24th April - the coronavirus COVID-19 compendium

All the latest research on coronaviruses and COVID-19

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This week there were 846 manuscript titles to scan through, of which 85 were original research. As the volume gets bigger, I have become slightly more selective in what I highlight and will no longer highlight case reports, or CT scans, unless they show new findings. Although reproducibility is absolutely key to good science, these observational studies are too numerous to cover here.

This week we learnt that SARS-CoV-2 may have originated from recombination between a bat coronavirus and another from pangolins, that treatment with hydroxychloroquine and azithromycin may increase the risk of cardiac death, and that Hong Kong has managed to keep its reproductive number below 1 for 8 weeks through effective social distancing.

Origins

None of the bat or pangolin coronaviruses so far sequenced represent the immediate ancestor for SARS-CoV-2. Most of its genome resembles that of a bat coronavirus, whereas the receptor binding domain is closest to a pangolin coronavirus, suggesting that SARS-CoV-2 may be the product of natural recombination between these two ancestor viruses. The authors, from the University of Hong Kong, add that there is no evidence that the virus was artificially created.

Animal models

Cynomolgus macaques can be infected with the coronaviruses that cause COVID-19, SARS, and MERS, and so provide a useful animal model to test new drugs and vaccines. For SARS-CoV-2, the virus was excreted from the nose and throat, with no signs of disease.

Transmission

Social distancing

The reproductive number of SARS-CoV-2 has remained at less than 1 for more than 8 weeks in Hong Kong. Non pharmaceutical interventions, such as social distancing, have also reduced influenza transmission there by 44%, an added benefit of these measures.

In contrast, the reproductive number of SARS-CoV-2 in Iran was estimated to be between 3.5 and 4.4 before social distancing, and 1.6 afterwards, using cases as reported in Wikipedia and official press releases. As the reproductive number is still above 1, the outbreak will continue to grow.

A new model of virus transmission includes the important role of asymptomatic carriers as well as those who are not diagnosed. The study shows that 70,000 people in Italy may die from COVID-19 if testing continues to be limited, and only for those with symptoms, as is the case now. However, with mass testing, including of all asymptomatic contacts, this can be reduced to 25,000 deaths. There have been 15,000 deaths so far.

16% of COVID-19 patients transmitted the virus to a household contact, according to a study of 105 index cases in China, although children were much less likely to be infected. Quarantine within a household was 100% effective at preventing household transmission. 

Large gatherings

35% of COVID-19 cases in Malaysia were linked to the Sri Petaling gathering, attended by more than 19,000 people of different nationalities. This likely explains why Malaysia has the highest number of cases in South East Asia. 16 cases of COVID-19 in Chicago, including three deaths, were linked to a funeral and a birthday partyIncidence of COVID-19 varies hugely across US states and cities, according to new study which should help with resource allocation.

Cases across the world

Another case of transmission from an asymptomatic patient in China is described, as is the first case of COVID-19 in Bhutan in an immunocompromised man who visited from the United States. The first case of COVID-19 in Florida occurred in mid-February, in a patient who travelled to and from Italy.

Disinfectants

Riboflavin and UV light can be used to inactive SARS-CoV-2 in plasma and platelet products, allowing prevention of theoretical transfusion transmission of the virus.

Door handles, sinks, and other environmental samples from isolation wards at Zhejiang University Hospital all tested negative for SARS-CoV-2, despite infectious patients there. Sewage tested positive for viral RNA, but not for live virus. A similar study found the same lack of virus in hospital rooms that housed a patient from the Diamond Princess cruise ship outbreak. 

Treatments

Another new anti-viral

Nafamostat mesylate prevents SARS-CoV-2 entering lung cells in vitro, by inhibiting TMPRSS2, and so should be tested in clinical trials as a potential anti-viral against COVID-19, as it has already been FDA approved for unrelated conditions.

Risk of cardiac death from hydroxychloroquine

Treatment with hydroxychloroquine and azithromycin increases the risk of sudden cardiac death by increasing the QT interval. It's effectiveness against COVID-19 is still not proven, and so its use should be accompanied by QT monitoring, although there were no cardiac deaths in the study. Hydroxychloroquine also caused liver toxicity in a patient, cautioning against its widespread use.

An IL-6 blocker

Treatment with an IL-6 blocker, Tocilizumab, led to an increase in circulating lymphocytes in this study of 54 COVID-19 patients, 28 of whom had severe respiratory failure. Severe COVID-19 disease is associated immune dysregulation or macrophage activation syndrome, with a reduction of T lymphocytes and NK cells, as well as an increase in IL-6 and TNF-alpha. 

