Summary of Important Articles: August 31, 2020

Summary of Important Articles: August 31, 2020 Nuvance Health/UVMLCOM Global Health Program

Cumulative Number of Reviewed Articles Since Inception: 1047

COVID-19 Statistics: Connecticut as of August 31, 2020

Fairfield Statistics:

Cases per 100,000 population: 2003
Total Cases: 18903
Current number of patients in hospitals: 14
Deaths: 1,414
Death Rate: 7.48%

Editorials, Perspectives, Commentaries and Reflections

Research and higher education in the time of COVID-19, Lancet August 29, 2020
COVID-19 vaccine trials should seek worthwhile efficacy, Lancet August 27, 2020
Surveillance is underestimating the burden of the COVID-19 pandemic, Lancet August 27, 2020
COVID-19 vaccines and neglected pregnancy, Lancet August 27, 2020
Health and medicine cannot solve COVID-19, Lancet August 29, 2020

Reviews

Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients, Lancet EClinicalMedicine, August 27, 2020
The psychology of protecting the UK public against external threat: COVID-19 and the Blitz compared, Lancet Psychiatry, August 27, 2020

Public Health

Filtration Efficiencies of Face Mask Alternatives During the COVID-19 Pandemic, NEJM Journal Watch, August 20, 2020
Prevalence of Surface Contamination With SARS-CoV-2 in a Radiation Oncology Clinic,JAMA Oncology August 27, 2020

Viral Dynamics

Symptomatic and Asymptomatic Viral Shedding in Pediatric Patients Infected With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Under the Surface, JAMA Pediatrics, August 28, 2020
Clinical Characteristics and Viral RNA Detection in Children With Coronavirus Disease 2019 in the Republic of Korea, JAMA Pediatrics, August 28, 2020

Pathophysiology

Physiological and biological heterogeneity in COVID-19- associated acute respiratory distress syndrome, Lancet Respiratory Medicine, July 27, 2020
Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study, Lancet Respiratory Medicine, July 27, 2020
Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study, Lancet Respiratory Medicine, July 27, 2020

Epidemiology

In the COVID-19 Era, In-Person Prenatal Visits Remain Safe, NEJM Journal Watch, August 20, 2020

Clinical Practice and Innovations in Care Delivery

Arizona Health Care Systems’ Coordinated Response to COVID-19—“In It Together”, JAMA Health Forum, August 24, 2020

Clinical Manifestations

Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: A retrospective cohort study of patients with and without COVID-19, Lancet EClinicalMedicine, August 27, 2020
Documenting Course of 2 Cases of Conjunctivitis in Mobile Hospitals During the Coronavirus Disease 2019 Pandemic, JAMA Ophthalmology, August 27, 2020

Diagnosis

Saliva or Nasopharyngeal Swab Specimens for Detection of SARS-CoV-2, NEJM August 28, 2020
Testing for responses to the wrong SARS-CoV-2 antigen?, Lancet August 28, 2020

Treatment

FDA’s Emergency Use Authorization for Convalescent Plasma for COVID-19 Seems To Be Fooling No One, NEJM Journal Watch, August 24th, 2020

Special Groups

Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study, Lancet Gastroenterol Hepatology, August 28, 2020
Patients with rheumatic diseases adhere to COVID-19 isolation measures more strictly than the general population, Lancet Rheumatology August 27, 2020
SARS-CoV-2 infection in the COPD population is associated with increased healthcare utilization: An analysis of Cleveland clinic’s COVID-19 registry, Lancet eClinicalMedicine, August 27, 2020

Special Countries

Bangladesh’s COVID-19 testing criticised, Lancet August 29, 2020 Page 56

Editorials, Perspectives, Commentaries and Reflections

Lancet August 29, 2020

Research and higher education in the time of COVID-19

Editor

Considering health research and education as a system, rather than focusing on individual components, can help build a more complete picture of the challenges and opportunities ahead.

Protecting and strengthening research in the midst of COVID-19 will require thoughtful and concerted efforts on the part of governments, funders, universities, and academic communities to collaboratively develop, implement, and fund long-term plans that elevate the voices of students and researchers in national policy decisions. Sustainable research systems are vital, not just to the success of pandemic responses but also to the health of all societies the world over.

Health research systems, like care systems, comprise several multidimensional and interacting pillars. First, a workforce with the skills, training, experience, relationships, and networks needed for research excellence. Second, the necessary resources, including funding, infrastructure, workplace conditions and rights, management, incentive structures, research cultures, and academic freedom. Third, multidisciplinary perspectives that are supported by science beyond medicine, public health, and policy, including social and behavioural sciences, such as anthropology, psychology, sociology, and media and communication studies. Together with basic and translational sciences, such multidisciplinary research is fundamental to the development and uptake of treatments, vaccines, and diagnostics.

Each of these pillars is under threat, and the impacts might be felt for years to come. The research workforce is contending with the need to develop new online learning resources for teaching, increased domestic responsibilities associated with closures of schools and child-care facilities, and challenges such as decreased access to laboratory space, problems procuring equipment and reagents, difficulties recruiting study participants, and the pausing or permanent closure of clinical trials. It is unclear how funders will account for decreased research output when assessing future grant applications, including consideration of the gendered dimensions of this problem. The training of the next generation of scientists and doctors hangs in the balance as universities grapple with ensuring physical distancing, decisions about in-person teaching, and how to deliver quality and accessible education online. Spending on education and research is imperilled by economic downturns with university budgets squeezed by COVID-19, jeopardising jobs and research funding. Recovering shattered research and educational programmes after funding and expertise are lost will be an enormous task.

Lancet August 27, 2020

COVID-19 vaccine trials should seek worthwhile efficacy

Philip Krause, et al

Funders, vaccine developers, researchers, and government institutions have signed an international statement of collaboration in vaccine research. Several of these developers and more than 250 research sites intend to join the WHO Solidarity Vaccines Trial in the hope of bringing forward the time when the world will move beyond the widespread disease, death, and disruption from the COVID-19 pandemic. The trial costs will be a fraction of the societal costs of COVID-19, and this global collaboration could rebut detrimental vaccine nihilism and vaccine nationalism.

Three issues are crucial in planning COVID-19 vaccine trials: (1) whether to demand not only proof of some vaccine efficacy but also proof of worthwhile efficacy; (2) whether the initial trials of vaccine against placebo should prioritise not only single-vaccine trials but also a multi vaccine trial; and (3) whether to assess safety, protection against severe disease, and duration of protection by continuing blinded follow-up of the vaccine and placebo groups after definite evidence of short-term efficacy has emerged, but before an effective vaccine has been deployed locally in the general population.

Figure: Selected design features of the WHO Solidarity Vaccines Trial: The primary outcome is laboratory-confirmed symptoms >14 days after vaccination is completed. Analyses of each vaccine after about 40, 70, and 100 primary outcomes occur in the placebo group will report success if they show ≤10 versus 40, ≤30 versus 70, or ≤50 versus 100 outcomes. The third analysis is reported regardless of its findings. In all cases placebo-controlled follow-up continues until at least month 12 (or local deployment of an effective vaccine) to assess safety, disease severity, and duration of protection.

For a one-dose or two-dose vaccine that halves risk the main result on short-term efficacy should emerge within 3–6 months, unless definite results for a highly effective vaccine emerge in interim analyses. Placebo-controlled follow-up then continues until at least month 12, or until an effective vaccine is deployed locally. This approach increases the reliability of the evidence on younger and older adults, duration of protection, efficacy against severe disease, and any disease enhancement.

Lancet August 27, 2020

Surveillance is underestimating the burden of the COVID-19 pandemic

Nisreen A Alwan

Improving the reporting of non-laboratory-confirmed clinical cases by practically establishing how existing systems can do so is vital. Public health bodies must also universally agree definitions of what constitutes recovery, to estimate the true burden of ill health associated with SARS-CoV-2 infection.

Across the world, some people with symptoms of COVID-19 are not being tested for SARS-CoV-2 infection because tests are either not available or inaccessible, particularly in low-resourced contexts. Some people do not seek testing when they experience symptoms of COVID-19 because of worries about income, caring responsibilities, or stigma implications of testing positive for SARS-CoV-2 and having to isolate. Some people might test negative, particularly if testing takes place too early or too late in the course of SARS-CoV-2 infection.1 We need to count this wider pool of cases, including people who either test negative or are not tested but fulfill clinical criteria for COVID-19.

A universal surveillance case definition of recovery from COVID-19 is still absent. Many people have prolonged symptoms, ill health, and reduced functionality for months, even if they were not hospitalised for SARS-CoV-2 infection.4 We must move long-haul COVID from anecdote to something that is routinely quantified and monitored, as is currently being done with deaths and positive tests.5 To make this move, we must count COVID-19 cases beyond positive test statistics. We also need to define recovery, taking into account symptom duration, fluctuation, severity, quality of life, and functionality, and not base this definition solely on testing negative for active SARS-CoV-2 infection or discharge from hospital.

