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28th April 2020
In addition, several reports have indicated that there is a theoretical increased risk of worse outcomes in patients with hypertension prescribed angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) if they become infected with COVID-19.2,3
Under normal circumstances, angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, which is a potent vasoconstrictor and this effect is blocked by ACEis whereas, ARBs, block the action of angiotensin II. Studies have shown that a related form of ACE, angiotensin converting enzyme 2 (ACE2) acts to oppose the actions of ACE by breaking down angiotensin II. ACE2 is present in several different tissues in the body and appears to have a protective role, improving the symptoms of acute lung injury that result from viral infection.4
In 2005 researchers discovered that the severe acute respiratory syndrome (SARS) virus, which is related to COVID-19, utilised ACE2 on alveolar epithelial cell membranes, to gain entry to cells and subsequently replicate and that SARS also downregulated ACE2.5 The recent concerns over ACEis and ARBs have arisen out of work which showed that intravenous infusion of both types of antihypertensive, lead to an increase the amount of ACE,2,6 raising the possibility that patients prescribed either of these types of drugs could experience worse outcomes if infected with COVID-19.
In an effort to address these potential concerns, a recent retrospective analysis published in JAMA Cardiology has observed that these theoretical risks in those prescribed either ACEi or ARBs are unfounded.7 The study reviewed 1178 patients hospitalised with COVID-19 infection, of which, 362 (30.7%) were prescribed antihypertensives. In total, 189 (52.2%) of these patients were prescribed either an ACEi or ARBs. Compared to those not taking an ACEi/ARB, there were no differences in the laboratory profiles, apart from a higher alkaline phosphatase level in those NOT taking ACEi/ARBs. When the authors compared both disease severity and survival, there were no significant differences between patients taking either ACEi or ARBs and those not prescribed these drugs. For example, in terms of survival, the composite of ACEi/ARBs versus those without these drugs, was 27.3% vs 33.0%, p = 0.34. The authors also explored whether there were differences in outcomes based on comorbidities between those taking ACEi/ARBs and those without and again found no difference. They concluded that it was hypertension per se which remains an important factor increasing the risk of mortality rather than the type of antihypertensive used.
In light of the reported risks in the media from taking either ACEi or ARBs, the European Society of Cardiology released a statement on 13 March, prior to the most recent publication, stating that there is a lack of evidence supporting harmful effect from ACEi or ARBs in the context of the pandemic COVID-19 outbreak.8 Finally, a report from the UK found that of 205 patients with COVID-19, 53 died. While based on a small sample size, the authors found that for patients receiving ACEi, there was a lower risk of death.9
In summary, it seems that the theoretical risk that treatment with either an ACEi or ARB by increasing ACE2, could potentially worsen infection with COVID-19, the available evidence does not support this risk. Patients should be advised to continue with their treatment unless otherwise advised by their doctor.
References
27th April 2020
A joint project between Edith Cowan University (ECU) in Australia and CSIRO has revealed key insights about the proteins causing two of the most common types of wheat sensitivity – non-coeliac wheat sensitivity and occupational asthma (baker’s asthma).
With an estimated 10% of people suffering from wheat sensitivity or allergy causing a raft of chronic health issues, researchers are developing tests that will help the production of low-allergen wheat varieties in the future.
ECU Professor of Food and Agriculture Michelle Colgrave led the investigation.
“We have known for a long time that certain wheat proteins can trigger an immune response in some people, but now we have developed a way to detect and quantify these proteins,” Professor Colgrave said.
“We looked a group of proteins called alpha-amylase/trypsin inhibitors (ATIs), which are known to trigger the intestinal inflammation and chronic ailments associated with wheat intolerance in some people.
“These ATI proteins are commonly found in wheat and play an important role in plant defence against pests and also act as an important nutrient for plant growth and human nutrition.”
The research has resulted in a reference map of wheat ATI proteins across a diverse range of wheat varieties that represent more than 80% of the genetic diversity found in commercial bread wheats.
The researchers developed an innovative new technique to specifically measure 18 of these proteins, which will help breeders to select varieties with low ATI protein levels in the future or food manufacturers to detect these proteins in food.
