Caenorhabditis elegans is a type of tiny soil-dwelling worm, found to accept certain human genes into their own genome . These ‘humanised’ worms are a very useful tool to study human disease, with researchers at the University of Liverpool now using them to study human epilepsy and discover new anti-epileptic drugs  .
What is epilepsy?
Epilepsy is one of the most common conditions affecting the brain, shaping the lives of an estimated 50 million people worldwide . In the UK alone, there are an estimated 600,000 epilepsy patients, which is almost 1 in every 100 people, with 87 people diagnosed every day . There are a lot of different causes of epilepsy, and it can affect people of all ages .
Those with epilepsy suffer from recurrent seizures, which is caused by sudden bursts of electrical activity within the brain. The most well-known seizure type affects movement, causing muscle jerking, twitching, and/or weakness. Lesser known seizures affect the person’s awareness to their surroundings and can cause changes in sensation or emotion .
Currently, there are over 20 anti-epileptic drugs available with many different drug targets . These drugs try to stop the sudden uncontrolled bursts of electrical activity within the brain. However, these anti-epileptic drugs do not work for one third of patients, named ‘refractory epilepsy’, with the reason for this not fully understood . Therefore, new drugs are desperately needed for those patients with refractory epilepsy.
Why worms for drug development?
Making new drugs is controversial as testing on mammals, like mice and primates, has many ethical and financial issues. As these worms are invertebrates, less complex animals, they do not require extensive ethical training for use . Also, these worms have a short reproduction time (~3 days) and lifespan (~3 weeks) and do not need expensive equipment take care of them, making them a much cheaper alternative . Therefore, it is beneficial to test new drugs on less complex animals first, and then move onto more complex animals later in the drug development process. However, it is hard to justify using tiny soil-dwelling worms to test drugs for humans when we are so different .
Humanising the worm
To tackle this, researchers led by Professor Alan Morgan at the University of Liverpool have created humanised worms to study severe forms of epilepsy, such as Ohtahara syndrome . This was achieved, in part, using the highly specialised gene editing process CRIPSR-Cas9 and which is used to insert, delete, or substitute target genes, to fix or introduce gene mutations .
GABA is a neurotransmitter (a biological chemical) which can prevent sudden electrical activity in the human brain. Studies by multiple different research teams have found GABA mutations (more specifically GABAA receptors) in patients with a spectrum of epileptic encephalopathies, such as Lennox-Gastaut syndrome and West syndrome .
In this project we aim to introduce mutated human GABAA receptor genes found in epilepsy patients into worms. We will then induce seizures in the worms and test a range of new anti-seizure drugs to see which compounds are most effective. Therefore, we will be able to assess the effect the new anti-seizure drugs may have in humans with the same genetic mutations.
Using these humanised worms as a first step in drug development is beneficial as it gives researchers the opportunity to fast-track the selection process, whittling down large numbers of drug candidates to a select few in a short space of time .
1. Zhu, B., et al., Functional analysis of epilepsy-associated variants in STXBP1/Munc18-1 using humanized Caenorhabditis elegans. Epilepsia, 2020. 61(4): p. 810-821.
2. Wong, S.Q., et al., A Caenorhabditis elegans assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action. J Neurosci Methods, 2018. 309: p. 132-142.
3. Organization, W.H., Epilepsy: a public health imperative. 2019: World Health Organization,.
7. Loscher, W., et al., New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov, 2013. 12(10): p. 757-76.
8. Kwan, P. and M.J. Brodie, Early identification of refractory epilepsy. N Engl J Med, 2000. 342(5): p. 314-9.
9. Cunliffe, V.T., et al., Epilepsy research methods update: Understanding the causes of epileptic seizures and identifying new treatments using non-mammalian model organisms. Seizure, 2015. 24: p. 44-51.
10. Chen, X., et al., Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases. Chem Cent J, 2015. 9: p. 65.
11. Zhang, F., Y. Wen, and X. Guo, CRISPR/Cas9 for genome editing: progress, implications and challenges. Hum Mol Genet, 2014. 23(R1): p. R40-6.
12. O’Reilly, L.P., et al., C. elegans in high-throughput drug discovery. Adv Drug Deliv Rev, 2014. 69-70: p. 247-53.
13. Hernandez, C.C. and R.L. Macdonald, A structural look at GABAA receptor mutations linked to epilepsy syndromes. Brain Res, 2019. 1714: p. 234-247.
The global COVID-19 pandemic picture is still unclear as the novel coronavirus outbreak shifts constantly around the world. While the number of cases rise critically in South America’s first wave, the UK and European countries have begun to lift their lockdown measures amidst this COVID-19 pandemic. At the same time, South Korea and China, where coronavirus cases seemed to have disappeared, have seen a second wave of infections. However, a common question emerges among this COVID-19 rollercoaster: Will we have a vaccine soon?
A matter of time
Timing is crucial in vaccine research. More than five months have passed since the genetic sequence of SARS- CoV-2, the virus that causes COVID-19, which was published on 11th January 2020. This discovery sparked an unprecedented global research effort to develop a vaccine against this disease1, involving next-generation technology platforms and novel approaches with a hope to speed up this process. However, vaccine development involves a multi-stage process of research and testing, which typically takes more than ten years to be completed2 (Fig. 1). Therefore, we must remain cautious in light of a new vaccine.
What is the current picture?
A recent overview of the global landscape of COVID-19 vaccines by the World Health Organisation (WHO) included more than 140 vaccine candidates from different research groups and developers around the world3. From those, 129 candidate vaccines are under preclinical evaluation, which means a preliminary laboratory exploration but not yet in human trials. On the other hand, 13 candidate vaccines have entered the clinical evaluation stage, which is a three-phase process involving human subjects (Fig. 2).
OK, but can we speed up this process?
In terms of vaccine research time we are progressing at super-fast speed in this scenario. Just consider that the first set of COVID-19 cases, a new type of viral pneumonia, were reported to WHO on 4th January 2020 (Fig.3). Two months later, the first COVID-19 vaccine entered first-in-human trials within record breaking time on 16th March 2020. Scientists and international organizations around the world are still racing to produce and deliver a safe and effective vaccine within an 18-month period1-3.
So, do we have a vaccine yet?