Lancet August 27, 2020

COVID-19 vaccines and neglected pregnancy

Pradip Dashraath,et al

Unfortunately, pregnant women have historically been excluded from pharmaceutical research, owing to well intentioned, but sometimes misguided, concerns about fetal safety.

On June 18, 2020, WHO presented a strategic framework to ensure the equitable allocation of scarce COVID-19 resources, including vaccines.1 Health-care workers, people older than 65 years, and people with cardiovascular disease, chronic respiratory disease, cancer, diabetes, or obesity will be prioritised for initial vaccination. Pregnant women do not appear to constitute a high-priority group, despite representing a cohort who are at increased risk for severe complications of COVID-19.

Two trials of adenovirus-vectored vaccines (phase 1/2 and phase 2) for COVID-19 have shown sustained T-cell and neutralising antibody responses against the trimeric spike glycoprotein of severe acute respiratory syndrome coronavirus 2 in healthy adult participants who were not pregnant. Replication-defective adenoviruses, when chemically attenuated, are ideal vectors because of their ability to accommodate large transgenes and encode proteins without viral integration into the host cell genome.

ChAdOx1, the chimpanzee adenovirus-vectored vaccine platform that was used in the Oxford trials, has previously been shown to safely induce potent humoral and cell-mediated immune responses that confer robust protection from Rift Valley fever disease in pregnant sheep that were vaccinated in the first trimester, without risks of maternal viraemia or miscarriage. Murine studies of gorilla adenovirus-vectored vaccines for Zika virus have similarly been shown to prevent in-utero transmission of Zika virus. The immunity paradox during pregnancy that favours tolerance to the fetus (ie, stops the maternal immune system from rejecting the fetus), but leaves the mother susceptible to viral infections, can be opportunistically leveraged by simian adenoviral vectors. The ChAdOx1 vaccine platform is non-replicating and could be used to deliver proteins to the mother for the induction of an immune response without adversely affecting the fetus. Transplacental transfer of maternal induced antibodies can ensue, but without transfer of the virus vector to the fetus.

Lancet August 29, 2020

Health and medicine cannot solve COVID-19

Amy K McLennan, et al

Collective interventions will create the new normal that we will inhabit in the future. Yet, the pandemic is framed primarily as a global health crisis, and so the public expects health interventions—a vaccine, new public health measures and hygiene behaviours, and effective treatments—to end COVID-19 and permit a return to the old normal. We caution against this framing. Medicine is well placed to change the narrative and make space for joined-up thinking about a different future with or without COVID-19.

COVID-19 has exposed the complex and interdependent systems of everyday life. Health, politics, economics, technology, environment, education, policing, engineering, transport, food systems, communication, and more all intersect as complex expert systems. Any intervention continually shapes, and is shaped by, other parts of these systems. For example, lockdown-related transport disruption is impeding routine vaccination programmes, reshaping education, and improving air quality. At the same time, health improvements could come from fields well outside of health. An example of this from London's recent past is the radical re-engineering of city landscapes and construction of sewer systems, which substantially reduced infectious disease burden.

Reviews

Lancet EClinicalMedicine, August 27, 2020

Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients

Baranca Buijsers, et al

Coronavirus disease-2019 (COVID-19) is associated with severe inflammation in mainly the lung, and kidney. Reports suggest a beneficial effect of the use of heparin/low molecular weight heparin (LMWH) on mortality in COVID-19. In part, this beneficial effect could be explained by the anticoagulant properties of heparin/LMWH. Here is the summarise of potential beneficial, non-anticoagulant mechanisms underlying treatment of COVID-19 patients with heparin/LMWH, which include: (i) Inhibition of heparanase activity, responsible for endothelial leakage; (ii) Neutralisation of chemokines, and cytokines; (iii) Interference with leukocyte trafficking; (iv) Reducing viral cellular entry, and (v) Neutralisation of extracellular cytotoxic histones. Considering the multiple inflammatory and pathogenic mechanisms targeted by heparin/LMWH, it is warranted to conduct clinical studies that evaluate therapeutic doses of heparin/LMWH in COVID-19 patients. In addition, identification of specific heparin-derived sequences that are functional in targeting non-anticoagulant mechanisms may have even higher therapeutic potential for COVID-19 patients, and patients suffering from other inflammatory diseases.

Due to the multiple inflammatory and pathogenic mechanisms targeted by heparin/LMWH, it is warranted to conduct clinical studies that evaluate therapeutic doses of these compounds in COVID-19 patients. Although a prophylactic dose of LMWH is associated with a reduced HPSE activity in non-ICU COVID-19 patients, regarding the other possible non-anticoagulant effects, no data is currently available as to whether heparin/LMWH in their usual prophylactic, or therapeutic dosage are effective to prevent viral entry, to neutralize cytokines and histones, and to interfere with leukocyte trafficking. In fact, the optimal anticoagulant dosing in patients with COVID-19 is currently uncertain. Studies suggest a high rate of thromboembolic complications among hospitalized patients with COVID-19, particularly in patients admitted to the ICU, and often despite prophylactic-dose anticoagulation. This has led some experts to recommend a higher-intensity thromboprophylaxis with intermediate or even therapeutic dosages of LMWH in critically ill patients with COVID-19. The balance between the risks of thrombosis, and the possible beneficial non-coagulant effects of higher LMWH dosing on the one hand, and the risks of bleeding on the other hand await further study. Considering the structural diversity of heparin/LMWH, in the long term well-defined, heparin-derived structures should be identified that interfere with SARS-CoV-2 cellular entry, COVID-19 related HPSE activity, chemokine binding, leukocyte trafficking, and histone neutralisation, in analogy to the heparin-based pentasaccharide (Arixtra/Fondaparinux) that mediates anticoagulation via antithrombin III. A mixture of these well-defined, heparin-derived compounds could be beneficial for the outcome of COVID-19 patients, as well as for patients suffering from other inflammatory diseases.

Lancet Psychiatry, August 27, 2020

The psychology of protecting the UK public against external threat: COVID-19 and the Blitz compared

Edgar Jones

The COVID-19 outbreak is often presented as a unique challenge, implying that there is no direct evidence base from which to make behavioural science recommendations. Furthermore, findings from the 2009 H1N1 influenza pandemic showed that people's responses are influenced by cultural differences. A comparative study of preventive behaviours in five nations showed clear differences among uptakes of recommended measures, such as hand washing and wearing face masks. However, the comparison with the Blitz suggests that similar or related events are not without value and contribute to an understanding of people's behaviour when they are subjected to threat.

Because emotions drive behaviour, government policy in the COVID-19 pandemic delay and lockdown phases was directed towards increasing vigilance and adherence to rules by sensitising people to the risks of the virus. The value of anxiety as a driver to action was learned during the phoney war period, when most people had been reluctant to change their behaviour or prepare. To maintain production and preserve vital industries, the wartime government fostered adaptation. In part, adaptation occurred naturally as understanding of the risks increased, but was also encouraged by tailoring protective measures to people's preferences, and changes made to work practices. During the lockdown, worry and altruism were used to keep people at home and away from public places on the grounds that this saved lives. Encouraging people to return to work and use public transport is a substantial challenge, because of the inherent attraction of home, and because lockdown left little opportunity to foster elements of normal functioning. The lesson from the Blitz is that resilience is not a given, and has to be managed with cultural understanding.

The COVID-19 pandemic and the World War 2 aerial bombing campaign against the UK between 1939 and 1945 both exposed the civilian population to a sustained threat. Risk, whether from exposure to viral load or the density of the bombing, led to a range of protective measures and behavioural regulations being implemented. The V1 and V2 missiles used in summer and autumn, 1944, functioned as a second wave of bombing, arriving after people believed the danger had passed. Adherence to lockdown and a reluctance to return to work after the lifting of lockdown during the COVID-19 pandemic in the UK were mirrored in the preference for using home-based bomb shelters during the air raids. Heightened sensitivity to risk, or a so-called deep shelter mentality, did not materialise even during the second wave of bomb attacks and some deep bomb shelters were closed because of low occupancy. The most popular protective measures were those that reflected people's preferences, and not necessarily those that provided the greatest safety. As with the COVID-19 pandemic, the public drove government policy as much as they followed it.

Unprecedented is a term commonly used about the COVID-19 pandemic. Yet there are substantial parallels with earlier threats to people's lives, not least the 1918 and 2009 influenza outbreaks. However, this Historical Review compares the current COVID-19 health crisis in the UK with the aerial bombing of its towns and cities (known as the Blitz) during World War 2. The response to the Blitz is one of the earliest examples of a government seeking to protect people from harm and maintain national production, informed by behavioural science and psychological understanding. An emerging interdisciplinary scholarship has begun to address the parallels between these events that have been drawn by commentators and politicians. People's occupation of air raid shelters offers a comparison with people remaining at home during the lockdown. The threat of a second wave of COVID-19 infection was mirrored by the V1 and V2 missiles launched in summer and autumn, 1944, when Londoners who had survived the Blitz of 1940–41, and the Baby Blitz of spring, 1944, believed that the war was effectively over. Then, as now, the government commissioned studies into the new types of threat faced by the nation, to inform the character of protective measures and information campaigns to sustain resilience. Parallels exist between the COVID-19 pandemic and the aerial bombing campaign in terms of the planning, preparation, and exposure phases. This Historical Review compares the psychological responses and behaviour of the UK people during periods of threat to identify common patterns to inform understanding for future health emergencies.