“This is a promising step towards future wheat breeding programs that aim to produce safe and healthy wheat varieties to meet the needs of consumers that currently rely on total wheat avoidance,” Professor Colgrave said.
A new study published in Nature Communications suggests that a species of beetle could help control an invasive and highly allergenic weed at the root of many people’s allergies.
Allergies caused by the common ragweed, Ambrosia artemisiifolia, impact millions, and in Europe alone, around 13.5 million people suffer with symptoms, resulting in 7.4 billion Euros worth of health costs per year, according to the research. The study suggests the leaf beetle, Ophraella communa, could reduce the number of people affected by the pollen and the associated economic impacts, since the beetle – itself a recent arrival in Europe – loves to munch on the invasive plant.
Using data from the European Pollen Monitoring Programme, a team of researchers including co-first authors Sandro Steinbach of UConn’s Agricultural and Resource Economics Department and Urs Schaffner of the Centre for Agriculture and Bioscience International, mapped seasonal total ragweed pollen in Europe from 2004-2012. They then determined ragweed sensitization rates in the European population to estimate the number of allergy sufferers.
They estimate that 13.5 million people were affected by seasonal ragweed pollen allergies, with economic costs of approximately 7.4 billion Euros per year, including factors such as medical costs and work absences. These numbers are prior to the unintended arrival of O. communa in Europe in 2013.
By modelling the number of generations of the beetle across its suitable habitat range in Europe, the authors project that biological control of common ragweed could reduce the number of people suffering from the ragweed allergy to approximately 11.2 million, and bring the health costs down to 6.4 billion Euros per year.
“Our conservative estimates indicate that biological control of A. artemisiifolia by O. communa will reduce the number of patients by approximately 2.3 million and the health costs by Euro 1.1 billion per year,” says Steinback. “Future costs of this management approach will be basically zero since the beetle has established permanently and is propagating by itself.”
Though this research is specific for Europe, this method of biological control is already happening in China where the beetle is reared and distributed for the control of ragweed. Fortunately, the authors note that previous studies suggest the beetle would have no negative impacts on native or ornamental plants in Europe, so this form of biological control may have no unintended consequences on the local landscape.
This research also underscores the need for more work to be done on the human health impact of invasive alien species, since the benefits of management strategies are likely greatly undervalued, as shown by the authors’ estimated public health costs being higher than previously reported.
Schaffner says another aspect the team is currently looking into is how climate change will affect the distribution of the weed and the beetle and whether the beetle’s impact on pollen production by A. artemisiifolia will increase or decrease in the future.
Lung diseases such as asthma are a major global health burden, with an estimated 330 million asthma sufferers worldwide. The most effective treatments are through direct inhalation of medicine to the lungs. However, generating the aerosols for inhalation is a scientific challenge because of our limited knowledge of the microstructure of drug products before they are aerosolised.
University of Manchester-based scientists have demonstrated how they have used X-ray CT scanning to quantify the tiny microstructures of individual particles from the drug product at the nano-scale.
This is the first time that the 3D microstructure has been revealed and gives scientists and pharmaceutical producers a better understanding of the behaviour of the drug product under aerosolisation.
Lead author of the research, Dr Parmesh Gajjar said: “We have been able to visualise a drug-blend in 3D, and see the interplay between drug and non-drug particles in the medicine. This is important for final quality control of asthma medicines to check the actual amount of drug and to help formulate improved asthma medications.”
Due to the new technological innovation the findings was initially announced at the Respiratory Drug Delivery (RDD) 2020 conference. The group’s work was selected to be a key presentation at the global conference, originally scheduled to take place in Palm Springs but now occurring in a digital format as a result of the global COVID19 pandemic.
The work was made possible through the high-resolution x-ray computed tomography (XCT) instruments in the word leading Henry Moseley X-ray Imaging Facility (HMXIF) at The University of Manchester that provide the capability to analyse a sample at up to 50 nanometres in resolution.
This is particularly important for the inhalation medicines which require aerosolisation to generate particles small enough to be adsorb via the lungs. In this project the particles measured less than 5µm to reach the deepest parts of the lungs.