From the array of advanced COVID-19 candidates under clinical development, only one promising study has started their phase 3 trial in Brazil4 (Fig. 4). This a non-replicative viral vector vaccine developed by the University of Oxford and the British-Swedish company AstraZeneca5. As we previously described, this candidate works as an inactive vaccine by using a different non-live virus to deliver coronavirus genes into our cells. In other terms, it can´t reproduce itself but it can still provoke an immune response.
Currently, this vaccine is also moving to Phase II/III in England and will hopefully deliver positive results by next year. A different approach has been employed by The Murdoch Children’s Research Institute in Australia. The experimental coronavirus vaccine, which is currently in phase 3 trial, utilises the Bacillus Calmette-Guerin vaccine6. The BCG vaccine is made from a weakened strain of tuberculosis bacteria and been widely used since the 1920s to fight TB7.
Researchers expect to observe partial protection against SARS-COV-2 as observed for other diseases7,8. Only data and results will decide if the remaining vaccine candidates could progress to phase 3 human trials and if this global effort could be translated into a successful vaccine by early 2021.
Usher AD. COVID-19 vaccines for all?. Lancet. 2020;395(10240):1822-1823. doi:10.1016/S0140-6736(20)31354-4
Thanh Le T, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19(5):305-306. doi:10.1038/d41573-020-00073-5
On May 10th, 2020 the UK Government announced that Secondary Schools, Sixth Forms and Further Education Colleges could provide some face-to-face support for year 10 and year 12 students after June 1st 2020. This was subsequently deferred to start on 15th June (1). Students in these year groups have national exams in Summer 2021. This means this time in year 10 and year 12 is critical as the bulk of the curriculum is delivered.
To reduce the spread of COVID-19 in schools on the return of students, the government has advised the regular cleaning of frequently touched surfaces, changing classroom layouts to reduce student contact and to stagger timetables (2). However, what are the students’ views on returning to school?
It was important to me to get this question answered, so I designed a study in aim to voice the views of students.
Why is this research important?
It is not apparent that the Government has engaged with the school students affected most by this decision. Students have not been given a platform to raise their concerns about returning to education. Their views have not been heard.
This motivated me to conduct a prospective study to collate the views of young people and publicise their concerns. It is important to involve young people in decisions that affect their situation so that they engage with the policy (3). Year 10 and year 12 students are also of an age where their opinions should be taken into account.
Aims of the research project:
This study was conducted to explore the opinions of year 10s and 12s concerning returning to partial school after the first wave of the covid-19 outbreak in June 2020. The aim was to provide a voice to young people on returning to partial schooling in June 2020.
Students were invited to express:
Their preferences on returning to school
Their views about safety with respect to government guidance on return to school
How they feel COVID-19 will impact on their future
How COVID-19 has impacted on their education
This study will inform members of the public and policy makers about the opinions of year 10 and 12 students returning to school in the UK at the end of the first wave of the SARS-CoV-2 outbreak.
How the research was conducted:
The aims of this study were addressed with qualitative research using a prospective survey conducted from the 20th to 27th May 2020. Participants were year 10 (age 14 to 15 years old) and year 12 (age 16 to 17 years old) school students in the United Kingdom.
A 12-question survey was compiled on Google Forms™ with 9 close-ended questions and 3 open-ended questions. The survey was distributed to the students via two online Facebook™ forums specific to their year groups: The A level Forum (6,500 members) and a GCSE forum (36,000 members). The survey was accessible on multiple platforms (computers and smartphones) and multiple web browsers.
The 3 open ended questions were subject to Braun and Clarke themed analysis. Thematic analysis is a method for identifying and interpreting patterns of meaning across qualitative data. This meant recurring themes in the written data could be addressed and the reasons behind students’ answers could be found without influence. Braun and Clarke analysis provides a qualitative six phased method of thematic analysis. Firstly, I familiarised myself with the qualitative data and noted general ideas. NVIVO (v12) software was used to group the qualitative data into codes (similar patterns in the data). Themes were then put together by grouping the codes. I then reviewed and defined each theme in relation to the research measures.
There was a rapid uptake from students with 1534 responses in 7 days.
Year 10 and 12 school students are evenly divided in opinion about whether they should return to school on 15th June. This uncertainty appears based on the majority of students having concerns about schools’ ability to comply with government guidance, particularly around social distancing and the risk of transmission. Some students recognised a need to return to education despite this perceived risk. This uncertainty could be addressed by better engagement from policy makers with school students. School students expressed desire that their students’ concerns are addressed by the Government and better explanation of the reasoning behind returning certain students to school at this time whilst other members of the community continue to isolate.
Policy makers should standardise remote learning. This will ensure all students receive some educational support during pandemics, ensuring the educational divide caused by a lockdown is minimized.
1. Actions for schools during the coronavirus outbreak [Internet]. GOV.UK. 2020 [cited 2020 Jun 9]. Available from: https://www.gov.uk/government/publications/covid-19-school-closures/guidance-for-schools-about-temporarily-closing
2. Coronavirus (COVID-19): implementing protective measures in education and childcare settings [Internet]. GOV.UK. 2020 [cited 2020 Jun 9]. Available from: https://www.gov.uk/government/publications/coronavirus-covid-19-implementing-protective-measures-in-education-and-childcare-settings/coronavirus-covid-19-implementing-protective-measures-in-education-and-childcare-settings
3. Mitchell C. “The Girl Should Just Clean Up the Mess”: On Studying Audiences in Understanding the Meaningful Engagement of Young People in Policy-Making. Int J Qual Methods [Internet]. 2017 Dec 1 [cited 2020 Jun 6];16(1):1609406917703501. Available from: https://doi.org/10.1177/1609406917703501
A second simultaneous Ebola outbreak has been confirmed in the Democratic Republic of Congo (DRC), (World Health Organization, 2020). This marks the 11th Ebola outbreak in central Africa which comes at a time when the continent also battles the COVID-19 pandemic.
First discovered in 1976, ebola viruses have since re-emerged across the African continent. The virus reached international attention during the longest and most extensive Ebola outbreak in West Africa between 2013 – 2015.
Historical Ebola outbreaks have fatality rates as high as 88%, almost 9 out of 10 people would die as a result of infection. The West Africa outbreak, however, saw a drastic reduction in fatality rate, to around 40%. The reduction in fatality rate was likely a result of the increased basic support, advanced and more appropriate care for those infected and earlier case detection, allowing for better management of both patients and outbreak spread (Baseler et al., 2017).
