Top 10: May 24

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By Christian Hoffmann &
Bernd S. Kamps

24 May

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Summary

First, take notice of the probable COVID-19 career end of two improbable drugs, cloroquine and hydroxychloroquine. The short message: Don’t use them anymore, alone or in combination, for the prophylaxis or treatment of SARS-CoV-2 infection. This recommendation stems from a large multinational registry analysis from 671 hospitals on six continents, 14,888 patients treated with these drugs were compared with 81,444 control patients. Each cloroquine or hydroxychloroquine regimen was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias.

Afterwards, discover seeding patterns of SARS-CoV-2 in Saudi Arabia; quantify the reduction in daily global CO2 emissions during the early COVID-19 pandemic; administer an adenovirus type-5 vectored COVID-19 vaccine to 108 healthy adults, measure neutralizing antibodies and determine the frequency of fever, fatigue, and headache; try and understand which healthcare workers in Tongji hospital, Wuhan, were more likely to be infected with SARS-CoV-2: HCWs in fever clinics or wards or HCWs in other clinical departments; and discuss with your friends that there is no direct evidence indicates that public mask wearing protects either the wearer or others, but that the possible benefit of a modest reduction in transmission likely outweighs the possibility of harm.

Finally, review evidence regarding the benefits and harms of ventilation techniques; discuss with your colleagues the role of systemic inflammation and vascular endothelial damage in the development of fatal organ failure; assess endothelial cell dysfunction which might explain the vascular microcirculatory complications seen in different organs in patients with COVID-19; and discover that 6% of 1, 353 health-care workers reporting fever or respiratory symptoms were found to be infected with SARS-CoV-2. How many of the 86 infected HCWs continued working while symptomatic?

Epidemiology

Le Quéré C, Jackson RB, Jones MW et al. Temporary reduction in daily global CO2 emissions during the COVID-19 forced confinement. Nat Clim Chang 2020. Full-text: https://doi.org/10.1038/s41558-020-0797-x

The global CO2 emissions have decreased by 17% by early April 2020 compared with the mean 2019 levels, just under half from changes in surface transport (cars, truck, buses). More than one billion tons of carbon emissions less. At their peak, emissions in individual countries decreased by an average of 26%, admittedly extreme and probably unseen before, but just to the level of emissions in 2006. The impact on 2020 annual emissions will depend on the duration of the confinement, with a low estimate of –4% if pre-pandemic conditions return by mid-June, and a high estimate of –7% if some restrictions remain worldwide until the end of 2020. These figures are comparable to the rates of decrease needed year-on-year over the next decades to limit climate change to a 1.5 °C warming.

 

 

Memish ZA, Aljerian N, Ebrahim SH. Tale of three seeding patterns of SARS-CoV-2 in Saudi Arabia. Lancet Infect Dis. 2020 May 19:S1473-3099(20)30425-4. PubMed: https://pubmed.gov/32442522. Full-text: https://doi.org/10.1016/S1473-3099(20)30425-4

With regard to case numbers, Saudi Arabia already ranks #15 in the world. Beside routine travel, authors describe two factors driving the epidemic. First, each month about 1 million incoming pilgrims from 180 countries merge with about 1 million Saudi national Sunni pilgrims at Saudi Arabia’s two holy sites. Second is the returning Shiite Saudi national pilgrims (4·9 million Shiite population in Saudi Arabia) who travel to Iran for pilgrimage. Of note, men and woman older than 60 years are overrepresented among pilgrims. Bad prospects.

 

Vaccine

Zhu FC, Li YH, Guan XH. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet May 22, 2020. Full-text: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31208-3/fulltext

Open-label Phase I trial of an Ad5 vectored COVID-19 vaccine, using the full-length spike glycoprotein. A total of 108 healthy adults aged between 18 and 60 years from Wuhan, China, were given three different doses. ELISA antibodies and neutralising antibodies increased significantly and peaked 28 days post-vaccination. Specific T cell response peaked at day 14 post-vaccination. Follow-up is still short and the authors are going to follow up the vaccine recipients for at least 6 months, so more data will be obtained. Of note, adverse events were relatively frequent, encompassing pain at injection sites (54%), fever (46%), fatigue (44%) and headache (39%). Phase II studies are underway.

 

Transmission

Marjolein F. Q. Kluytmans-van den Bergh MF, Buiting AG, Pas SD, et al. Prevalence and Clinical Presentation of Health Care Workers With Symptoms of Coronavirus Disease 2019 in 2 Dutch Hospitals During an Early Phase of the Pandemic. JAMA Netw Open. 2020;3(5):e209673. https://doi.org/10.1001/jamanetworkopen.2020.9673

Of 9,705 HCWs from the Netherlands, 1353 (14%) reported fever or respiratory symptoms and were tested. Of those, 86 HCWs (6%) were infected. Hospital acquisition was unlikely to explain the vast majority of cases. Of note, 54 HCWs (63%) mentioned having worked while being symptomatic.

