COVID-19 Statistics

• Rate of Positive Tests: 45440/370638 = 12.26%
• Death Rate: 4226/45440 = 9.30%

Fairfield Statistics:

• Cases per 100,000 population: 1,737
• Total Cases: 16,398
• Current number of patients in hospitals: 64
• Deaths: 1,352
• Death Rate: 8.24%

Editorials, Perspectives, Commentaries and Reflections

Lancet, June 17, 2020

From Literature to Medicine: Seeing COVID-19 Through José Saramago’s Blindness

Daniel Marchalik, et al

One day, COVID-19, too, shall pass. What will remain? Many will remember the solitude of the quarantine and suffer from the financial recession that is sure to follow; others will remember the loss of a loved one. But the memories of suffering and sacrifice will inevitably fade. Health-care workers' and patients' writings, social media posts, podcasts, and photographs, testifying to what they have seen inside the hospital walls, will help those on the outside see in and resist our desire to forget. Because forgetting this moment is something we cannot afford.

The novel chronicles an unprecedented epidemic of blindness that sweeps across an unnamed country. It opens with one man at a traffic stop, his world suddenly enveloped in a milky whiteness. He is taken to an ophthalmologist's office where, after walking through a busy waiting room, he leaves the whole clinic, including the doctor, infected. The group is quarantined in an old asylum by the ministry of health. The doctor and his wife, who miraculously maintains her sight, are sequestered there as well.

Inside the asylum, panic spreads “faster than the legs that carry it”. The doctor's wife quickly learns how fear and the feeling of being unseen—and therefore unjudged for your actions—can lead to moral depravity as she and others are subjected to rape, extortion, and murder by fellow wardmates.

Finally, when the entire city turns blind and the quarantined group emerges, they find their city in ruins. Wandering the abandoned streets, they find themselves in a church where holy statues have their eyes covered in white cloth and paintings have their eyes obscured by white paint. This is a world that appears forever changed. In that world, even the saints did not deserve to see amid the suffering of the blind.

Then, as quickly as it came, the blindness recedes. The world buzzes with optimism, as if awakened from a nightmare. But the doctor's wife—who saw the realities inside the asylum walls—fears that the suffering will have been in vain. The people of her city, she knows, will soon forget, even as she cannot. That is her sacrifice: to witness the horrors others could ignore and to serve as the historical record for what really happened behind the asylum walls.

She learns the paradox of this epidemic of blindness is that it illuminated more than it obscured. As the doctor's wife reflects: “I don't think we did go blind, I think we are blind, Blind but seeing, Blind people who can see, but do not see.” The citizens of the city chose to not see the cruelty hiding under the surface in themselves and in others. It took an epidemic to shed a blinding light on the darkness that was always beneath.

The same is true of the COVID-19 pandemic, which has exposed many entrenched injustices and inequalities. Pushing health-care systems and resources to their limits in many countries, this global pandemic has brought prescient issues such as systemic racism, the state of social safety nets, and variations in access to health care into focus. And for a brief time, we have lost our ability to look away, as death counts and videos of the critically ill in hospital wards invade our consciousness.

And yet, many appear to be refusing to look or are already forgetting. It is a story of two worlds. In some countries, disinformation about COVID-19 has led to protests demanding the lifting of quarantine outside the hospital walls; meanwhile, inside, fatigued health-care workers in intensive care units provide dedicated care and support for countless patients who are scared, severely ill, and alone. More than ever, the contemporary records of health-care professionals' and their patients' experiences are needed to counterbalance the emerging narratives from some quarters that downplay the extent of the pandemic.

One day, COVID-19, too, shall pass. What will remain? Many will remember the solitude of the quarantine and suffer from the financial recession that is sure to follow; others will remember the loss of a loved one. But the memories of suffering and sacrifice will inevitably fade. Health-care workers' and patients' writings, social media posts, podcasts, and photographs, testifying to what they have seen inside the hospital walls, will help those on the outside see in and resist our desire to forget. Because forgetting this moment is something we cannot afford.

NEJM. June 16, 2020

“We Signed Up for This!” — Student and Trainee Responses to the Covid-19 Pandemic

Thomas H. Gallagher, et al

In their seminal paper on AIDS and occupational risk for physicians, Zuger and Miles wrote, “Medicine is an inherently moral enterprise, the success and future of which depend to a great extent on the integrity of individual professionals as they face the duties the calling of healer entails.”4 Watching our students and trainees step up during the Covid-19 pandemic despite their fears gives us hope that the profession’s future is in good hands.

Covid-19 has brought forward new ethical dilemmas for trainees, some of whom are considering the implications of intubating certain patients when ventilators are in short supply or wondering whether they should join an attending for procedures that would help them fulfill criteria to sit for board exams but would require the use of additional PPE. Many students reported moral distress associated with watching patients be isolated from loved ones and described feeling distant from patients while wearing PPE. Trainees not providing Covid-19 care because of personal health issues expressed guilt that colleagues had to step in. Students frequently reported disappointment and frustration about not being able to help. Many people faced challenges that were largely practical, such as needing child care.

Feelings of anxiety and vulnerability among students and trainees compete internally with a desire and commitment to serve the sick. Many have done more than has been required of them for patient care and within the community, despite risks and challenges. When one program called on residents to fill extra shifts through the end of April, all slots were filled by volunteers within 10 minutes.

Down the road, disruptions such as Covid-19 will prompt us to revisit routines and traditions. Which of the new practices that are being developed during the Covid-19 pandemic can be adopted more broadly to enhance educational and clinical experiences? How do we simultaneously provide the safest care and the safest education? What is the role of new technology and other innovations in the future of medical care and clinical learning?

Medicine and medical education are based on a strong tradition of partnership and of one generation passing down knowledge to the next. Students and trainees have experienced considerable loss — loss of routines and traditions, expertise, educational opportunities, and social connections — and many are witnessing frequent loss of life. Most are worried about more losses yet to come in all these areas.

NEJM, June 16, 2020

Making the Call

Jessica C. Stuart

The content of our conversations varies. Sometimes she likes to tell me about the kind of person Mr. A. is, since I have never been able to speak to him. He sings in their church choir every Sunday and is an excellent guitar player, she tells me. He likes Beethoven, but he also likes Elvis Presley. She laughs into the phone as she corrects herself: really, there’s no music Mr. A. doesn’t like — she even caught him listening to the country music station a few weeks ago. Her tone suddenly becomes serious: Do I think that playing music would help him get better? I say I think it’s an excellent idea. We are planning to try to wake him up — to lift his medically induced coma — in the coming days, and I think having familiar music playing will help him relax. Wonderful, Ms. A. says. I miss him so much. They have been married for over 40 years.

I then rotated off the ICU and onto a different floor, but a few days later, I received a phone call from another intern who is now taking care of Mr. A. I should come visit him today, my co-intern said cryptically. He knew I’d developed a bond with the patient’s family. I finished my shift and furtively entered the unit. I peered through the glass window into Mr. A.’s room, not wanting to waste personal protective equipment on a noncritical visit. There was Mr. A. sitting up in bed, awake, and breathing comfortably without a breathing tube. There was music playing on the TV.

I felt myself crying. I felt myself smiling under my mask. I felt myself wanting nothing more than to finally meet Ms. A. in person, to hug her and cry with her and celebrate with her, with Elvis Presley playing in the background.

My intuition had told me this would not happen. I had spent all year painstakingly cultivating my clinical gestalt, and it had failed me here. But I had never been so happy to be wrong.

Viral Dynamics

NEJM, June 17, 2020

Genomewide Association Study of Severe Covid-19 with Respiratory Failure

David Ellinghaus, et al

This study identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.)

Authors conducted a genomewide association study involving 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain. In total, they analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case–control panels.

This study detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10−8) in the meta-analysis of the two case–control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.15×10−10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P=4.95×10−8, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus.

In this cohort, a blood-group–specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10−4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10−5).

The main events and milestones of the study are summarized in the plot. Samples from patients in three Italian hospitals (hospital A: Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan; hospital B: Humanitas Clinical and Research Center, IRCCS, Milan; and hospital C: UNIMIB School of Medicine, San Gerardo Hospital, Monza) and four Spanish hospitals (hospital A: Hospital Clínic and IDIBAPS, Barcelona; hospital B: Hospital Universitario Vall d’Hebron, Barcelona; hospital C: Hospital Universitario Ramón y Cajal, Madrid; and hospital D: Donostia University Hospital, San Sebastian) were obtained around the peak of the local epidemics, and ethics applications were quickly obtained by means of fast-track procedures (i.e., every local ethics review board supported studies of coronavirus disease 2019 [Covid-19] studies by providing rapid turn-around times, thus facilitating this fast de novo data generation). All the obtained blood samples were centrally isolated, genotyped, and analyzed within 8 weeks. Control data were obtained from control participants and from historical control data in Italy and Spain. The rapid workflow from patients to target identification shows the usefulness of GWAS, a standardized research tool that often relies on international and interdisciplinary cooperation. One center alone could not have completed this study, not to mention the increase in statistical power that was available because of the contribution of patients from multiple centers. The speed of data production depended heavily on laboratory automation, and the speed of analyses reflects existing analytic pipelines and the support of public so-called imputation servers (here, the Michigan imputation server of the G. Abecasis group). QC denotes quality control.

Shown is a Manhattan plot of the association statistics from the main meta-analysis (controlled for potential population stratification). The red dashed line indicates the genomewide significance threshold of a P value less than 5×10−8.

Using a pragmatic approach with simplified inclusion criteria and a complementary team of clinicians at the European Covid-19 epicenters in Italy and Spain and scientists in the less-burdened countries of Germany and Norway, we performed a GWAS that included de novo genotyping for Covid-19 with respiratory failure in approximately 2 months. We detected a novel susceptibility locus at a chromosome 3p21.31 gene cluster and confirmed a potential involvement of the ABO blood-group system in Covid-19.