Public Health

NEJM Journal Watch, August 20, 2020

Filtration Efficiencies of Face Mask Alternatives During the COVID-19 Pandemic

Paul S. Mueller, MD, MPH, FACP reviewing Sickbert-Bennett EE et al. JAMA Intern Med 2020 Aug 11 Dugdale CM and Walensky RP. JAMA Intern Med 2020 Aug 11

Expired or reused sterilized N95 masks, and even some surgical masks, effectively filtered aerosol particles.

Procuring sufficient personal protective equipment (PPE) has been challenging during the COVID-19 pandemic. As a result, healthcare organizations have considered nonstandard practices, including using expired masks and reusing masks after sterilization. In this study, researchers tested the fitted filtration efficiencies (FFEs) for 29 different face mask alternatives.

For each mask alternative, FFEs were determined by sampling aerosol inside the face mask for one man and one woman. Nearly all new National Institute for Occupational Safety and Health (NIOSH)-approved N95 respirators had FFEs >95%. NIOSH-approved respirators with intact elastic straps that were expired (as long as 11 years) or reused after sterilization (e.g., with ethylene oxide) also had FFEs >95%. In contrast, two CDC-approved, but not NIOSH-approved, respirators and all non approved respirators had FFEs <95%. Surgical masks with ties and those with ear loops had FFEs of 72% and 38%, respectively.

COMMENT

The CDC recommends use of N95 respirators while caring for patients with confirmed or suspected COVID-19, especially during aerosol-generating procedures (e.g., intubation). “N95” means the respirator filters ≥95% of 0.3-µm particles and, therefore, airborne pathogens. In this study, new, expired, and reused sterilized NIOSH-approved N95 respirators had FFEs >95%, which is reassuring for organizations that are considering nonstandard PPE practices. And, as noted by editorialists, care of the patient with COVID-19 when both patient and healthcare worker are wearing surgical masks is not considered to be high risk and “no outbreaks have been linked to settings in which surgical masks were assiduously used in lieu of N95 masks.”

JAMA Oncology August 27, 2020

Prevalence of Surface Contamination With SARS-CoV-2 in a Radiation Oncology Clinic

Imraan Jan, et al

A total of 128 environmental samples were taken in the radiation oncology department, and 0 were positive for SARS-CoV-2. The environmental samples were organized into 3 categories: (1) 80 samples taken from patient areas, (2) 19 samples taken from staff areas, and (3) 29 samples taken from department equipment. Of the 128 samples, 15 were taken from objects used by the patient with COVID-19. None of these 15 samples were positive for SARS-CoV-2.

Systematic testing of environmental surfaces in the radiation oncology clinic revealed no detectable SARS-CoV-2 RNA. Patients, staff, and physicians may be concerned about the potential risks of SARS-CoV-2 transmission in a hospital-based or outpatient clinic. Moreover, radiation oncology clinics are often housed in tertiary care hospitals that can have a high prevalence of patients with COVID-19, perhaps intensifying fears of infection. Many of the patients with cancer at this clinic have deferred or canceled their scheduled follow-up visits because of fears about COVID-19, and many radiation oncology clinics have experienced substantial decreases in patient volume because of the pandemic. Although rescheduling follow-up visits or converting selected follow-up visits and consultations to telemedicine is good practice during the pandemic, some patients or clinicians may delay or decline important cancer therapies that can substantially affect quality of life and cancer outcomes. The authors believe that appropriate patient care should not be delayed because of the pandemic. The results of this study suggest that following strict prevention protocols and routine cleaning and disinfecting seem adequate for limiting surface contamination with SARS-CoV-2.

Viral Dynamics

JAMA Pediatrics, August 28, 2020

Symptomatic and Asymptomatic Viral Shedding in Pediatric Patients Infected With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Under the Surface

Roberta L. DeBiasi, et al

The study by Han et al highlights that a large percentage of infected children may be asymptomatic or presymptomatic despite infection with SARS CoV-2 and that both asymptomatic and symptomatic individuals may shed virus for prolonged periods of time (2 to 3 weeks) regardless of symptoms. These findings are highly relevant to the development of public health strategies to mitigate and contain spread within communities, particularly as affected communities begin their recovery phases.

No prior studies have systematically focused on the frequency of asymptomatic infection in children or the duration of symptoms and viral shedding in both asymptomatic and symptomatic children.

Han and colleagues provide data accumulated from 22 centers throughout South Korea that address this important knowledge gap. The unique structure of the South Korean public health system facilitated large-scale testing, aggressive contact tracing and testing, and isolation/direct observation of asymptomatic or mildly symptomatic children in designated health care facilities (rather than home quarantine). This structure allowed for the sequential observation, testing (median testing interval of every 3 days), and comparison of 91 asymptomatic, presymptomatic, and symptomatic children with mild to moderate upper and lower respiratory tract infection, identified primarily by contact tracing from laboratory-proven cases.

A major strength of this study is the inclusion of asymptomatic children (20 of 91 [22%]), presymptomatic children (18 of 91 [20%]), and symptomatic children (53 of 91 [58%]). Most symptomatic infected children had experienced symptoms a median (range) of 3 (1-28) days prior to being diagnosed by testing, despite the fact that they were presumably under closer scrutiny by nature of being identified as a known contact. Presymptomatic children remained symptom free for a median (range) of 2.5 (1-25) days before exhibiting any symptoms, despite detectable virus. Only a minority of children (6 [7%]) were identified as infected by testing performed concurrent with onset of their symptoms. This highlights the concept that infected children may be more likely to go unnoticed either with or without symptoms and continue on with their usual activities, which may contribute to viral circulation within their community.

In this study, the authors estimate that 85 infected children (93%) would have been missed using a testing strategy focused on testing of symptomatic patients alone.

Although the majority of symptomatic children (41 of 71 [58%]) had upper respiratory tract disease, there was no difference in the duration of symptoms between those with upper vs mild or moderate lower respiratory tract infection. This suggests that even mild and moderately affected children remain symptomatic for long periods of time.

Asymptomatic children had detectable virus for a mean (SD) of 14.1 (7.7) days after their initial positive test result, and 4 asymptomatic children (20%) continued to have detectable virus 21 days after initial detection. The authors appropriately note that the duration of viral shedding in asymptomatic patients could have been even longer because the date of initial infection cannot be known with clarity. There was no difference in the mean (SD) duration of detectable virus in children with upper respiratory tract infection (18.7 [5.8] days) compared with those with lower respiratory tract infection (19.9 [5.6] days). Fully half of symptomatic children with both upper and lower tract disease were still shedding virus at 21 days. These are striking data, particularly since 86 of 88 diagnosed children (98%) either had no symptoms or mild or moderate disease.

JAMA Pediatrics, August 28, 2020

Clinical Characteristics and Viral RNA Detection in Children With Coronavirus Disease 2019 in the Republic of Korea

Mi Seon Han, et al

Symptom screening fails to identify most COVID-19 cases in children, and SARS-CoV-2 RNA in children is detected for an unexpectedly long time.

This case series of children with COVID-19 was conducted in 20 hospitals and 2 nonhospital isolation facilities across the country from February 18, 2020, to March 31, 2020. Children younger than 19 years who had COVID-19 were included.

A total of 91 children with COVID-19 were included (median [range] age, 11 [0-18] years; 53 boys [58%]). Twenty children (22%) were asymptomatic during the entire observation period. Among 71 symptomatic cases, 47 children (66%) had unrecognized symptoms before diagnosis, 18 (25%) developed symptoms after diagnosis, and only 6 (9%) were diagnosed at the time of symptom onset. Twenty-two children (24%) had lower respiratory tract infections. The mean (SD) duration of the presence of SARS-CoV-2 RNA in upper respiratory samples was 17.6 (6.7) days. Virus RNA was detected for a mean (SD) of 14.1 (7.7) days in asymptomatic individuals. There was no difference in the duration of virus RNA detection between children with upper respiratory tract infections and lower respiratory tract infections (mean [SD], 18.7 [5.8] days vs 19.9 [5.6] days; P = .54). Fourteen children (15%) were treated with lopinavir-ritonavir and/or hydroxychloroquine. All recovered, without any fatal cases.

In conclusion, the findings of this study suggest that suspecting and diagnosing COVID-19 in children based on their symptoms without epidemiologic information and virus testing is very challenging. Most of the children with COVID-19 have silent disease, but SARS-CoV-2 RNA can still be detected in the respiratory tract for a prolonged period. The potential role of children in transmitting disease in the community needs to be further elucidated, and strategies to contain COVID-19 should reflect its effects. Heightened surveillance using laboratory screening will allow detection in children with unrecognized SARS-CoV-2 infection.