 

Lai X, Wang M, Quin C, et al. Coronavirus Disease 2019 (COVID-2019) Infection Among Health Care Workers and Implications for Prevention Measures in a Tertiary Hospital in Wuhan, China. JAMA Netw Open May 21, 2020;3(5):e209666. Full-text: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2766227

Overall, 110 of 9,684 HCWs in Tongji Hospital tested positive, with an infection rate of 1.1%. Most infections occurred at the early stage of the epidemic (before January 25), before protective measures were taken. Of those who worked in fever clinics or wards, 17/3110 were infected, indicating an infection rate of 0.5% among first-line HCWs. Of note, a higher rate of infection was found in non-first-line HCW (93/6.574, 1.4%). Authors speculate that this was due to insufficient protective measures available in clinical departments other than fever clinics and wards.

 

Clase CM, Fu EL, Joseph M, et al. Cloth Masks May Prevent Transmission of COVID-19: An Evidence-Based, Risk-Based Approach. Ann Int Med 2020, May 22. Full-text: https://www.acpjournals.org/doi/10.7326/M20-2567

According to the authors, there is high-quality, consistent evidence that many (but not all) cloth masks reduce droplet and aerosol transmission and may be effective in reducing contamination of the environment. No direct evidence indicates that public mask wearing protects either the wearer or others. However, the possible benefit of a modest reduction in transmission likely outweighs the possibility of harm.

 

Severe COVID-19

Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020 May 19:S0140-6736(20)31189-2. PubMed: https://pubmed.gov/32442528. Full-text: https://doi.org/10.1016/S0140-6736(20)31189-2

More on critically ill patients. Among 1,150 adults who were admitted to two NYC hospitals with COVID-19 in March, 257 (22%) were critically ill. The median age of patients was 62 years (IQR 51-72), 67% were men and 82% patients had at least one chronic illness. As of the end of April, 101 (39%) patients had died and 94 (37%) remained hospitalised. 203 (79%) patients received invasive mechanical ventilation for a median of 18 days, 66% received vasopressors and 31% received renal replacement therapy. In the multivariable Cox model, older age, chronic cardiac disease (adjusted HR 1.76), chronic pulmonary disease (2.94) were independently associated with in-hospital mortality. This was also seen for higher concentrations of interleukin-6 and D-dimer, highlighting the role of systemic inflammation and endothelial-vascular damage in the development of organ dysfunction. Studies on immunomodulating and anticoagulant drugs are urgently needed.

 

Varga Z, Flammer AJ, Steiger P, et al. Electron microscopy of SARS-CoV-2: a challenging task – Authors’ reply. Lancet. 2020 May 19:S0140-6736(20)31185-5. PubMed: https://pubmed.gov/32442527. Full-text: https://doi.org/10.1016/S0140-6736(20)31185-5

Endothelial cell dysfunction may explain the vascular microcirculatory complications seen in different organs in patients with COVID-19. The authors discuss the framework of endotheliitis, providing explanation for the unique predilection of SARS-CoV-2 in those individuals with hypertension, diabetes, or established cardiovascular disease, groups known to have pre-existing endothelial dysfunction.

 

Schünemann HJ, Khabsa J, Solo K, et al. Ventilation Techniques and Risk for Transmission of Coronavirus Disease, Including COVID-19. A Living Systematic Review of Multiple Streams of Evidence. Ann Int Med 2020, May 22. Full-text: https://www.acpjournals.org/doi/10.7326/M20-2306

The authors reviewed evidence regarding the benefits and harms of ventilation techniques. Indirect and low-certainty evidence suggests that use of non-invasive ventilation, similar to invasive mechanical ventilation, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers.

 

Treatment

Mehra MR, Desai SS, Ruschitzka F, Patel AM. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet May 22, 2020 Full-text: https://doi.org/10.1016/S0140-6736(20)31180-6

Probably the end of chloroquine. And the end of hydroxychloroquine. And the end of chloroquine plus azithromycin or clarithromycin. And, yes, the end of hydroxychloroquine plus azithromycin or clarithromycin. We should no longer use these four drug regimens as COVID-19 treatments! In this incredible large multinational registry, analysis from 671 hospitals in six continents, 14,888 patients treated with these regimens were compared with 81,444 control patients. Each drug regimen was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias. However, the study (including a 20-page supplement) is too complex to be discussed here in a few words.  We will come back to this soon.