On chromosome 3p21.31, the peak association signal covered a cluster of six genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1), several of which have functions that are potentially relevant to Covid-19. A causative gene cannot be reliably implicated by the present data. One candidate is SLC6A20, which encodes the sodium–imino acid (proline) transporter 1 (SIT1) and which functionally interacts with angiotensin-converting enzyme 2, the SARS-CoV-2 cell-surface receptor.28,29 However, the locus also contains genes encoding chemokine receptors, including the CC motif chemokine receptor 9 (CCR9) and the C-X-C motif chemokine receptor 6 (CXCR6), the latter of which regulates the specific location of lung-resident memory CD8 T cells throughout the sustained immune response to airway pathogens, including influenza viruses. Flanking genes (e.g., CCR1 and CCR2) also have relevant functions, and further studies will be needed to delineate the functional consequences of detected association.

Nongenetic studies that were reported as preprints have previously implicated the involvement of ABO blood groups in Covid-19 susceptibility, and ABO blood groups have also been implicated in susceptibility to SARS-CoV-1 infection. Our genetic data confirm that blood group O is associated with a risk of acquiring Covid-19 that was lower than that in non-O blood groups, whereas blood group A was associated with a higher risk than non-A blood groups. The biologic mechanisms undergirding these findings may have to do with the ABO group per se (e.g., with the development of neutralizing antibodies against protein-linked N-glycans) or with other biologic effects of the identified variant, including the stabilization of von Willebrand factor. The ABO locus holds considerable risk for population stratification, which is increased by the inclusion of randomly selected blood donors in the current study (for which there is an inherent risk of blood group O enrichment). Alignment of the allele frequencies at the ABO locus in our control population with those in several non–blood-donor control populations would suggest that this is not a major bias, and at least one study that tested for association with blood type used disease controls with no affiliation to blood donors.

Nature Medicine, June 18, 2020

Clinical and Immunological Assessment of Asymptomatic SARS-CoV-2 Infections Quan-Xin Long, et al

These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.

The authors studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT–PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Of the 37 asymptomatic individuals, the median age was 41 years (range, 8–75 years) and 22 were female. Twenty-eight individuals had a confirmed history of contact with an RT–PCR-confirmed patient with COVID-19. Asymptomatic individuals were admitted to the government-designated Wanzhou People’s Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15–26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6–10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8–38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines.

a, CT scan of a 45-year-old female showing focal ground-glass opacities in the lower lobe of the left lung (arrow). b, CT scan of a 50-year-old female showing ground-glass opacities and stripes coexisting in the lower lobe of the right lung (arrows).

a, The Ct values of ORF1b and N obtained with RT–PCR that were detected in nasopharyngeal swabs from asymptomatic (n = 37) and symptomatic (n = 37) groups. The box plots show the medians (middle line) and the first and third quartiles (boxes), whereas the whiskers show 1.5× the IQR above and below the box. Unpaired, two-sided Mann–Whitney U test P values are depicted in the plots, and the significant P value cutoff was set at 0.05. b, The Kaplan–Meier method was used to estimate the positive rate of viral RNA, and the two-sided log-rank test was applied to evaluate the significance difference of the duration of viral shedding in the symptomatic and asymptomatic groups.

a, The comparison of virus-specific antibody levels in asymptomatic patients (n = 37) and symptomatic patients (n = 37) with acute infections. b, IgG levels in patients with convalescent-phase COVID-19 who were discharged from the hospital. c, Dynamic changes in virus-specific IgG levels in the acute and convalescent phases. d, Dynamic changes in neutralizing serum antibodies in the acute and convalescent phases. Results are expressed as the average of two independent experiments. e, IgG-positive proportions of patients with COVID-19 in the acute and convalescent phases. The box plots in a and b show the medians (middle line) and first and third quartiles (boxes), and the whiskers show 1.5× the IQR above and below the box. Unpaired, two-sided Mann–Whitney U test P values are depicted in the plots, and the significant P value cutoff was set at 0.05.

The early convalescent phase : 8 weeks after they were discharged from the hospital.

Samples from asymptomatic (n = 37) and symptomatic (n = 37) patients with COVID-19 were collected in the acute phase during hospitalization, and assays were performed to measure the concentrations of 48 cytokines and chemokines. The box plots show the medians (middle line) and first and third quartiles (boxes), and the whiskers show 1.5× the IQR above and below the box. Unpaired, two-sided Mann–Whitney U test P values are depicted in the plots, and the significant P value cutoff was set at 0.001.

Of the 178 laboratory-confirmed patients, 37 who never developed any symptoms throughout the disease course were included in this study. Our data showed that 20.8% of these patients had asymptomatic infections. However, this might not be an accurate estimation of the proportion of asymptomatic infections in the general population owing to the fact that asymptomatic infections were identified from those who were at high risk for infection (including close contacts and individuals with a history of travel to Wuhan) and not from a random sample of people. Therefore, the proportion of asymptomatic infections needs to be determined through population screening. Additionally, the proportion of asymptomatic infections might be even higher as some cases might be missed by RT–PCR testing. Our group has successfully identified seven patients with SARS-CoV-2 infection from 148 cases with negative RT–PCR results and no symptoms by using an antibody test. Therefore, timely RT–PCR and serological testing should be used in conjunction, which would benefit accurate estimation of the asymptomatic proportion. However, serological testing has limitations, and tests vary in their specificity and sensitivity. Results might also be confounded by previously existing antibodies to SARS-CoV, MERS-CoV or common cold coronaviruses.

Recently, several studies characterizing adaptive immune responses to SARS-CoV-2 infection have reported that most COVID-19 convalescent individuals have detectable neutralizing antibodies, which correlate with the numbers of virus-specific T cells. In this study, we observed that IgG levels and neutralizing antibodies in a high proportion of individuals who recovered from SARS-CoV-2 infection start to decrease within 2–3 months after infection. In another analysis of the dynamics of neutralizing antibody titers in eight convalescent patients with COVID-19, four patients showed decreased neutralizing antibodies approximately 6–7 weeks after illness onset. One mathematical model also suggests a short duration of immunity after SARS-CoV-2 infection. Together, these data might indicate the risks of using COVID-19 ‘immunity passports’ and support the prolongation of public health interventions, including social distancing, hygiene, isolation of high-risk groups and widespread testing. Additional longitudinal serological studies profiling more symptomatic and asymptomatic individuals are urgently needed to determine the duration of antibody-mediated immunity. In addition, low levels of anti-viral IgG in asymptomatic patients, who might be more likely to become seronegative, further support the need for timely serosurvey to study the true infection rate.

Lancet Microbe, June 18, 2020

Host range of SARS-CoV-2 and implications for public health

Joanne M Santini, et al

Once SARS-CoV-2 circulates more widely beyond humans, it will be challenging to trace natural transmission between species because the viral genome is essentially identical in humans, and existing epidemiological methods of contact tracing are equipped to identify transmission between humans to interrupt it. The aforementioned studies thus prematurely categorise the risks as low, medium, or high when based on early probability estimates of simple infection. A low probability of a high-impact outcome, such as a new reservoir species also needs to be considered. Assessing these risks includes reviewing our ability to isolate, protect, or contain animals in domestic, agricultural, and wildlife settings. Domestic species whose population numbers are sufficient to act as a reservoir include cats and dogs, which is consistent with the case reports noted earlier, and studies showing or predicting infectivity. Farmed wildlife such as mink and pigs could also become reservoir species. In addition to wild bats, rodents could potentially act as a reservoir species because they have sufficient numbers and densities for continuous transmission; this possibility is supported by a modelling study that predicted squirrels to be infected, yet other studies showed a probable low or no risk of infection for mice and rats. These considerations should lead to strategies for implementing early surveillance and precautionary mitigation measures on different species.

Physics of Fluids; June 16, 2020

Can a Toilet Promote Virus Transmission? From a Fluid Dynamics Perspective

Y. Li, et al

Toilets are a daily necessity but also become dangerous if used improperly, especially against the current scenario of a global pandemic. This paper has used the CFD approach to clarify how toilet flushing can promote virus transmission. The flushing processes of two different types of toilets (single-inlet flushing and annular flushing) have been simulated, and in particular, the fluid flow characteristics and the movement of aerosol particles during flushing have been investigated. Several alarming conclusions can be summarized as follows:

• Strong turbulence has been observed to be generated by both flushing methods.
• An upward velocity of as much as 5 m/s is produced, which is certainly capable of expelling aerosol particles out of the toilet bowl.
• Some 40%–60% of the total number of particles can rise above the toilet seat to cause large-area spread, with the height of these particles reaching 106.5 cm from the ground.
• Even in the post-flushing period (35 s–70 s after the last flushing), the upward velocity of the diffused particles can reach 0.27 cm/s–0.37 cm/s, and they continue to climb.
• The data analysis indicates that given the same amount of water and the same gravitational potential energy, annular flushing causes more virus spread.
• Faced with these alarming results, we advocate several safe procedures to adopt when using a toilet:

1. Put the toilet lid down before flushing, which can basically prevent virus transmission.
2. Clean the toilet seat before using it, since floating virus particles could have settled on its surface.
3. Wash hands carefully after flushing, since virus particles may be present on the flush button and door handle.

This paper may also enlighten toilet manufacturers and prompt them to produce better designed toilets in which the lid is automatically put down before flushing and cleaned before and after flushing.

