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16th June 2020
However, there have been calls from various factions of society to reduce this distance with critics arguing that current distancing will be virtually impossible to observe, especially in the hospitality sector. In addition, there does not appear to be a universally accepted social distance. Advice from the World Health Organization suggests a distance of at least 1m,1 and although several countries including China, Denmark and France have adopted this measure, others, for example, Australia, Germany and Italy suggest 1.5m whereas the UK, Canada and Spain have decided upon 2m. In the UK, the government has consistently maintained that policy decisions are informed by the science. But what is the nature of the science behind social distancing measures and how good is the evidence upon which they are based?
Efforts directed towards reducing the spread of an infectious disease primarily seek to contain the community spread of the infection through non-pharmacological approaches including hand washing, travel restrictions, school closures which are collectively referred to as mitigation strategies. Such an approach is designed to buy time before the development of an effective treatment such as a vaccine and cannot continue indefinitely. One aspect of any mitigation strategy, is social distancing which has proven to reduce the rate of infection as witnessed in a systematic review of 15 studies which found that workplace social distancing reduced the cumulative attack rate of influzena by 23% especially when combined with other mitigation strategies.2 However, the authors noted that there were few epidemiological studies conducted in actual settings and called for more research to assess the effectiveness of social distancing. Nevertheless, while social distancing is undoubtedly an important strategy for minimising the spread of a virus, a more relevant and practical question is what is the minimum effective distance required, especially given the variation in the rule adopted in different countries.
Airborne transmission
The ease with which a virus can spread depends on the different routes of transmission. Clearly direct contact, for example, touching an infected individual can lead to infection but many infections are spread through droplet and airborne contact. Droplet infection occurs when the infected material is carried through the air inside the expelled mucosalivary droplets created after someone coughs, sneezes or talks and these subsequently enter the eyes, mouth or nose of another person. These droplets can also settle on surfaces, providing a further source of infection, referred to as fomite transmission. Fortunately, the relatively large size of mucosalivary droplets means that they can only travel through air for short distances such as 1-2m, a fact established in the 1930s.3 In contrast, as expelled droplets transition from the warm, moist environment of the lungs into the colder atmosphere, water evaporates from the droplets, leaving residual particulates, known as aerosols, which travel much further distances through the air and enter the body via the airways. Clearly then, infection becomes more likely when in close proximity to an infected individual. But how far can the coronavirus travel in the air? There is still uncertainty over this crucial point. Some studies have found evidence of viral RNA more than 2m from infected patients4 whereas other have found no virus 2 to 5m from infected patient’s beds.5 Early evidence from Wuhan, China suggested that the virus could be detected in air up to 4m from infected patients.6
With such uncertainty and a desire to reduce the social distance to the minimal level required for safety, a recent study published in the Lancet sought to provide some much-needed clarity on the person-person transmission of COVID-19.7 The authors analysed data from 172 observational studies and 44 comparative studies in both health-care and non-healthcare settings with a total of 25,697 patients. Due to a small number of studies with COVID-19, the authors combined data on the middle east respiratory syndrome (MERS), severe acute respiratory syndrome (SARS) with any COVID-19 studies. Their analysis revealed that when comparing distances of >1m vs <1m (that is, no social distancing), the risk of infection reduces from 12.8% to 2.6%, that is, keeping at least 1m apart reduces the risk of infection from approximately 13% to 3%.
The researchers also found that “for every 1m further away in distancing, the relative effect might increase by 2.02 times”. This provides crucial support for the current 2m social distancing rule in the UK. It suggests that by reducing this distance from 2m to 1m, the risk of infection would double. This latter point is reinforced in the paper when the authors state that “our current review supports the implementation of a policy of physical distancing of at least 1m and, if feasible, 2m or more”. The study also revealed that the use of masks reduced the risk of infection by 85% though this was only more effective in healthcare settings and that eye protection reduced the risk by 78%.
While the finding from the Lancet paper offer support for the current UK recommendation, it is important to recognise that the study had some limitations. For instance, the authors were unable to assess the effect of exposure duration since this factor varied considerably in studies up to an hour. Another limitation was that not all studies give precise distances and no study quantitatively evaluated whether distances of more than 2m were more effective.