The most recent outbreak is in Mbandaka in the Équateur region, 600 miles from the ongoing Kivu Ebola epidemic in the North Kivu and Ituri provinces. The cases in Mbandaka are thought to be separate from the Kivu Ebola epidemic and instead the result of a new ‘spillover’ event from an animal reservoir to humans.
As of the 10th of June, a total of 12 cases have been reported; 9 confirmed cases, 3 suspected cases and 6 deaths, (Bujakera, Holland and Heavens, 2020)*. Positive samples were confirmed via testing at the Institut National de Recherche Biomédicale (INRB) – the countries national medical research organisation.
Although case number is relatively small at present, this is likely to rise as contacts are traced and the incubation period of 2-21 days elapses. Whilst the outbreak has presented at an already challenging time, scientists and doctors are on the ground with capacity to trace and diagnose. This service was expanded and refined in 2018 in response to previous outbreaks (World Health Organization, 2020).
The Kivu Ebola epidemic began in August 2018, over 3,400 people have been infected and sadly 2,200 lives lost despite the implementation of aggressive control measures. A number of factors have hindered this operation including; stigmatization, civil unrest and logistical issues.
Community level prevention and outbreak measures are dependent on the public trusting local authorities, however 31.9% of 961 individuals surveyed in North Kivu trusted that local authorities were acting in their best interests. The same survey reported 25.5 % of those surveyed believed the outbreak was a hoax, (Vinck et al., 2019). Complicating this were populist politicians publishing their own doubts on the outbreak validity to gain support in the 2018 elections. The country had not yet had a peaceful transition of power since decolonialisation in 1960, (Moran, 2018).
However, deployment of an experimental vaccine, coupled with rapid diagnostics helped to halt the outbreak. Following emergency use in 2016, the Ervebo vaccine was finally approved for use in 2019, after clinical trial demonstrated safety and efficacy; 97.5% efficacy in preventing Ebola infection compared to no vaccination, (Regules et al., 2015; World Health Organization, 2019).
Although an effective vaccination is now available, this is by no means the end of the problem. Availability, difficulties in contact tracing and public perception are all challenges that must be addressed to manage the outbreak during an already arduous time.
It is hoped that authorities and individuals alike can action their learnings from previous outbreaks, to bring this new outbreak to a swift end.
The DRC is currently contending with outbreaks of cholera, SARS-CoV-2, measles and two separate Ebola clusters. This serves as a stark reminder that whilst the world fights against the SARS-CoV-2 pandemic, Ebola outbreaks will stop for no country and no person.
Viruses emerge, or spillover often in nature, ebola virus is an example of this. Check out our blog on viral emergence here, or our post about bats and viruses.
*Please note that this article is not by a scientific body and reports figures from a WHO press conference which could not be confirmed on WHO.int.
Written by Charlotte Rigby
Baseler, L. et al. (2017) ‘The Pathogenesis of Ebola Virus Disease’, Annual Review of Pathology: Mechanisms of Disease, 12(1), pp. 387–418. doi: 10.1146/annurev-pathol-052016-100506.
Bujakera, S., Holland, H. H. and Heavens, A. (2020) Up to 12 infected in Congo’s new Ebola outbreak: WHO, Reuters.
Moran, B. (2018) ‘Fighting Ebola in conflict in the DR Congo’, The Lancet. Elsevier, 392(10155), pp. 1295–1296. doi: 10.1016/S0140-6736(18)32512-1.
Regules, J. A. et al. (2015) ‘A Recombinant Vesicular Stomatitis Virus Ebola Vaccine’, New England Journal of Medicine. Massachusetts Medical Society, 376(4), pp. 330–341. doi: 10.1056/NEJMoa1414216.
Vinck, P. et al. (2019) ‘Institutional trust and misinformation in the response to the 2018–19 Ebola outbreak in North Kivu, DR Congo: a population-based survey’, The Lancet Infectious Diseases, 19(5), pp. 529–536. doi: https://doi.org/10.1016/S1473-3099(19)30063-5.
World Health Organization (2019) Preliminary results on the efficacy of rVSV-ZEBOV-GP Ebola vaccine using the ring vaccination strategy in the control of an Ebola outbreak in the Democratic Republic of the Congo: an example of integration of research into epidemic response. doi: 10.1016/j.surfcoat.2019.125084.
World Health Organization (2020) New Ebola outbreak detected in northwest Democratic Republic of the Congo; WHO surge team supporting the response. Available at: https://www.who.int/news-room/detail/01-06-2020-new-ebola-outbreak-detected-in-northwest-democratic-republic-of-the-congo-who-surge-team-supporting-the-response (Accessed: 2 June 2020).
Written by Rebekah Penrice-Randal and Lucia Livoti
Features of 20,133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study 1 was published in The British Medical Journal (BMJ) this week. This report defines clinical characteristics of patients in hospital in the UK, using the ISARIC WHO Clinical Characterisation Protocol. We have written a brief summary to define what this means, discuss the report itself and highlight the key findings to aid public understanding.
You can follow the study on twitter for more updates: @CCPUKstudy
What is the ISARIC WHO Clinical Characterisation Protocol?
A research protocol is the set of documents that includes the instructions for conducting a study, the participant information sheets and consent forms. A clinical research protocol has to be approved by an independent Research Ethics Committee to ensure patient safety and dignity, and in the UK, by the Health Research Authority to ensure that health care resources are used appropriately.
In other words, the study was set up in advance of an outbreak to ask the “who, what and why” of a new disease. Who is affected means, age, sex, ethnicity and underlying medical problems. What means, what does the disease cause any of: breathing problems, diarrhoea, vomiting, sepsis or bleeding.
The ISARIC WHO CCP allows for the collecting of clinical data and biological samples, and their analysis and processing to be done in a globally-harmonised manner. This protocol has been curated by multidisciplinary experts across the world 2, and employed in response to outbreaks such as:
Middle Eastern Respiratory Virus Syndrome coronavirus (MERS-CoV) in 2012,
Influenza in 2013,
Ebola virus in 2014,
Monkeypox and MERS-CoV in 2018,
Tick-borne encephalitis virus (TBEV) in 2019 and
SARS-CoV-2 in 2020.
The ISARIC WHO CCP has been central to the swift and cohesive research response to COVID-19. As a free, readily available resource it has been instrumental in the standardised collection of samples and data for the COVID-19 outbreak. This in turn has allowed clinical investigation to progress as quickly as possible. Global generic documents can be accessed here. Countries are also encouraged to develop “localised” instructions and seek local research permissions. The documents pertaining to UK protocols are available here.