Pathophysiology

Lancet Diabetes and Endocrinology, June 18, 2020

Association Between High Serum Total Cortisol Concentrations and Mortality From COVID-19

Tricia Tan, et al

During the study period (admissions from March 9 to April 22, 2020; follow-up to May 8, 2020), a total of 621 patients were admitted with suspected COVID-19 who had at least one cortisol measurement during their admission. We included only baseline cortisol measurements made within 48 h of admission for suspected COVID-19 or diagnosis of COVID-19 during a hospital admission. 403 patients were diagnosed with COVID-19 on the basis of either a positive result from real-time RT-PCR testing of a nasopharyngeal swab (356 [88%] patients) or a strong clinical and radiological suspicion of COVID-19, despite negative swab testing (47 [12%] patients). 132 (25%) individuals in this cohort were not diagnosed with COVID-19. In the group of patients with COVID-19, the mean age of the patients was 66·3 years (SD 15·7) and 240 (59.6%) were men. The most frequent comorbidities in the cohort of patients with COVID-19 were hypertension (191 [47·4%] patients), diabetes (160 [39·7%] patients), cardiovascular disease (94 [23·3%] patients), chronic kidney disease (50 [12·4%] patients), and a current diagnosis of cancer (38 [9·4%] patients). 112 (27·8%) of patients with COVID-19 died during the study period, compared with 9 (6·8%) of patients without COVID-19 (p<0·0001). Median cortisol concentration in the group of patients with COVID-19 was 619 nmol/L [IQR 456–833] versus 519 nmol/L [378–684] in the patient group who did not have COVID-19 (p<0·0001).

Univariable analysis of the group of patients with COVID-19 by Cox proportional hazards regression modelling showed that age 75 years and older had the highest risk of acute mortality, and age younger than 75 years was associated with a reduced relative risk of acute mortality. The presence of diabetes, hypertension, current diagnosis of cancer, chronic kidney disease, or cardiovascular disease was significantly associated with acute mortality. Increased cortisol, CRP, neutrophil to leukocyte ratio, and creatinine were predictive of acute mortality.

Multivariable analysis showed that a doubling of cortisol concentration was associated with a significant 42% increase in the hazard of mortality, after adjustment for age, the presence of comorbidities, and laboratory tests (appendix p 3). An optimal cutoff for cortisol was selected by use of maximally selected rank statistics. Patients with COVID-19 whose baseline cortisol concentration was equal to or less than 744 nmol/L (268 patients [67%]) had a median survival of 36 days [95% CI 24–not determined]; whereas, patients with COVID-19 whose cortisol value was more than 744 nmol/L (135 patients [33%]) had a median survival of 15 days [10–36] (log-rank test p<0·0001).

To our knowledge, our analyses show for the first time that patients with COVID-19 mount a marked and appropriate acute cortisol stress response and that this response is significantly higher in this patient cohort than in individuals without COVID-19. In other words, our cohort did not obviously exhibit an adrenal insufficiency with SARS-CoV-2 infection in the acute setting. Furthermore, we found that high cortisol concentrations were associated with increased mortality and a reduced median survival, probably because this is a marker of the severity of illness.

Epidemiology

JAMA Infectious Diseases, June 16, 2020

Case Isolation, Contact Tracing, and Physical Distancing Are Pillars of COVID-19 Pandemic Control, Not Optional Choices

Chandini Raina MacIntyre

If you do not trace, you leave a chain of transmission free to grow undetected and exponentially. With 80% of cases being mild, it might take several generations of silent epidemic growth before a new outbreak is even recognised.

In Kucharski and colleagues' study, combinations of case isolation with contact tracing reduced transmission by 47% (self-isolation combined with app-based tracing) to 64% (self-isolation combined with manual contact tracing of all contacts) compared with mass testing and case isolation alone, which reduced transmission by 2% (mass random testing of 5% of the population each week) to 37% (self-isolation plus household quarantine).

The lowest Reff in Kucharski and colleagues' study was achieved with a combination of case finding and isolation, contact tracing, quarantine, and social distancing (limiting outside contacts to four per day). For case finding, the authors showed that random testing (undertaken in some countries) barely reduced Reff and was not an efficient use of resources. Targeted testing of high-risk contacts in outbreak settings, regardless of symptoms, is much more efficient, especially given that asymptomatic infections are common. For contact tracing, Kucharski and colleagues looked at manual contact tracing with self-isolation, which reduced transmission by 57%, and app-based tracing with 53% uptake, which improved that somewhat when in combination with manual tracing. However, the real value of app-based tracing is when case numbers are high and human resources stretched. Each case requires ten to 25 contacts to be traced, so the human resources requirement for manual tracing can easily be exceeded in a large epidemic. In that case, the use of an app might become essential for epidemic control. Without contact tracing, isolation alone will not reduce Reff below 1 and will result in a blow-out of the epidemic.

JAMA Infectious Diseases, June 16, 2020

Effectiveness of Isolation, Testing, Contact Tracing, and Physical Distancing on Reducing Transmission of SARS-CoV-2 in Different Settings: A Mathematical Modelling Study

Adam J Kucharski, et al

A high proportion of cases would need to self-isolate and a high proportion of their contacts to be successfully traced to ensure an effective reproduction number lower than 1 in the absence of other measures. If combined with moderate physical distancing measures, self-isolation and contact tracing would be more likely to achieve control of severe acute respiratory syndrome coronavirus 2 transmission.

Authors use data from more than 40 000 individuals to assess contact patterns and potential SARS-CoV-2 transmission in different settings and compare how combinations of self-isolation, contact tracing, and physical distancing could reduce secondary cases. We assessed a range of combined physical distancing and testing and tracing measures, including app-based tracing, remote working, limits on different sized gatherings, and mass population-based testing. They also estimated the number of contacts that would be quarantined under different strategies.

Authors estimated that combined isolation and tracing strategies would reduce transmission more than mass testing or self-isolation alone: mean transmission reduction of 2% for mass random testing of 5% of the population each week, 29% for self-isolation alone of symptomatic cases within the household, 35% for self-isolation alone outside the household, 37% for self-isolation plus household quarantine, 64% for self-isolation and household quarantine with the addition of manual contact tracing of all contacts, 57% with the addition of manual tracing of acquaintances only, and 47% with the addition of app-based tracing only. If limits were placed on gatherings outside of home, school, or work, then manual contact tracing of acquaintances alone could have an effect on transmission reduction similar to that of detailed contact tracing. In a scenario where 1000 new symptomatic cases that met the definition to trigger contact tracing occurred per day, authors estimated that, in most contact tracing strategies, 15 000–41 000 contacts would be newly quarantined each day.

JAMA, June 15, 2020

Hospital-Wide SARS-CoV-2 Antibody Screening in 3056 Staff in a Tertiary Center in Belgium

Deborah Steensels, et al

In this hospital-wide screening study for SARS-CoV-2 antibodies among hospital staff, neither being directly involved in clinical care nor working in a COVID-19 unit increased the odds of being seropositive, while having a suspected COVID-19 household contact did.

The epidemic curve is shown as the number of patients with coronavirus disease 2019 (COVID-19) admitted at the institution each day. The first case was detected March 13. Serosurvey of staff was initiated from April 22, 2020, to April 30, 2020. Details of the infection prevention measures are depicted below the curve. FFP indicates filtering facepiece; RT-PCR, reverse transcriptase–polymerase chain reaction; TAT, turnaround time.

All 4125 staff were invited and 3056 (74%) participated (306 physicians, 1266 nurses, 292 paramedical staff, 555 technical staff, 445 administrative staff, and 192 others, including students and volunteers). At least one-third of those not tested were individuals not at work during the period. Overall, 197 staff (6.4% [95% CI, 5.5%-7.3%]) had IgG antibodies for SARS-CoV-2. Age and sex were not statistically significantly different among staff with or without antibodies (mean age, 39.5 [SD, 13.1] vs 41.3 [SD, 12.4] years; 38/197 [19%] vs 614/2859 [21%] men). Being involved in clinical care, having worked during the lockdown phase, being involved in care for patients with COVID-19, and exposure to COVID-19–positive coworkers were not statistically significantly associated with seroprevalence (Figure 2A). In contrast, having a household contact with suspected or confirmed COVID-19 was associated with antibody positivity (81/593 [13.7%] with household contacts vs 116/2435 [4.8%] without household exposure; P < .001), with an odds ratio of 3.15 (95% CI, 2.33-4.25).

A high proportion of staff mentioned at least 1 prior symptom (2294/3052 [75%]). Of those with antibodies, 30 of 197 (15%) reported no symptoms. Prior anosmia was associated with the presence of antibodies, with an odds ratio of 7.78 (95% CI, 5.22-11.53), as well as fever and cough (Figure 2B).

JAMA Global Health, June 15, 2020

COVID-19: Rethinking Risk

Nina Schwalbe, et al

An increased understanding of risk factors, including the effects of social determinants and their interplay, provides an opportunity to target mitigation strategies and helps to allay the popular misconception that everyone is at equal risk of severe illness. It is time to evolve from a one-size-fits-all approach to one that centres on those most at risk. This will need to happen at both the individual and community level. Considering the relevance of social determinants, such an approach requires urgently improving communication about COVID-19; increasing access to health services, including palliative care, for those already socially vulnerable; and providing economic support to cope with the mitigation. Enhanced primary health care will help to monitor health and social care and engage individuals and families in chronic NCD management and the COVID-19 response.

The SARS-CoV-2 pandemic is forcing us to face the fact that progress towards the Sustainable Development Goals is fragile, as those populations on the path towards leaving poverty are now at increased risk of falling behind. It also shows the need to strengthen the nexus between underlying conditions, their risk factors, and infectious diseases. This requires acknowledging the importance of interventions to address structural inequity, universal health coverage, and wider social protection schemes as part of the response. It is time to acknowledge that we are not all at equal risk of severe outcomes from COVID-19 and to work together with those most affected to tailor an effective response.

JAMA Global Health, June 15, 2020

Global, Regional, and National Estimates of the Population at Increased Risk of Severe COVID-19 Due to Underlying Health Conditions in 2020: A Modelling Study

Andrew Clark, et al

An estimated 1.7 billion people, 22% of the world population, have at least one underlying health condition that could increase their risk of severe COVID-19 if infected, according to a modelling study that uses data from 188 countries. However, the authors estimate that fewer individuals worldwide would require hospitalisation if infected – around 4% of the world population – suggesting that for many with underlying conditions, the increase in risk may be modest. The share of the population with at least one underlying health condition is highest in countries with ageing populations, African countries with high HIV/AIDS prevalence, and small island nations with high diabetes prevalence. As lockdown restrictions are eased, governments could use the estimates to understand who should be prioritised for enhanced physical distancing measures and vaccination, if available.

