The Lancet – 22 May 2020

  1. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis.
  2. Chloroquine or hydroxychloroquine for COVID-19: why might they be hazardous?
    >>> Full-text

COVID Reference International

3rd Edition, 222 pages

Content of the next edition

The COVID epidemic began in December 2019. In many countries, the first quarantine shock has evaporated, infection numbers are falling, and the lifting of lockdowns is being discussed or already in place. But are appearances deceptive? Is a second wave coming, and if so when?

Science continues to make giant strides. With millions of infected people and and hundreds of thousands dead, it must. The first drug trials will soon yield results, the first vaccines are being tested. More than 10,000 COVID-19 papers are now searchable on PubMed. No doubt: Research is spinning the big wheel of science at an incredible speed.

COVID Reference integrates the knowledge.

Daily Top 10 | Diagnosis | Clinical Manifestation | Treatment | Pediatrics | Epidemiology | Virology | Immunology | Severe Covid-19 | Comorbidities | Timeline | Publication history | Disclaimer



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By Christian Hoffmann &
Bernd S. Kamps

26 May

The daily Top 10 papers will be presented at 19:00 CEST.
(Never go to bed without reading them. Let COVID Reference be your Sandmännchen…)

25 May

Top 10 Special >>>

Voice: Google Cloud Text-to-Speech / US

A brief (and probably the last) review on hydroxychloroquine and chloroquine

A few months ago, lab experiments suggested that hydroxychloroquine (HCQ) and chloroquine (CQ) might have some antiviral effects against SARS-CoV-2 due to an increase in the endosomal pH value which disrupts the virus-cell fusion and some post-entry steps (Wang 2020, Yao 2020). An early enthusiastic mini-review stated “results from more than 100 patients” showed that chloroquine phosphate would be able to alleviate the course of the disease (Gao 2020).  Continue >>>

24 May

The Top 10 >>>

Voice: Google Cloud Text-to-Speech / UK

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?

The Top 10 >>>

23 May

The Top 10 >>>

Voice: Google Cloud Text-to-Speech / UK

First, continue following the antiviral saga. You’ll finally read the ‘preliminary report’ of a study that randomized 1,063 COVID-19 patients to receive remdesivir or placebo. (Remember: the data were pre-announced three weeks ago during a hastily arranged press conference in the wake of the publication of a study by Wang and collaborators who found no clinical benefit for remdesivir in a randomised, double-blind, placebo-controlled, multicentre trial (The Lancet: Wang 2020)). The preliminary report, now published in the New England Journal of Medicine, suggests that remdesivir may shorten the time to recovery in hospitalized adults by a few days. Mortality was somewhat but not significantly lower in patients who received remdesivir.

Afterwards, simulate three transmission modes including close contact, respiratory droplets and aerosol routes in naive h ACE2 mice; publish the cryo-electron microscopic structure of the SARS-CoV-2 RdRp in its active form; evaluate different DNA vaccine candidates expressing different forms of the spike protein in 35 rhesus macaques in regard to neutralizing antibody titers; discuss with your colleagues the administration of thymosin alpha 1 (subcutaneous injections of 10 mg) to 76 patients with severe COVID-19; describe clinical characteristics, imaging findings, and outcomes among 24 patients who presented with acute hypoxemic respiratory failure; explore why immunity passports are a bad idea; present clinical data from 20,133 patients, admitted to (or diagnosed in) 208 acute care hospitals in the UK until April 19, and discuss overall mortality (26%) and mortality of patients admitted to high-dependency or intensive care units (32%) and of those who received mechanical ventilation (37%).

Finally, investigate viral and host factors related to the clinical outcome of COVID-19. You’ll find that up to now, different viral clades did not exhibit significant difference in clinical features, mutation rate or transmissibility. However, lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts, was predictive of disease progression. High levels of IL-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age, lymphocytopenia, and its associated cytokine storm.

The Top 10 >>>

22 May

The Top 10 >>>

Voice: Google Cloud Text-to-Speech / US

First, design natural sunlight representing a clear day at sea level during summer solstice at 40oN latitude and determine the time needed to inactivate 90% percentage of infectious virus; investigate the potential of UVB radiation from sunlight as a potential virucide; and re-challenge 9 rhesus macaques 35 days after initial infection with SARS-CoV-2.

Afterwards, find out that a positive RT-qPCR result may not necessarily mean the person is still infectious or that they still have any meaningful disease; compare daily incidence in 8 Iowa counties bordering Illinois with those in the 7 Illinois counties bordering Iowa; and evaluate the expression of ACE in nasal epithelial samples in children 4 to 9 years old and discuss the implications.

Finally, discuss with your colleagues why the 4.65% prevalence of SARS-CoV-2-specific antibodies found in Los Angeles may be biased; discuss with your patients why hydroxychloroquine doses tolerable for humans are too low to have any effect on SARS-CoV-2 in vivo; and examine lungs from 7 deceased COVID-19 patients with lungs from 7 patients who died from ARDS secondary to influenza A and 10 age-matched, uninfected control lungs. What will you discover?

The Top 10 >>>

21 May

COVID Reference Special >>>

An update on HIV infection in the current crisis

HIV infection is of particular interest in the current crisis. First, many patients take antiretroviral therapies that are thought to have some effects against SARS-CoV-2. Second, HIV serves as a model of cellular immune deficiency. Third and by the far most important point, the collateral damage caused by COVID-19 in the HIV population may be much higher than that of COVID-19 itself.