Cohort: a cohort of patients are a group of individuals affected by a common factor, such as a disease, treatments or environmental factors.
Cohort study: cohort studies are central to the study of epidemiology and are often used in the fields of medicine, nursing, psychology and social sciences.
Comorbidity: presence of one or more medical conditions in addition to the condition being studied.
Epidemiology: the study and analysis of factors contributing to disease and health outcomes. In this case it may refer to the frequency and pattern of COVID-19 infection, risk factors, super-spreader events and study of specific populations.
Median: the median is defined as the ‘middle’ value of a data set, such that other values are equally likely to be above or below.
Risk factor: a factor that increases an individual’s risk or susceptibility to a disease.
Aim of the study:
To rapidly understand the clinical characteristics of people severely affected by COVID-19. Severely affected, meaning those who need hospital care.
Why is this work important?
This work is essential to appreciate the clinical features of patients that present with COVID-19 and identify risk factors associated with poor outcome. It is only through the understanding of such aspects that public policy can be informed, particularly around shielding of vulnerable groups and planning of resources such as oxygen and ventilator provision.
Who took part?
20,133 hospital in-patients with COVID-19 from 208 acute care hospitals across the UK were enrolled into the study. Clinical data was collected from patients admitted to hospital between 6th February and 19th April 2020. Patient outcomes are described as known on 3rd May 2020, as people admitted on the 19th April need at least 14 days to complete their admission or “declare the nature of their illness”.
The ISARIC WHO CCP-UK is a large ongoing study of patients hospitalised with COVID-19. This study found that the mortality rate was high in those admitted to hospital. Certain risk factors were associated with higher mortality rate such as; increasing age, male sex, and chronic comorbidity, including obesity. This report provides the first clinical insight of hospital patients with COVID-19 in the UK. The data gathered throughout this study will assist decision-making in the management of COVID-19, from patient to nation.
This report acknowledges the 2648 frontline NHS clinical and research staff, volunteer medical students and many researchers, who have worked tirelessly to make this study happen. Thank you to all involved and congratulations from The Science Social.
A note on ‘open access’
Open access journal articles are available to everyone and are not behind a pay wall. This article is freely available to all, if you would like to read the original article click here.
1 Docherty, A. B. et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ369, m1985, doi:10.1136/bmj.m1985 (2020).
2 Dunning, J. W. et al. Open source clinical science for emerging infections. The Lancet Infectious Diseases14, 8-9, doi:10.1016/S1473-3099(13)70327-X (2014).
Thank you to Professor Calum Semple (@tweediechap), an ISARIC investigator and co-author of the original article for permission to write this blog, and for the valuable comments.
All feedback and comments are welcome, get in touch:
COVID-19, caused by SARS-CoV-2, currently has no available cure or vaccine (although not through lack of trying!). At the moment we have to rely on supportive treatments to alleviate symptoms; these can range from taking antipyretics like paracetamol at home to reduce a fever, to mechanical ventilation in intensive care units. It can be scary to face an illness where the only options for patients are to manage symptoms and wait for recovery, so are there any other treatments that could be explored? The Chinese government seem to think so: during the peak of the epidemic in China more than 85% of those treated for COVID-19 in hospitals also received treatment with traditional Chinese medicine (TCM).
What is traditional Chinese medicine?
TCM has been used for thousands of years to treat a whole host of illnesses. It differs a bit from the ‘old wives tales’ you might associate with alternative medicine in that it is based on a theory of ‘syndrome differentiation’; patients are treated according to their individual symptoms, using a holistic approach. This differs from the typical disease-specific treatment offered by conventional medicine, in which the patient’s diagnosis will determine their treatment. TCM can include physical therapies such as acupuncture or targeted exercise, but here we are focusing on herbal medicines, comprised of a mixture of ingredients tailored to an individual’s symptoms. These are usually taken in the form of teas, broths or powders. The Chinese government are currently endorsing a combination of conventional medicine and TCM to treat COVID-19, so could this have any benefit to patients?
Does it actually work?
A huge number of COVID-19 patients in China are receiving TCM. A variety of treatments are in use as each case is taken individually, so there is no standardised “treatment”against COVID-19. One of the more common suggested TCM formulations is Qing Fei Pai Du Tang, a composition of 21 different herbal substances claimed to aid in ‘ventilating the lungs’. This has been widely used in China by COVID-19 patients and is commercially available but contains ingredients which are banned in a number of other countries. The national administration of traditional Chinese medicine claims that after the treatment of a group of 214 patients with this remedy, 60% improved over the course of treatment, with 30% showing stabilisation of their condition. Supporters of TCM claim that remedies can shorten the duration of symptoms by up to 2 days, reduce the chance of illness becoming severe, and provide relief from symptoms such as cough and fever. Usually these claims are supported by anecdotal evidence, for example a bus driver in Wuhan who was admitted to hospital for COVID-19 symptoms. In additional to conventional supportive care he was given a herbal broth, and following a few days of treatment his symptoms subsided. These claims all sound very promising, but how much of this can we believe?
Headline taken from The Economist, 11 April 2020.
TCM makes bold claims about its ability to treat conditions like COVID-19, but how are these claims backed up? As explained above, anecdotal evidence is key in the claims proponents of TCM make. Often individual patients’ recovery after treatment is taken as definite evidence of its efficacy. In the case of COVID-19 in particular, this is suspect as the vast majority of cases resolve quickly and do not progress to severe illness; the patients who are held up as an example of the success of TCM would have likely recovered on their own without intervention. Clinical trials investigating the use of TCM do exist, including those conducted during the 2002-2004 SARS epidemic. However, these trials are frequently funded by those with a vested interest in proving the effectiveness of TCM and are poorly controlled with significant flaws in methodology. While at the time of the SARS epidemic it was claimed that TCM may be beneficial to patients, literature reviews since have shown no difference in mortality between those receiving both TCM and conventional medicine, and conventional medicine only. There are at least 50 ongoing clinical trials examining TCM in China, but again results from these will need to be taken with cation as these are not the double blind, placebo-controlled trails that are the standard in evidence-based medicine.
But it’s just herbs, right? What’s the harm?