About one in five individuals worldwide could be at increased risk of severe COVID-19, should they become infected, due to underlying health conditions, but this risk varies considerably by age. Our estimates are uncertain, and focus on underlying conditions rather than other risk factors such as ethnicity, socioeconomic deprivation, and obesity, but provide a starting point for considering the number of individuals that might need to be shielded or vaccinated as the global pandemic unfolds.

We estimated that 1·7 billion (UI 1·0–2·4) people, comprising 22% (UI 15–28) of the global population, have at least one underlying condition that puts them at increased risk of severe COVID-19 if infected (ranging from <5% of those younger than 20 years to >66% of those aged 70 years or older). We estimated that 349 million (186–787) people (4% [3–9] of the global population) are at high risk of severe COVID-19 and would require hospital admission if infected (ranging from <1% of those younger than 20 years to approximately 20% of those aged 70 years or older). We estimated 6% (3–12) of males to be at high risk compared with 3% (2–7) of females. The share of the population at increased risk was highest in countries with older populations, African countries with high HIV/AIDS prevalence, and small island nations with high diabetes prevalence. Estimates of the number of individuals at increased risk were most sensitive to the prevalence of chronic kidney disease, diabetes, cardiovascular disease, and chronic respiratory disease.

If a safe and effective vaccine is produced, then our estimates provide an indication of the volumes that would be required for vaccination of at-risk individuals globally. In the absence of a vaccine, at-risk individuals might need to be shielded by more intensive physical distancing measures than individuals in the wider population. This approach could be especially important at times and places where health systems risk being overwhelmed by cases.

Lancet Infect Diseases, June 15, 2020

Seroconversion in Household Members of COVID-19 Outpatients

Rebecca J Cox, et al

In a recent publication, the household secondary attack rate, as detected by repeated RT-PCR tests, was approximately 11%. Here the authors have found substantially higher attacks rates in western Norway through detection of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The first case of COVID-19 in Norway was identified in Bergen on Feb 28, 2020, before the outbreak was declared a pandemic, allowing rigorous testing of suspected cases before and during the rise in confirmed cases. All suspected COVID-19 cases in the peak period between Feb 28 and April 4 were referred to the Bergen municipality emergency room for centralised evaluation and testing according to a strict exposure likelihood algorithm, allowing an overview of the early virus spread in the population. If a family was exposed, only the index case was tested for SARS-CoV-2 infection. Both cases and household members were tested for specific antibodies to the receptor binding domain of SARS-CoV-2 at 6 weeks after the index patient tested positive by RT-PCR.

Of 158 cases, 125 (79%) tested positive for antibodies and 12 (8%) were defined as borderline. In 77 household members, 24 (31%) tested positive and two (3%) were borderline. Our results show that detection of seroconversion might provide a more accurate picture of attack rates in households than intermittent RT-PCR testing.

Clinical Practice

Lancet Respiratory Medicine, June 16, 2020

Delivering Evidence-Based Critical Care for Mechanically Ventilated Patients with COVID-19

Jorge I F Salluh, et al

Currently, more than 50% of patients in the ICU require invasive mechanical ventilation and up to 20% need dialysis.

Considering the severity and unparalleled number of cases of COVID-19 pneumonia in ICUs, we must ensure the delivery of high-quality care for mechanically ventilated patients. More than adjunctive treatments or expensive immune therapies, for which evidence of efficacy is lacking, the focus should be on the careful application of evidence-based approaches associated with improved outcomes in ARDS over the past three decades.

Clinical Manifestations

Lancet Hematology, June 18, 2020

Prognosis of Patients with Sickle Cell Disease and COVID-19: A French Experience

Jean-Benoît Arlet, et al

The results of this study suggests that COVID-19, even if potentially severe, does not seem to carry an increased risk of morbidity or mortality in patients with sickle cell disease, as most patients worldwide have the SS/Sβ0 genotype and are younger than 45 years. Our findings also suggest that vaso-occlusive crisis can complicate COVID-19 infection, occurring in around half of inpatients with sickle cell disease. The hypothesis of a protective effect against COVID-19 in patients with the SS/Sβ0 variant should be explored.

France is the country with the highest prevalence of sickle cell disease in Europe, with more than 26 000 patients diagnosed with the condition in 2018. Most of these patients are of sub-Saharan African origin.1 Patients with sickle cell disease are thought to be at increased risk of COVID-19 complications. Aside from specific COVID-19-related morbidities, infections in patients with sickle cell disease can provoke painful vaso-occlusive crises and life-threatening acute chest syndrome. Thus, COVID-19 could be devastating for regions such as Africa or India, where an estimated 8–12 million patients with sickle cell disease live, or in the USA and Brazil, with more than 100 000 patients in each country. Nevertheless, there is currently no data on the outcomes of patients with sickle cell disease and COVID-19.

83 inpatients with sickle cell disease infected by SARS-CoV-2 from 24 centres were enrolled. The median age was 33·5 years (range 19–68) for the 66 (80%) adults and 12 years (0·3–17) for the 17 (20%) children (defined as patients <18 years). 48 (58%) of 83 patients had a past medical history of acute chest syndrome, with a median of 2 episodes (range 1–10); 38 (46%) were being treated with hydroxyurea at admission (30 [51%] of 59 patients in the SS/Sβ0 subpopulation). Vaso-occlusive crisis was associated with COVID-19 in 44 (54%) of 81 inpatients and acute chest syndrome was associated with COVID-19 in 23 (28%) of 82 inpatients.

The prevalence of ICU admission was significantly different between patients with sickle cell disease younger than 45 years and those 45 years or older; 9 (13%) of 68 patients with a median age of 28 years (range 0·3–44) versus eight (53%) of 15 patients with a median age of 54 years (45–68), p=0.0017. Compared with all other inpatients who tested positive for COVID-19 with the same age range, a biphasic trend was observed: a lower risk of ICU admission for young adults (15–44 years) with sickle cell disease than those without the condition (13% vs 24% admitted to ICU; odds ratio (OR) 0·44, 95% CI 0·16–0·99; p=0·039) and a higher but nonsignificant risk for older inpatients (45–64 years) with sickle cell disease (50% vs 36%; OR 1·76, 0·53–5·89; p=0·28, table 2). However, these data should be interpreted with caution because of a lack of statistical power to detect differences. A further limitation of this comparison is that the reasons for hospital admission in the patients without sickle cell disease with COVID-19 could be different (eg, respiratory complaints) compared with patients with sickle cell disease, in part because of sickle cell disease-related complications (eg, vaso-occlusive crisis). Nevertheless, this bias should affect age groups similarly. Moreover, we confirmed that 30 (71%) of 42 patients with sickle cell disease in this study had findings of COVID-19 pneumonia on chest CT scans.

Lancet Child Adolesc Health, June 15, 2020

Renal Dysfunction in Hospitalised Children with COVID-19

Douglas J Stewart, et al

In the UK, approximately half of hospitalised paediatric cases of COVID-19 show evidence of renal dysfunction, and more than a quarter meet acute kidney injury diagnostic criteria. Of those with acute kidney injury, six (40%) were in the most severe category 3 (ie, serum creatinine 3 times greater than the ULRI).

Authors present the findings of 52 paediatric patients (age 0–16 years) admitted to Great Ormond Street Hospital for Children NHS Foundation Trust (London, UK) since March 25, 2020, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Of 52 inpatients, 24 (46%) had a serum creatinine greater than theage-specific upper limit of reference interval (ULRI), and 15 (29%) met the the British Association of Paediatric Nephrology (BAPN) diagnostic criteria for acute kidney injury. Most cases of acute kidney injury occurred in those admitted to the paediatric ICU (14 [93%] patients), and in those with paediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2 (PIMS-TS; 11 [73%] patients). Unsurprisingly, patients with acute kidney injury were more likely to have diarrhoea and vomiting at presentation, thereby suggesting prerenal involvement.

Among our 52 paediatric patients, a minority (22 [42%]) were screened for proteinuria by either urinalysis or urine albumin to creatinine ratio. Haematuria was more likely to be detected as urine was often sent for microscopy as part of a septic work-up (for 40 [77%] patients. Of the acute kidney injury cohort, five (33%) had abnormal renal ultrasound findings that showed enlarged kidneys greater than the 95th percentile for age in bipolar length. We found no evidence of reduced corticomedullary differentiation or increased echogenicity in any of the ultrasound imaging. None of the patients with acute kidney injury required kidney biopsy or continuous renal replacement therapy, and only one case did not show a decrease in serum creatinine to lower than the ULRI value during admission. This patient has previously had recurrent episodes of acute kidney injury associated with an underlying metabolic disorder.

Specific mechanisms for kidney injury secondary to COVID-19 have been proposed. The virus spike (S) protein binds to angiotensin-converting enzyme 2 (ACE2), attached to the outer surface of cells in the lungs, vascular endothelium, kidneys, heart, and intestines. In doing so, it activates angiotensin II. Transmembrane protease serine 2 (TMPRSS2) cleaves and primes the S protein, allowing the release of viral fusion peptides, thus facilitating membrane fusion. Co-expression of ACE2 and TMPRSS2 is therefore believed to have an important role in allowing SARS-CoV-2 to enter host cells.Transcriptome analysis has shown high co-expression of ACE2 and TMPRSS2 in podocytes and straight tubular cells. By viral invasion, SARS-CoV-2 might have a direct cytopathic effect on these kidney cell types. Quantification of SARS-CoV-2 viral load in autopsy tissue of patients who have died from COVID-19 shows tropism for renal tissue, particularly in those with more than two organ systems involved, and this is unrelated to underlying chronic kidney disease. Viral load is detectable in all renal compartments with an apparent affinity for the glomeruli.