24th April 2020
The INTERCOVID study will provide women, families, health care providers and policy makers with high-quality evidence regarding the effects of COVID-19 in pregnancy on the health of the mother, foetus and newborn.
The information is needed quickly and at scale to optimise pregnancy care, reduce maternal anxiety, inform decision-making about the allocation of resources, and guide the process toward social adaptation. Although it is generally believed that pregnant women with COVID-19 are at similar risk to the general population, there is limited data available, principally from small studies without controls, which cannot answer fundamental questions relating to the effects of the disease on maternal and neonatal outcomes.
The researchers will be recruiting women who have been exposed and not-exposed to SARS-CoV-2 at any stage of pregnancy, and following them and their newborns until hospital discharge to quantify the risks associated with the exposure. Exposed pregnant women are defined as having:
a) laboratory confirmed COVID-19;
b) radiological findings suggestive of COVID-19;
c) symptoms compatible with COVID-19 according to a predefined list, or;
d) no symptoms, whilst in close interaction with a person(s) with confirmed COVID-19 infection (a proxy for asymptomatic cases, one of the main problems in controlling the pandemic).
For every exposed pregnant woman, two not-exposed pregnant women will be recruited as representative of the general population.
Professor José Villar of the University’s Nuffield Department of Women’s & Reproductive Health, (NDWRH) who is leading the research, said: ‘This large study benefits from the University having hosted, over the last 12 years, a network of researchers across the world who have participated in the INTERGROWTH-21st Project, which has produced new international standards for monitoring growth and development from early pregnancy to 2 years of age.
‘As a result, we have in place trained research staff and standardised data collection forms focused on outcomes, such as preterm birth and neonatal morbidity. All the work is done via an online data collection system that provide information almost in real-time. For the present study, we have simply expanded to include COVID-19, which explains why we are able to start immediately’.
Professor Aris Papageorghiou (NDWRH), who is jointly leading the research, said: ‘The response from colleagues around the world has been truly remarkable. Already over 60 medical institutions in 29 countries have agreed to participate, which means the study should have sufficient power to provide invaluable answers, in a short time period, regarding the risks to pregnant women who are exposed to SARS-CoV-2. However, we welcome additional institutions who would like to join this important study’.
Professor Stephen Kennedy (NDWRH), who is jointly leading the research, said: ‘The translational value of the INTERCOVID Study is that we will be collecting invaluable baseline outcome data, as recommended by the Pregnancy Research Ethics for Vaccines, Epidemics and New Technologies (PREVENT) Report to inform risk-benefit analyses for future vaccine trials in pregnant women by providing “potential risk relationships between vaccination and adverse events”. Failure to obtain that information runs the risk of pregnant women being denied priority access to a new vaccine or therapy, as has occurred so many times in the past.’
Patient communication
NG171 emphasises the importance of communicating with patients, their families or carers to support their mental wellbeing during the COVID-19 pandemic and signposts them to the UK government guidance on mental health and wellbeing aspects of COVID-19. NG171 also signposts those with newly diagnosed myocardial injury to various relevant charities including the British Heart Foundation, Pumping Marvellous Foundation, Arrhythmia Alliance, Atrial Fibrillation Association and Cardiomyopathy UK, all of which have current and relevant patient information on COVID-19. NG171 recommends that health professionals should also provide patients, families and carers with information that meets their communication needs as described in NHS England’s’ Accessibility information standard.
Minimising patient and healthcare worker risks
Where patients are either known or suspected of having COVID-19, all healthcare staff involved in any aspects of patient contact, which includes receiving, assess and caring for patients are advised by NG171 to follow the UK government guidance on infection prevention and control. However, in cases where COVID-19 is diagnosed at a later stage and the patient was not initially isolated, NG171 advises staff to follow the government guidance on management of exposed healthcare workers in patients in hospital.
Diagnosis of acute myocardial injury in patients with suspected or confirmed COVID-19
NG171 alerts UK health professionals to the fact that evidence from Italy found that 9.5% of those dying with COVID-19 had acute myocardial injury or its complications. Moreover, these symptoms were similar to the respiratory complications of COVID-19 and could develop at any stage of infection.