Pathophysiology

Lancet Respiratory Medicine, July 27, 2020

Physiological and biological heterogeneity in COVID-19- associated acute respiratory distress syndrome

Lorraine B Ware

Is COVID-19-associated ARDS intrinsically different from ARDS unrelated to COVID-19? Is COVID-19-associated ARDS a uniform syndrome, or can phenotypes be identified?

To address the first question, Giacomo Grasselli and colleagues studied clinical and laboratory characteristics of 301 adults with COVID-19-associated ARDS admitted to intensive care units (ICUs) in seven Italian hospitals over a 2-week period in March, 2020. Lung mechanics were assessed in the first 24 h of ICU admission and compared with findings in historical cohorts of patients with classical ARDS. Similar to classical ARDS, the distribution of values for static compliance of the respiratory system was broad. Although patients with COVID-19-associated ARDS had higher median static compliance (41 mL/cm H2O [IQR 33–52]) than those with classical ARDS (32 mL/cm H2O [25–43]), this difference diminished in multivariable models controlling for other clinical characteristics. Furthermore, almost all of those with COVID-19-associated ARDS (280 [94%] of 297 patients) had static compliance values below the 95th percentile of reported values for classical ARDS, and the extent of pulmonary oedema in patients with COVID-19, measured by calculation of total lung weights from lung CT scans, was similar to that of patients with classical ARDS. D-dimers in 261 patients with COVID-19 were associated with ventilatory ratio, which is a surrogate for dead-space ventilation. A subgroup of patients with D-dimer concentrations greater than the median and static compliance equal to or less than the median (high D-dimers, low compliance [HDLC]) had markedly worse 28-day mortality than the others subgroups of high D-dimers, high compliance (HDHC); low D-dimers, low compliance (LDLC); and low D-dimers, high compliance (LDHC). 28-day mortality was 56% (40 of 71 patients) in the HDLC group, 27% (18 of 67 patients) in the LDHC group, 22% (13 of 60 patients) in the LDLC group, and 35% (22 of 63 patients) in the HDHC group. This worse survival in the HDLC group suggests that the intersection of more severe dysregulation of coagulation and fibrinolysis with more severe lung injury in COVID-19-associated ARDS is highly deleterious, supporting a pathophysiological role for pulmonary microvascular thrombosis in COVID-19-associated ARDS, as has been reported in classical ARDS. Overall, the findings of this large, systematic, multicentre study provide new evidence that lung physiology in COVID-19-associated ARDS is heterogeneous and not fundamentally different from that of classical ARDS, in contrast to previous single-centre reports in small groups of patients that suggested otherwise. As such, these findings support recent calls for the application of evidence-based ARDS care, such as lung-protective mechanical ventilation and proning, in COVID-19-associated ARDS.

The Article from Pratik Sinha and colleagues7 addresses the question of whether the previously described hyperinflammatory and hypoinflammatory phenotypes of classical ARDS are present in COVID-19-associated ARDS. Validated models for phenotype classification were applied to 39 patients with COVID-19-associated ARDS, using point-of-care biomarker measurements at the bedside. Patients could be classified into the two phenotypes with a high degree of certainty, suggesting that the previously identified ARDS phenotypes are robust in this new patient population. Overall mortality in COVID-19-associated ARDS was higher (17 [44%] of 39 patients had died by day 28 of the study) than in a matched cohort of patients with classical ARDS from the HARP-2 study (132 [24%] of 539). Consistent with classical ARDS, mortality in the hyperinflammatory phenotype (five [63%] of eight patients) was substantially higher than in the hypoinflammatory phenotype (12 [39%] of 31). Yet, in COVID-19-associated ARDS, only four (10%) to eight (21%), depending on cutoffs applied, were classified as hyperinflammatory, which was considerably lower than the proportion with this phenotype in the HARP-2 matched cohort (186 [35%] of 539). These findings are surprising, given the prevalent speculation in the literature that severe COVID-19 is characterised by an excessive inflammatory response or so-called cytokine storm. However, a report comparing interleukin-6 (IL-6) levels in patients with COVID-19-associated ARDS to levels measured in classical ARDS showed that IL-6 levels, on average, were lower in the patients with COVID-19 than in those with classical ARDS. Taken together, these findings suggest that the pathophysiology of COVID-19-associated ARDS is more complex than a simple overproduction of cytokines, and that there is heterogeneity within COVID-19 that is similar to that of classical ARDS, albeit with different distributions.

Lancet Respiratory Medicine, July 27, 2020

Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study

Giacomo Grasselli, et al

Patients with COVID-19 can develop acute respiratory distress syndrome (ARDS), which is associated with high mortality. The aim of this study was to examine the functional and morphological features of COVID-19-associated ARDS and to compare these with the characteristics of ARDS unrelated to COVID-19.

This prospective observational study was done at seven hospitals in Italy. Authors enrolled consecutive, mechanically ventilated patients with laboratory-confirmed COVID-19 and who met Berlin criteria for ARDS, who were admitted to the intensive care unit (ICU) between March 9 and March 22, 2020. All patients were sedated, paralysed, and ventilated in volume-control mode with standard ICU ventilators. Static respiratory system compliance, the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air, ventilatory ratio (a surrogate of dead space), and D-dimer concentrations were measured within 24 h of ICU admission. Lung CT scans and CT angiograms were done when clinically indicated. A dataset for ARDS unrelated to COVID-19 was created from previous ARDS studies. Survival to day 28 was assessed.

Between March 9 and March 22, 2020, 301 patients with COVID-19 met the Berlin criteria for ARDS at participating hospitals. Median static compliance was 41 mL/cm H2O (33–52), which was 28% higher than in the cohort of patients with ARDS unrelated to COVID-19 (32 mL/cm H2O [25–43]; p<0·0001). 17 (6%) of 297 patients with COVID-19-associated ARDS had compliances greater than the 95th percentile of the classical ARDS cohort. Total lung weight did not differ between the two cohorts. CT pulmonary angiograms (obtained in 23 [8%] patients with COVID-19-related ARDS) showed that 15 (94%) of 16 patients with D-dimer concentrations greater than the median had bilateral areas of hypoperfusion, consistent with thromboembolic disease. Patients with D-dimer concentrations equal to or less than the median had ventilatory ratios lower than those of patients with D-dimer concentrations greater than the median (1·66 [1·32–1·95] vs 1·90 [1·50–2·33]; p=0·0001). Patients with static compliance equal to or less than the median and D-dimer concentrations greater than the median had markedly increased 28-day mortality compared with other patient subgroups (40 [56%] of 71 with high D-dimers and low compliance vs 18 [27%] of 67 with low D-dimers and high compliance, 13 [22%] of 60 with low D-dimers and low compliance, and 22 [35%] of 63 with high D-dimers and high compliance, all p=0·0001).

Patients with COVID-19-associated ARDS have a form of injury that, in many aspects, is similar to that of those with ARDS unrelated to COVID-19. Notably, patients with COVID-19-related ARDS who have a reduction in respiratory system compliance together with increased D-dimer concentrations have high mortality rates.

The proportion of patients with COVID-19 who are diagnosed with ARDS on the basis of oxygenation criteria ranges between 20% and 67% in patients admitted to hospital and is 100% in mechanically ventilated patients. However, few data are available that link the physiological, laboratory, and imaging features of these patients. This information is important because several studies have suggested that patients with COVID-19-associated ARDS have markedly higher lung compliances than do patients with ARDS unrelated to COVID-19 (so-called classical ARDS), so typical protective ventilatory settings might not be indicated in patients with COVID-19-related ARDS. Additionally, patients with COVID-19-associated ARDS are thought to have substantial pulmonary thrombotic injury, associated with increased D-dimer levels. If confirmed, these findings could have major implications in terms of treatment strategies and prognosis.

Patients with COVID-19-related ARDS have a median compliance 28% higher than the median in classical ARDS cohorts. Regardless, only 5·7% of patients with COVID-19 related ARDS had static compliance greater than the 95th percentile of those with classical ARDS. Notably, other published case series of critically ill patients with COVID-19 have reported median static compliance of 20–43 mL/cm H2O, similar to those in classical ARDS. In the three most recent and largest studies, median static compliance was 27 mL/cm H2O (IQR 22–36; n=257), 28 mL/cm H2O (IQR 23–38; n=267), and 35 mL/cm H2O (IQR 27–45; n=296). Furthermore, by quantitative analysis of lung CT scans, we found that total lung weight was similar to that in classical ARDS and was virtually identical to classical ARDS, when normalised to ARDS severity. Together, these data strongly suggest that patients with COVID-19-related ARDS have values of static compliance that overlap those in classical ARDS.