In summary, and with no obvious end in sight for the current pandemic, governments around the world face the unenviable challenge of balancing the health and economic needs of their countries. While policy decisions are the responsibly of government, the current easing of lockdown measures is likely to make social distancing much harder to maintain in practice. In such circumstances, it would seem sensible, based on the conclusions of the Lancet study, to ensure that face and eye protection becomes mandatory, not just on public transport, but in all premises to help minimise the risk of infection.
References
This is according to early results from the Co-SPACE study, asking parents and carers about their children’s mental health through the COVID-19 crisis.
Over a one-month period in lockdown:
More than 10,000 parents have now taken part in the Co-SPACE (COVID-19 Supporting Parents, Adolescents, and Children in Epidemics) survey led by experts at the University of Oxford.
Parents/carers also reported that their children’s behaviour had got worse over time, with an increase in behaviours such as temper tantrums, arguments and children not doing what they are asked. Parents/carers in the survey also reported that their children showed greater levels of restlessness/fidgety behaviour and difficulties concentrating over the one month period.
Perhaps surprisingly, the same pattern was not seen in the older age group of 11-16 year olds. Teenagers themselves reported no change in their emotional difficulties between the two time points and their parents/carers reported that they felt that their child’s emotional difficulties had actually improved. Neither teenagers nor their parents reported any changes in their behaviour over this time but parents felt that their children were more restless and had more difficulty concentrating over time.
Tom Madders, Campaigns Director at YoungMinds, said, ‘This research suggests that many younger children have found it increasingly hard to cope as the lockdown period has gone on, which may be because of loneliness, fears about the coronavirus or a loss of the routines and support that come with school.
‘The picture appears to be more variable for older children in this study. Following the anxiety and uncertainty of going into lockdown, some are likely to have found the restrictions more difficult as time as gone on, while others – including those who feel safe and secure at home but who find school challenging – may have adapted well to their new reality. For those young people, going back to school after a long break may well be tough, and it’s vital that there’s a re-adjustment period where wellbeing is prioritised.
‘It’s also important to recognise that some of the most vulnerable young people in our society – including those who have experienced abuse, violence or neglect – are often the hardest to identify. We need to ensure that effective support is available for all children who need it now and as restrictions lift.’
Professor Cathy Creswell, Professor of Developmental Clinical Psychology, University of Oxford, and co-leading the study, said, ‘Prioritising the mental health of children and young people throughout the Covid-19 pandemic and beyond is critical. These findings highlight that there is wide variation in how children and young people have been affected, with some finding life easier but others experiencing more difficulties. Our findings have identified some sources of variation but we need to continue to gain a better understanding of which families are struggling and what they need to help direct the right advice and support going forward to ensure that this does not have long-lasting consequences.’
10th June 2020
Excessive exposure to UV radiation increases the risk of skin cancer which explains the importance attached to public health sun protection messages.
In a digital era in which millions of individuals possess a smartphone, could short message service (SMS) texting, which can reach a large audience and is relatively low-cost, provide an effective means for disseminating these messages?
Although a few clinical trials have explored the value of this method, its overall effectiveness has not been evaluated and so for this new study, a team from Peru conducted a systematic review of all available trials.
A total of five randomised trials were identified although a major problem was that the trials assessed different outcomes. Two trials examined “having a sunburn anytime during the follow-up” and this was taken as the primary outcome in the analysis.
The results showed that SMS messaging had no effect on the primary outcome and contradictory findings were obtained for sunscreen use and sun protection habits. In fact, two studies which personalised the SMS based on the health belief model, which effectively targets participant’s perception of the message, had little impact.
The authors noted that while their analysis showed no impact of SMS texting, the variable nature of the included studies precluded any meaningful assessment of the value of the intervention.
Reference
Chambergo-Michilot D et al. Text message reminders for improving sun protection habits: a systematic review. 2020 PloS ONE 2020;15(5):e0233220.
For example, in a cohort of 183 patients in Wuhan, non-survivors had significantly higher D-dimer, fibrin degradation products and longer prothrombin times.1 Furthermore, in that same study, 71% of the non-survivors met the diagnostic criteria for disseminated intravascular coagulation (DIC), a rare, but serious condition in which small blood clots develop throughout the bloodstream blocking vessels and in more serious cases precipitating multiple organ failure. Case reports have also identified clinically significant coagulopathy and antiphospholipid antibodies (which increases the risk of blood clots) in COVID-19 patients2 and in a further study of 94 patients with confirmed COVID-19 infection, those who tested positive had higher D-dimer, fibrin/fibrinogen degradation products and fibrinogen levels.3 Given that coagulopathy appears to be a complication of infection with COVID-19, is it possible that patients treated with systemic anticoagulants are less likely to experience more severe disease and have a greater chance of survival? Emerging data suggests that this might be the case although the evidence is far from clear-cut.