NG171 defines potential acute myocardial injuries in those with COVID-19 which include:
• Acute coronary syndrome/arrhythmias/cardiac arrest
• Cardiogenic shock
• Cardiomyopathy
• Heart failure
• Myocarditis
• Pericarditis and pericardial effusion
NG171 defines the symptoms of acute myocardial injury in patients with COVID-19 which include:
Diagnostic tests
Health professionals are advised by NG171 that in patients who display and signs or symptoms of acute myocardial injury, it is important to measure high sensitivity troponin I (hs-cTnl) or T (hs-cTnT) or NT-proBNP and to perform an EGC.
These tests can help inform a diagnosis, in particular:
NG171 also advises that clinicians need to be aware that elevated troponin levels may actually reflect a cardiac inflammatory response to severe illness rather than acute coronary syndrome and that all information should be viewed within the clinical context of the patient.
Managing myocardial injury in those with suspected or known COVID-19 infection
It is advised in NG171 that all patients with a suspected or confirmed acute myocardial injury should be monitored in a setting that allows for any cardiac and respiratory deterioration to be rapidly identified. In addition, continuous ECG monitoring should be undertaken as well as regular blood pressure, heart rate and fluid balance checks.
NG171 recommends that where there is a clear diagnosis of myocardial injury, health professionals obtain specialist cardiology advice on treatment, any further relevant tests or imaging and to follow local treatment protocols.
In cases where there is a high suspicion of myocardial injury but no clear diagnosis, NG171 advises health professionals to repeat high sensitivity troponin and daily ECGs which may help to establish a clear diagnosis. NG171 suggests that staff seek specialist cardiology advice on the need for any further investigations to assist in the diagnosis such as transthoracic echocardiography.
NG171 also notes how drugs such as azithromycin and hydroxychloroquine, which have been used in some cases to treat COVID-19, can prolong the QTc interval.
NG171 stresses the importance of keeping patients, the families and carers fully involved and to discuss all of the possible risks and benefits from the different treatment options to enable them to make an informed decision about any treatment.
If patients require critical care, NG171 suggests that clinicians have a clear treatment plan in place which addresses how the proposed treatment will lead to agreed outcomes and whether the plan and the outcomes are clinically realistic. Guidance on such decision-making is available from the British Medical Association and the Royal College of Physicians.
Finally, NG171 suggests that clinicians stop critical care treatment in cases where it becomes apparent that the desired outcomes are no longer achievable. Any such decisions should be fully recorded and discussed with the patient, family or carers.
NG171 is available online and interested readers should check this version for further updates.
23rd April 2020
The vaccine has been in development since January 2020 and is based on a chimpanzee adenovirus vector (ChAdOx1) which is a weakened version of the adenovirus that causes the common cold. Previous work has shown how chimpanzee adenoviruses can generate a strong immune response from a single vaccination. The adenovirus has genes added to make the spike proteins that are present on the outer surface of COVID-19. After vaccination, the spiked proteins are produced in the host which primes the body’s immune system to attack the virus if encountered at a later date. The vaccine is non-replicating and does not lead to infection and is suitable for use in adults, children, the elderly and patients with a pre-existing chronic condition such as diabetes.
The current trial will recruit 1112 healthy volunteers (aged 18 to 55 years) who will receive either the test vaccine or a control vaccine but will be blinded to their treatment allocation. Participants will be assessed at eight visits over a period of six months.
While at this stage the results of the trial are unknown, production of the vaccine is being scaled up for larger trials and possible deployment if successful.
Further information can be found on the trial the website (https://covid19vaccinetrial.co.uk/about).
22nd April 2020
One strategy attracting much interest in the media is the importance of achieving sufficient vitamin D levels, and the topic has also been the subject of recent academic articles.1,2 While both articles discuss the potential role of vitamin D in the immune system, they also highlight the lack of direct clinical studies in those with COVID-19. However, a recent research letter3 provides some tentative evidence of the impact of vitamin D status on the severity of COVID-19 symptoms.