JAMA Infect Diseases, June 16, 2020

Clinical Characteristics and Morbidity Associated With Coronavirus Disease 2019 in a Series of Patients in Metropolitan Detroit

Geehan Suleyman

In this review of urban metropolitan Detroit, Michigan patients with COVID-19, most were African American with a high prevalence of comorbid conditions and high rates of hospitalization, intensive care unit admission, complications, and mortality due to COVID-19.

African American residents make up 32% of the state population, but accounted for more than 56% of COVID-19 deaths as of May 14, 2020.

Of 463 patients with COVID-19 (mean [SD] age, 57.5 [16.8] years), 259 (55.9%) were female, and 334 (72.1%) were African American. Most patients (435 [94.0%]) had at least 1 comorbidity, including hypertension (295 patients [63.7%]), chronic kidney disease (182 patients [39.3%]), and diabetes (178 patients [38.4%]). Common symptoms at presentation were cough (347 patients [74.9%]), fever (315 patients [68.0%]), and dyspnea (282 patients [60.9%]). Three hundred fifty-five patients (76.7%) were hospitalized; 141 (39.7%) required intensive care unit management and 114 (80.8%) of those patients required invasive mechanical ventilation. Male sex (odds ratio [OR], 2.0; 95% CI, 1.3-3.2; P = .001), severe obesity (OR, 2.0; 95% CI, 1.4-3.6; P = .02), and chronic kidney disease (OR, 2.0; 95% CI, 1.3-3.3; P = .006) were independently associated with intensive care unit admission. Patients admitted to the intensive care unit had longer length of stay and higher incidence of respiratory failure and acute respiratory distress syndrome requiring invasive mechanical ventilation, acute kidney injury requiring dialysis, shock, and mortality (57 patients [40.4%] vs 15 patients [7.0%]) compared with patients in the general practice unit. Twenty-nine (11.2%) of those discharged from the hospital were readmitted and, overall, 20.0% died within 30 days. Male sex (OR, 1.8; 95% CI, 1.1-3.1; P = .03) and age older than 60 years (OR, 5.3; 95% CI, 2.9-9.7; P < .001) were significantly associated with mortality, whereas African American race was not (OR, 0.98; 95% CI, 0.54-1.8; P = .86).

Lancet Infectious Diseases, June 18, 2020

Negative SARS-CoV-2 PCR in Patients with Chilblain-Like Lesions

Thomas Hubiche, et al

Chilblain-like lesions are associated with mild or asymptomatic SARS-CoV-2 infection and probably have negative PCR results at the time of presentation.

The literature on duration of viral shedding and serology in asymptomatic patients is confusing!

We did a prospective cohort study in patients with cutaneous manifestations who were referred to Centre Hospitalier Universitaire de Nice, France, between April 9 and 17, 2020, with suspected SARS-CoV-2 infection. 40 consecutive patients (21 [53%] female) with chilblain-like lesions were included. Consistent with previous reports, most patients were young, with a median age of 22 years (range 12–67; IQR 15–28). 26 (65%) patients were tested for SARS-CoV-2 RNA with RT-PCR using primers and probes recommended by WHO, and all patients were tested for SARS-CoV-2-specific IgA, IgM, and IgG antibodies with ELISAs (IgM and IgG with EDI Novel Coronavirus COVID-19 ELISA Kits [Epitope Diagnostics, San Diego, CA, USA]; and IgA and IgG with Euroimmune ELISAs [Euroimmun, Lübeck, Germany]).

25 (63%) patients were asymptomatic on physical examination, and the remaining patients had only mild symptoms compatible with COVID-19. 24 (60%) patients reported contact with a person suspected of having COVID-19. However, no patient was PCR positive at the time of consultation, a finding that is inconsistent with the PCR positivity of all three cases reported by Guarneri and colleagues. Our results are not surprising considering no patient reported having fever or signs of upper or lower respiratory tract infection in the past 3 days. However, COVID-19 serology was positive in 12 (30%) patients: seven had only IgA antibodies, three had only IgG antibodies, one had IgM and IgG antibodies, and one had IgA and IgG antibodies. This proportion is substantially higher than expected for our area (estimated at 3·4%6). Although these results require further investigation, they suggest that in young patients SARS-CoV-2 is completely suppressed before a humoral immune response is induced.

Lancet Rheumatology, June 18, 2020

COVID-19 in Patients with Rheumatic Diseases in Northern Italy: A Single-cCentre Observational and Case–Control Study

Micaela Fredi, et al

Between Feb 24 and May 1, 2020, authors collected data from 1525 patients with rheumatic and musculoskeletal diseases: 117 (8%) presented with symptoms that were compatible with COVID-19. 65 patients had a swab confirmation of SARS-CoV-2

infection, whereas 52 presented with a spectrum of symptoms indicative of COVID-19 but were not swab tested. Patients with confirmed COVID-19 were older than those with suspected COVID-19 (median age 68 [IQR 55–76] years vs 57 [49–67] years; p=0·0010) and more likely to have arterial hypertension (33 [51%] vs 14 [27%] patients; odds ratio [OR] 2·8 [95% CI 1·3–6·1]; p=0·031) and obesity (11 [17%] vs 1 [2%]; OR 11·0 [1·3–83·4]; p=0·0059). We found no differences in rheumatological disease or background therapy between confirmed and suspected COVID-19 cases. 47 (72%) of the 65 patients with confirmed COVID-19 developed pneumonia that required admission to hospital. 12 (10%) deaths occurred among the 117 patients with confirmed or suspected COVID-19 (ten in those with confirmed COVID-19 and two in those with suspected COVID-19). Deceased patients with confirmed COVID-19 were older than survivors (median age 78·8 years [IQR 75·3–81·3] vs 65·5 years [53·3–74·0]; p=0·0002). We observed no differences in sex, comorbidities, or therapies between the deceased patients and survivors. The case–control study comprised 26 patients with rheumatic and musculoskeletal diseases and COVID-19 pneumonia and 62 matched controls. We found no significant differences between cases and controls in duration of COVID-19 symptoms before admission, duration of stay in hospital, or the local chest X-ray scoring system. Glucocorticoids were used for severe respiratory manifestations related to lung involvement in 17 (65%) of 26 cases and tocilizumab in six (23%) of 26; thrombotic events occurred in four (15%) of 26 cases. Four (15%) of 26 cases and six (10%) of 62 controls died during the study period.

The presence of biomarkers of hyperinflammation (lymphocyte count, lactate dehydrogenase, ferritin, and D-dimer concentrations), evaluated within the first 7 days of hospital admission, did not differ significantly between cases and controls. However, we observed a significant difference in the lowest number of lymphocytes, with a more profound lymphopenia in cases than in controls (560 cells per mm3 vs 810 cells per mm3, p=0·021). No cases presented with leukopenia or lymphopenia at the last rheumatological evaluation.

A thrombotic event during hospital admission occurred in four cases (15%) and four controls (6%). Among the four cases, one presented with a venous thrombosis and three had an arterial thrombotic event. None of these patients had a known positivity for antiphospholipid antibodies. No difference in death rate was reported between four (15%) of 26 cases and six (10%) of 62 controls.

These data reinforce the hypothesis that the prognosis of SARS-CoV-2 infection is more likely to be related to the presence of other risk factors rather than the rheumatic and musculoskeletal disease itself or the background therapy. In fact, in our cohort, older age represented the main risk factor for hospital admission and death.

Prevention

NEJM, June 18, 2020

Amplifying RNA Vaccine Development

Deborah H. Fuller, et al

Nucleic acid vaccines are now a major hope for solving this pandemic crisis. This comes as no surprise. From their earliest conception, nucleic acid vaccines were recognized as a possible solution for a rapid pandemic response. The need for only the sequence of a pathogen in order to generate the vaccine and its simplicity in manufacture have long been recognized as superpowers in nucleic acid vaccines with regard to the delivery of a rapid response to an emerging epidemic. The ability of self-amplifying RNA vaccines, and now trans-amplifying RNA vaccines, to provide amplified and durable production of antigen in vivo, coupled with potent inherent innate immune-stimulating properties, adds to these powers and may provide the dose-sparing (i.e., getting the same immune responses with smaller doses of vaccine) that will probably be needed to meet global demands. We can only hope that their deployment will render the Covid-19 pandemic crisis into a more manageable challenge, saving lives and decreasing morbidity.

Recent interest in messenger RNA (mRNA) vaccines has been fueled by methods that increase mRNA stability and protein production and improve delivery. These methods include the use of modified nucleosides as well as the development of nanoparticle-delivery technologies that stabilize mRNA, enhance cellular uptake, and improve the bioavailability of the mRNA once it is inside the cell. Avoidance of the risk of integration into the host genome is considered a comparative advantage of mRNA (with respect to DNA vaccines), although extensive studies have eased this concern about DNA vaccines. A clear advantage of mRNA vaccines is that, unlike DNA vaccines, they do not need to enter the nucleus to express the antigen. Instead, once inside the nucleus, a DNA vaccine will produce many copies of mRNA molecules, resulting in the production of more antigen per transfected cell. Of interest, then, are self-amplifying RNA vaccines, such as those involved in the strategy described by Beissert et al. to increase the yield of antigen expressed by mRNA vaccines.

Self-amplifying RNA vaccines are derived from the genome backbone of an alphavirus in which the genes encoding the viral RNA replication machinery are intact but those encoding viral structural proteins are replaced with a transgene encoding the vaccine antigen. A self-amplifying RNA vaccine can be delivered in the form of plasmid DNA, viruslike RNA particles, and in vitro transcribed RNA and can elicit substantially stronger immune responses than mRNA. This immunogenicity, coupled with the ability to deliver self-amplifying RNA with the use of synthetic formulations in a cell-free and potentially highly scalable manner, makes the approach particularly attractive. DNA plasmid–based self-amplifying RNA vaccines combine the advantages of a more stable DNA nucleic acid product with greater levels of antigen expression of self-amplifying RNA vaccines to elicit stronger immune responses in preclinical models than conventional DNA vaccines.