CT angiogram studies showed filling defects or occlusions of the pulmonary vasculature that were more prominent in patients with high D-dimer concentrations. Although limited by the experimental algorithm used to identify clots, this finding is similar to that observed in patients with H1N1-associated ARDS who had a significantly higher incidence of pulmonary embolism than patients with ARDS of different causes. Although increased D-dimer concentrations might be driven by inflammatory mechanisms and dead-space ventilation might be due to mechanisms other than microclots, this study suggests that intravascular pathology plays a major role increasing dead space and causing hypoxaemia in COVID-19-related ARDS. This role could explain the observation that static compliance and PaO2/FiO2 were not correlated in COVID-19-related ARDS, but were correlated in classical ARDS.

Lancet Respiratory Medicine, July 27, 2020

Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study

Pratik Sinha, et al

In this exploratory analysis of 39 patients, ARDS due to COVID-19 was not associated with higher systemic inflammation and was associated with a lower prevalence of the hyperinflammatory phenotype than that observed in historical ARDS data. This finding suggests that the excess mortality observed in COVID-19-related ARDS is unlikely to be due to the upregulation of inflammatory pathways described by the parsimonious model.

In acute respiratory distress syndrome (ARDS) unrelated to COVID-19, two phenotypes, based on the severity of systemic inflammation (hyperinflammatory and hypoinflammatory), have been described. The hyperinflammatory phenotype is known to be associated with increased multiorgan failure and mortality. In this study, we aimed to identify these phenotypes in COVID-19-related ARDS.

In this prospective observational study done at two UK intensive care units, we recruited patients with ARDS due to COVID-19. Demographic, clinical, and laboratory data were collected at baseline. Plasma samples were analysed for interleukin-6 (IL-6) and soluble tumour necrosis factor receptor superfamily member 1A (TNFR1) using a novel point-of-care assay. A parsimonious regression classifier model was used to calculate the probability for the hyperinflammatory phenotype in COVID-19 using IL-6, soluble TNFR1, and bicarbonate levels. Data from this cohort was compared with patients with ARDS due to causes other than COVID-19 recruited to a previous UK multicentre, randomised controlled trial of simvastatin (HARP-2).

Between March 17 and April 25, 2020, 39 patients were recruited to the study. Median ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) was 18 kpa (IQR 15–21) and acute physiology and chronic health evaluation II score was 12 (10–16). 17 (44%) of 39 patients had died by day 28 of the study. Compared with survivors, patients who died were older and had lower PaO2/FiO2. The median probability for the hyperinflammatory phenotype was 0·03 (IQR 0·01–0·2). Depending on the probability cutoff used to assign class, the prevalence of the hyperinflammatory phenotype was between four (10%) and eight (21%) of 39, which is lower than the proportion of patients with the hyperinflammatory phenotype in HARP-2 (186 [35%] of 539). Using the Youden index cutoff (0·274) to classify phenotype, five (63%) of eight patients with the hyperinflammatory phenotype and 12 (39%) of 31 with the hypoinflammatory phenotype died. Compared with matched patients recruited to HARP-2, levels of IL-6 were similar in our cohort, whereas soluble TNFR1 was significantly lower in patients with COVID-19-associated ARDS.

Little is understood about the pathophysiology of COVID-19, though many have speculated that a central pathophysiological abnormality associated with severe COVID-19 is an exaggerated systemic inflammatory response or a so-called cytokine storm. However, no objective data-driven evidence supports this theory.

Considerable evidence does exist for the presence of subgroups of ARDS with exaggerated inflammation. In secondary analyses of five ARDS randomised controlled trials, two phenotypes, termed hyperinflammatory and hypoinflammatory, have been consistently identified using latent class analysis (LCA).The hyperinflammatory phenotype is associated with exaggerated inflammation evidenced by greatly increased levels of circulating proinflammatory cytokines and increased incidence of shock. Mortality rates in the phenotype with lower systemic inflammatory responses are about 20% and consistently 20% lower than in the hyperinflammatory phenotype. Further, in three of these randomised controlled trials, differential treatment responses to randomised interventions were observed in the two phenotypes. These findings suggest that the hyperinflammatory phenotype might be useful for prognostic and predictive enrichment in ARDS.

The hyperinflammatory phenotype of ARDS is associated with higher circulating levels of proinflammatory biomarkers such as IL-6, IL-8, and soluble TNFR1 and lower levels of vitamin K-dependent protein C. Further, this phenotype is associated with increased evidence of multiorgan failure and shock. The low prevalence of the hyperinflammatory phenotype in COVID-19 ARDS challenges the hypothesis of the cytokine storm in its pathogenesis and suggests that it might not be as ubiquitous as purported, and might be less frequently encountered than in ARDS secondary to other causes.

It is also worth noting that the APACHE II scores in our COVID-19 population were significantly lower than those in the HARP-2 cohort despite higher mortality in this cohort. All patients with COVID-19 in this study were managed in ICUs at surge capacity with a reduced nursing ratio, which might, in part, explain this finding. Overwhelmed ICU capacity might have an effect on outcomes in COVID-19 and lower mortality rates have been reported in ICUs that have operated under more conventional conditions and staffing ratios in patients with COVID-19 with similar APACHE II scores. The low APACHE II scores are also in keeping with those reported by the Intensive Care National Audit and Research Centre in 9777 patients admitted to the ICU in the National Health Service hospitals in the UK, where the median APACHE II score in patients with COVID-19 was 14 (IQR 11–18) and the mortality rate was greater than 40%. These consistent findings suggest that the APACHE II score might not be valid for prognostication in COVID-19. Taken together, the findings of the low APACHE II score and high mortality suggest that alternative phenotyping approaches might be needed to identify biologically and clinically homogeneous clusters using novel biomarkers that might, in turn, enhance our understanding of pathogenesis and improve prognostication in COVID-19-related ARDS.

Notably, the prevalence of vasopressor use at baseline was similar between patients with the hyperinflammatory phenotype and those with the hypoinflammatory phenotype, whereas in previous studies of ARDS unrelated to COVID-19, vasopressor use was significantly higher in those with the hyperinflammatory phenotype.

This might in part be explained by the fact that in previous studies, the risk factor for ARDS differed between the phenotypes with sepsis predominantly featuring in the hyperinflammatory phenotype. In COVID-19, given the uniformity of cause, it might be that there are additional drivers of vasopressor use that are disease specific and extraneous to inflammatory phenotypes, such as cardiovascular complications.

It is also known that cause is an important determinant of the signature of circulating biomarkers. For example, indirect causes of lung injury, such as sepsis, are associated with higher levels of endothelial injury, whereas direct lung injury is associated with higher levels of markers of epithelial injury. Biomarkers pertaining to severity of epithelial injury and cell death might be more informative in COVID-19-associated ARDS because the primary source of injury is presumed to be a viral pneumonitis.

Epidemiology

NEJM Journal Watch, August 20, 2020

In the COVID-19 Era, In-Person Prenatal Visits Remain Safe

Anna Wald, MD, MPH reviewing Reale SC et al. JAMA 2020 Aug 14

Among pregnant women, COVID-19 status was unrelated to the number of prenatal visits, suggesting that such visits are not risky for SARS-CoV-2 infection.

Concern about acquiring COVID-19 may dissuade people from attending medical appointments for other health issues. As pregnant women are scheduled for frequent in-person visits, investigators assessed whether the number of prenatal visits beginning in mid-March 2020 (the probable initial period of SARS-CoV-2 community transmission in Boston) was associated with risk for SARS-CoV-2 infection.

Mean number of in-person visits was 3.1 among the 93 women who tested positive for COVID-19 and 3.3 among 372 matched controls (women who tested negative).

COMMENT

The finding of no difference between the number of prenatal visits among women with versus without COVID-19 provides reassurance that healthcare settings are unlikely places of exposure to the virus. This result may be useful to share with patients who express concerns about medically necessary in-person visits.

Clinical Practice and Innovations in Care Delivery

JAMA Health Forum, August 24, 2020

Arizona Health Care Systems’ Coordinated Response to COVID-19—“In It Together”

Sharon L. Feldman and Patricia A. Mayer

Putting their duty to plan, safeguard, and guide the community through this public health emergency above their commercial interests, Arizona’s health systems facilitated the implementation of statewide Crisis Standards of Care, created allocation policies, and supported the development of an efficient patient transfer system. These measures limit duplication of efforts, safeguard the health care workforce, and protect the most vulnerable in the community by ensuring a fair distribution of resources across the state. At a health systems level, statewide coordination serves the fundamental goal of triage to maximize lives saved. The coordination and cooperation among Arizona’s health systems is supporting this essential goal.

In late March, while 3500 beds were free in other New York hospitals, hundreds of patients waited for care and many died at Elmhurst hospital in Queens, New York. The lesson was clear: accurately tracking and managing critical resources “becomes a matter of life and death when one hospital encounters a surge”.

In mid-June, Arizona was one of the hardest hit regions in the world, with 212 cases per million residents. Hospitals across the state enacted their surge plans to increase bed capacity by 50%. Hundreds of crisis assignment health care workers were deployed, and clinicians operated under expanded scopes of practice to care for the patients doubled-up in intensive care unit (ICU) rooms and occupying newly opened ICU wards. Reasons cited for Arizona’s alarming COVID-19 prevalence rate include the governor’s early reopening of the state on May 15 and the absence of a statewide mask mandate. But having learned the importance of regional networking from national and global colleagues, leaders from Arizona’s health care systems had already collaborated with one another and the Arizona Department of Health Services to craft an innovative, coordinated response. Recognizing the power of global information sharing, 3 of Arizona’s key statewide initiatives are shared here in the hope that they will help others.

