In the past week, we learnt from the COVID-19 symptom tracker app that only 0.4% of those with symptoms have been tested, that transmission is rare six days after symptoms, and that drugs for hypertension are safe to take, despite their predicted effects on the ACE-2 receptor.

Virology

Model systems

A reverse genetics platform to grow and engineer SARS-CoV-2 in yeast marks a crucial development in allowing researchers to understand the biology of this new virus and the role of mutations.

The coronaviruses causing SARS and COVID-19 can both grow in intestinal epitheilium, with significant titres of infectious virus produced. The human small intestinal organoids used to grow the virus could be a useful model system to understand virus biology and test antiviral drugs.

Mutations

A 27 amino acid deletion in the SARS-CoV-2 protein orf7a was found in the virus in Arizona, with an estimated prevalance of just over 1%. The consequence of this mutation is unknown. A genetic analysis of the SARS-CoV-2 3a protein was presented. ACE-2, the coronavirus receptor, was overexpressed in a number of human cancers, most likely due to changes in methylation.

Anti-virals

Co-structures

The structure of the coronavirus RNA-dependent RNA polymerase, bound to RNA and to the anti-viral drug remdesivir, showed how the drug acts to prevent viral replication. The structure will also allow the design of new anti-virals with a similar mechanism of action.

Similarly, the structure of the coronavirus protease in combination with carmofur, a drug used in colorectal cancer, showed how it binds to the catalytic site and prevents virus replication. Carmofur is a candidate anti-viral for larger human trials.

Interactions

Affinity-purification mass spectrometry was used to identify human proteins that interact with 26 different SARS-CoV-2 proteins. 66 druggable targets were found, two of which displayed anti-viral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. The COVID-19 disease map, an open collaborative dataset of virus-host interactions, was announced in a comment in Scientific Data. 

Trials

A randomised controlled clinical trial of 199 patients showed that the HIV drugs lopinavir-ritonavir were not effective in reducing time to clinical improvement, in a set back for this potential treatment. Gastrointestinal adverse events were also more common in the those given the drugs (this paper was published online in March, but hasn't yet made it into my weekly briefing).

A method for measuring remdesivir in serum was developed, which will be a useful tool for clinical trials of this potentially effective anti-viral.

Tocilizumab, an IL-6 inhibitor, was given to COVID-19 patients and well tolerated, but the lack of a control group meant that its effectiveness was hard to measure.

Another study showed that hydroxychloroquine causes electrocardigram abnormalities, and increases the QT interval, putting patients at risk of cardiac death. The effects were increased when used in combination with azithromycin.

Screenings

Two FDA-approved drugs, niclosamide and ciclesonide, showed anti-viral effects against SARS-CoV-2 in a screen of approved drugs.

Structure based screenings of potential anti-virals against the coronavirus protease yielded 28 drug candidates that can now be tested against the virus; a screen of alkaloids and terpenoids derived from African plants yielded more.

The use of extracorporeal membrane oxygenation (ECMO) in treating patients in Shanghai was described, and recommended, although its use remains controversial. 

Technology

Apps

The COVID-19 symptom tracker was launched in the UK and the US in March and already has more than 2.8 million users. This app, developed by researchers at Kings College London and Massachusetts General Hospital will allow data to be gathered about symptoms and transmission, and found that only 0.4% of those with suspected COVID-19 had been tested. Those with 3 or more symptoms were more likely to be positive for the virus, with individual symptoms showing a poor predictive power. The app will also allow an analysis of at risk groups, as more data is gathered. 

Human mobility data from internet company Baidu accurately tracked how the virus spread from Wuhan to other locations in China. Once drastic control measures were enacted, local measures such as social distancing were more important that travel restrictions. 

Pre-prints

The reproductive number was communicated to the public and policy makers from manuscripts on pre-print servers, before those papers were peer reviewed. This shows the value of such servers in communicating science quickly, although the authors caution that some erroneous claims were also made on pre-prints, which were later deleted and never published in a journal.