Beissert et al. describe a strategy that is based on two RNA vectors — one retaining the replicase-encoding gene and the other encoding the antigen. The replicase machinery is therefore provided “in trans” (i.e., two genes acting together but on different RNAs) by a self-amplifying RNA or a nonreplicating mRNA and mediates replication of the antigen-encoding RNA. The safety benefit stems from the fact that the use of two separate RNAs avoids the risk incurred with self-amplifying RNAs that are engineered to express budding-competent viral glycoproteins that could, in theory, find their way into extracellular vesicles and transfer to new host cells.

Plasmid DNA carries replicase genes (encoding proteins that replicate RNA) and the transgene (which encodes the vaccine antigen) into the nucleus, where it is transcribed, generating replicon RNA (the part that encodes replicase proteins). Replicon RNA is then transported to the cytoplasm, which is then followed by RNA self-replication (also called self-amplification), messenger RNA (mRNA) production, and translation of vaccine antigen (red) (Panel A). Viruslike RNA particles that are produced in a separate packaging step (not shown) deliver replicon RNA to the cytoplasm by means of receptor-mediated endocytosis (Panel B). In vitro transcribed replicon RNA is delivered to cells either in saline or in synthetic formulations (Panel C). Common to each approach, the replicase protein complex is translated from the upstream two thirds of the replicon RNA genome (purple). The replicase initiates RNA-dependent RNA polymerase–mediated transcription of a negative strand (−RNA) using the 3′ nontranslated (NTR) region (green) and, using the −RNA as a template, also transcribes a positive strand (+RNA) from the 5′ NTR region (green), as well as a subgenomic promoter (arrow) to initiate transcription into mRNA. Many antigen proteins (Ag) are translated directly from the mRNA by cytoplasmic ribosomes. A dual strategy was described recently by Beissert and colleagues in which a replicon RNA encodes the replicase machinery “in trans” to the co-delivered antigen-encoding RNA (Panel D). The authors found immunogenicity when the replicase genes were flanked by NTR regions to facilitate intracellular replication (Panel E). They observed enhanced immunogenicity when the replicase genes were optimized for translational efficiency (and lacked flanking regions). CGMP denotes Current Good Manufacturing Processes, and E. coli Escherichia coli.

JAMA, June 15, 2020

Effects of Sterilization With Hydrogen Peroxide and Chlorine Dioxide on the Filtration Efficiency of N95, KN95, and Surgical Face Masks

Changjie Cai, et al

Although surgical masks should not be used as a substitute for N95s owing to lower fit quality, a randomized clinical trial by Radonovich et al found that there was no significant difference in the incidence of laboratory-confirmed influenza among health care personnel who used N95s vs surgical face masks.

This quality improvement study found that the sterilization processes had different effects on the filtration efficiencies of different masks. Sterilization with H2O2 had fewer negative effects than ClO2. In addition to considering the overall filtration efficiency, the filtration efficiency for particles similar to infectious agents should be considered.

Treatment

JAMA, June 15, 2020

Monoclonal Antibodies for Prevention and Treatment of COVID-19

Mary Marovich, et al

The majority of monoclonal antibodies isolated to date specifically target the receptor-binding domain on the spike protein that allows SARS-CoV-2 to make contact with the ACE 2 receptor.

SARS-CoV-2 monoclonal antibodies have the potential to be used for both prevention and treatment of infection. In the largest study to date, Joyner et al administered 1 to 2 units of convalescent plasma to 5000 patients with severe or life-threatening SARS-CoV-2 infection. The investigators reported an incidence of less than 1% for severe adverse events and a 7-day mortality rate of 14.9%, which is consistent with the natural history of severe infection. Liu et al reported a benefit from convalescent plasma with a neutralizing titer dilution of greater than 1:320 when provided to hospitalized patients who did not require intubation.

Given the long half-life of most monoclonal antibodies (approximately 3 weeks for IgG1), a single infusion should be sufficient. Newer technologies that modify the Fc region of the antibody to extend the half-life of monoclonal antibodies can provide potentially protective levels for months, depending on the monoclonal antibody concentrations required.

There is also some concern for immune enhancement of COVID-19 because vaccine-associated enhanced disease has been observed in animal models of SARS-CoV and for other animal coronaviruses. Categories of possible disease enhancement include antibody-mediated enhancement of viral entry and replication in target cells (Fc-bearing monocytes or macrophages) and virus-antibody immune complexes and the associated cytokine release. For the former, antibody-mediated enhancement is classically defined as Fcγ-receptor–mediated enhanced disease in the presence of subneutralizing concentrations of antibodies or nonneutralizing antibodies.

Lancet Infect Diseases, June 15, 2020

Appropriate Selection of Convalescent Plasma Donors for COVID-19

Richard S Tedder, et al

The absence of a clinically relevant therapeutic benefit in patients with Ebola virus infection described by Griensven and colleagues, and more recently the finding of no therapeutic benefit in a small trial in patients with COVID-19 in Zhengzhou, China, will be used to question the usefulness of convalescent plasma in COVID-19. In the Guinea-Bissau Ebola study, no attempt was made to select donors for the potency of their neutralising antibody. In the COVID-19 study, seropositive donors were recruited only after IgM antibody to SARS-CoV-2 was no longer detected, and no attempt to quantify the antibody response was reported.

The writers of this correspondence previously described the levels of detectable antibody and the inferred level of neutralising antibody in convalescent plasma donors for patients with Ebola virus disease in Sierra Leone, showing 100-fold differences in the level of neutralising antibody. They described a strategy for selecting donors with the highest levels of neutralising antibody, which was not undertaken in donors in the Guinea-Bissau or Zhengzhou studies. For planned interventions in the treatment of patients with COVID-19 severe disease, they strongly recommend selection and qualification only of donors who carry the highest levels of detectable neutralising antibody to SARS-CoV-2. In this respect, they have data which indicate that quantification of specific antibody to the receptor-binding domain will indicate levels of neutralising antibody (unpublished). Commercial assays based on the receptor-binding domain alone, although not intended for the purpose of identifying suitable convalescent plasma donors, will probably be able to serve this need.

Lancet Infectious Diseases, June 16, 2020

Hydroxychloroquine Use in COVID-19: What is the Basis for Baseline Tests?

TP Afra, et al

If this drug is found to be beneficial in COVID19, the fear of haemolysis should not deter one from the prescription of hydroxychloroquine.

G6PD deficiency is the most common human enzymatic deficiency that affects 400 million people worldwide. In red blood cells, G6PD is the only pathway available to generate NADPH, an important scavenger of reactive oxygen species. When G6PD-deficient individuals are exposed to particular pharmacological or microbiological insults, haemolysis occurs because of the accumulation of free radicals.

Hydroxychloroquine (a derivative of chloroquine) has been used in dermatology and rheumatology settings for more than 50 years, and unlike its related drug primaquine (an 8-aminoquinoline), hydroxychloroquine (a 4-aminoquinoline) does not induce haemolysis in G6PD-deficient individuals. This finding was substantiated by a seminal study, which ruled out the occurrence of hydroxychloroquine-related haemolysis in G6PD-deficient individuals. In the largest US study2 to evaluate the frequency of G6PD deficiency in patients taking hydroxychloroquine, there were no reported episodes of haemolysis in more than 700 months of hydroxychloroquine exposure among the 11 G6PD-deficient patients. Even though similar studies of chloroquine are not available, there are no reports of haemolysis associated with chloroquine monotherapy either.

Lancet Respiratory Medicine, June 16, 2020

Therapeutic Blockade of Granulocyte Macrophage Colony-Stimulating Factor in COVID-19-Associated Hyperinflammation: Challenges and Opportunities

Puja Mehta, et al

An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. The hyperinflammatory condition haemophagocytic lymphohistiocytosis (HLH) is characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure, usually manifesting with cytopenia and abnormal liver function. When caused by genetic abnormalities, this disorder is referred to as primary or familial HLH. Secondary HLH is a hyperinflammatory syndrome triggered by infection, rheumatic disorders, and malignant disease (usually lymphoproliferative disorders). Cytokine storm syndromes can be termed macrophage activation syndrome (when associated with rheumatic disease), macrophage activation-like syndrome (in sepsis), and cytokine release syndrome (after chimeric antigen receptor [CAR] T-cell therapy). A subset of patients with severe COVID-19 shows evidence of hyperinflammation and might, therefore, potentially benefit from immunomodulation.Clinical trials of existing approved immunomodulatory agents, including inhibitors of the IL-6 pathway (eg, with tocilizumab) and IL-1 pathway (eg, with anakinra), are ongoing or about to start in patients with COVID-19.

Granulocyte macrophage colony-stimulating factor (GM-CSF), which signals via the JAK-STAT pathway and induces the production of interleukin-6 and other proinflammatory cytokines, could serve as a link between T-cell-driven acute pulmonary inflammation and an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation.

ARDS is a heterogeneous clinical disorder characterised by refractory hypoxaemia, with mortality of 35–55% despite supportive standard of care, including low tidal volume ventilation. Cohort data from Wuhan, China, show that ARDS occurs in approximately 30% of hospitalised patients with COVID-19 and is associated with high mortality. Clinical trials of pharmacological agents in ARDS have been met with limited treatment successes, but unbiased latent class analysis of clinical and biomarker characteristics from randomised trial data has identified two distinct ARDS subphenotypes—a hypoinflammatory endotype and a hyperinflammatory endotype—with distinct clinical characteristics, biomarker profiles, clinical outcomes, and treatment responses. Therefore, it is increasingly recognised that a tailored therapeutic approach to individual ARDS patients will be needed to improve clinical outcomes.

