This week researchers solved the crystal structure of the SARS-CoV-2 spike protein binding to its receptor, showed that SARS-CoV-2 mainly infects the upper respiratory tract and can infect the eye, and learnt how to manage patients with hypertension. 

You might want to also read last week's update.

Transmission

SARS-CoV-2 grows in the upper respiratory tract

Christian Drosten has become something of a celebrity in Germany due to his calm and authoritative handling of the COVID-19 outbreak. He shows with this paper in Nature just why his reputation is so well deserved. In a study co-led with Clemens Wendtner at Klinikum München-Schwabing, Munich, they identified infectious virus from the upper respiratory tract of patients very early during disease. This is important, as SARS was rarely isolated from the upper respiratory tract, and was more prevalent in the lower respiratory tract - meaning it was more likely to cause pneumonia, but perhaps spread less easily. 

Interestingly, no infectious virus was found after day 8 of symptoms, despite high levels of viral RNA. Similarly, they also found viral RNA, but not infectious virus, in stool samples, and no evidence of virus in urine or blood. This shows that caution must be taken with studies that only detect viral RNA, as they may be detecting dead virus that is no longer infectious. They therefore recommend that patients be discharged 10 days after symptoms, when viral load in sputum is below a certain level. There is a full description of the clinical outcomes, but I noted that 4 out of 9 patients showed loss of taste and smell, confirming other studies.

Patients are infectious before symptoms

Yet more evidence that people can be infectious before symptoms (pre-symptomatic spread) comes from this family cluster in China. The index patient was treated with the HIV drugs lopinavir and ritonavir, and recovered, although we can't conclude much from a single case study.

Stool and sputum could be used for diagnostics

Sputum and faeces remained positive for SARS–CoV-2 by PCR up to 39 and 13 days respectively, according to a study of 22 COVID-19 patients in China. This may not be infectious virus, but could be useful for diagnostics.

Treatment

Managing hypertension in COVID-19 patients

A special report in the New England Journal of Medicine looks at Renin–Angiotensin–Aldosterone System (RAAS) inhibitors, which are used to treat hypertension, but may worsen COVID-19 disease, due to the drugs' effects on ACE2, the SARS-CoV-2 receptor. The authors conclude that there is not enough evidence to advise taking patients off these drugs, and indeed doing so may put patients at risk.

Indeed, a study of hospital patients in China found that patients with hypertension and COVID-19 infections, that took RAAS (abbreviated to RAS in this study) inhibitors were associated with reduced IL-6 and less lung injury. This suggests that these drugs may improve COVID-19 disease outcome in patients with hypertension.

Inhibiting fusion

Lipopeptides derived from a pan-coronavirus fusion inhibitor were effective at preventing membrane fusion in vitro, as well as inhibiting the growth of several coronaviruses, including SARS-CoV-2, when grown in tissue culture. This new drug will no doubt be explored as a potential anti-viral, although no studies have yet been conducted in humans.

Headaches and mental health

Face masks cause headaches

Use of personal protective equipment (PPE), including face masks and protective eyewear, were associated with an increase in headaches in 158 nurses, doctors, and paramedics in Singapore, who responded to a survey on the topic. PPE seems to cause new headaches (in 81% of respondents) as well as exacerbating existing headaches (91%).

Anxiety in students

More than 7000 students at Changzhi Medical College were surveyed about their mental health during the COVID-19 outbreak. 21% showed mild anxiety with a further 2.7% with moderate anxiety and 0.9% with severe anxiety. Family income and social support were both protective.

How good is your COVID-19 knowledge?

A knowledge, attitudes, and practices (KAP) questionnaire taken by almost 7000 participants in China tested their knowledge of COVID-19. Twelve questions about the virus were asked, as well as two about their attitudes, and two about their own practices. Overall, 90% of questions were answered correctly, showing high knowledge of the virus in this self-selecting group.

Supporting good mental health for medical workers

The pressure that medical workers are under was highlighted in 37 interviews from staff in the emergency department, Peking Union Medical College Hospital, Beijing. The interviews were conducted by the Department of Psychological Medicine, to support frontline health workers who lived at the hospital for 2-3 weeks while working, before a week in an isolated vocational resort, before going home. Video chats or telephone calls were cited as the most popular coping strategy, but there are lots of interesting lessons that will be applicable to healthcare workers the world over.