Inexplicably, information on the HIV population is still scarce.  More >>>

20 May

The Top 10 >>>

First, investigate high SARS-CoV-2 attack rates at church events; show competency in putting on and removing personal protective equipment (PPE); and edit consensus guidelines and recommendations on the conduct and management of tracheostomy during the COVID-19 pandemic.

Afterwards, build multiple monoclonal antibodies targeting SARS-CoV-2 S identified from memory B cells; establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 risk; calculate the incidence of deep vein thrombosis in 143 patients from Wuhan; and describe the dynamic relationship between D‐dimer level and the progression of COVID‐19 in 279 patients.

Finally, explain the decline in acute myocardial infarction in California after March 4; analyze 525 patients with inflammatory bowel disease from 33 countries and search for risk factors for severe COVID-19; and discuss available antifibrotic therapies with your colleagues for fibrotic lung disease following SARS-CoV-2 infection.

The Top 10 >>>

19 May

The Top 10 >>>

First, travel to Nembro in the Northern Italian Province of Bergamo, a city of 11,500. Discover that from January 1 until April 4, 2020, 175 people older than 64 died. For comparison: over the same time period in the years 2015 to 2019, a mean of 36 individuals of the same age died (see Table 1). Most deaths in 2020 occurred between March 1 and April 4. From the outbreak onset until 11 April 2020, only 85 confirmed deaths from COVID-19 were recorded. The authors conclude that the full impact of the COVID-19 pandemic can only be assessed after careful comparison of all-cause mortality in 2020 vs the preceding years.

Afterwards, go to Lyon and determine the prevalence of obesity among adult inpatients with COVID-19; present a detailed description of existing SARS-CoV-2 serology assays at your weekly journal club; analyze 26 studies to learn more about the duration of fecal viral shedding after a negative nasopharyngeal swab; and test 290 serum samples from patients with rheumatoid arthritis, systemic lupus erythematosus, and Sjogren’s syndrome, for cross-reactivity against SARS-CoV-2 IgG and IgM antibodies.

Finally, describe neurologically devastating intra-parenchymal hemorrhage in two patients on extracorporeal membrane oxygenation; discuss with your colleagues a review about psychiatric and neuropsychiatric presentations associated with severe COVID-19; write a review of the literature on thromboembolic events associated with COVID-19; and while awaiting the results of several ongoing randomized controlled trials, present the possible role of favipiravir in the treatment of SARS-CoV-2 infection.

The Top 10 >>>


18 May

The Top 10 >>>

First, identify 14 potent neutralizing antibodies by high-throughput single B-cell RNA- sequencing; investigate the transmission rate from households with confirmed COVID-19 cases to their dogs; and tell your friends to stop making assumptions on the effect of sunlight on SARS-CoV-2 transmission.

Afterwards, design a rhesus macaque model that recapitulates COVID-19 in humans; transmit SARS-CoV-2 from inoculated Golden Syrian hamsters to naïve hamsters by direct contact and via aerosols; and determine changes in host-cell pathways upon SARS-CoV-2 infection.

Finally, make an in-depth enquiry of COVID-19-associated headache; discuss with your colleagues the hypothetical use of alisporivir; follow 21 transplanted patients (10 kidney, 5 liver, 1 pancreas, 1 lung, 1 heart and 3 combined transplantations); and describe a cohort of 168 children and adolescents with laboratory-confirmed COVID-19.

The Top 10 >>>

17 May

We have published the third French Edition. A great thanks to Bruno Giroux and Georges Mion.


The Top 10 >>>

First, investigate a 2.5 hour choir practice involving a 61 person choir with 32 confirmed and 20 probable secondary cases of SARS-CoV-2 infection. Transmission was likely facilitated by close proximity (within 6 feet) during practice and augmented by the act of singing. The superspreading event underscores the importance of physical distancing, including avoiding gathering in large groups, to control the spread of COVID-19.

Afterwards, build an online tool for understanding excess mortality in the UK; determine infectiousness before or on the day of symptom onset in a German outbreak; use cryoelectron microscopy to determine a 2.9 angstrom resolution structure of the virus’s RNA synthesizing machine; and show the total excess of all cause deaths in New York by COVID-19.

Finally, analyze the host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and… COVID-19 patients! In particular measure type I and III interferons as well as chemokines and IL-6; demonstrate that the overabundance of ACE2 in the lungs of smokers may partially explain why smokers are significantly more likely to develop severe COVID-19; propose prone positioning to non-intubated patients with hypoxemic acute respiratory failure requiring oxygen supplementation; and discuss with your colleagues an editorial which summarizes the current knowledge on the prone position.

The Top 10 >>>


16 May

The Top 10 >>>

First, acknowledge that health care workers on the frontline are facing a substantial risk of infection during the COVID-19 outbreak. Discover that among 2,457 SARS-CoV-2-infected health care workers in Wuhan, China, more than half were nurses, while 33% were doctors. Importantly, most infected cases among health care workers were female: 72%. It is essential to improve protective measures for HCWs. Ensuring an adequate supply of PPE is just the first step. Other measures should be considered, including a nutritious food supply, adequate rest time, and societal, familial, and psychological support.

Afterwards, discuss with your colleagues a comprehensive overview about current knowledge (and knowledge gaps) about treatment of patients who develop severe disease; grant an FDA emergency use authorization for a clustered regularly interspaced short palindromic repeats (CRISPR)-based SARS-CoV-2 fluorescent assay; and use data from Germany to build a model that detects change points in the effective epidemic growth rate that correlate with the times of publicly announced interventions (including kind regards to Boris et al.).