The link between the acute inflammation induced by a severe infection and activation of the coagulation system has been known for many years with damaged endothelial cells playing a key role in the orchestration of events. Several studies of viral infections such as influzena have revealed that dysfunctional coagulation is a common complication of severe influenza-induced pneumonia,4 indicating that the innate immune and haemostatic systems are intimately linked. This interrelationship was clearly illustrated in a study in which infection with streptococcus pyogenes led to a rapid entrapment and killing of the microorganism within a clot.5 In other words, recognition of an invading pathogen by the innate immune system was able to activate the coagulation system which then facilitated killing of the organism.
Viral infection of endothelial cells damages the cells and this leads to the production of pro-inflammatory cytokines which apart from having anti-viral properties, are also responsible for damage to the host. In fact studies of the H1N1 virus (‘swine flu”) demonstrated how it can lead to over-expression of pro-inflammatory cytokines producing what has become known as a “cytokine storm”.6 In addition, the damaged endothelial cells release the membrane-bound protein, tissue factor which subsequently activates the coagulation system.7 The clinical picture of virally-induced over-activity of the coagulation system presents with both haemorrhagic and thrombotic events and this has been observed in those with H1N1.8,9 Nevertheless, other pathogens, such as those responsible for urinary tract infections can also increase the risk of thrombotic events.10
Because a consequence of viral infections is activation of a hypercoagulatory state, it is theoretically possible that the use of anticoagulant therapy could attenuate this effect in patients with COVID-19 and some preliminary data offers support for this theory. In a study of 2,075 hospitalised Spanish patients who were positive for COVID-19, it was found that the use of heparin was associated with a significant reduction in mortality (adjusted hazard ratio, HR = 0.55).11 A further Chinese study of 449 patients found that the use of heparin for 7 or more days resulted in a lower 28-mortality in patients (40% vs 64.2%) among patients with sepsis-induced coagulopathy compared to those without the condition.12 However, the study did not find a difference in 28-day mortality between those with and without heparin, i.e., the reduced mortality was only apparent in the more severe cases and not necessarily directly related to heparin use. Finally, in a US study of 2,773 hospitalised COVID-19 patients, of those requiring mechanical ventilation (n = 395), mortality fell from 62.7% to 29.1% for those prescribed systemic anticoagulants.13
The problem in trying to establish a causal relationship between anticoagulant use and reduced mortality is confounded by the fact that unless contra-indicated, the majority of those hospitalised because of the virus, will receive low molecular weight heparins on admission for immobility. It therefore remains to be seen whether anticoagulant use offers any enhanced protection against the virus although such treatment will reduce chance of thromboembolic events which might also prove to be fatal.
References
5th June 2020
This was the question recently posed by researchers from the Department of Paediatrics, Alberta, Canada. In this pilot study, researchers recruited 51 parents who received a hard copy of the electronic medical record (EMR) from a paediatric outpatient pulmonologist clinic at the end of first visit to evaluate their child’s asthma.
The EMR is the letter routinely sent to the patient’s GP and includes a summary of the condition of the child, their medical history, examination results and treatment recommendations. After receiving the letter, the parents were asked to complete an evaluation questionnaire, which asked about their perceptions of the letter, its accuracy and questions which asked about how helpful they found the EMR.
In total, over 90% of parents agreed that the EMR was an accurate summary of their consultation and more than 80% felt that the content helped them to understand more about their child’s condition and the different tests and examinations. There was also a strong perception that parents felt more in control of their child’s health and that the letter increased their perceived ability to take care of their child.
An interesting final statistic was how 98% wanted to receive similar letters from other specialist highlighting the value of such communication.
Reference
Amirav I et al. An asthma specialist’s consult letter: what do parents think about receiving a copy? J Asthma Allergy 2020;13:179-86.
A team from McMaster University in Ontario, Canada, followed 202,072 individuals in 27 countries, aged between 35 and 70 from urban and rural communities for a median of 9.5 years. The researchers systematically examined the differences in risk factors, treatments, cardiovascular disease incidence and mortality among people from high-income, middle-income and low-income countries. Using two different cardiovascular risk factor scoring systems (INTERHEART and Framingham), women had a lower cardiovascular risk burden and primary prevention strategies such as healthy lifestyle behaviours and medicine use were more common in women.