Anti-coagulation

An anticoagulation agent, dipyridamole, was identified as a potential treatment for COVID-19 associated hypercoagulability, which is seen in some patients. 8 patients treated with the drug showed improvement. 

BTK inhibitor and interferon

Ibrutinib, a BTK-inhibitor, may provide protection against lung injury during COVID-19 disease, according to a study of Waldenstrom’s Macroglobulinemia patients, who take this drug daily. Patients in China are treated with interferon-alpha, although its effectiveness is not known.

ECMO

Extracorporeal membrane oxygenation continues to be controversial, but this study of 32 patients found that it can be beneficial, although they caution that more research is needed. 

Structural biology

Two high-resolution crystal structures of the SARS-CoV-2 Nsp15 endoribonuclease NendoU are presented and discussed.

Potential protease inhibitors were designed using structure-based ligand design and molecular modelling.

Immunity

HLA genotypes

HLA genotypes show different affinities for SARS-CoV-2 antigens, suggesting that this genetic variation may predict severe disease.

Antibodies

High levels of IgG were detected in 5 patients who recovered from COVID-19, showing strong immunity, and one patient was treated with convalescent plasma. Indeed, antibodies can be detected as soon as 4 days after symptoms.

Two patients with X-linked agammaglobulinemia, who cannot produce any antibody due to a lack of B cells, developed COVID-19 pneumonia. Neither required ventilation and both survived, an intriguing finding that antibodies are not necessary to overcome the infection.

Lymphopenia

Another study from Wuhan confirmed that T cell immunity was suppressed during severe infection, as did one from Xiangya Second Hospital, and another from Beijing.

Autoimmune disease

Evidence of some autoimmune characteristics in COVID-19 patients were found in Hubei province, China.

Co-morbidities

Hypertension

Clinical characteristics of more than 5000 patients admitted to hospital in New York City found that hypertension, obesity, and diabetes were common comorbidities for severe COVID-19 disease. Two thirds of those treated in the intensive care unit were men. A similar study from a community hospital in Manhattan found that of 393 patients, 61% were men, and 36% were obese. Unlike in China, gastrointestinal symptoms were uncommon. 

Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers reduced mortality in COVID-19 patients with hypertension, in a large study of 1100 patients. Fears that this treatment would increase mortality, due to effects on the coronavirus receptor ACE-2, proved unfounded.

Coagulation disorders

More evidence for coagulation disorders in COVID-19 came from a studies showing that D-dimer levels, a marker of venous thromboembolism, predict fatal infection, and are dramatically increased during severe infection. Elevated D-dimer levels were also seen in 18 patients with myocardial injury with ST-segment elevation. A case study described three patients with clinically significant coagulopathy, antiphospholipid antibodies, and multiple infarcts, another described a patient with pulmonary embolism, and a third in a patient with venous thrombosis

Immunosuppression

Immunosuppressed kidney transplant patients had more severe pneumonia than the general population, according to a small study of 10 cases in Wuhan, China. Patients with inflammatory bowel disease may be at risk of severe disease, due to the immunosuppressive drugs they take. Advice for their care, including a recommendation to consider stopping taking medication for IBD, is published.

Personal protective equipment

Three healthcare workers, none of whom wore PPE, contracted the virus from an infected patient in hospital in Solano County, California. 121 healthcare workers were exposed.

Medical face masks and N95 respirators can be steamed over boiling water for 2 hours to sterilise them, allowing their re-use, in a study using an avian coronavirus.

43% of healthcare workers have received skin injuries caused by PPE, such as pressure inquiries and tears, in a large survey of more than 4000 medical staff at multiple hopsitals.

Diagnostics

Serology

A protocol for expressing antigens from the SARS-CoV-2 spike protein is described in this useful study, as well as instructions for setting up your own ELISA to detect antibodies.

A serology study of 1400 people in Wuhan, China, found that 10% of the population had antibodies against SARS-CoV-2. Another study found that both severe and non-severe COVID-19 patients seroconverted, but only 1 of the 5 asymptomatic carriers in the study developed an antibody response.

Duration of viral shedding

Another study, this time from Zhejiang, found that COVID-19 patients have viral RNA in their stool for longer than in respiratory samples, as did a study from Hong Kong. Another study found viral RNA up to 6 weeks after infection. None of these studies showed evidence for live, infectious virus. 