Finally, evaluate anakinra in 29 patients with moderate-to-severe ARDS and hyperinflammation (serum C-reactive protein, CRP ≥100 mg/L) and in 8 patients with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hypercoagulation, acute kidney injury and hepatobiliary dysfunction; discover that pulmonary arterial thrombosis in COVID-19 may occur despite the use of prophylactic anticoagulation; read a well-balanced editorial on the same subject; and read four critical letters about the remdesivir compassionate use program.

The Top 10 >>>


15 May

The Top 10 >>>

First, determine the false-negative rate of RT-PCR on the day of symptom onset and three days later; discuss with your colleagues if antibody testing for SARS-CoV-2 can be used in low prevalence areas; and detect SARS-CoV-2−reactive CD4 T cells in unexposed individuals.

Afterwards, use optical coherence tomography (OCT) in patients with COVID-19 and describe retinal changes; and correlate perforin+ NK cell number to disease severity in COVID-19 patients.

Finally, randomize patients with mild to moderate COVID-19 to receive lopinavir/r, arbidol (200 mg TID) or no antiviral medication as control; find out why the treatment of COVID-19 with lopinavir/r at the currently used dose is unlikely to be effective; and analyze a group of 177 pediatric patients and find out how many were hospitalized and/or critically ill.

The Top 10 >>>

14 May

Today, we have published theTurkish Edition of COVID Reference. A great thanks to Zekeriya Temircan and Füsun Ferda Erdoğan.


The Top 10 >>>

First, inoculate three domestic cats with SARS-CoV-2. One day later, cohouse an uninfected cat with each of the inoculated cats. Find out how many cats become infected, measure antibody titers on day 24 and count the number of infected cats that show symptoms. If cats are silent intermediate carriers of SARS-CoV-2, what would we recommend to cat owners?

Afterward, describe a scalable serological enzyme-linked immunosorbent assay (ELISA) for the screening and identification of human SARS-CoV-2 seroconverters; build a model to estimate the percentage of infected individuals who were hospitalized in France and how many died; establish an expandable organoid culture system of bat intestinal epithelium; and quantify SARS-CoV-2 viral load in autopsy tissue samples from 22 patients. You will detect the highest levels in the respiratory tract. Where will you find the lowest viral loads?

Finally, discuss with your colleagues what we know about SARS-CoV-2 infection in children; find out that BCG vaccination does not protect against SARS-CoV-2 infection; isolate human-origin monoclonal antibodies from a convalescent patient that show neutralization abilities; and develop and validate a clinical risk score to predict the risk of critical illness in hospitalized patients with COVID-19.

The Top 10 >>>


13 May

The Top 10 >>>

First, put 8 dermatologists and 6 scientists (index patient + n=13) into an advisory board meeting (a conference room of about 70 m2 with a U-shaped set-up of tables separated by a central aisle >1 m wide); serve refreshments buffet style in the same room 4 times during a 9.5 hour meeting; let all participants have dinner in a nearby restaurant; let them shake hands during farewell with a few short hugs (no kisses); and let the index patient share a taxi with three colleagues for about 45 min. How many of the 13 individuals were infected by the asymptomatic index patient?

Afterwards, take a random sample of 7914 COVID-19 patients admitted to New York metropolitan hospitals and investigate if treatment with hydroxychloroquine or azithromycin or both drugs combined is associated with significantly lower in-hospital mortality (you probably know the answer); learn how many of 48 children with COVID-19 admitted to ICUs had significant preexisting comorbidities; read a retrospective review of 22 children and adolescents with acute chilblain-like lesions; and discuss with experts a critical review of the evidence for low-dose radiation treatment of COVID-19 pneumopathy.

Finally, investigate knowledge gaps on postinfection immunity and possible inaccuracies of “COVID passports”; calculate the transmission rate between 35 index cases and 148 household contacts in Zhuhai, China; optimize leukemia management in COVID-19 times; and perform a meta-analysis of 15 studies to assess the severity and mortality associated with COPD and smoking in patients with COVID-19.

The Top 10 >>>

12 May

The Top 10 >>>

First, randomize 127 patients with mild-to-moderate COVID-19 to receive lopinavir/r only or a triple combination of interferon beta-1b, lopinavir–ritonavir (lopinavir/r), and ribavirin; build a smartphone app and test if a combination of symptoms, including anosmia, fatigue, persistent cough and loss of appetite is appropriate to identify individuals with COVID-19; and measure hydroxychloroquine concentrations in 57 patients.

Afterwards, discuss an unprecedented cluster of eight children (all previously fit and well) with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome; show how SARS-CoV-2 infects epithelial cells and alters the immune landscape in patients with severe disease; evaluate tissue and cellular tropism of SARS-CoV-2 in the human respiratory tract and conjunctiva; and demonstrate what happens during the second week, when resident macrophages initiating lung inflammatory responses are unable to contain SARS-CoV-2.

Finally, appreciate that not all world leaders use Twitter in response to the COVID-19 pandemic (…); find out that it is difficult to establish a clear cause-effect relationship between COVID-19 infection and MRI findings; and develop a pathway for an effective vaccine with Anthony Fauci.

The Top 10 >>>


11 May

First, collect samples from 227 bats in Yunnan and find a close relative of SARS-CoV-2; determine the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient; and revisit closing citywide public transport and entertainment venues as well as banning public gatherings.

Afterwards, pool the data of 3,428 COVID-19 infected patients (1,455 severe cases and 1,973 mild cases) and correlate serum levels of ALT, AST, bilirubin and albumin with severity of COVID-19; find out that there is no excess COVID-19 morbidity and mortality among HIV-infected patients; dissect conspiracy theories and the “infodemic” (WHO) of incorrect information about SARS-CoV-2 (or not if you have no time to waste); and measure ACE2 concentrations in 1485 men and 537 women with heart failure.