Despite the lack of evidence for the efficacy of holistic treatments like TCM, many people are still tempted to try them because they are presumed to be ‘natural’ and therefore safe. Aside from not being proven effective, they can also be harmful. TCM is very poorly regulated in most countries; in the UK, TCM is monitored by the medicines and healthcare products regulatory agency (MHRA) but they aren’t actually tested before being put on the market. Instead, manufacturers are relied upon to accurately declare the contents of their products. One research group in Australia set out to test how reliable this information was. 26 different TCM formulations were purchased over the counter and examined for three key areas of non-compliance to the standards needed for legal sale: presence of undisclosed animal DNA, presence of heavy metals (lead, arsenic or cadmium), and adulteration with pharmaceutical products.
Their results were, frankly, frightening, 92% of the TCM remedies tested contained some form of contamination not disclosed on the ingredients list. Half the tested samples contained DNA of an animal not listed, ranging from snow leopard to rat. Ingredients derived from endangered species like leopard and shark are often added deliberately for their perceived therapeutic benefits, but others such as rat, mouse and cat DNA could indicate serious contamination issues during manufacture. The number of TCM formulations containing heavy metals was also concerning. More than 75% of the 25 tested samples contained at least one heavy metal, with 15 exceeding the recommended daily dose. Several samples even contained more than 10 times the maximum daily dose of lead!
Other research has indicated that up to a quarter of TCM formulations contain undeclared pharmaceuticals, but another study found that the true number could be closer to half. More than 50% of tested samples contained at least one pharmaceutical adulterant, many of which were at clinically significant doses. One such TCM contained six pharmaceutical products at doses which would normally require a doctor’s prescription, including amoxicillin and warfarin. None of these were mentioned on the label, and the interactions of a medicine containing analgesics, antibiotics, stimulants and antihistamines aren’t certain. As well as proving potentially dangerous to patients, pharmaceutical adulterants can distort the data from any clinical trials of these TCM formulations. It is very likely that any TCM product containing a clinically relevant dose of an undisclosed pharmaceutical would outperform a placebo, so this gives false data about the efficacy of the TCM formulation itself. These pharmaceuticals are often added to give the desired effect without being listed as part of the formulation of the TCM, so it is very difficult for patients to know what they are getting.
Adapted from Coghlan et al, 2015.
Overall, all but two of the 26 formulations tested were non-compliant with standards posed by Australian regulations, which are very similar to UK MHRA standards. It is concerning that these so-called medicines, which could actually pose a serious health risk in some cases, can be commercially available without a transparent ingredients list. Given TCM formulations are being given to patients ill with COVID-19, it is possible for them to cause harm. Holistic treatments marketed as ‘natural’ can have sinister effects or ingredients, so it is extremely important to discuss any alternative therapies with a doctor.
So why are we talking about it?
Although TCM may be ineffective or even dangerous, some ingredients could hold promise for treatments of viral infections including COVID-19. Natural products can be isolated from plant extracts that make up TCM remedies; some of these possess real therapeutic benefit. For example, artemisinin is a current frontline therapy used in the treatment of malaria. In 1971, Chinese scientist Youyou Tu extracted this compound from wormwood, a traditional remedy for fever, and found it was able to cure malaria in mouse and primate models. She later won a Nobel prize for her work. Another example is the finding that an extract from the common TCM ingredient liquorice root, known as glycyrrhizin, showed activity against a strain of coronavirus isolated during the SARS epidemic. When present in very high concentration (4000mg/L), glycyrrhizin was able to fully inhibit viral replication. This seems promising, but the mechanism for this isn’t fully understood and a lot more research is needed before any compound derived from TCM could be used as a treatment for SARS-CoV or indeed COVID-19.
TCM and other holistic therapies are clearly very divisive. Some wholeheartedly believe in their power, having heard anecdotes of miraculous cures. Others write it off completely due to the lack of good science or reliable evidence of its effectiveness. In truth, there is likely to be some benefit to investigating TCM as a potential treatment for COVID-19, just perhaps not in the way it would traditionally be applied. A huge number of potential drug candidates in the form of natural products may be present in the ingredients that make up TCM formulations. For these to be useful as medicines in the fight against COVID-19 and other viral infections, there needs to be rigorous testing, valid and reliable clinical trials, and thorough and transparent regulation of emerging treatments.
- Fung, Y. F. and Linn, Y. C. 2015. Developing Traditional Chinese Medicine in the Era of Evidence-Based Medicine: Current Evidences and Challenges. Evidence-Based Complementary and Alternative Medicine.2015, article no: 425037 [no pagination].
- Yang, Y., Islam, M. S., Wang, J., Li, Y., and Chen, X. 2020. Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective. International Journal of Biological Sciences.16(10), pp1708-1717.
- Ren, J. L., Zhang, A. H., and Wang, X. J. 2020. Traditional Chinese Medicine for COVID-19 Treatment. Pharmacological Research.155, article no: 104743 [no. pagination].
- Xu, X. W. et al. 2020. Clinical Findings in a Group of Patients Infected With the 2019 Novel Coronavirus (SARS-CoV-2) Outside of Wuhan, China: Retrospective Case Series. The bmj.8235, article no:2020;368:m606 [no pagination].
- Coghlan, M. L., Maker, G., Crighton, E. et al. 2015. Combined DNA, Toxicological and Heavy Metal Analysis Provides an Auditing Toolkit to Improve Pharmacovigilance of Traditional Chinese Medicine (TCM). Scientific Reports. 5, article no: 17475 [no pagination].
- Tu, Y. 2011. The Discovery of Artemisinin (Qinghaosu) and Gifts from Chinese Medicine. Nature Medicine. 17, pp1217-1220.
 Cinatl, J. et al. 2003. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. The Lancet. 361, pp2045-2046.
“SARS-COV-2 was already spreading in France in late December 2019” – A Scientific Perspective.
A French study has recently made the claim that SARS-CoV-2, the causative agent of COVID-19, was detected in France on December 27th after re-testing samples from patients diagnosed with unknown pneumonias. A single sample, belonging to a French man, tested positive for SARS-CoV-2 DNA multiple times by PCR.
Figure 1: The original paper published in ‘International Journal of Antimicrobial Agents’.
Does this explicitly mean he had COVID-19?
Not necessarily, however, more evidence is required before drawing any final conclusions. The claim is based on a PCR experiment which suggested segments of the SARS-CoV-2 genome were present in this sample. False positives can occur in this type of experiment. The investigators compensate for this by running the PCR twice. Other methods the investigators could have used to further validate this claim include are viral genome sequencing, use of phylogeny to study how closely related this viral genome is to others that the science community have sequenced and finally serology, to detect antibodies that would have been produced by the immune system during infection.