Nasopharangeal swabs are more sensitive than oropharangeal swabs for detecting SARS-CoV-2; another study found that sputum was the most reliable bodily fluid for diagnostics. Several commercial diagnostic tests were assessed.

RT-LAMP

Two reverse transcriptional loop-mediated isothermal amplification (RT-LAMP) diagnostic tests have been developed, by different groups, to detect SARS-CoV-2.

Digital health, surveys, and social media

Patient examinations via iPad were used by doctors at Massachusetts General Hospital, reducing the risk of transmission of SARS-CoV-2 to healthcare workers.

Global interest in coronaviruses, as measured by Google Trends, peaked on 31st January and again on 5th April, with interest decreasing since then, despite an increase in cases.

7% of tweets by G7 world leaders were political, compared to 83% that were classed as informative, and 29% that linked to government sources. A survey found that Americans would prefer the CDC director or NIH director to lead the US response to the outbreak, rather than the President or Congress.

A survey of more than 18000 people tracked the course of the outbreak in China between January and February, and found that male sex, advanced age, and lung diseases were associated with a higher risk of fever. Self-reporting of fever peaked around 8th February, which corresponds with other data from China, showing the usefulness of such surveys. Another study found that Sina Microblog, a social media site in China, can be used to measure public attention to the COVID-19 outbreak.

A global survey of more than 400 healthcare workers tested their knowledge of COVID-19 and the coronavirus that causes it, showing some gaps in their knowledge. A similar survey amongst the Egyptian population found that they mainly get their knowledge from social media.

Clinical findings

Sepsis

A hypothesis article in The Lancet suggests that COVID-19 may cause viral sepsis. Indeed, a case of severe COVID-19 in a three week old boy with sepsis was managed with standard paediatric intensive care unit protocols. He survived.

New symptoms

Taste and smell disorders were more common in COVID-19 patients than a control group of influenza patients, adding to the evidence that this should be included as a symptom. Myalgia and chills were also commonly seen in COVID-19 patients in King County, Washington, and so should be included in screening for disease.

Unusual symptoms

Viral RNA could be detected in the serum of severely ill COVID-19 patients, potentially indicating viraemia, and correlated with high levels of IL-6. Live virus was not detected. Co-infection with SARS-CoV-2 and group A Streptococcus was found, complicating treatment for this individual. A case of myocarditis in a COVID-19 patient with hypertension was also described. It can also cause Guillain-Barré Syndrome, a rare consequence of some viral infections. Another study found viral RNA in the eye of an infected patient. Age was again shown to be the main risk factor for severe disease in a study from Shanghai. 

Pregnancy

There were no deaths in 118 pregnant women with COVID-19 in China, and no evidence of transmission to the baby, showing that pregnant women are not at risk of severe disease. However, a single case study from Iran in a severely ill patient with COVID-19, found that the virus could be detected in the amniotic fluid and in the baby, suggesting vertical transmission, although the authors cannot rule out contamination. The mother sadly died, but the baby is doing well. 

Intestinal inflammation

COVID-19 disease sometimes includes abdominal pain and can be detected using abdominopelvic CT scans. The virus also causes intestinal inflammation in some patients, as well as diarrhoea in 31% of patients. 

Neurological symptoms

Altered mental status in an older patient with no fever or cough was seen, and highlighted as an unusual symptom of COVID-19. COVID-19 can also cause rare neurological manifestations, Miller Fisher syndrome and polyneuritis cranialis. In contrast, the virus does not cause seizures, according to a retrospective multi-centre study. 

Psychosis

And finally, an unusual case of COVID-19 related psychosis in a German man with schizophrenia was described. The patient was not infected himself, but he experienced acoustic hallucinations of his neighbours accusing him of neglecting his parents during the pandemic. The authors speculate that extensive media coverage of COVID-19 contributed to these paranoid delusions.

Go to the profile of Ben Johnson

Ben Johnson

Head of Communities & Engagement, Springer Nature

I gained my first degree in virology from the University of Warwick and a PhD in influenza virus immune evasion from Public Health England and the University of Reading, UK. My research interests then moved on to smallpox vaccines, viral ion channels, and cell adhesion, while a postdoc at Imperial College London. I joined open access publisher BioMed Central in 2011 as an Acquisitions Editor and then Associate Publisher, and was responsible for launching new journals, including Microbiome, Zoological Letters, and Movement Ecology. I have been Head of Communities & Engagement at Springer Nature since 2016, running our online community blogs, and a Consulting Editor at Nature Medicine since June 2020, handling COVID-19 papers. I am based in our London office.

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