Finally, confront 16 recommendations for acute management of COVID-19 with your own experience; analyze 131 patients undergoing maintenance hemodialysis with a mean age of 63 years; discuss JAK kinase inhibitors as a way of managing the cytokine storm in severe COVID-19 patients and possible side effects; and listen to Peter Piot (71), one of the discoverers of the Ebola virus in 1976 and former UNAIDS director, discussing a severe case of COVID-19: his own.

>>> The Top 10

10 May

The Top 10

First, develop ‘shield immunity’ at the population scale; savor a review on current knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection; and establish correlation between neutralization antibody titers and the numbers of virus-specific T cells.

Afterwards, present autopsy findings where 7/12 patients with COVID-19 had venous thromboembolism; investigate five cases of cor pulmonale; and determine the incidence of influenza among adults who received a prescription for an ACE inhibitor from 1998 through 2016.

Finally, analyze the association of higher body mass index (BMI) with severe COVID in younger patients; participate in the race for antibodies that might stop the new coronavirus; and identify neutralizing cross-reactive VHH camelid antibodies, which may serve as potential therapeutic candidates.

The Top 10

9 May

>>> Top 10 Special

Kawasaki-like syndrome in children – A new twist in this new pandemic: at the end of March 2020, Jones et al. described the case of a six-month-old baby girl with fever, rash and swelling characteristic of a rare pediatric inflammatory condition, Kawasaki syndrome (Jones 2020).  >>> Read more

8 May

The Top 10

First, savor an observational study of hydroxychloroquine in 1,376 hospitalized patients; investigate COVID-19 on the African continent; and explain why 95/100 of deceased Italian doctors were men.

Afterwards, discover the pathogenicity of SARS-CoV-2 in transgenic mice bearing human ACE2; isolate SARS-CoV-2-related coronavirus from 25 Malayan pangolins; and use T cell subset counts in peripheral blood as biomarkers for diagnosis and severity prediction of COVID-19.

Finally, rehabilitate COVID-19 patients after intensive care; learn about the number of cases and deaths among detained persons and staff members in correctional and detention facilities in the US; and discuss with your colleagues off-the-shelf SARS-COV-2-specific HLA-matched cytotoxic T cells prepared from convalescent COVID-19 patients.

The Top 10


7 May

The Top 10

First, test how often you can heat N95 respirators at 85°C; explain the problems of immunity passports (“COVID passports”); and describe how to interpret RT-PCR and IgM and IgG ELISAs and how the results may vary over time.

Afterwards, determine the incidence of venous thromboembolism in 198 hospitalized patients at 7, 14, and 21 days; examine three patients with ulcers in the oral cavity; and discover thrombocytopenia as an initial manifestation of COVID­-19.

Finally, reveal glycan structures of the SARS-CoV-2 spike that facilitate immune evasion; check mAb 47D11, a human monoclonal antibody that neutralizes SARS-CoV-2; and discuss why lopinavir/r may still be a potential therapeutic agent against COVID-19, especially when given earlier.

>>> The Top 10


6 May

>>> The Top 10

First, write a thrilling feature on what you know about SARS-CoV-2; then, discover a summary of what you always knew about risk factors for coronavirus infections in HCWs; and revisit the power of early detection and isolation of cases.

Afterwards, build a yeast-based synthetic genomics platform to genetically reconstruct RNA viruses; and use a hamster model to create less pathogenic SARS-CoV-2 variants.

Finally, assess the impact of the insomnia drug dexzopiclone on survival in hospitalized patients; present a predictive model for in-hospital mortality; analyze 100 children with COVID-19; and discuss with your colleagues how to interpret a Swiss study where two thirds of 21 autopsied patients had blood group A.

>>> The Top 10

5 May

Top 10 Special on Remdesivir

Get it done!


On remdesivir, rumors of recovery, rolling reviews, and random noise

“That’s very exciting. Get it done, Daniel.” If you want to get an idea about the incredible pressure on and expectations from researchers, then please read the protocol from the White House (Trump 2020). NIAID’s Anthony Fauci and Gilead’s CEO Daniel O’Day make heroic attempts to explain the situation to decision makers. This pressure has its consequences.  >>> Read more


4 May

Top Ten Special on

ACE inhibitors/ARBs – continue them (or start them up again)!

There has hardly been a topic in the last weeks of this pandemic that has kept doctors (mainly internists) and their patients as busy as the question of whether ACE inhibitors or angiotensin-receptor blockers (ARBs) can cause harm to patients. Early observations of an increased risk for mortality or severe COVID-19 in patients with hypertension, cardiovascular diseases and diabetes (Guan 2020) raised concerns.

The Top 10

3 May

The Top 10

First of all, create a group of more than 100 colleagues and map the interaction landscape between SARS-CoV-2 proteins and human proteins; express more than 20 of the 29 SARS-CoV-2 proteins in human cells and identify at least 300 high-confidence SARS-CoV-2-human PPIs; and identify pharmacological agents that display antiviral activity. (We give you a hint: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors.)

Thereafter, using contact survey data for Wuhan and Shanghai, build a model that predicts the impact of lockdown and show that daily contacts were reduced 7-8-fold during the social distancing period; generate 53 genomes from infected individuals in Guangdong to deduce where the first infections came from; and show how remdesivir might  inhibit SARS-CoV-2 RdRp activity.