Receptor binding

The structure of the SARS-CoV-2 receptor

In a feat of biophysics, researchers at the University of Minnesota have determined the crystal structure of the SARS-CoV-2 receptor-binding domain whilst in complex with the human ACE2 receptor. They find that this virus forms a closer, more compact bond with the receptor than SARS did, perhaps explaining why COVID-19 has spread so fast around the globe. A related bat coronavirus also bound well to human ACE2, suggesting the virus may have jumped directly to humans, without an intermediate host. Of the two related viruses found in pangolins, one binds well to ACE2, but the other does not, questioning the role of this animal in human transmission. Finally, the structure will allow antibody therapy to be targeted to the right parts of the virus, as well as guiding vaccine design.

Diagnostics

New antibody test

An antibody test for SARS-CoV-2 was developed using an ELISA with recombinant nucleocapsid or spike protein. The tests successfully identified COVID-19 patients in 68%-77% of cases, depending on the test (IgM or IgG; N or S), and was most effective 10 days after onset of disease, to allow time for antibodies to form.

Alternatives to virus transport medium

Many news outlets have commented on the lack (or not) of testing reagents for COVID-19. One of these is viral transport medium, a yellow liquid used to store nose and throat swabs on their journey to the diagnostic lab. This study looked at alternatives and found that Minimal Essential Media, Phosphate Buffered Saline, or plain saline all worked just as well when carrying out PCR diagnostics.

Failure of a new antibody test

There have been a plethora of new testing kits developed for SARS-CoV-2, but it is important that they are tested before use. A 15 minute antibody test didn't cross react with other human coronaviruses, or show any false positives, but failed to pick up an infection in many positive cases, performing considerably worse than the gold standard RT-PCR test. It's use is not recommended.

Immune response

Lymphocytes levels are low in COVID-19 patients

Several studies show the immune response in those infected with the virus. Total lymphocytes were decreased in COVID-19 patients, and levels of CD8+ T lymphocytes seem to be a predictor of severe disease. A detailed transcriptomic analysis of immune cells during COVID-19 infection is presented in this study of SARS-CoV-2 infected patients. Finally, a study of 94 patients in Shenzhen Third People’s Hospital measured IL-6 and C reactive protein in patients, as well as treated some with the HIV drugs lopinavir/ritonavir, and interferon alpha.

Clinical findings

SARS-CoV-2 can infect the eye

One third of COVID-19 patients have ocular abnormalities, including conjunctivitis, according to a study of 38 people in Yichang Central People’s Hospital, China. Two of the patients secreted virus from the eyes, suggesting that this could be a route of transmission.

CT scan for diagnostics

A small but important study from China found that three patients showed clear evidence of COVID-19 infection by CT scan lung abnormalities, even when they were negative for virus by PCR. All three were eventually positive for the virus, but only several days later. This again shows the potential use of including CT scans as part of the diagnostic mix.

Outbreaks across the world

On 29th January a Chinese couple were hospitalised in the National Institute for Infectious Diseases, Rome, with fever and respiratory symptoms. This was the first known case of COVID-19 in Italy, which is now the global epicentre of infections, and is described in this study.

The outbreak now exists in many locations across the world, each of which can be described. The first cases of COVID-19 in Europe began in France on 24th January, and are described in this study. The COVID-19 outbreak in Seattle, Washington State, is described in this case series of critically ill patients. An outbreak at the Department of Ophthalmology at Oslo University Hospital, Norway, which was imported from Italy, is described, as are the symptoms of those infected in Macau. An analysis of 54 fatal cases of COVID-19 in South Korea found that the average time from infection to death was 10 days, and reminded us that the overall mortality rate there is a relatively low 0.7%.

Several studies report on the clinical findings of those ill with COVID-19 in China. A study of 273 COVID-19 patients in a Chinese hospital showed that those with markers of heart injury have more severe disease, highlighting the importance of this as a risk factor. A study of 25 COVID-19 infected patients in a Chinese hospital were analysed, as well as a couple of new case reports, and more data on CT scans of infected patients.

Good news for pregnant women, and the kidney

Finally, some welcome good news. An emergency Caesarean was carried out on a SARS-CoV-2 infected patient, with success, and news that COVID-19 does not include acute kidney injury amongst its symptoms will I'm sure be celebrated in nephrology departments across the world.