3 vaccine trials. Two 30 000-person trials, led by Moderna and a joint effort of Pfizer and BioNTech, began on July 27. AstraZeneca was expected to start US recruitment to test its vaccine, developed with Oxford University, in August, followed by Johnson & Johnson in September and Novavax later this fall.

Drawing tens of thousands of people of color into clinical trials would be a heavy lift anytime in the US health care system, which is rife with distrust and racial divisions. But social distancing due to the pandemic—along with social unrest sparked by the police killing in Minneapolis of George Floyd—are adding to the challenge.

Tried-and-true outreach strategies such as talks at community gatherings are off the table, replaced by Facebook posts, Zoom calls, and news media interviews.

People of color are also 3 times more likely to become infected with the novel coronavirus, according to New York Times reporting based on demographic data that the newspaper sued the CDC to obtain. Experts interviewed for the article noted that Black and Latino individuals are at higher risk because they more frequently live in crowded, multigenerational homes and hold jobs they can’t do remotely. The Times reported that Latino adults aged 40 to 59 years have been infected at 5 times the rate of White adults of the same age.

Meanwhile, studies show persistent minority underrepresentation in clinical trials, even for conditions that affect them disproportionately. As recently as May, a study in the Journal of the American Heart Association showed Black people accounted for only 4% of 300 000 participants in trials of cardiovascular and diabetes medications approved by the US Food and Drug Administration (FDA) from 2008 to 2017, and Hispanic individuals accounted for 11%.

To help them connect with minority communities, investigators have drawn upon a range of experts, including the NIH’s own National Institute on Minority Health and Health Disparities as well as academic medical centers that serve large minority populations. In early July a website launched by the National Institute of Allergy and Infectious Diseases (NIAID) went live to educate potential volunteers.

Investigators also are leveraging strategies cultivated though decades of HIV research, such as partnering with Black churches and other trusted community leaders and hiring diverse staffs. Some vaccines in the Operation Warp Speed effort will be tested through the COVID-19 Prevention Trials Network, which combines the expertise of 4 NIAID-funded trial networks, 3 of which focus on HIV and AIDS.

The pharmaceutical industry also feels pressure to include people of color in COVID-19 vaccine clinical trials.

Hispanic communities harbor additional fears about running afoul of immigration authorities.

Other barriers exist, as well. Although potential NIH grantees must include information on their minority recruitment plans in their applications, Collins said the agency has less direct control over private contract research organizations that manufacturers may hire to help recruit some of the 30 000 or more people needed for each phase 3 trial.

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