Arizona launched the Arizona Surge Line, a centralized system for load-balancing COVID-19 patients across the state. This new program required the cooperation and agreement of state health care systems, normally corporate competitors, during a time of acute financial strain. With surge capacity, Arizona has approximately 12 500 licensed hospital beds across 127 hospitals, 18% of which are ICU beds.

Any provider in the state can call the Surge Line to arrange timely transfer of a patient with COVID-19 to an appropriate level of care. Patients with COVID-19 are allocated among Arizona’s health care systems in proportion to the systems’ market shares. As of late July, over 2300 patients with COVID-19 had been transferred through the Surge Line.

Arizona also activated its Crisis Standards of Care plan (CSC plan). Arizona’s CSC plan offers templates and tactics for the ethical management of scarce “space, stuff, and staff” during a crisis. The enactment of the CSC plan also provided additional legal protections for health care practitioners acting in good faith during the emergency.

The CSC plan is supplemented by the COVID-19 Addendum, which outlines adult and pediatric triage protocols to be adopted by all acute-care facilities in the state if triage is needed. Integral to the Addendum is the intention that all Arizona health care systems coordinate and collaborate to share resources. Rather than working in isolation to design resource allocation policies for patients presenting to individual facilities or systems, Arizona’s health care leaders decided their duty to plan encompassed the entire state. Implementing a statewide allocation protocol helped ensure patients across the state would be treated equally.

Clinical Manifestations

Lancet EClinicalMedicine, August 27, 2020

Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: A retrospective cohort study of patients with and without COVID-19

Sachin J. Shah, et al

While authors found differences in clinical features of COVID-19 compared to other acute respiratory illnesses, there was significant overlap in presentation and comorbidities. Patients with COVID-19 were more likely to be admitted to the hospital, have longer hospitalizations and develop ARDS, and were unlikely to have co-existent viral infections.

Most data on the clinical presentation, diagnostics, and outcomes of patients with COVID-19 have been presented as case series without comparison to patients with other acute respiratory illnesses.

Authors here examined emergency department patients between February 3 and March 31, 2020 with an acute respiratory illness who were tested for SARS-CoV-2. They determined COVID-19 status by PCR and metagenomic next generation sequencing (mNGS). They compared clinical presentation, diagnostics, treatment, and outcomes.

Among 316 patients, 33 tested positive for SARS-CoV-2; 31 without COVID-19 tested positive for another respiratory virus. Among patients with additional viral testing (27/33), no SARS-CoV-2 co-infections were identified. Compared to those who tested negative, patients with COVID-19 reported longer symptoms duration (median 7d vs. 3d, p < 0.001). Patients with COVID-19 were more often hospitalized (79% vs. 56%, p = 0.014). When hospitalized, patients with COVID-19 had longer hospitalizations (median 10.7d vs. 4.7d, p < 0.001) and more often developed ARDS (23% vs. 3%, p < 0.001). Most comorbidities, medications, symptoms, vital signs, laboratories, treatments, and outcomes did not differ by COVID-19 status.

While many clinical features of COVID-19 overlap with those of other acute respiratory illnesses, several unique characteristics were identified. Patients with COVID-19 had a longer duration of symptoms, particularly fatigue, fever, and myalgias, were more likely to be admitted to the hospital and for a longer duration, were unlikely to have co-existent viral infections, and were more likely to develop ARDS. Though this health system has not experienced a surge in COVID-19 cases, these key clinical characteristics may, in part, explain the observed differences in the propensity of COVID-19 to strain health systems. While we did find meaningful differences that may inform one's clinical suspicion for COVID-19, we did not find significant differences in cardiopulmonary comorbidities, ACE inhibitor/ARB use, or mortality rate. These findings enhance understanding of the clinical characteristics of COVID-19 in comparison to other acute respiratory illnesses.

In contrast to other areas in the United States, the Bay Area has not yet experienced a large surge in cases of COVID-19. The fact that resources were not strained may have affected the clinical course and outcomes observed. For example, while the sample size is not sufficient to evaluate differences in mortality, only one of the 33 with COVID-19 died (3%), which is lower than in other studies of hospitalized U.S. patients. There is speculation that variations in circulating SARS-CoV-2 strains may affect pathogenicity and contribute to geographic differences in case fatality rates. Exploratory phylogenetic analysis presented here demonstrated a diversity of strains among the COVID-19 patients requiring ICU care without a predominant clade; larger studies are needed to assess any potential relationship.

JAMA Ophthalmology, August 27, 2020

Documenting Course of 2 Cases of Conjunctivitis in Mobile Hospitals During the Coronavirus Disease 2019 Pandemic

Chaohua Deng, et al

For patients with suspected COVID-19 with ocular manifestations (eg, conjunctival congestion) as the initial or concomitant symptoms, performing conjunctival swabs simultaneously with nasopharyngeal swabs might detect potential ocular infection in advance.

However, the detection rate of SARS-CoV-2 in the tears or conjunctiva appears to be very low, ranging from 0% to 5.26%. Furthermore, it remains unclear whether the virus has the capacity to transmit from person to person via the conjunctival route.

The authors document the course of 2 cases of confirmed COVID-19 with conjunctivitis in a mobile hospital. One is a 29-year-old male patient, who noted conjunctival congestion of the right eye before admission to the mobile hospital. Health care workers did not notice the patient's ocular symptoms and the potential transmission risk by conjunctivitis. After the patient entered the mobile hospital, an ophthalmologist noted and reported the conjunctivitis. Conjunctival swab of both eyes was performed and SARS-CoV-2 was detected in the sample. Digital polymerase chain reaction was used for the detection of virus, and the copy number was 89.3 copies/mL (>50 copies/mL is considered as positive for the detection). While unproven as a treatment, antiviral ganciclovir eyedrops were given; the patient was isolated from other patients to potentially prevent nosocomial infection. Further investigation is warranted to elucidate the potential antiviral efficacy of ganciclovir against COVID-19.

+ indicates positive; −, negative; COVID-19, coronavirus disease 2019; CT, computed tomography; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

In a second case, a 51-year-old woman presented with ocular symptoms 10 days after admission to the mobile hospital. She had conjunctival congestion, epiphora, and watery secretions in the right eye, and similar findings were noted in the left eye 2 days later. Severe acute respiratory syndrome coronavirus 2 detection was detected in the tears. Digital polymerase chain reaction was used for the detection of virus, and the copy number was 116.1 copies/mL (the threshold for determining a positive test was >50 copies/mL). Chest computed tomography demonstrated lung infection compared with her previous computed tomography results. The patient showed symptoms of hypoxemia and was transferred to a tertiary hospital for further intensive treatment, and in the meantime, antiviral ganciclovir eyedrops were also given to the patient. While the association of conjunctivitis with worsening of the pulmonary infection cannot be determined from one case, these findings are consistent with a study that suggested that patients in China with ocular abnormalities may progress more frequently to more severe systemic symptoms of COVID-19.

+ indicates positive; -, negative; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Diagnosis

NEJM August 28, 2020

Saliva or Nasopharyngeal Swab Specimens for Detection of SARS-CoV-2

Anne L. Wyllie, et al

Collection of saliva samples by patients themselves negates the need for direct interaction between health care workers and patients. This interaction is a source of major testing bottlenecks and presents a risk of nosocomial infection. Collection of saliva samples by patients themselves also alleviates demands for supplies of swabs and personal protective equipment. Given the growing need for testing, our findings provide support for the potential of saliva specimens in the diagnosis of SARS-CoV-2 infection.

A total of 70 inpatients with Covid-19 participate in our study. After Covid-19 was confirmed with a positive nasopharyngeal swab specimen at hospital admission, we obtained additional samples from the patients during hospitalization. We tested saliva specimens collected by the patients themselves and nasopharyngeal swabs collected from the patients at the same time point by health care workers.

We detected more SARS-CoV-2 RNA copies in the saliva specimens (mean log copies per milliliter, 5.58; 95% confidence interval [CI], 5.09 to 6.07) than in the nasopharyngeal swab specimens (mean log copies per milliliter, 4.93; 95% CI, 4.53 to 5.33). In addition, a higher percentage of saliva samples than nasopharyngeal swab samples were positive up to 10 days after the Covid-19 diagnosis. At 1 to 5 days after diagnosis, 81% (95% CI, 71 to 96) of the saliva samples were positive, as compared with 71% (95% CI, 67 to 94) of the nasopharyngeal swab specimens. These findings suggest that saliva specimens and nasopharyngeal swab specimens have at least similar sensitivity in the detection of SARS-CoV-2 during the course of hospitalization.