This resulted in a lower incidence of cardiovascular disease in women compared to men (4.1% vs 6.4%) as well as all-cause mortality (4.5% vs 7.4%). Interestingly, however, secondary prevention treatments such as cardiac investigations and coronary revascularisations were less frequent in women among those with existing cardiovascular disease. Despite this lower level of secondary prevention interventions, women still had a lower incidence of recurrent cardiovascular events than men (20% vs 27.7%) and a significantly lower 30-mortality after such events (22% vs 28%) and the authors were unable to account for these differences.
Nevertheless, an important finding was that there were larger gaps in disease management and outcomes in both women and men in poorer compared with richer countries.
Reference
Walli-Attaei M et al. Variations between women and men in risk factors, treatments, cardiovascular disease incidence, and death in 27 high-income, middle-income, and low-income countries (PURE): a prospective cohort study. Lancet 2020;May 20.
In a new study, researchers from the department of epidemiology at the Sacker Faculty of Medicine, Tel Aviv, Israel, suggest that even low levels of PA have a beneficial effect in the primary prevention of cancer.
The team recruited a group of 1542 older adults (mean age 73 years) who were initially free of cancer and followed them for an average of nine years. Leisure-time PA was self-reported via personal interviews based on two questionnaires; one enquired about vigorous PA whereas the other addressed any form of PA which lasted at least 10 minutes, for instance, walking outdoors, jogging, swimming cycling etc. Based on their answered participants were categorised as “sufficiently active’, insufficiently active” or “inactive”.
There were a total of 254 new cancers during the nine-year follow-up period and leisure-time PA was inversely related to cancer incidence with adjusted hazard ratios of 0.66 and 0.59, for the insufficiently active and sufficiently active groups compared to the inactive group.
In other words, even among those who were deemed not sufficiently active, there was still a reduced risk of cancer compared to those who were inactive which highlights the importance of PA as individuals age.
Reference
Cohen G et al. Leisure-time physical activity and cancer risk among older adults: a cohort study Mayo Clin Proc Inn Qual Out 2020;4(2):115-25.
29th May 2020
In a Lancet study, researchers from Harvard Medical School performed an extensive analysis of real-world evidence for the effectiveness of both hydroxychloroquine (HCQ) or chloroquine (CQ) in patients with COVID-19. The international observational registry included data on patients with a positive test for COVID-19 who were hospitalised from 671 hospitals across six continents.
Researchers identified 96,032 patients of whom, 14,888 had been treated with either HCQ and CQ alone or each drug in combination with a macrolide antibiotic within the first 48 hours after diagnosis. Patients who did not receive either of these drugs were considered as the control group. The main outcome outcomes of interest were in-hospital mortality and the occurrence of de novo ventricular arrhythmias. After adjustment for confounding factors such as age, sex, ethnicity, body mass index and various underlying health conditions (for example, cardiovascular disease, diabetes, lung disease etc), in-hospital mortality rates were 9.3% (control group), 18% HCQ, 23.8% HCQ and macrolide, 16.4% CQ and 22.2% CQ and macrolide. In addition each drug regime was associated with an increased risk of de novo ventricular arrhythmias compared with the control group.
In light of these findings, the World Health Organization has temporarily halted clinical trials of hydroxychloroquine for COVID-19.
Reference
Mehra MR et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 2020; May 22.
It will test a drug that could raise oxygen levels in the blood in COVID-19 patients in order to improve their chances of recovery. Raising oxygen levels is important in COVID-19, because many patients with the disease die when oxygen levels in their arterial blood fall to levels that are too low to support life.
Currently, supportive therapy for COVID-19 in hospitals aims to keep oxygen levels sufficiently high with treatments such as supplementary oxygen or by using ventilators to artificially support the body’s breathing process. In normal circumstances, if the oxygen becomes too low in a part of the lung, the blood vessels in that part constrict to redirect the blood flow to other regions of the lung where the oxygen is higher. In COVID-19 patients, however, the Oxford University researchers hypothesise that this mechanism is not working properly. Consequently, the blood flow is going to the most diseased and non-functioning parts of the lung where the oxygen is low, and is not getting diverted to the healthier parts of the lung where the oxygen is higher. This means that too much blood flows through the lungs without picking up oxygen.