Sequencing is the process of determining the sequence of nucleotides within DNA or RNA. Knowing this can mean the virus can be compared to ‘reference genomes’ of other viruses to see if there is a match. This sequence can also be used to construct phylogenetic trees which show the evolutionary relationships between organisms, including viruses. The more closely related the virus is the more similar it usually is. These methods would show that the virus was present in the sample and also confirm where the virus belonged on the evolutionary tree, allowing scientists to pinpoint whether this virus was closely related to the viruses observed at the beginning of the outbreak.
Finally, serological evidence would prove that infection had occurred. Serological evidence is based on antibodies, a protein produced during the innate immune response to neutralise pathogens. The presence of RNA doesn’t necessarily mean infection (see the recent stir created by RNA being detected in dogs for example), antibody production does as it proves an immune response was mounted. Scientists would require a blood sample from this patient, many different tests can be performed but for SARS-CoV-2 it’s likely a simple colour change test would be used – similar to a pregnancy test(1).
Figure 2: Methods for validating identities of infectious diseases.
So, should we discount the study?
No, we shouldn’t. A result is still a result and knowledge of this is important. However, when information isn’t communicated well, or an incomplete picture is presented a wave of misinformation can occur. It’s important now more than ever to think critically about information and our sources of information. Ultimately, this is what the Science Social is about – communicating science with non-scientists and encouraging critical thinking.
Have any questions about the content covered today? Drop us a message on any of our platforms.
1. Amanat F, Stadlbauer D, Strohmeier S, Nguyen T, Chromikova V, McMahon M, et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. medRxiv [Internet]. 2020 Jan 1;2020.03.17.20037713. Available from: http://medrxiv.org/content/early/2020/04/16/2020.03.17.20037713.abstract
We discussed the latest updates on drug therapies as countermeasures for COVID-19 here. Instead of treating diseases, vaccines have the capacity to prevent them.
No, really what is a vaccine and how do they work?
Like natural infections, vaccines work by initiating a first line immune response, known as the innate immune response. In turn this allows the body to remember the pathogen, preparing the body to defend itself on the pathogens next attack, known as an adaptive immune response 1. Each pathogen (or vaccine) contains unique and specific shapes that the body’s immune system is able to recognise. Once the pathogen is dealt with, the adaptive immune response establishes what we call immunological memory, which is essentially the main goal of vaccination 1.
There isn’t just one type of vaccine either, scientists have found different ways of getting your immune system ready and prepared for infectious diseases.
Two main types of vaccines
Vaccines can be split into two main categories 2:
Live attenuated vaccines
This is when scientists take the causative agent of the disease, i.e. the virus or the bacteria and weaken it so it can no longer cause disease in healthy people. This is not an appropriate vaccination method for those with an immune system that does not work 1,2.
Live attenuated vaccines tend to be produced for viral diseases, as viruses have fewer genes and weakening these pathogens can be achieved more reliably 1.
Examples of Live Attenuated Vaccines used in the UK are as follows:
Measles Mump and Rubella Vaccine
If you are big on your travelling, you may have had the Yellow Fever Vaccine or the oral typhoid vaccination.
These types of vaccines contain either; the whole bacteria or virus that have been “killed”. OR, small elements of the disease-causing agents such as associated proteins or sugars. All of which cannot cause disease, even in those with severely weakened immune systems. The immune response produced by these vaccines aren’t always as powerful as those observed in a live attenuated vaccine, and because of this may require boosters 1,2.
Adjuvants are often added to inactivated vaccines to help boost the immune response and thus make them more protective.
So, an adjuvant is actually an aluminium salt that is added to vaccines to help produce an immune response, such as aluminium hydroxide, aluminium phosphate or potassium aluminium sulphate.
This is not like injecting an aluminium can into your body, by the way. Aluminium is actually a very natural metal found naturally in water, food and the earth itself. The amount used in vaccines is very tiny and is a vital element for these types of vaccines to protect you2.
“Whole killed” vaccines
Some examples of diseases prevented with inactivated “whole killed” vaccines are; poliovirus, hepatitis A, Rabies and Japanese Encephalitis 2.
There are 3 types of subunit vaccines; toxoid, conjugate and recombinant vaccines. All of which essentially take a subunit of the pathogen and turn this into a vaccine 2. When scientists say subunit, they are referring to only a part, or an element of the pathogen as opposed to the whole thing.
Many bacteria release toxins during an infection. Our bodies are able to recognise these toxins and produce an immune response. Therefore, making these a good target for vaccines. Examples of toxoid vaccines are Diptheria, tetanus and pertussis (whooping cough) 2.
The work “conjugate” means connected or joined. Sometimes, the subunit of a pathogen doesn’t elicit a good enough immune response by itself, so the subunit is joined to something else. Quite often the subunit is joined to the tetanus or diphtheria toxoid. Examples of conjugate vaccines are Haemophilus influenzae B, Meningitis C, Pneumococcal and Meningococcal vaccines 2.
These types of vaccines take the genetic code (DNA) from the virus or bacteria that we want to protect ourselves from. In the case of the Hepatitis B vaccine, the DNA is inserted into yeast cells, which are able to produce surface proteins of the pathogen. This is then purified and used as the active part of the vaccine. Examples of recombinant vaccines: Hepatitis B, Human Papilloma Virus and Meningitis B vaccines 2.
Vaccine trials are essential
Like we discussed in our article about drugs, all medicines have to go through a robust clinical trial. This is to ensure that the vaccine is not only safe, but to test whether the vaccine works and provide sufficient protection.
Phase I: a small-scale trial to assess whether the vaccine is safe in health people.
Phase II: more participants are recruited, and the study assess the efficacy of the vaccine, vaccine safety and the immune response is studied.
Phase III: The vaccine is studied under natural disease conditions, hundreds to thousands will be recruited to the study.
If the vaccine retains safety and works well over a defined period of time, the manufacturer of the vaccine is able to apply for a licence to market the product for human use.
Phase IV: The vaccine has been licensed and approved for use, however, data is still collected to monitor adverse effects and to determine the longevity and effectiveness of the vaccine 3,4.