Finally, feed >300,000 CT images into an AI system and test if it does better than junior radiologists; check HbA1c because it might lower mortality; learn that the  COVID-19 outbreak led to a 32% decline in percutaneous coronary interventions for acute coronary syndromes; and discuss with your colleagues  a review on current immunotherapies.

The Top 10


2 May

The Top 10

Dermatology Special Issue

This has been the week of the dermatologists: numerous studies reported on cutaneous manifestations seen in the context of COVID-19. The most prominent phenomenon, the so-called “COVID toes”, are chilblain-like lesions which mainly occur at acral areas [chilblain: Frostbeule (de), engelure (fr), sabañón (es), gelone (it), frieira (pt), 冻疮 (cn)]. These lesions can be painful (sometimes itchy, sometimes asymptomatic) and may represent the only symptom or late manifestations of SARS-CoV-2 infection. Of note, in most patients with “COVID toes”, the disease is only mild to moderate. It is speculated that the lesions are caused by inflammation in the walls of blood vessels, or by small micro clots in the blood. However, whether “COVID toes” represent a coagulation disorder or a hypersensitivity reaction is yet to be known. In addition, in many patients, SARS-CoV-2 PCR was negative (or not done) and serology tests (to proof the relationship) are still pending.

The Top 10

1 May

The Top 10

First, question a previous publication about a more aggressive and more quickly spreading SARS-CoV-2 subtype and demonstrate that the authors were wrong; then use mobile phone geolocation data to compute aggregate population movements in China.

Thereafter, savor a brilliant overview of SARS-CoV-2 pathophysiology; investigate if heart fatty acid-binding protein (HFABP) can be an indicator of severe COVID-19; and search for genetic variants which might indicate a predisposition for severe COVID-19 disease.

Finally, analyze sex-specific clinical characteristics and prognosis of COVID-19 in Wuhan; don’t use convalescent plasma too late; and develop a diagnostic pathway for COVID-19 patients with STEMI aimed at protecting healthcare providers.

The Top 10

30 April

The Top 10

First, admire a graphical review on current vaccine development; learn that a still-to-be-published clinical trial on remdesivir reminds Anthony Fauci of the AZT discovery in the 1980s (ask you 60+ year-old colleagues what that means); and discover which New York City borough had the highest rate COVID-19-related hospitalization and death.

Furthermore, discover where have the STEMIs gone during COVID-19; investigate patients with immune-mediated inflammatory disease (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, inflammatory bowel disease, or related conditions) and confirmed or highly suspected symptomatic Covid-19; create a negative-pressure aerosol cover made out of readily available operating room materials; and explain an increase of out-of-hospital cardiac arrest in the four North-Italian provinces of Lodi, Cremona, Pavia, and Mantua.

Finally, analyze the first ever published randomized, double-blind, placebo-controlled trial of remdesivir (no difference in time to clinical improvement) and listen to Bill Gates talking about a once-in-a-century pandemic and billions of dollars.

The Top 10

29 April

The Top 10

First, do research in the patient’s toilet area, determine the seropositivity rate in a large homeless shelter in Boston and find out if pregnant mothers transmit SARS-CoV- to their newborns.

Thereafter, assess acute antibody responses in 285 patients (14% of whom were treated in ICUs), read a review about coagulation abnormalities in COVID-19 patients and check if statin therapy could improve the clinical course of patients with COVID-19.

Finally, examine five cases of large-vessel stroke in patients 33 to 49 years old and discuss with your colleagues the current knowledge on the risk during intubation.

The Top 10

28 April

The Top 10

First, find out how mobile phone data can help to better target and design measures to contain and slow the spread of the COVID-19 pandemic, and why SARS-CoV-2 is most likely adapted better to humans than SARS-CoV-1.

Thereafter, enquire the natural history and transmission of SARS-CoV-2 infection, define the incubation period, and assess the secondary attack rate; discuss what we know about COVID-19 protective immunity; and consider serological testing of vaccine trial participants.

Finally, discover the proportions of COVID-19-exposed health care workers with symptoms of depression, anxiety, insomnia and distress; and manage a 73-year-old man with hypertension and chronic obstructive pulmonary disease who has had a fever (maximal temperature, 38.3°C) and a dry cough for the past 2 days.

The Top 10

27 April

The Top 10

First, review 6000+ Chinese patient records and find that many survivors had been suffering from chronic heartburn and were on famotidine. Then test people in homeless shelter – if you have more than one positive case, you are likely to have a cluster.

Thereafter, check if living at an altitude of above 3,000 m makes you less susceptible to SARS-CoV-2 infection, if old-fashioned vaccines work in rhesus macaques and who did not become infected in an outbreak in a pediatric dialysis unit.

Finally, measure viral RNA in different body fluids and interpret the presence of nucleic acid, follow the seroconversion patterns of IgM and IgG antibodies in  41 patients and guess how many Bioethics Program Directors did not have ventilator triage policies.

The Top 10

26 April

The Top 10

Today, we have adverse winds for Chloroquine (a randomized clinical trial was terminated by the data safety monitoring board after enrolling 81/440 individuals) and hydroxychloroquine (from a case series of 17 systemic lupus erythematosus patients).

Furthermore, papers about the devastation COVID-19 can inflict to organs other than the lung, tobacco smoking which might increase the risk for viral binding and entry of SARS-CoV-2 in lungs of smokers, and about other topics of concern such as muscle atrophy and weakness, mental problems and cognitive impairment after leaving long-term intensive care. And CARDs may not be ARDS.

Finally, good news from 21 healthcare workers who had contact with an initially undiagnosed COVID-19 case.