Knowledge

Online searches for "coronavirus" increased by 36% after the first announcement about the outbreak in the US, but decreased in less than a week or two, showing the challenges in maintaining awareness. Misinformation and racism were widely circulated in Italy during the outbreak, according to an analysis of Google Trends.

The more knowledge of COVID-19 that Americans have, the more likely they are to take part in positive behaviour, according to a new survey. Democrats were less likely to attend mass gatherings than Republicans, but also less likely to wear face masks, showing a complex role for political views. Frequent use of social media was associated with information overload and overconcern and has also spread panic about COVID-19 in the Kurdistan region of Iraq.

Digital medicine

Telemedicine was used to provide pharmacy services at Children’s Mercy Kansas City, to reduce the risk of transmission to and from healthcare workers, and also for coronavirus screening by physicians at a medical centre in Fort Worth. 

Mental health

Women healthcare workers at Tongji hospital in Wuhan lived apart from their families during the outbreak, and a high proportion showed symptoms of stress, depression and anxiety.

Levels of depression, anxiety, and stress in the Italian population were measured using a survey of almost 3000 people. An online survey via WeChat also found that one fifth of people in Wuhan experienced probable anxiety and probably depression.

Sleep disturbance was prevalent among paediatric healthcare workers in Wuhan, according to a survey of 123 people.

Vaccines

The coronavirus spike protein shows unusual glycan processing, which may have a role in immune evasion and have implications for vaccine development. Another study also looked at O and N-linked glycosylation of the spike protein.

An in silico design of epitopes was used to create a multi-epitope vaccine against SARS-CoV-2

Transmission

Early detection

Despite lockdown relatively early on, there was still a more than 50% risk of the virus spreading from Wuhan to 369 cities in China, according to a modelling study. Travel restrictions were also shown to be effective at limiting spread in the EU, and in Veneto, Italy. The reproductive number in Switzerland is now below 1.

Early detection and isolation of cases was estimated to have prevented more infections than travel restrictions and contact reductions in China. Without these measures, cases would have been 67-fold higher, according to this modeling study in Nature.

Contact tracing

Passengers disembarking from the Diamond Princess cruise ship for a 1-day tour of Taiwan had potential contact with 627,386 people, according to an analysis using mobile sensor data. Stay at home advice was sent via SMS and anyone with symptoms was offered testing - no confirmed cases of COVID-19 were found. 

Pregnancy

COVID-19 during pregnancy and childbirth seems to be manageable, according to a study of 7 women in Tongji Hopsital, Wuhan, who were infected and delivered their babies via caeserian section. Most mothers had fever, but all of the babies were well, and only one contracted the virus, 36 hours after birth.

Asymptomatic spread

Asymptomatic spread was important during the outbreak in Taiwan, and showed the limits of contact tracing, as well as the importance of household spread. Those exposed to an infected individual 6 days after their symptoms started did not catch the virus. Asymptomatic spread was also important during the early outbreak in South Korea, and are an important factor in whether interventions targeting those with symptoms will be effective.

Healthcare

Many emergency medical service providers in the US have limited access to N95 respirators. Heat can be used to sterlise N95 respirators up to 50 times, without compromising their effectiveness. A self-adhesive hydrocolloid dressing can relieve pressure and pain from the bridge of the nose whilst facemasks are worn. 

70% of doctors in the ASST–Papa Giovanni XXIII hopsital in Lombardy were treating patients for COVID-19, regardless of their speciality, during the peak epidemic there. Lessons learnt from the outbreak are discussed, as are similar lessons from Parma University Hospital.

Almost 20,000 COVID-19 patients were hopsitalised in Wuhan during the epidemic, almost 10,000 of whom were in a serious condition. In contrast, only 15 patients were in critical condition during the epidemic peak in Guangzhou, due to strict control measures. This analysis allows the impact of a Wuhan-style outbreak in other locations to be predicted.

At risk groups

Hypertension

Use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) did not increase the risk of SARS-CoV-2 infection, and so their use can be continued during the global pandemic. A study of more than 18,000 patients at the Cleveland Clinic in Ohio and Florida and another of more than 12,000 patients in New York City should put this matter to rest.