Eradication of disease
In May 1980, the world was declared free of smallpox 5. The last naturally occurring case of this disease was observed in Somalia in 1977 5. Edward Jenner in 1796 observed that those who contracted cowpox, a disease known to be very mild, developed immunity against smallpox 6. This inspired Jenner to prepare a vaccine containing material from cowpox lesions, where he knew “the annihilation of smallpox must be the final result of this practice”. Despite this ground breaking discovery, it took nearly 200 years to eradicate smallpox 5. Smallpox remains the only human infection eradicated by vaccination.
Of course, it is not only humans that are vaccinated against infectious agents, but our pets and our livestock are also vaccinated. Rinderpest is known as the most devastating infectious disease of cattle, associated with a mortality rate more than 70% 7. Rinderpest is a virus belonging to the same virus family as measles. In 1918, the first vaccine was developed in Korea as an inactivated virus. This later got developed into a live attenuated vaccine until 1989 where the first recombinant rinderpest vaccine was developed 7. However, before the recombinant vaccine got to trial, eradication was achieved with the use of Plowright’s live attenuated vaccine 7.
Vaccines will allow us to prevent the disease, protect vulnerable members of our communities through herd immunity and in turn reduce the pressure on healthcare systems.
There is currently no vaccine for any of the known coronaviruses. Despite massive research efforts, it is not expected that a vaccine against SAR-CoV-2 will be available in less than 18 months 8. Keep an eye out for a break down on SARS-CoV-2 vaccines that are going through trial over the next couple of weeks.
1 Vetter, V., Denizer, G., Friedland, L. R., Krishnan, J. & Shapiro, M. Understanding modern-day vaccines: what you need to know. Annals of Medicine50, 110-120, doi:10.1080/07853890.2017.1407035 (2018).
Schizophrenia is a mental health disorder that is characterised by repeated psychotic episodes and this blog post is about my own personal experiences of psychotic episodes. You can check out my post about schizophrenia here if you just want to know more about the condition.
This is a long story, so I’ve broken it into three parts:
I’d like to start with a disclaimer of sorts. This is about my own battles with psychosis and by no means is meant to be a typical account, I doubt if there ever could be such a thing. Psychosis is subjective and variable by its very nature, if you had 100 schizophrenic patients in a room, the way that the disease affects and impacts each one could be completely different. The outcomes for people who are treated in early intervention teams for psychotic disorders vary wildly, and unfortunately, sometimes the interventions don’t work. I was one of the lucky ones.
Building Fictional Worlds: Developing Psychosis
I had my first psychotic episode when I was 19 years old. This is quite common; most psychotic disorders first develop in late adolescence. My psychosis presented itself in the form of delusional thinking at first, this can be hard to explain to people who’ve never experienced anything like it, but I started to move into another reality with different rules and a different worldview. This would come on suddenly, I would often get a sensation like butterflies in my stomach followed by a sinking feeling and a sense of impending doom. Then the racing thoughts would come, a rush of epiphanies that provided proof and collected evidence for my new, delusional, reality. These thoughts would snowball on top of each other, one leading to the next big epiphany that started the next chain of thinking off. Sometimes this would end with a panic attack and me rushing out of whatever situation I was in. Sometimes it would just stop of its own accord, leaving me shaken and confused about what had happened.
The delusions were often persecutory in nature, but the type of persecution would change. I would be in the middle of a vast conspiracy, like The Truman Show, where everyone around me was keeping up a façade of normal life whilst really they were actors. I’d hear someone talking on the radio and swear they were talking about me or an advertisement on the TV would be referencing the thoughts I was having. Sometimes I would be in a world where I was the only person who existed, everyone else was simply me at another point along my timeline, I would even “remember” being in the shoes of the person I was looking at.
The worst by far were the delusions where I was in Hell. I was being punished for all of my misdeeds in a past life, the people around me were demons and devils, all there to gain my trust, before leading me to ruin and humiliating me, this one was particularly bad because I could use it to explain the transitory nature of the other delusions. OF COURSE! The demons are pretending to be me to trick me! Or, they’ve made me think I’m in the Truman Show, it’s all part of my punishment.
As time went on, I started to collect “evidence” for my theories and figuring out what it all meant. I created a hydra in my mind. Each new episode would be like chopping off the serpent’s head, for each question answered, seven more would grow in its place. I started building a more complex web of coincidences that I had linked together with faulty logic. I spent many an hour in the grips of delusional thought, I felt like my mind was a tumultuous ocean and I was wrestling for something solid to hold on to. Even in my more lucid moments, when the confusing fog had lifted and I was thinking normally (or at least as normally as I was before this had started) I spent a long time, mostly when sitting up alone at night, simply debating the nature of my reality with myself.
All the while that this was going on, I was desperately trying to keep the fact that I was experiencing this from those around me. In the lucid moments I kept it hidden because I feared being labelled as crazy and locked away in some institution. In my delusional moments, well, they were part of the conspiracy, telling them would only let them know I’d seen through their tricks, and then what might happen? What new horrors would they unleash on me if they knew they’d been foiled?
So I tried to keep things together in front of those around me, but people aren’t so easily fooled. In hindsight, I often think back to how strange the conversations I had with my friends must have been. On the surface I’m listening to what they’re saying, but really, I’d be scanning their speech, looking for signs of deception, hidden clues they might be giving me or sly digs they might be making cryptically. This of course would be detected by them, my reactions just weren’t right for the situation. I started to distance myself from those around me, spending more time alone, or if I was in a group, staying quiet and just watching, being there, but not being “there”, so to speak. Those who knew me well could clearly see something was wrong, I had been extroverted and confident, now I was timid and anxious, but I dismissed any attempts to help, I still don’t really know why, I think partly it was because I didn’t want to show anyone how deeply broken I was, partly it was doubt that anything could help.
It stayed like this for a year before things really started deteriorating. The hallucinations started appearing alongside the delusions. I would hear two people discussing my actions as I did them, weighing up the merit of them and how close each action took me to “breaking out” of their trap. Sometimes these were neutral voices, sometimes they were the devil and God himself, fighting over me. Sometimes I would “just know” that everyone around me could read my thoughts, I would then of course start thinking of my most shameful moments, my deepest fears, all the things I wouldn’t want broadcast to everyone around me and I’d have to leave the situation immediately. I once got off a bus, miles away from where I intended to, because I was having such a moment and a man across from me had made eye contact and smiled. He was probably only wondering why the teenager across from him had suddenly started shaking with fear and staring around the bus with an expression of absolute terror on his face, but that eye contact and smile was all the evidence I needed in the grips of my delusion to confirm that I was right. I walked for nearly 3 hours back to my parent’s house, too scared to get back on a bus and too scared to go back to the halls of residence I was living in at the time. This was one of many such occurrences. The episodes had been infrequent at first, now I was in the grips of an episode more than I was lucid. I couldn’t concentrate on anything, my uni work was near impossible, my relationships were becoming strained. I was at breaking point.