SARS-CoV-2 RNA Titers in Saliva Specimens and Nasopharyngeal Swab Specimens: Samples were obtained from 70 hospital inpatients who had a diagnosis of Covid-19. Panel A shows SARS-CoV-2 RNA titers in the first available nasopharyngeal and saliva samples. The lines indicate samples from the same patient. Results were compared with the use of a Wilcoxon signed-rank test (P<0.001). Panel B shows percentages of positivity for SARS-CoV-2 in tests of the first matched nasopharyngeal and saliva samples at 1 to 5 days, 6 to 10 days, and 11 or more days (maximum, 53 days) after the diagnosis of Covid-19. Panel C shows longitudinal SARS-CoV-2 RNA copies per milliliter in 97 saliva samples, according to days since symptom onset. Each circle represents a separate sample. Dashed lines indicate additional samples from the same patient. The red line indicates a negative saliva sample that was followed by a positive sample at the next collection of a specimen. Panel D shows longitudinal SARS-CoV-2 RNA copies per milliliter in 97 nasopharyngeal swab specimens, according to days since symptom onset. The red lines indicate negative nasopharyngeal swab specimens there were followed by a positive swab at the next collection of a specimen. The gray area in Panels C and D indicates samples that were below the lower limit of detection of 5610 virus RNA copies per milliliter of sample, which is at cycle threshold 38 of our quantitative reverse-transcriptase polymerase chain reaction assay targeting the SARS-CoV-2 N1 sequence recommended by the Centers for Disease Control and Prevention. To analyze these data, we used a linear mixed-effects regression model that accounts for the correlation between samples collected from the same person at a single time point (i.e., multivariate response) and the correlation between samples collected across time from the same patient (i.e., repeated measures).

Recent studies have shown that SARS-CoV-2 can be detected in the saliva of asymptomatic persons and outpatients. We therefore screened 495 asymptomatic health care workers who provided written informed consent to participate in our prospective study, and we used RT-qPCR to test both saliva and nasopharyngeal samples obtained from these persons. We detected SARS-CoV-2 RNA in saliva specimens obtained from 13 persons who did not report any symptoms at or before the time of sample collection. Of these 13 health care workers, 9 had collected matched nasopharyngeal swab specimens by themselves on the same day, and 7 of these specimens tested negative. The diagnosis in the 13 health care workers with positive saliva specimens was later confirmed in diagnostic testing of additional nasopharyngeal samples by a CLIA (Clinical Laboratory Improvement Amendments of 1988)–certified laboratory.

Lancet August 28, 2020

Testing for responses to the wrong SARS-CoV-2 antigen?

Carolina Rosadas, et al

The UK Government's decision to facilitate use of Abbott' assay was intemperate. Anti-NP is insensitive in the field: why was this insensitivity not recognised by those who validated its use in the UK? Moreover, Abbott's assay does not indicate accurately the presence of neutralising and potentially protective antibodies in the convalescent individual. Those who might still deign to use this assay as the sole marker of past infection would be wise to consider confirmatory algorithms to better inform individuals investigated for anti-NP.

Two commercial antibody tests (Abbott SARS-CoV-2 IgG, Abbott Diagnostics, Abbott Park, IL, USA; and Roche Elecsys Anti-SARS-CoV-2, Roche Diagnostics, Basel, Switzerland), both targeting antibodies to nucleoprotein (anti-NP), constitute the cornerstone of the UK Government's response to the COVID-19 pandemic. The test manufactured by Abbott, which is widely used in Europe and the USA, claims a specificity and sensitivity of greater than 99% at 14 days or more after symptoms started and has been validated by Public Health England.

Authors received 2204 serum samples from staff and patients previously screened for anti-NP on the Abbott platform as part of the routine diagnostic service by the UK National Health Service. These samples, principally selected in the Abbott binding ratio range of 0·25–2·5, were further tested using an in-house double binding antigen ELISA (Imperial Hybrid DABA; Imperial College London, London, UK), which detects total antibodies to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD). This assay has a specificity of 100% (95% CI 99·6–100), defined by testing 825 serum samples that predated the COVID-19 pandemic, and a sensitivity of 98·9% (96·8–99·8) when evaluating 276 serum samples from individuals with RT-PCR-confirmed SARS-CoV-2 infection.

Among 511 samples with Abbott binding ratios of 0·25 to less than 1·4, 294 (58%) had detectable anti-RBD antibodies (ranging from 34% for binding ratios 0·25–0·5 to 94% for binding ratios 1·25–1·4; appendix). Discordant samples were classified into five groups based on their Imperial Hybrid DABA binding ratio. Eight serum samples from each group were randomly selected and assayed by a second in-house assay, an S1 G and M capture ELISA, to verify the anti-RBD findings. Anti-S1 antibodies were detected in 28 (88%) of 32 samples that were reactive for anti-RBD but unreactive for anti-NP. The four serum samples not confirmed by the S1 capture ELISA had low binding ratios in the Imperial Hybrid DABA, the S1 non-reactivity being consistent with the lower sensitivity of the capture assay compared with the Imperial Hybrid DABA. Eight serum samples selected at random from 76 reactive only in the Abbott assay were unreactive for antibody to S1.

There are two possible explanations for these findings: either the Abbott assay results constitute false-positive reactions; or these patients did not mount a detectable humoral response to S1, as can happen with asymptomatic or mild infection.

Treatment

NEJM Journal Watch, August 24th, 2020

FDA’s Emergency Use Authorization for Convalescent Plasma for COVID-19 Seems To Be Fooling No One

Starting late Saturday night, and proceeding the next day — like a relentless series of coming attractions for a blockbuster summer movie or the finale of a reality TV series — we repeatedly heard word that the President planned to make an announcement Sunday evening about a “major therapeutic breakthrough” in treatment of COVID-19.

6 p.m. Eastern. Live. Get ready. Here it comes.

And, satisfying the ratings-hungry entertainer he once was (and some would say still is, though “entertainer” must be used cautiously in this context), we turned up to hear him cite this “powerful therapy” that “had an incredible rate of success.”

No, it’s not hydroxychloroquine.

This time it’s convalescent plasma. That liquid gold harvested from recovered COVID-19 patients, swimming in antibodies directed against SARS-CoV-2, and also containing a veritable secret sauce of illness-reversing substances that have fascinated doctors and scientists for decades.

Never mind that harvested convalescent plasma isn’t used commonly to treat any infection currently.

Or that the randomized trials of this treatment have so far been disappointing.

Or that the observational data the FDA used to justify their action come from an unpublished study not yet subject to peer review.

(Here’s the next best thing, for those inclined to take a deep dive into data analysis.)

Or that the very experts employed by the government to review plasma’s safety and efficacy have as recently as last week raised important concerns about the lack of convincing evidence for this treatment.

Or that this action by the FDA will almost certainly jeopardize any existing randomized trials of convalescent plasma in the United States.

Or that the person from the FDA who reviewed the plasma data had his name redacted from the memo.

Or that the emergency use authorization may make patient care more difficult, since this will necessarily be a limited resource — especially if antibody titer turns out to be a critical determinant of whether this works, and since antibodies appear to fade in many people soon after they have COVID-19.

Nope — no matter. On the evening of a major political event — timing that cannot be coincidental — the president got his ratings.

He had to do a little intimidation, but we’re getting used to that.

Special Groups

Lancet Gastroenterol Hepatology, August 28, 2020

Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study

Gwilym J Webb, et al

This study involving more than 700 patients, including 151 liver transplant recipients, suggests that previous liver transplantation is not independently associated with death following SARS-CoV-2 infection. Conversely, advanced age and medical comorbidities such as renal impairment were associated with SARS-CoV-2-related mortality. Thus, traditional risk factors for adverse outcomes from COVID-19 should be preferentially considered when considering the risks and benefits of hospital attendance, immunosuppression, and social-distancing requirements for liver transplant recipients during the ongoing COVID-19 pandemic.

Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47–66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44–84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p<0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p<0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI −7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients.

Cohort selection: (A) Liver transplant cohort. (B) Comparison cohort. SARS-CoV-2= severe acute respiratory syndrome coronavirus 2.

Figure 2, Major outcomes from severe acute respiratory syndrome coronavirus 2 infection in patients who have (n=151) and have not (n=627) undergone liver transplantation: Risk differences between groups are presented with 95% CIs and were calculated with Newcombe's method 10. ICU=intensive care unit.

Propensity score-matched models for the association between liver transplantation and death in patients with severe acute respiratory syndrome coronavirus 2 infection: The plot shows four separate propensity-score matched models with liver transplantation as the treatment variable and death as the outcome variable. Risk difference (95% CI) is presented for each model. For model 1, variables included in the calculation of propensity score were age, sex, obesity, white ethnicity, hypertension, diabetes, and serum creatinine. Subsequent models also included interactions with age (model 2), interactions with serum creatinine and age (model 3), and interactions with age but with serum creatinine concentration omitted (model 4). Seven (5%) of 151 transplant patients lacked baseline data for serum creatinine and were not included in models including serum creatinine.