Cancer and diabetes

Cancer patients are at a higher risk of severe COVID-19 disease, according to data from New York hospitals. Smoking was shown to be a risk factor for severe disease, as were several biomarkers. Those with type 2 diabetes were more likely to have severe COVID-19 disease, although control of blood sugar reduced the impact. Liver injury seems to be a marker of severe disease, although the mechanism, and whether this is a cause or effect, is unclear.

Age

The role of age distribution has been used to model the outbreak in different locations, and goes some way to eplain why COVID-19 was so severe in Italy.

Transplants

COVID-19 can be severe in kidney transplant patients, according to a study of 33 patients in Spain. Heart transplant patients, in contrast, do not seem to be at an increased risk of infection, as long as they take appropriate measures.

Homeless

A high proportion of residents and staff in homeless centres in the US tested positive for SARS-CoV-2 in two separate studies, showing their increased risk of catching the virus.

Diagnostics

Home testing

The Seattle Flu Study, where people with influenza-like illness home test themselves, was adapted to include COVID-19 testing. This allowed identification of the first human-to-human transmission in the USA and provides an effective model for community testing.

Saliva

Saliva samples can be used for SARS-CoV-2 detection as the virus is at high levels in this fluid early during infection, according to a study from Hong Kong. Samples can also be pooled with up to 32 together, using standard protocols, saving on reagents and costs.

Pathology

SARS-CoV-2 RNA can be detected in routine histopathological samples, such as biopsies, according to this pathology study.

ELISA

An ELISA to measure antibodies against SARS-CoV-2 was found to be specific and sensitive. Another new test used lanthanide-doped polysterene nanoparticles to detect antibodies against the virus.

Taste and smell

Loss of smell or taste was again shown to predict SARS-CoV-2 infection in this study of 145 participants, and also in a European study, where two thirds had such symptoms.

Immunology

Shield immunity

Individuals who have been infected with SARS-CoV-2, and so are immune, can be reintegrated into society without increasing the reproductive number. This concept, termed shield immunity, may allow those with immunity to carry out essential roles, although accurate, rapid, and widespread serology testing would be needed.

Monoclonal

A human monoclocal antibody that binds to and neutralises SARS-CoV-2 was described in Nature Communications. This could be a useful tool for diagnostics and vaccine development, and potentially as a treatment itself.

Epitopes

Potential T cell epitopes against SARS-CoV-2 were identified that should bind to commonly seen HLA variants in the Japanese population, aiding vaccine design. IgG antibody is produced from around 10 days and seems to be long lasting, with more kinetics described in another study, although longer experiments are needed.

Dysregulation

Immune dysregulation, especially IL-6 increase, is a predictor of severe disease, as is decreased lymphocyte count, findings backed up by another study. Immune dyregulation can also supplement traditional diagnostics to detect SARS-CoV-2 infection. This immune dysregulation was compared to the findings in SARS and MERS.

Clinical findings

Viral particles that looked like SARS-CoV-2 were found in the renal tubular epithelium in a single patient who died of COVID-19, perhaps explaining the findings of altered kidney function in some patients.

None of the children with COVID-19 in paediatric emergency departments in Italy had a fatal infection, confirming previous studies that found mild disease in children. Another study of the illness in children was described.

An analysis of post mortems found diffuse alveolar damage in COVID-19 patients; most patients had comobidities.

Thrombotic complications were common in patients hospitalised in France; Myocardial dysfunction and hypercoagulability were described in another five patients with severe disease at Emory Healthcare, Atlanta; deep venous thrombosis was seen in seven patients in the state of Hamburg; and arterial vascular complications in three patients in New York. Anticoagulation therapies can be safely used for venous thrombosis, according to a letter in the New England Journal of Medicine.

7 cases of COVID-19 associated autoimmune hemolytic anemia (AIHA) in Belgium and France were described. 

And finally, more evidence of chilblains, this time in children with otherwise mild disease, were described, as well as cases in adults. Mouth ulcers have also been seen in three patients with the virus.