Emerging experience suggests that the hyperinflammatory response in COVID-19 does not fit the classic profile of secondary HLH or cytokine release syndrome. Although ferritin levels predict mortality in COVID-19, ranges are lower than those reported in patients with secondary HLH, and the clinical syndrome is lung dominant, typically without substantial cytopenia. Of note, lymphopenia is almost universal in patients with severe COVID-19, but the lymphocyte lineage is not classically affected in secondary HLH; in the context of COVID-19, therefore, lymphopenia might be the outcome of a viral driver. Whether patients with COVID-19 pneumonia present an atypical form of ARDS has also been debated, but it is increasingly felt that ARDS associated with COVID-19 might not be dissimilar to the phenotype associated with other viral drivers. A management approach for COVID-19-associated ARDS has been proposed and is continuously evolving as clinical experience accumulates.

The potential benefits of targeting GM-CSF in the context of a virally driven disorder such as COVID-19 need to be carefully balanced with potential risk associated with blocking the role of this cytokine in tissue homoeostasis, including maintenance of alveolar capillary barrier integrity in host defence and epithelial repair.

Once patients need ventilatory support, the purported window of opportunity for therapeutic intervention might already have been missed, and patients might tip into an accelerated state, during which time initiation of treatment could be less effective or even futile. The ideal window of opportunity for immunomodulation might be before patients develop severe disease and need invasive mechanical ventilation (intubation). However, robust predictive biomarkers for poor outcomes and in-depth characterisation of the host immune response across disease stages, to minimise the effect of immunomodulatory agents on the antiviral response, are urgently needed.

Strategies targeted at specific endotypes in ARDS are regarded as essential for optimum clinical outcomes.

Lancet Rheumatology, June 16, 2020

GM-CSF in the Treatment of COVID-19: A New Conductor in the Pathogenesis of Cytokine Storm?

Ennio Giulio Favalli, et al

Interaction between SARS-CoV-2 and the immune system has led to the identification of a massive release of pro-inflammatory mediators linked to an aberrant immune response as the main cause of infection evolution towards life-threatening respiratory impairment.

This aberrant immune response closely resembles a similar reaction observed following the oncological use of chimeric antigen receptor (CAR) T cells, known as cytokine release syndrome. A high concentration of interleukin-6 (IL-6) observed in cytokine release syndrome, suggesting a pivotal role of this cytokine in the pathogenesis of this condition, paved the way for use of IL-6 inhibitors to treat this complication. Similarly, the anti-IL-6 agent tocilizumab was the first biological drug used in the treatment of severe COVID-19 and is still being tested in several ongoing randomised trials. However, the first published results on this approach are controversial and, so far, have not confirmed the effectiveness of IL-6 blockade. In addition, inhibitors of other pro-inflammatory mediators involved in the development of cytokine release syndrome are being tested as potential treatment targets in COVID-19.

GM-CSF has very complex immunological activity, ranging from the well known haematopoietic effect to the more recently demonstrated pro-inflammatory role, which has made it a potential target for the treatment of immune-mediated diseases such as rheumatoid arthritis, spondyloarthritis, and giant-cell arteritis. Undoubtedly, within the inflammatory cascade, this effect can be placed further upstream compared with other cytokines such as IL-1, tumor necrosis factor, and IL-6.

For an example, a Chinese study reported that atypical pathogenic T helper 1-cells expressing GM-CSF have been detected only in patients with more severe COVID-19 compared with both patients with less symptomatic patterns and healthy controls.These findings seem to confirm a crucial and upstream role of GM-CSF in the pathogenesis of SARS-CoV-2-related hyperinflammation.

The following article reports a prospective analysis aimed at evaluating the effect of mavrilimumab, a granulocyte–macrophage colony-stimulating factor (GM-CSF) receptor inhibitor, in the treatment of non-mechanically ventilated patients with COVID-19 pneumonia and systemic hyperinflammation. The authors observed that, by day 28 of follow-up, all 13 patients who received mavrilimumab showed clinical improvement compared with 17 (65%) of 26 patients in the control group (p=0·030), who received standard care provided at the hospital at the time of the study, including hydroxychloroquine, azithromycin, and lopinavir–ritonavir. Furthermore, no patients who received mavrilimumab died, but seven (27%) patients in the control group died by day 28. The study is certainly affected by some potential limitations. The small sample size, the absence of randomisation, and the short follow-up period might reduce the fully generalisability of observed results. However, the inclusion of an overall well matched control group represents a strength compared with other studies evaluating biological drugs for the same indication.

Lancet Rheumatology, June 16, 2020

GM-CSF Blockade with Mavrilimumab in Severe COVID-19 Pneumonia and Systemic Hyperinflammation: A Single-Centre, Prospective Cohort Study

Giacomo De Luca, et al

The pathogenesis of COVID-19 pneumonia involves a maladaptive, detrimental inflammatory response in the lungs. Post-mortem studies of patients with COVID-19 revealed inflammatory exudates and rich infiltration of neutrophils and myeloid cells in air spaces.23 Detrimental inflammation in the lungs is paralleled by elevations in serum CRP and ferritin, which are markers of disease severity.

GM-CSF is a cytokine with a cardinal role in innate inflammation and is a potential mediator of the cytokine storm. The concentration of circulating GM-CSF is low under physiological conditions, and increases in inflammatory settings, being produced by several cell types at the site of inflammation and functioning as a feedforward inflammatory amplifier.6, 8 Moreover, GM-CSF regulates pulmonary surfactant homoeostasis and alveolar macrophage-mediated innate host defence.

Mavrilimumab is an anti-GM-CSF-Rα monoclonal antibody, which inhibits the GM-CSF signalling axis in granulocytes and myeloid cells. In previous phase 2 studies in patients with rheumatoid arthritis, mavrilimumab dampened inflammation, improved clinical outcomes, and was well tolerated.9, 10 Notably, in clinical studies with mavrilimumab, there was no causal association apparent between administration of mavrilimumab and clinically significant respiratory disease. This finding is of great clinical importance considering the observation that high levels of autoantibodies against GM-CSF, as well as mutation of the α or β subunits of the GM-CSFR, have been associated with idiopathic and hereditary pulmonary alveolar proteinosis, respectively.

This single-centre prospective cohort study included patients aged 18 years or older who were admitted to San Raffaele Hospital (Milan, Italy) with severe COVID-19 pneumonia, hypoxia, and systemic hyperinflammation. Patients received a single intravenous dose (6 mg/kg) of mavrilimumab added to standard care given by the hospital at the time. The control group consisted of contemporaneous patients with similar baseline characteristics who received standard care at the same hospital. The main outcome was time to clinical improvement (defined as improvement of two or more points on the seven-point ordinal scale of clinical status). Other outcomes included proportion of patients achieving clinical improvement, survival, mechanical ventilation-free survival, and time to fever resolution. Adverse events were monitored daily.

Between March 17 and April 15, 2020, 13 non-mechanically ventilated patients (median age 57 years [IQR 52–58], 12 [92%] men) received mavrilimumab and 26 patients (median age 60 [IQR 53–67], 17 [65%] men) in the control group received standard care. During the 28-day follow-up, no patients in the mavrilimumab group died, and seven (27%) patients in the control group died (p=0·086). At day 28, all patients in the mavrilimumab group and 17 (65%) patients in the control group showed clinical improvement (p=0·030), with earlier improvement in the mavrilimumab than in the control group (mean time to improvement 8 days [IQR 5 to 11] vs 19 days [11 to >28], p=0·0001). By day 28, one (8%) patient in the mavrilimumab group progressed to mechanical ventilation compared with nine (35%) patients in the control group who progressed to mechanical ventilation or died (p=0·14). By day 14, fever resolved in ten (91%) of 11 febrile patients in the mavrilimumab group, compared with 11 (61%) of 18 febrile patients in the control group (p=0·18); fever resolution was faster in mavrilimumab recipients versus controls (median time to resolution 1 day [IQR 1 to 2] vs 7 days [3 to >14], p=0·0093). Mavrilimumab was well tolerated, with no infusion reactions. Three (12%) patients in the control group developed infectious complications.

Chest, June 15, 2020

Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized COVID-19 Patients: Survival and Clinical Outcomes

Christina C.Price, et al

An observational study of consecutive COVID-19 patients hospitalized from 03.10-31.20 and followed through 04.21.20 was conducted by chart review. Patients were treated with tocilizumab (a humanized anti-IL-6 receptor monoclonal antibody) using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified by disease severity designated at admission (severe, ≥3L supplemental oxygen to maintain oxygen saturation >93%). For tocilizumab-treated patients, a pre/post analyses of clinical response, biomarkers and safety outcomes was assessed. Post-hoc survival analyses were conducted for race/ethnicity.

Among 239 patients, median age was 64 years; 36% and 19% were Black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; p<0.001), greater proportion requiring MV (44% vs 5%; p<0.001) and longer median MV days (5.5 vs 1.0; p=0.003). Tocilizumab-treated patients (N=153, 64%) involved 90% of severe patients; 44% of non-severe patients received it for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission hsCRP levels (120 vs 71mg/L; p<0.001), received tocilizumab sooner (2 vs 3 days; p<0.001), but survival was similar to non-severe patients (83% vs 91%; p=0.11). For tocilizumab-treated patients requiring MV, survival was 75% (95%CI=64%-89%). After tocilizumab, few adverse events occurred, oxygenation and inflammatory biomarkers (e.g., hsCRP, IL-6) improved; however, D-dimer and sIL2R levels increased significantly. Survival in Blacks and Hispanics, after controlling for age, was significantly higher than in whites (log-rank p=0.002).

