This week, as with last, more than 600 papers were published on COVID-19. Of those, 87 were original research and so have been summarised below. This is somewhat higher than the 51 papers I read last week. This growth in content is good for science, and society, but a bit worrying for my ability to continue this weekly report. I await next week with interest, and trepidation!
This week we learnt that infectiousness starts 2-3 days before symptoms, how the anti-viral drug remdesivir kills coronaviruses, and how social media searches can predict the spread of COVID-19.
Infectiousness before (or without) symptoms
6% of the entire Icelandic population has been tested for SARS-CoV-2, as reported in a landmark study which sheds light on virus spread, symptoms, and risk factors. 13% of those considered at higher risk tested positive, mainly in those who had recently travelled to China and the Alps. Only 0.6% of the general population were positive, a significant minority of whom had recently travelled to the UK, suggesting relatively early spread of the disease there. Interestingly, only 57% of these had any symptoms, which is the highest figure yet for asymptomatic carriers, at 43%, although this will certainly include some who later developed symptoms. Women and children under 10 had a lower risk of infection, with no infections in children under 10 in the general population, and only a few in children who had recently travelled.
Another important study, this time in Nature Medicine, found that infectiousness generally started 2-3 days before symptoms. The researchers also looked at transmission pairs from infector to infectee, and found that 44% of secondary cases were infected during the presymptomatic phase of disease, again showing the crucial importance of contact tracing.
An asymptomatic carrier passed the virus to seven young contacts in Anhui province, China, with an average incubation period of just 2 days. All had mild disease. Asymptomatic spread was also important in an outbreak in the French Alps, as was presymptomatic spread in Singapore.
Social distancing works
A massive study of more than 30,000 cases of COVID-19 in China showed that the reproduction number fluctuated above 3 before 26th January, then decreased to below 1 in February, and decreased further to less than 0.3 after 1st March, due to progressively stricter control measures. Local healthcare workers were more likely to be infected that the general population. This study should be influential in other locations, whose outbreaks are ongoing.
No vertical transmission
Another study confirms that SARS-CoV-2 does not pass from mother to child, and also tests whether CT scans can be used as a diagnostic in pregnant women - with inconclusive results. A similar study from Australia reported an uncomplicated vaginal birth in a mother with COVID-19, as did a study in the USA, and another of 19 neonates in China, although another study sadly reported the first death of a pregnant woman with COVID-19 in Iran.
Infections in children
A modelling study from the USA predicted that 3.7 million children could become infected with SARS-CoV-2, overwhelming paediatric intensive care units, despite the disease being generally mild in children.
Older patients have detectable viral RNA for longer than younger patients, according to a study from Henan province, although live virus was not measured.
Transmission in healthcare settings
A study from Huoshenshan Hospital in Wuhan found SARS-CoV-2 RNA on hospital floors, computer mice, trash cans, and sickbed handrails. They also found viral RNA in air up to 4 metres from patients, which may indicate aerosol transmission. However, the study only detected viral RNA, which could indicate dead virus, and showed no evidence of infectious virus. Indeed, none of the staff in the hospital had become infected at the time of writing, showing how effective control measures can be.
A survey of doctors in Italy found that one in five had symptoms suggestive of COVID-19 and only half had PPE from the local health department, highlighting the importance of protecting front line medical staff. Several groups are developing home-made PPE: a simple protective shield made from a carton has been designed for use during intubation by a group of doctors in Taiwan; as has a simple shield to use when taking nose and throat swabs.
A study of 23 health care workers from Wuhan found that only 2 of them worked in hospitals with COVID-19 patients, suggesting that they acquired the virus in the community during the early stages of the outbreak. In their letter to the New England Journal of Medicine, the authors state that none of the 42,600 health workers who went to Hubei province to care for those with COVID-19 have been infected with SARS-CoV-2, in contrast to the recent findings from Italy.
A diagnostic test for SARS-CoV-2 RNA based on CRISPR-Cas12 was developed and shown to be as sensitive and specific as the gold standard qRT-PCR. The test is easy to perform, uses standard off the shelf reagents, and gives a fluorescent reading, making detection simpler, and potentially allowing its use outside of the lab, for example in airports and emergency departments.
A field-effect transistor (FET) based biosensor that detects SARS-CoV-2 was developed, and shown to be highly sensitive. The sensor uses graphene sheets coated with a SARS-CoV-2 antibody and can detect the virus directly in swabs, with no pre-treatment needed. Another study in the same journal describes a dual-functional plasmonic biosensor which detects viral RNA using gold nanoislands.
Samples for testing
Serology testing can be effective where RT-PCRs are negative, according to a family cluster study from China. Faecal swabs may also be useful here, as viral RNA could be detected for up to four weeks, a finding also seen in another study from China, although this may not represent live virus and so may not be infectious. Throat wash from gargling is another potential bodily fluid for virus testing.
Ultrasound and CT scans
Lung ultrasound can be used as a diagnostic tool for COVID-19, at least in severe patients. CT scans continue to be promoted as a potential diagnostics tool, with glass opacity the main clinical sign of disease, even in those with no symptoms, a finding backed up by a study from the USA, and another from China. Chest CT scans of a patient with HIV and mild COVID-19 are described, and present slightly differently to other patients.
A new triplex RT-PCR was developed, which should use less reagents than existing tests. The use of urea dissociation tests was shown to reduce false positives in ELISAs for serology testing, and a new diagnostic test from Roche was shown to be effective.
A busy week for remdesivir
Remdesivir is touted as a potential antiviral for coronavirus infection. Its mechanism of action is described in this nice study of inhibition kinetics, showing how it acts as a nucleotide analogue in inhibiting the viral RNA-dependent RNA polymerase, thereby preventing viral RNA being produced. A related structural study showed how a remdesivir metabolite binds to the coronavirus polymerase.