The Top 10

25 April

The Top 10

Dai W, Zhang B, Su H, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020 Apr 22. pii: science.abb4489. PubMed: https://pubmed.gov/32321856 . Full-text: https://doi.org/10.1126/science.abb4489

More on a key enzyme, SARS-CoV-2’s main protease (Mpro). Authors synthesized two lead compounds (11a and 11b) targeting Mpro, exhibiting good inhibitory activity, good PK properties and low toxicity in animal experiments. Pre-clinical.

24 April

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Chorin E, Dai M, Shulman E. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nature Medicine. Published: 24 April 2020. Full-Text: https://www.nature.com/articles/s41591-020-0888-2

Check ECG if you do this! In this important study, authors followed the corrected QT (QTc) interval in a consecutive cohort of 84 patients receiving hydroxychloroquine and azithromycin which were administered orally for 5 days. A prolongation of the QTc from a baseline average of 435 ± 24 ms to a maximal average value of 463 ± 32 ms was found, occurring on day 3.6 ± 1.6 of therapy. In a subset of nine (11%) patients, the QTc was severely prolonged to >500 ms, a known marker of high risk of malignant arrhythmia and sudden cardiac death. Five of nine patients with severe QTc prolongation had a normal QTc at baseline.

23 April

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Cowling BJ, Ali ST, Ng TWY, et al. Impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an observational study. Lancet Public Health. 2020 Apr 17. pii: S2468-2667(20)30090-6. PubMed: https://pubmed.gov/32311320. Full-text: https://doi.org/10.1016/S2468-2667(20)30090-6

Detailed paper from Hong Kong modelling the effects of non-pharmaceutical interventions (NPIs, including border restrictions, quarantine and isolation, distancing, and changes in population behaviour). NPIs were associated with reduced transmission of COVID-19 and were also likely to have substantially reduced influenza transmission. Findings strongly suggest that social distancing and population behavioural changes – that have a social and economic impact that is less disruptive than a total  lockdown – can  meaningfully  control COVID-19.

22 April

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Cowling BJ, Ali ST, Ng TWY, et al. Impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an observational study. Lancet Public Health. 2020 Apr 17. pii: S2468-2667(20)30090-6. PubMed: https://pubmed.gov/32311320. Full-text: https://doi.org/10.1016/S2468-2667(20)30090-6

Detailed paper from Hong Kong modelling the effects of non-pharmaceutical interventions (NPIs, including border restrictions, quarantine and isolation, distancing, and changes in population behaviour). NPIs were associated with reduced transmission of COVID-19 and were also likely to have substantially reduced influenza transmission. Findings strongly suggest that social distancing and population behavioural changes – that have a social and economic impact that is less disruptive than a total  lockdown – can  meaningfully  control COVID-19.

20 April

The Top 10

Today, discover a phantastic overview about current knowledge and the pathways leading to cytokine release syndrome, a report of five patients with COVID-19–associated Guillain–Barré syndrome, a paper on neurological complications which are probably due to an aberrant immune response, and an animal study showing that SARS-CoV-2-infected macaques provide a new model to test therapeutic strategies.

Furthermore, you’ll find that the tighter you control the infected, the less restriction you have to impose on the uninfected and that mass masking  for  source  control  is  a  useful  and   low-cost   adjunct   to   social   distancing   and   hand   hygiene. You’ll be advised not to stop your sartans or ACE inhibitors and find guidance for management of inflammatory bowel disease during the COVID-19.

Finally, it’s not only age. A Multivariate analysis of a retrospective cohort of 1590 hospitalized subjects with COVID-19 throughout China revealed the following factors associated with mortality: age 75 or, age 65-74 years, coronary heart disease, cerebrovascular disease, dyspnea,  procalcitonin>0.5ng/ml, AST>40 U/L. Nothing truly new, the paper reports the largest cohort so far.

The Top 10

19 April

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Chow EJ, Schwartz NG, Tobolowsky FA, et al. Symptom Screening at Illness Onset of Health Care Personnel With SARS-CoV-2 Infection in King County, Washington. JAMA. 2020 Apr 17. pii: 2764953. PubMed: https://pubmed.gov/32301962. Full-text: https://doi.org/10.1001/jama.2020.6637

Detailed analysis of symptoms of all laboratory-confirmed SARS-CoV-2 infections in HCP residing in King County. Ccreening only for fever, cough, short-ness of breath, or sore throat might have missed 17% of symptomatic HCP at the time of illness onset; expanding criteria for symptoms screening to include myalgias and chills may still have missed 10%.

18 April

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Anfinrud P, Stadnytskyi V, Bax CE, Bax A. Visualizing speech-generated oral fluid droplets with laser light scattering. N Engl J Med. https://doi.org/10.1056/NEJMc2007800.

You remember Depeche Mode’s hit ‘Enjoy the Silence’? Then look at this video, a person saying “stay healthy”, a laser light-scattering experiment in which speech-generated droplets and their trajectories were visualized. The louder the speech, the higher the numbers of flashes. The number of flashes was highest when the “th” sound in the word “healthy” was pronounced. Depeche Mode were right: “Words are very unnecessary/They can only do harm”.