The research team aims to address this problem by preferentially constricting the blood vessels going through the diseased parts of the lung, thereby redirecting the blood towards the healthy parts where it can pick up oxygen. To do this, they will use an old drug first developed in France called almitrine bismesylate, which is known in the scientific community to have this effect when treating acute respiratory distress syndrome (ARDS). The drug acts to increase the sensitivity of the acute oxygen sensing mechanisms of the body. According to Lead Researcher Professor Peter Robbins: “We know that almitrine can increase oxygen levels in patients with acute respiratory distress syndrome by constricting the blood vessels in regions of the lung where the oxygen is low. We want to see if almitrine will also have this effect in COVID-19 patients.”
The team will work with the UK pharmaceutical industry to produce almitrine for clinical use and will run a trial of the drug in selected UK locations. The trial will be split into two phases. Phase A is to administer one oral dose of the drug to patients needing respiratory support to ascertain whether it is successful in increasing oxygen levels in the arterial blood. Phase B aims to administer the drug to patients for a seven-day period to ascertain whether it reduces the amount of other respiratory support the patient needs. Professor Robbins said: “If almitrine can add to the overall effectiveness of respiratory support, then the hope is that clinicians will need to mechanically ventilate fewer patients, and that they will be able successfully to support more seriously ill patients throughout the course of their illness.”
“People can recover from COVID-19 in the same way that they recover from other viral illnesses. That’s by fighting off the virus with the body’s normal defence mechanisms. But if the lung becomes so damaged that blood just doesn’t pick up enough oxygen, then the body never gets the chance to finish the job and the patient dies from the low level of oxygen. So, what we are really trying to do with supportive therapy is help the patient to continue to function whilst their body fights off the infection in the normal way.”
The trial is a close collaboration between academic staff located across different departments at Oxford University and NHS hospital consultants. The researchers include Professor Peter Robbins and Professor Keith Dorrington at the Department of Physiology, Anatomy and Genetics, Professor Najib Rahman at the Nuffield Department of Medicine,
Professor Chris Schofield at the Department of Chemistry, Dr Stuart McKechnie and Dr Matthew Rowland (Kadoorie Centre for Critical Care Research), Dr Nayia Petousi and Dr Nick Talbot (Respiratory Medicine) at Oxford University Hospitals’ John Radcliffe Hospital, Dr Matthew Frise at the Royal Berkshire Hospital in Reading, and Dr Matthew Wise at the University Hospital of Wales in Cardiff.
The almitrine will take three months to manufacture. Once the almitrine becomes available, it is anticipated that phase A of the study will take one month to complete, and phase B will take four months to complete. The results should become available one month after completion of the last patient.
This study is being supported by a grant from the medical research charity LifeArc, as part of its activities to address the need for new therapies for COVID-19. LifeArc has made £10m available to repurpose existing medicines or those in the late stage of development as this approach offers one of the fastest routes to develop new treatments that could tackle the virus and its impact.
In the global race to create a vaccine, Chinese researchers from the Beijing Institute of Biotechnology have reported positive results from the first-in-human trial of a recombinant adenovirus type-5 vectored vaccine for COVID-19.
The vaccine which expresses the spike glycoprotein of COVID-19 was administered to 108 healthy adults with an age range of 18 to 60 years (mean age 36). Patients were split into three groups and received one of three different intramuscular doses. The primary outcome for the study was adverse events in the 7 days after vaccination and safety was assessed after 28 days. The results showed that neutralising antibodies were generated against COVID-19 after 14 days and peaked after 28 days. The higher dose was the most effective at generating antibodies and in total 81% of patients experienced adverse effects although there were no differences between in the incidence of these effects between the groups. Typically, patients experienced pain at the injection site, fever, headache, fatigue and muscle pain which were mild to moderate in severity and occurred after 24 hours but had resolved by 48 hours.
The authors concluded that while the study included only a small number of patients, it did reveal that the vaccine was both effective and well-tolerated. An ongoing Phase II trial is planned to provide further information on the safety and immunogenicity of the vaccine.
Reference
Zhu FC et al. Safety, tolerability and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose escalation open label, non-randomised, first-in-human trial. Lancet 2020; May 22 doi.org/10.1016/ S0140-6736(20)31208-3.