Figure 4 Case fatality rate of severe acute respiratory syndrome coronavirus 2 infection according to age group and liver transplantation status: n denotes the total number of patients in each age group for each cohort.

The proportions of liver transplant recipients who were hospitalised with SARS-CoV-2 infection (82%) and who died (19%) were similar to those in a previous European case series, which reported that 81% of patients were hospitalised and 16% died, with some patients in that series still part way through their disease course. Among liver transplant recipients in the current study, advanced age, increased baseline creatinine concentration, and the presence of non-liver cancer were independently associated with an increased risk of mortality. By contrast, the type of immunosuppressants used and the time from transplantation were not independently associated with mortality. In further contrast to findings from other, smaller cohorts, biological age rather than time from transplantation was most strongly correlated with death.

Upon diagnosis of SARS-CoV-2 infection, liver transplant recipients frequently had gastrointestinal symptoms, with 30% having abdominal pain, vomiting, or diarrhoea, compared with 12% of patients without liver transplant. Clinicians should therefore be vigilant and consider having a lower threshold for SARS-CoV-2 testing in transplant patients presenting with gastrointestinal symptoms. Frequencies of kidney injury and liver injury were not significantly different between patients who had and those who had not received a liver transplant, suggesting that transplanted livers were no more susceptible to injury and that calcineurin inhibitor-based immunosuppression was not associated with renal injury in SARS-CoV-2 infection.

Lancet Rheumatology August 27, 2020

Patients with rheumatic diseases adhere to COVID-19 isolation measures more strictly than the general population

Femke Hooijberg, et al

The observation that the presence of a rheumatic disease and use of immunosuppressive medication are not associated with a higher incidence or worse disease outcome of COVID-191, might, in whole or in part, be caused by strict isolation measures taken by individual patients with inflammatory rheumatic diseases such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, and especially those receiving biological DMARDs with potential extra risk. This phenomenon might occur in other vulnerable patient groups as well. Therefore, the assessment of risk of COVID-19 in vulnerable patients should include an evaluation of isolation measures they have actually taken.

During the first wave of COVID-19 in the Netherlands, all adult patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis from the Amsterdam Rheumatology and Immunology Center (Reade, Amsterdam, Netherlands) were invited to participate in this study.

Between April 26, 2020, and May 27, 2020, 979 consecutive patients with rheumatoid arthritis, 215 patients with ankylosing spondylitis, 261 patients with psoriatic arthritis, and 414 consecutive healthy controls were included in this study. Demographic characteristics were as expected in these populations, but unfortunately the control group was much smaller than the patient group and not completely matched. 877 (60%) of 1455 patients were on treatment with conventional disease-modifying antirheumatic drugs (DMARDs). The majority of patients with rheumatoid arthritis (595 [61%] of 979) and patients with psoriatic arthritis (135 [52%] of 261) were on methotrexate, compared with a minority of patients with ankylosing spondylitis (six [3%] of 215). In addition, 646 (44%) of 1455 patients were receiving biological DMARDs, most of which were tumour necrosis factor inhibitors (563 [39%] of 1455 patients overall, 336 [34%] of 979 patients with rheumatoid arthritis, 106 [49%] of 215 of patients with ankylosing spondylitis, and 121 [46%] of 261 patients with psoriatic arthritis).

During this study, the Dutch Government encouraged the general population to stay indoors as much as possible and to keep 1·5 m distance from each other. 666 (46%) patients adhered to strict isolation measures (448 [46%] of 979 patients with rheumatoid arthritis, 98 [46%] of 215 patients with ankylosing spondylitis, and 120 [46%] of 261 patients with psoriatic arthritis), compared with 122 (29%) healthy controls. After adjusting for age, sex, smoking status, body-mass index, and presence of comorbidities, patients were almost twice as likely to adhere to strict isolation measures compared with healthy controls (odds ratio [OR], 1·8, 95% CI 1·5–2·4, p<0·01). This association remained significant for all disease subgroups compared with controls.

Sex was found to be a significant effect modifier: preference for strict isolation was higher in women than in men. In patients with rheumatic disease, those receiving biological DMARDs took stricter isolation measures than patients not receiving biological DMARDs (OR 1·3, 95% CI 1·1–1·7; p=0·02).

Lancet eClinicalMedicine, August 27, 2020

SARS-CoV-2 infection in the COPD population is associated with increased healthcare utilization: An analysis of Cleveland clinic’s COVID-19 registry

Amy A Attawaya, et al

The analysis demonstrated that COPD patients with COVID-19 had a higher risk for healthcare utilization, although adjusted in-hospital mortality risk was not different than the non-COPD patients with COVID-19.

We sought to determine whether COPD conferred a higher risk for healthcare utilization in terms of hospitalization and clinical outcomes due to COVID-19.

A cohort study with covariate adjustment using multivariate logistic regression was conducted at the Cleveland Clinic Health System in Ohio and Florida. Symptomatic patients aged 35 years and older who were tested for SARS-CoV-2 between March 8 and May 13, 2020 were included.

15,586 individuals tested for COVID-19 at the Cleveland Clinic between March 8, 2020 and May 13, 2020 met our inclusion criteria. 12.4% of COPD patients (164/1319) tested positive for COVID-19 compared to 16.6% (2363/14,267) of the non-COPD population. 48.2% (79/164) of COVID-19 positive COPD patients required hospitalization and 45.6% (36/79) required ICU admission. After adjustment for covariates, rates of COVID-19 infection were not significantly different than the non-COPD population (adj OR 0.97; CI: 0.89–1.05), but COPD patients had increased healthcare utilization as demonstrated by risk for hospitalization (adj OR 1.36; CI: 1.15–1.60), ICU admission (OR 1.20; CI: 1.02–1.40), and need for invasive mechanical ventilation (adj OR 1.49; CI: 1.28–1.73). Unadjusted risk for in-hospital mortality was higher in the COPD population (OR 1.51; CI: 1.14–1.96). After adjusting for covariates however, the risk for in-hospital mortality was not significantly different than the non-COPD population (adj OR 1.08: CI: 0.81–1.42).

A potential risk factor for poor outcomes among patients with COPD who have COVID-19 is the use of inhaled corticosteroids (ICS) for the routine management of chronic stable disease. There has been concern that steroid usage increases the risk for contracting COVID-19 and developing severe disease due to immunosuppression and enhanced viral shedding. However our findings suggest that the usage of corticosteroids was associated with a lower rate of COVID-19 infection in the COPD population. The results of this study is reassuring that COPD patients can be maintained on ICS during the COVID-19 pandemic. Interestingly, recent studies have shown that ICS is linked to down-regulation of the ACE2 receptor and potentially could impart a protective effect for COVID-19 infection which supports the current findings.

Another concern has been that active smoking increases the risk for COVID-19 severity given that smoking upregulates the ACE2 receptor expression in lung epithelial cells and increases the risk for SARs-CoV-2 entry into host cells. The authors in this study did not find an increased risk for COVID-19 infection in current smokers with COPD who tested positive for COVID-19 infection. However, this study was focused primarily on COPD patients and not current smokers alone.

Special Countries

Lancet August 29, 2020

Bangladesh’s COVID-19 testing criticised

Sophie Cousins Reports

They've applied a charge for testing in the public sector, which just means that the poor are excluded.

Public health experts in Bangladesh have expressed concern about the government's decision to charge people for COVID-19 tests amid a sharp decline in the number of tests being done. In late June, the government decided to charge 200 taka (£1·80) for testing done at government facilities and 500 taka (£4·50) for samples collected from home to “avoid unnecessary tests”. The private sector charges 3500 taka (£32) per test. Almost one in four Bangladeshis live below the national poverty line.

Since the decision, testing rates have fallen to around 0·8 tests per 1000 people per day, with a low of just 0·06 tests per 1000 people in August. Bangladesh is administering on average between 12 000 and 15 000 tests per day for a population of 168 million, and has recorded almost 275 000 confirmed cases and more than 3600 deaths.

In mid-July a Bangladesh hospital owner was arrested over allegations he issued thousands of fake negative COVID-19 test results, further shining a light on the country's unregulated private sector.

Shamim Talukder, head of Eminence, a Bangladeshi public health research organisation, told The Lancet that the pandemic had exposed the country's ”unethical” health-care system. “From the beginning of the pandemic, the government wanted to control the COVID-19 testing system”, he said. “At the beginning it didn't allow the private sector to do the tests and now they've applied a charge for testing in the public sector, which just means that the poor are excluded.”

Talukder said that the pandemic had further exposed the country's failing health-care system, which spends just 0·69% of the country's gross domestic product on health, making Bangladesh one of the lowest spenders on health globally. Moreover, two-thirds of health expenditure is out of pocket and borne by households, many of whom are propelled into poverty by catastrophic health-care costs.

Talukder called for a complete restructuring of the health-care system, which would include banning doctors who work in the public sector from supplementing their income with private practice, which has led to the neglect of patients in public facilities, among other interventions. “Most people do not like to go to the hospital due to the poor quality of services and they do not want to go to the private sector because of the high price”, he said.

Appreciate