17 April

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He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020 Apr 15. pii: 10.1038/s41591-020-0869-5. PubMed: https://pubmed.gov/32296168. Full-text: https://doi.org/10.1038/s41591-020-0869-5

Important work on viral shedding: this may begin 2 to 3 days before the appearance of the first symptoms and infectiousness profile may more closely resemble that of influenza than of SARS.  Analyzing a total of 414 throat swabs in 94 patients, highest viral load in throat swabs was found at the time of symptom onset. Infectiousness started from 2.3 days (95% CI, 0.8–3.0 days) before symptom onset and peaked at 0.7 days (95% CI, −0.2–2.0 days) before symptom onset. Authors estimated that 44% (95%CI 25-69%) of secondary cases were infected during the index cases´ presymptomatic stage. Infectiousness was estimated to decline quickly within 7 days.

16 April

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Comment on
Compassionate Use of Remdesivir for Patients with Severe Covid-19
N Engl J Med. 2020 Apr 10.

Today, we will not discuss the Top Ten Papers. Instead, we will talk about remdesivir and give you 10 good reasons to be careful.


15 April

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Gudbjartsson DF, Helgason A, Jonsson H, et al. Spread of SARS-CoV-2 in the Icelandic Population. N Engl J Med. 2020 Apr 14. PubMed: https://pubmed.gov/32289214. Full-text: https://doi.org/10.1056/NEJMoa2006100

SARS-CoV-2 in Iceland. As of April 4, a total of 1,221 of 9,199 tested persons (13.3%) were positive. Why is this of interest? Because the country serves as a perfect epidemiological model. Key findings: The percentage of participants who tested positive in population screening remained stable (0.8%) in March, and the infection rates in two screening groups (recruited through open invitation and through random sampling) were not substantially different. Notably, 43% of the participants who tested positive reported having no symptoms.

14 April

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Monteil V, Kwon H, Patricia Prado P, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020. DOI: 10.1016/j.cell.2020.04.004. https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdf

This study shows that human recombinant soluble ACE2 (hrsACE2) blocks SARS-CoV-2 infections of different cells, human blood vessel organoids and human kidney organoids. In ARDS patients, hrsACE2 was ineffective but safe at a broad range of doses. Apeiron Biologics plans a randomized study on 200 COVID-19 patients in April.

13 April

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Gao Y, Yan L, Huang Y, et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 2020 Apr 10. pii: science.abb7498. PubMed: https://pubmed.gov/32277040. Full-text: https://doi.org/10.1126/science.abb7498

Using cryogenic electron microscopy, authors describe the structure of the RNA-dependent RNA polymerase, another central enzyme of the viral replication machinery. It is also shown how remdesivir and sofosbuvir bind to this polymerase.

12 April

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Wang Q, Zhang Y, Wu L, et al. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell. 2020 Apr 7. pii: S0092-8674(20)30338-X. PubMed: https://pubmed.gov/32275855 . Full-text: https://doi.org/10.1016/j.cell.2020.03.045

Atomic details of the crystal structure of the C-terminal domain of SARS-CoV-2 spike protein in complex with human ACE2 are presented. hACE2-binding mode of SARS-CoV-2 seems to be similar to SARS-CoV, but some key residue substitutions slightly strengthen the interaction and lead to higher affinity for receptor binding. Antibody experiments indicated notable differences in antigenicity between SARS-CoV and SARS-CoV-2.

11 April

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Wang X, Xu W, Hu G, et al. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cell Mol Immunol. 2020 Apr 7. pii: 10.1038/s41423-020-0424-9. PubMed: https://pubmed.gov/32265513 . Full-text: https://doi.org/10.1038/s41423-020-0424-9

It remains unclear whether SARS-CoV-2 can also infect T cells, resulting in lymphocytopenia. Using a model with pseudoviruses, authors showed that SARS-CoV-2 infects (but does not replicate in) T cells through S protein-mediated membrane fusion. T-cell lines were significantly more sensitive to SARS-CoV-2 infection when compared with SARS-CoV. Of note, a very low expression level of hACE2 was found, indicating that a novel receptor might mediate SARS-CoV-2 entry into T cells.

10 April

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Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020 Apr 6. pii: 10.1007/s00405-020-05965-1. PubMed: https://pubmed.gov/32253535. Full-text: https://doi.org/10.1007/s00405-020-05965-1

This important study shows that in Europe, otolaryngological symptoms are much more common than in Asia (it remains unclear whether this is a true difference). Among 417 mild-to-moderate COVID-19 patients (from 12 European hospitals), 86% and 88% reported olfactory and gustatory dysfunctions, respectively. The vast majority was anosmic (hyposmia, parosmia, phantosmia did also occur), and the early olfactory recovery rate was 44%. Females were more affected than males. Olfactory dysfunction appeared before (12%), at the same time (23%) or after (65%) the appearance of other symptoms. There is no doubt that sudden anosmia or ageusia need to be recognized as important symptoms of COVID-19.

9 April

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Cheung KS, Hung IF, Chan PP, et al. Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis. Gastroenterology. 2020 Apr 3. pii: S0016-5085(20)30448-0. PubMed: https://pubmed.gov/32251668 . Full-text: https://doi.org/10.1053/j.gastro.2020.03.065

In a meta-analysis of 60 studies, comprising 4,243 patients, the pooled prevalence of gastrointestinal symptoms was 17.6% (95% CI, 12.3%-24.5%). Prevalence was lower in studies from China than other countries. Pooled prevalence of stool samples that were positive for virus RNA was 48.1% and could persist for up to ≥33 days from illness onset even after viral RNA negativity in respiratory specimens. Stool viral RNA was detected at higher frequency among those with diarrhea.