JAMA, June 17, 2020

Prone Positioning in Awake, Nonintubated Patients With COVID-19

Necessity Is the Mother of Invention

Aartik Sarma, et al

Prone positioning has several beneficial effects on pulmonary physiology in patients with ARDS. In the supine position, pulmonary edema accumulates in basilar regions, and the heart and abdominal contents further compress these dependent lung regions. This leads to heterogenous ventilation, with increased volume delivered to apical and anterior lung units, which are also the regions that receive less of the pulmonary circulation. Together, these factors lead to perfusion of poorly ventilated lung units and hypoxemia. Prone positioning of the patient leads to a more homogeneous distribution of ventilation, thus decreasing the shunt fraction and improving matching of ventilation and perfusion. Moreover, homogeneous ventilation may decrease lung injury by more evenly distributing mechanical force from the ventilator across the lung during inhalation.

Despite compelling experimental evidence of these physiologic changes, most of the early randomized clinical trials of the prone position in mechanically ventilated patients with ARDS did not demonstrate a benefit compared with standard care. These trials, however, may have been limited by the late initiation and short duration of the use of the prone position. To address these limitations, the Proning Severe ARDS Patients (PROSEVA) trial, published in 2013, randomized patients with a ratio of arterial oxygen tension (Pao2) to fraction of inspired oxygen (Fio2) less than 150 mm Hg within 36 hours of intubation to be placed in the prone position for long durations—on average, 17 hours a day. The comparison group was patients ventilated in the supine position. The trial found a hazard ratio for death of 0.39 (95% CI, 0.25-0.63) in the study arm with prone positioning compared with standard care (mortality at 28 days, 16.0% vs 32.8%). The findings have led to increased adoption of prone positioning for mechanically ventilated patients with moderate to severe ARDS.

In a report on 50 nonintubated hypoxemic patients with suspected COVID-19 who presented to an emergency department in New York City, Caputo and colleagues found a significant increase in Spo2 5 minutes after proning (preproning: 84%; interquartile range [IQR], 75%-85%; postproning: 94%; IQR, 90%-95%; P = .001). Elharrar et al conducted an observational study of prone positioning in patients with confirmed COVID-19 and posterior lung opacities on chest computed tomography who were admitted to a single center in France, most of whom were on 4 L or less of oxygen delivered via nasal cannula. Among 24 eligible patients, the majority (15 [63%]) were able to tolerate being prone for at least 3 hours, but oxygenation increased with the prone position in only 6 patients (25%). Finally, Sartini et al tested prone positioning in 15 patients admitted to a single center in Milan, Italy, who were hypoxemic despite 10 cm H2O continuous positive airway pressure and 0.6 Fio2, and Spo2 increased in all 15 patients. The report by Thompson et al adds to this body of observational evidence by demonstrating that many patients with severe acute hypoxemic respiratory failure yet not on positive pressure ventilation had improved oxygenation in the prone position.

Although promising, these case series should be interpreted with caution because of the lack of randomization. Even in this selected group of patients, not all patients tolerated the prone position, and nearly half the patients in the case series from Thompson et al eventually required intubation. Although improved oxygen saturation with the prone position is important, hypoxemia has not been a reliable surrogate biomarker for mortality in clinical trials of ARDS. Notably, in the National Heart, Lung, and Blood Institute ARDS Network trial of low tidal volumes, the Pao2/Fio2 ratio was higher in the high-tidal-volume arm than the low-tidal-volume arm on study days 1 and 3. Nonetheless, mortality was lower in the low-tidal-volume arm (31.0% vs 39.8%).

One potential concern with the use of the prone position in spontaneously breathing patients is that it could delay intubation and mechanical ventilation. The optimal timing of intubation and mechanical ventilation for patients with ARDS is not known, but delayed intubation has been associated with increased mortality in patients with ARDS.9 Spontaneously breathing patients with ARDS generate relatively large tidal volumes; the result could be inadvertent self-inflicted lung injury. Controlled modes of mechanical ventilation minimize progression of lung injury owing to barotrauma. These benefits should be balanced with the risks of mechanical ventilation, including the need for prolonged sedation and the risk of ventilator-associated pneumonia. Ongoing clinical trials of prone positioning in non–mechanically ventilated patients should help clarify the role of this simple, low-cost approach for patients with acute hypoxemic respiratory failure.

JAMA, June 17, 2020

Prone Positioning in Awake, Nonintubated Patients With COVID-19 Hypoxemic Respiratory Failure

Alison E. Thompson, et al

In this small single-center cohort study, we found that the use of the prone position for awake, spontaneously breathing patients with COVID-19 severe hypoxemic respiratory failure was associated with improved oxygenation. In addition, patients with an Spo2 of 95% or greater after 1 hour of the prone position was associated with a lower rate of intubation. Limitations of this study are the lack of control group and a small sample size.

Authors screened consecutive patients admitted to the Columbia University step-down unit (intermediate care unit) between April 6 and April 14, 2020 (N = 88). Inclusion criteria were laboratory-confirmed COVID-19 with severe hypoxemic respiratory failure defined as respiratory rate of 30 breaths/min or greater and oxyhemoglobin saturation (Spo2) of 93% or less while receiving supplemental oxygen 6 L/min via nasal cannula and 15 L/min via nonrebreather face mask.

Among 29 eligible patients, 25 had at least 1 awake session of the prone position lasting longer than 1 hour; 4 refused the prone position and were intubated immediately. One hour after initiation of the prone position, Spo2 increased compared with baseline.

The range of improvement in Spo2 was 1% to 34% (median [SE], 7% [1.2%]; 95% CI, 4.6%-9.4%). In all patients, the levels of supplemental oxygen were unchanged during the first hour of the prone position. One hour after initiation of the prone position, 19 patients had Spo2 of 95% or greater; subsequently, 7 (37%) required intubation. Among 6 patients whose Spo2 remained less than 95% 1 hour after initiation of the prone position, 5 (83%) were intubated. The mean difference in the intubation rate among patients with Spo2 of 95% or greater vs Spo2 less than 95% 1 hour after initiation of the prone position was 46% (95% CI, 10%-88%).

Special Groups

Lancet Infect Diseases, June 15, 2020

COVID-19 in Africa: Between Hope and Reality

Francine Ntoumi, et al

A question that Republic of the Congo and other member states in the region must ask themselves is why are we seeing only a gradual increase in the detection of cases? Are we missing infections? A probable answer is that people with symptoms do not present to health-care facilities because of their concerns about fragile health systems, social stigma, and quarantine in suboptimal facilities. Other questions still to be resolved are related to the dynamics of viral transmission across geographical regions, between humans, across different ecosystems, and within different genetic backgrounds, and to whether any protective herd immunity exists.

Given the fragile health systems in most sub-Saharan African countries, new and re-emerging infectious disease outbreaks can paralyse health systems and existing structures. Yet the COVID-19 pandemic poses a challenge not only for sub-Saharan African countries but also for those with well functioning health systems.

NEJM, June 16, 2020

Facing the Monster in Haiti

Bernard Liautaud, et al

Haiti is susceptible to natural disasters and epidemics. But we are also resilient, creative, and relentless when faced with overwhelming challenges. We have overcome worse, and we will overcome Covid-19. We hope that our suggestions help our colleagues in other low-income countries.

Unlike prior humanitarian crises, when resources and international technical experts were rushed into Haiti, during this one we’re on our own. For example, Haiti has 41 centers that could perform Covid-19 testing nationwide using the Cepheid platform, but the U.S. manufacturer is not distributing the tests to Haiti. Consequently, only the Haitian National Laboratory and GHESKIO can perform polymerase-chain-reaction testing, using other platforms. These laboratories are working in unison, sharing resources and technical staff, and Haitian businesses and the Haitian diaspora have provided support for this national effort.

As of June 2, 2020, there were more than 2500 confirmed cases and the doubling time was 5 days. Future reported figures will be a fraction of actual rates, since testing capacity is now overwhelmed.

The same factors that contribute to deaths from natural disasters make Haiti susceptible to a viral pandemic: poverty, food insecurity, lack of clean water and sanitation, scarce health care resources, low educational attainment, political division, and densely populated slums that are controlled by gangs and inaccessible to public officials. As Covid-19 surges in Latin America and Africa, lessons learned in Haiti will be applicable in other low-income countries with similar vulnerabilities.

Stigmatization of people with Covid-19 impedes care. Rumors posted on social media (e.g., Covid-19 is a government ruse to seek international funding; Covid-19 is transmitted by contaminated testing swabs; and hospitals are using patients with Covid-19 for vaccine experiments) travel faster than truths reported in the traditional media. Hospitals treating patients with Covid-19 have been physically attacked. Health care workers have been threatened and MSPP mobile-testing teams stoned. GHESKIO is engaging community leaders to overcome this mistrust and stigma.

Medical Education

NEJM, June 16, 2020

Can Covid Catalyze an Educational Transformation? Competency-Based Advancement in a Crisis

Mary Ellen J. Goldhamer, et al

Historically, GME relied on immersion in patient care with informal supervision and assessment; residents graduated if they completed the prescribed duration of training without evidence of significant shortcomings. In 1999, the Accreditation Council for Graduate Medical Education (ACGME), which accredits training programs, articulated six core competencies, establishing a more structured and deliberate approach to physician training and thereby paving the way for the development of competency-based program curricula and assessment. Subsequent delineation of entrustable professional activities and specialty-specific milestones have advanced a framework for assessing physician competency.

The next logical step in this evolution is a transition from time-based to competency-based, time-variable (CB-TV) GME, in which each physician graduates from residency (or fellowship) to unsupervised practice when — and only when — the necessary competencies are achieved. Canada has launched a nationwide transition to CB-TV GME across all specialties, after completing pioneering pilot work in orthopedics.

Because Covid’s disruption to GME may continue — and because CB-TV GME has been a goal for educational reform — we should use this unexpected, uncontrolled experiment as an opportunity to learn how best to implement CB-TV GME. Studying outcomes of physicians who graduate without fulfilling case quotas or time requirements, and investing in evidence-based methods to assess physician competence, will help in charting the course ahead. In these ways, we hope that the Covid crisis will be used to capitalize on prior work and catalyze planning for a robust system of CB-TV GME, achieving sustainable improvement in how we train physicians.