Vitamin D3 is produced by the action of UVB radiation on 7- dehydrocholesterol present in the skin. This only occurs in the Northern hemisphere between April and September as the sun is too low during the winter months. Vitamin D3 is subsequently converted to 25-hydroxyvitamin D (25(OH)D) and finally in the kidneys to 1,25(OH)2D (calcitriol). Although calcitriol is the active metabolite, it is the level of 25(OH)D which is measured and used to monitor vitamin D status. The possible beneficial effects of vitamin D on COVID-19 are likely mediated through its multiple actions on the immune system.1 For instance, vitamin D enhances the production of various peptides by the innate immune system, which possess anti-microbial, anti-fungal and anti-viral activity. In addition, and in response to microbial or viral infections, the innate immune system generates several pro-inflammatory cytokines including tumour necrosis factor alpha and interferon γ. Vitamin D has been shown to not only reduce the production of these pro-inflammatory cytokines but to increase the expression of anti-inflammatory cytokines by macrophages. This may be of value given the proinflammatory cytokine milieu observed in those infected with COVID-194 and how this “cytokine storm” leads to acute respiratory distress syndrome.5
In light of the possible immune-enhancing effects, a recent retrospective analysis was undertaken of vitamin D status in patients with confirmed COVID-19 infection.3 Using a database from three hospitals in Southern Asian countries, the author categorised 212 cases of COVID-19 infections as mild, ordinary, severe and critical and matched these to 25(OH)D status. Normal was defined as 25(OH)D > 30ng/ml, insufficient, 21–29ng/ml and deficient as <20ng/ml. The analysis revealed that for those with mild infection, mean 25(OH)D levels were 31.2ng/ml, ordinary, 27.4 ng/ml, severe, 21.2ng/ml and critical the lowest at 17.1ng/ml. These differences were found to be statistically significant and hint at the possibly that patients with higher levels of 25(OH)D have less severe symptoms. Though an interesting observation, is any there other data to support the relationship between vitamin D levels and viral respiratory infections? Prior to COVID-19, several meta-analyses have explored the potential role of vitamin D in acute respiratory infections and the World Health Organization (WHO) offered a summary of these in 2017.6 They noted how results were inconsistent with significant heterogeneity in terms of the patients included, vitamin D regimes and baseline levels, making the generalisability of the findings more difficult. WHO suggested that future trials should explore whether the benefits are achieved once vitamin D status is satisfactory.
One group who are likely to benefit from supplementing with vitamin D are those with darker or black skin who probably obtain insufficient sun exposure. Recently, a trial in 260 black American women compared the effect of maintained and adequate 25(OH)D levels (>30ng/ml) from supplementation vs placebo on the incidence of acute respiratory infections (ARI) over a 3-year period and found no difference between the groups.7 These results were consistent with an earlier study conducted by the same group in which patients were given either 50mcg/day vitamin D or placebo for 12 weeks during the winter months. Although at baseline, both groups had vitamin D levels within the normal range, supplementation had no effect on the incidence of upper respiratory tract infections.8
In summary, while vitamin D is known to have immune-enhancing properties, in the absence of clinical studies, the value of either supplementing or maintaining adequate vitamin D levels to reduce the symptom burden in those with COVID-19 infection remain unclear. Nevertheless, based on the latest analysis,3 it would seem eminently sensible for clinicians to ensure that those infected with COVID-19 have adequate vitamin D levels because this may lessen the effects of the virus and possibly save more lives.
References
21st April 2020
But were these messages communicated effectively amongst the most vulnerable?
In this new US study, a telephone survey was conducted among high-risk, older adults with one or more chronic conditions to gauge their current understanding of several aspects of the pandemic including their perception of the seriousness of the threat, level of worry and concern over catching the virus.
Overall, 630 people responded to the survey with only a quarter (24.6%) being “very worried” about getting the virus. Perhaps more concerning was how 28% could not correctly identify symptoms or ways to prevent infection (30.2%) with one in four (24.6%) believing that they were “not at all likely” to get the virus. In multivariate analysis it was found that those who were black, living below the poverty line and with low health literacy were more likely to be less worried about the virus.
Although this was limited to participants in a single city, it paints a worrying picture of how those at most risk lacked sufficient understanding or knowledge of the potentially gravity of the pandemic but more importantly, how to protect themselves.