8 April

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Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS 2020, April 6. https://doi.org/10.1073/pnas.2004168117

A single dose (200 mL) of convalescent plasma was given to 10 patients (9 treated with umifenovir, 6 with methylprednisolone, 1 with remdesivir). In all 7 patients with viremia, serum SARS-CoV-2 RNA decreased to an undetectable level within 2-6 days. Meanwhile, clinical symptoms and paraclinical criteria rapidly improved within three days. Using antibodies from convalescents could be an option in severe cases. It’s now time for larger studies.

7 April

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Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6. PubMed: https://pubmed.gov/32250385. Full-text: https://doi.org/10.1001/jama.2020.5394Important work, providing sobering evidence about the burden of critical illness. Over a period of 28 days, 1,591 COVID-19 patients (88 % requiring endotracheal intubation and ventilatory support) were admitted to 72 Italian ICUs, an average of 22 patients per ICU (median length of stay was 9 days). Of note, 82 % were male and median age was only 63 years (IQR 56-70), suggesting that older age alone is not a risk factor for admission to the ICU. As of March 25, ICU mortality was 26 %. However, 58 % were still in the ICU. Scarifying study, telling us a lot about the fragility of health care systems in even the wealthiest countries.

5 April

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Bavishi C, Maddox TM, Messerli FH. Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers. JAMA Cardiol. 2020 Apr 3. pii: 2764299. PubMed: https://pubmed.gov/32242890. Full-text: https://doi.org/10.1001/jamacardio.2020.1282

This mini-review outlines the mechanisms by which RAAS inhibitors (ACEIs/ARBs) may be of benefit in COVID-19. Overview of the current recommendations for their use in infected patients. According to the authors, the biological plausibility of salutary effects of RAAS inhibitors is intriguing and several trials of starting losartan in patients with COVID-19 are currently being planned.

4 April

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Leung NH, Chu Dk, Shiu EY. Respiratory virus shedding in exhaled breath and efficacy of face masks. Nature Med 2020, April 3. https://doi.org/10.1038/s41591-020-0843-2

Do face masks work? Yes, but it depends. This important study from Hong Kong (performed 2013-16) quantified virus in respiratory droplets and aerosols in exhaled breath. In total, 111 participants (infected with seasonal coronavirus, influenza or rhinovirus) were randomized to wear (or not) a simple surgical face mask. Results suggested that masks could be used by ill people to reduce onward transmission. But note the small numbers: in respiratory droplets, seasonal coronavirus was found in 0/11 droplets (aerosols: 0/11) from participants wearing face masks, compared to 3/10 (aerosols: 4/10) without masks. Influenza viruses were detected in 1/27 (aerosols 6/27!) with face masks, compared to 6/23 (8/23) without. For rhinovirus, there were no significant differences at all. Of note, authors also identified virus in some participants who did not cough at all during the 30-min exhaled breath collection, suggesting droplet and aerosol routes of transmission from individuals with no obvious signs or symptoms.

3 April

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Shang J, Ye G, Shi K. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020, March 30. https://doi.org/10.1038/s41586-020-2179-y

How well does SARS-CoV-2 recognize hACE2? Better than other coronaviruses. Compared to SARS-CoV and RaTG13 (isolated from bats), ACE2-binding affinity is higher. Functionally important epitopes in SARS-CoV-2 RBM are described that can potentially be targeted by neutralizing antibody drugs.

2 April

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Wölfel R, Corman VM, Guggemos W. et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020, April 1. Full-text: https://doi.org/10.1038/s41586-020-2196-x

Important work, showing active virus replication in upper respiratory tract tissues (in contrast to SARS). In a detailed virological analysis of nine cases, pharyngeal virus shedding was very high during the first week of symptoms (peak at 7.11 × 108 RNA copies per throat swab, day 4), more than 1000 times higher than seen with SARS-CoV. Infectious virus was readily isolated from throat- and lung-derived samples, but not from stool samples, in spite of high virus RNA concentration. Blood and urine never yielded virus. Shedding of viral RNA from sputum outlasted the end of symptoms.

1 April

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Yazdany J, Kim AH. Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know. Ann Intern Med. 2020. DOI: 10.7326/M20-1334. Full-text: https://annals.org/aim/fullarticle/2764199/use-hydroxychloroquine-chloroquine-during-covid-19-pandemic-what-every-clinician

Extensive comment on someone’s swanky twitter claiming that the combination of HCQ and azithromycin has “a real chance to be one of the biggest game changers in the history of medicine” (March 21). Careful review about the risks of HCQ and how pretentious dissemination of overpromised data may cause severe harm.

31 March

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Yu F, Yan L, Wang N, et al. Quantitative Detection and Viral Load Analysis of SARS-CoV-2 in Infected Patients. Clin Infect Dis. 2020 Mar 28. pii: 5812997. PubMed: https://pubmed.gov/32221523. Full-text: https://doi.org/10.1093/cid/ciaa345

Is sputum sufficient for diagnosis? In a total of 323 samples from 76 pts, the average viral load in sputum (17429 copies/test) was significantly higher than in throat swabs (2552) and nasal swabs (651). Viral load was also higher in the early and progressive stages than in the recovery stage. If these data were confirmed, collection of specimen would be much easier.

30 March

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McMichael TM, Currie DW, Clark S, et al. Epidemiology of Covid-19 in a Long-Term Care Facility in King County, Washington. N Engl J Med. 2020 Mar 27. PubMed: https://pubmed.gov/32220208. Full-text: https://doi.org/10.1056/NEJMoa2005412

Important paper that highlights the severity of COVID-19 in older people. A total of 167 confirmed cases affecting 101 residents in a long-term care facility, 50 health care personnel (HCP), and 16 visitors. The case fatality rate for residents was 33.7% (34 of 101) and 0 % among HCP.