Of 61 severely ill patients treated with the drug across Europe, the USA, Canada, and Japan, 68% showed clinical improvement, in a study funded by Gilead Sciences, who make the drug. Randomised, placebo controlled trials are now needed.
Which treatments work?
Extracorporeal membrane oxygenation (ECMO) is not a promising treatment for COVID-19 patients, despite its widespread use, according to a study in Critical Care. Half of the patients treated with ECMO died from septic shock and multiple organ failure. In contrast, intravenous immunoglobulin appeared to reduce mortality from COVID-19 in a Wuhan hospital, as did convalescent plasma in two patients in South Korea. The effects of corticosteroids are unclear, but if you are interested in this lack of clarity, read this study from Anhui Provincial Hospital.
Peptide inhibitors, based on ACE2, that bind to the coronavirus spike protein, were designed in a computational study. These can now be tested for antiviral activity. Ethanol and isopropyl-based handrubs, as recommended by the WHO, are effective at killing SARS-CoV-2, confirming the effectiveness of handwashing.
Hydroxychloroquine, lopinavir, and ritonavir
80 COVID-19 patients with mild disease were treated with the antimalarial hydroxychloroquine, together with azithromycin, in a follow up study from Didier Raoult's group in Marseilles. This study was not a randomised controlled trial, the gold standard for testing new drugs, and there was no control group. A study of patients treated with the HIV drugs, lopinavir and ritonavir, or arbidol (an influenza treatment not widely used outside of Russia and China) was fairly inconclusive, as it also lacked a control group.
Surveys and digital health
Tracking the outbreak with social media
Posts about COVID-19 on social media can predict the spread of the outbreak, according to a study of content on Weibo, a Chinese social media platform. In another study, words searched for on social media giant WeChat were analysed, showing how public interest shifted from Wuhan, the virus, and symptoms, on to face masks and returning to school. Searching for loss of smell on google also seems to be correlated with the growth of the COVID-19 outbreak in several countries analysed, as did search terms about the virus, in a study from Iran.
Japanese citizens were asked in an online survey how often they took personal measures to prevent COVID-19. Of the 2400 who completed the survey, 80% implemented hand hygiene, respiratory etiquette, and self-isolation. Less common were social distancing (67%) and avoiding touching the eyes, nose, and mouth (60%).
Burnout in doctors
Doctors working with COVID-19 patients show lower rates of burnout than those working elsewhere in hospital, in a surprising finding from a survey of 220 Chinese medical staff.
Rick factors for severe disease
Older age, hypertension, and high cholesterol are risk factors for severe COVID-19 disease and death, according to a study of more than 500 cases from Tongji Hospital, China. This may explain why the death rate seems to be higher in men. Of 136 patients with COVID-19 and in hospital cardiac arrest, hypertension was the biggest risk factor and survival was poor. A study from Wuhan, Shanghai and Anhui also showed the importance of comorbidities in severe COVID-19 disease.
Out of 91 deaths in Renmin Hospital of Wuhan University, 83 had at least one complication, including acute respiratory distress syndrome, myocardial injury, liver injury, renal insufficiency, multiple organ dysfunction syndrome and pneumothorax.
31% of severe COVID-19 patients in a Dutch hospital had thrombotic complications, including pulmonary embolism. Diffuse intravascular coagulation (DIC), a symptom of severe avian influenza, was not seen, but physicians should be alert and ready to use anticoagulants.
Smoking was identified as a risk factor for severe disease in a study of 125 hospitalised patients in Fuyang, Anhui province, China.
Stomach problems are often seen
35% of COVID-19 patients have gastrointestinal symptoms, including diarrhoea, nausea, or vomiting, according to a case-control study from New York City. A similar study found digestive symptoms in 50% of patients, including lack of appetite.
Neurological findings are more common than thought
Neurological symptoms are also common in COVID-19 patients, especially in those with severe disease, according to a study of 214 patients in China. A case study of neurological symptoms was described in a separate study, where the patient experienced altered consciousness and psychiatric symptoms.
A meta analysis of cases confirmed that the most common symptoms of COVID-19 patients were fever, fatigue, cough and expectoration. Yet more studies confirmed that children generally have mild disease, including one from the USA, and another from China.
Myocarditis and immunology
A case of myocarditis was described in a COVID-19 patient in South Korea, another in China, and a third in Italy. A case study from France described a patient with low platelet count, or thrombocytopenia, possibly caused by COVID-19. More details of the immune response to infection are presented in this case study, and in this retrospective study from China. The neutrophil to lymphocyte ratio may predict severe disease, and another study blamed lower T cell counts.
Is the liver involved, or not?
In a contradiction of some previous studies, 37% of patients in a Shanghai hospital had abnormal liver function. However, chronic liver disease is not a predictor of severe infection, although at least one liver transplant patient has now died. A patient with multiple myeloma survived.
Endoscopies and transplants
The challenges of performing endoscopies on COVID-19 patients and others during an outbreak, is described in this study from Italy. Two transplant patients with COVID-19 were described - one developed acute rejection, the other did not, and both recovered.
Outbreaks across the world
A cluster of cases in Wuxi, China, was described, along with the outbreak in a Shenzhen hospital, as well as in the wider Shenzhen area, the clinical features of patients in Zhongnan hopsital in Wuhan, two studies on the outbreak in Guangzhou, an outbreak in Japan from travellers to Wuhan, an outbreak in an assisted living facility in Seattle, another in California.
Genetic risk factors
Finally, an intriguing case report from Iran described fatal cases in three brothers. Given that the brothers lived separately, and their spouses and children were unaffected, the authors suggest that they may have had a genetic risk factor for severe infection, something that will no doubt be a major area of research in the near future.