Reference
Wolf MS et al. Awareness, attitudes and actions related to COVID-19 among adults with chronic conditions at the onset of the US outbreak: a cross-sectional survery. Ann Intern Med 2020; Apr 9: M20-1239 [online ahead of print]
As a result, the National Institute for Health and Care Excellence (NICE) was asked to review and report on the evidence to determine whether:
• there is an increased risk of developing COVID-19 through acute use of NSAIDs
• acute use might increase the risk of developing more severe COVID-19 symptoms.
Prostaglandins are a group of lipids that have a key role in mediating pain, fever, inflammation, swelling and gastric protection. NSAIDs are drugs which inhibit the enzymes COX-1 and COX-2 involved in the production of prostaglandins. One of the most commonly used NSAIDs is ibuprofen which has been available over-the-counter since the early 1980s and is currently used to manage acute pain and fever in both adults and children. However, a study in 2007 found an increased risk of severe skin and soft tissue complications in children with varicella infections prescribed NSAIDs. This led to the recommendation in clinical knowledge summaries to avoid the use of ibuprofen in people with varicella infections such as chicken pox and shingles.
Although the data on NSAIDs related to varicella infections, it was reported in the BMJ that a French doctor reportedly commented on how four young and otherwise healthy patients with COVID-19, developed more serious symptoms after ingestion of NSAIDs. In the same BMJ piece, UK experts suggested that NSAID-induced worsening of symptoms was plausible given how the drugs “dampen down” the immune system and would therefore slow the recovery process in a COVID-19 infected person. Following this report, the French Health Ministry issued advice to avoid using NSAIDs to treat COVID-19 patients. In the UK, the MHRA issued a CAS alert in which paracetamol was suggested as the preferred analgesic in preference to ibuprofen in those with suspected or confirmed COVID-19 infections despite a lack of hard evidence that NSAIDs were actually harmful.
Evidence review
In addition to the two above questions, this evidence summary (ES23) also sought to determine if there were any subgroups of patients taking NSAIDs acutely who might be at a greater risk of developing COVID-19 or at a greater risk of developing a more serious illness due to COVID-19. ES23 made it clear that the review did NOT consider patients taking NSAIDs long-term for existing chronic conditions.
Results
A review of the available evidence failed to identify any relevant published data to address the primary research questions, that is, that acute use of NSAIDs increased the risk of developing COVID-19 or that acute NSAID use increased the risk of developing more severe symptoms of COVID-19.
The original advice to avoid NSAID use in COVID-19 from the French Health Ministry was based on a national pharmacovigilance evaluation in 2018 of ibuprofen and ketoprofen which found 337 cases of serious infectious complications in otherwise healthy children or adults using ibuprofen for the management of a range of conditions including fever, insect bites but also respiratory problems such as cough and pulmonary infections. However, despite this evaluation, the potential for ibuprofen to rarely cause serious skin reactions is well known and documented in the summary of product characteristics.
On 18 March 2020, the European Medicines Agency issued a press release stating that there is “no scientific evidence establishing a link between ibuprofen and worsening of COVID-19.”
ES23 makes reference to a CEBM review of NSAID use in acute respiratory infections. The review found that NSAIDs were associated with worsening outcomes in acute respiratory infections but as the authors note, sine their data were based on observational studies, it was difficult to interpret fully. In other words, NSAID use may be associated with worsening respiratory symptoms rather than a direct cause and because of this, the CEBM reviewed concluded that NSAIDs do not significantly reduce total symptoms or duration of respiratory infections. ES23 cites a further CEBM review that considered whether suppressing fever in acute respiratory infections affected outcomes, concluding that it had no impact.
Conclusions
ES23 concluded that at the present time, the decision to use NSAIDs for the management of symptoms associated with COVID-19 infections should be based on an extrapolation of the existing data from studies exploring the use of these drugs in other acute respiratory tract infections. Nevertheless and based on the currently available evidence, the ES23 review suggests that although NSAIDs may reduce acute symptoms such as fever, they either have no effect on, or worsen, long-term outcomes, possibly by masking symptoms of a deteriorating acute respiratory infection. The guideline adds that further evidence is required to confirm these initial findings and whether or not the findings are directly applicable to infection with COVID-19.
The full evidence summary is available online and interested readers should consult this for any further relevant updates.
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