What happened next changed the course of my life. I had started attending some local church services. I’d never really been religious in my youth but there were clear religious undertones to some of my delusions and whilst I was in the grips of some of my worst episodes, I’d desperately started praying and made promises to a God I didn’t believe in that if He helped me get a grip on my thoughts, I’d go to church. Plus, in my delusional logic, God was behind all of this, so I thought it best to go and find out more about Him.
There was a girl at this church who was about my age, and who one day very bravely spoke about her experiences with mental illness in front of an entire congregation. I’d met her a few times before and she seemed nice, I was in a fairly lucid state and her admission that she’d experienced something similar made me less afraid of her judgement, so I did what I hadn’t done with anyone so far. I told her what I was going through, as clearly and as fully as I could. She listened. More than that, she understood. She didn’t discount what I’d experienced or dismiss any of it. She helped me see that I really only had one of two explanations that from my perspective, could be true. Either I was the focal point of a divine conspiracy I didn’t know the full details of and was powerless to escape, or I was mentally ill. At least if it was the latter, I could try to do something about it. The very next day, I was sitting in my GP’s office, with her alongside me. I told my GP what I’d been going through and he booked an appointment with a psychiatrist who would start the process of diagnosis and putting together a treatment plan. The free-falling had stopped, but now I was at the bottom, it was time to start the long climb back out of the depths, it was going to be a long journey…
This is one of our long reads, grab yourself a coffee! 15 min read.
*SPOILER ALERT* At the present time, there is no quick-fix solution to the COVID-19 problem. The good news is, scientists are working on it!
Antibiotics do not work!
Antibiotics are not effective against viruses; they are entirely different microorganisms and therefore require different types of intervention. You may however, have heard of antibiotic use in the context of secondary infection. As the name suggests, this term describes when a patient acquires an infection secondary to the original [figure 1]. This is relatively common in patients with an infection of the lung (pneumonia), due to lowered immunity as a result of the original infection. This secondary infection may be viral or bacterial and so, may be treated with antibiotics (1,2).
A brief word on vaccinations…
Whilst there are several drug treatment options under investigation, the best way of protecting the population is through the development and deployment of a vaccination programme. Vaccines work by introducing a weakened version or fragment of the virus or bacteria to an individual’s immune system. This does not cause infection and instead elicits a mild immune response that allows the body to safely generate antibodies against the antigen. As part of this response, special memory cells that are part of the immune system, are trained to recognise and remember. Should you come across the real thing in future, your memory cells will fire into action and enable the production of antibodies to fight against it. As the immune system has already seen the antigen before, the response is more effective and much faster, making it highly efficient at eliminating the intruder and protecting your health (3,4).
Keep an eye out for our future blog post scratching beneath the surface of vaccination.
So, whatare the other options?
Whilst vaccinations are in the making, there are a number of options to explore to improve patient outcome. The unprecedented global collaboration has accelerated research into these options, from drugs to vaccinations and beyond but here’s the rub… they still need to go through the clinical trials process. Here we discuss several drugs under the scrutiny of clinical trial to identify their safety and efficacy against SARS-CoV-2.
The clinical trials process is of vital importance but remains extremely lengthy. It usually takes 10-15 years for a new drug to make it from start to finish, that is, from conception to approval for use. Clinical trials are essential as they serve to filter out the ineffective and unsafe. Just because a drug has made it to first-in-man (phase I) does not mean it’s a sure-fire win. In fact only 10% of medicines that enter phase I ever make it through to approval – at the cost of tens-to-hundreds of millions of pounds (5).
At present, there is tremendous focus on the repurposing of existing medications as opposed to generating new drugs. Drug repurposing is a crucial initiative, as it may greatly reduce the cost and time spent identifying treatment options for COVID-19. There are 4 treatment options under the investigation of the clinical trial named “Solidarity”, which has been launched by the WHO in collaboration with international partners (6).
What is it?
Remdesivir is a rising star in therapeutics against SARS-CoV-2. It is an investigational drug that was originally developed and trialled a treatment strategy against the Ebola virus. However, other treatment options showed greater efficacy against Ebola and remdesivir was subsequently shelved.
Why is it in trial?
Ongoing research has since demonstrated its broad antiviral activity and highlighted its promise in the fight against COVID-19. In in vitro testing, remdesivir was effective at inhibiting the replication of a range of coronaviruses including those that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Remdesivir works by targeting and incorporating itself into the genetic material of the virus, so it can no longer replicate (7). Pre-clinical testing has provided strong evidence that intravenous treatment is effective at reducing viral load and preventing progression to severe pneumonia in primates (8).
Where are we now?
Whilst remdesivir remains unlicensed and has not yet been approved for safe and effective use, it is in clinical trial to determine its utility. A Chinese study concluded that remdesivir afforded no clinically significant benefit to COVID-19 patients and demonstrated adverse events where the treatment was halted in 12% of patients. However, the authors state a key limitation of this study; the number of patients included was not great enough to detect clinical significance (9).
Recent data has shone a more promising light on remdesivir. An international study recruiting over 1000 patients has reported a 30% faster recovery time for remdesivir vs standard care, which was found to be statistically significant. The data also shows a trend towards reduced mortality rate in those receiving remdesivir however, the difference was not great enough to be significant. Although this is good news, we must still be cautious, the safety data has not yet been published and there are some concerns regarding adverse effects (10,11). Whilst it has been touted by leading scientists that remdesivir will become the new standard of care in the United States, there is still work to be done. There are many questions regarding safety, dosing regimen and patient suitability that need answering but so far so good… watch this space and we’ll keep you posted.
Hydroxychloroquine & chloroquine
What is it?
Hydroxychloroquine and its cousin chloroquine are also in the running having been publicised early on by the American Government for their effectiveness. They are similar in structure and function however hydroxychloroquine is less toxic and so much safer for a patient (12). Both drugs have already made it through to the clinical trial finish line for use in other applications, where they can be used to prevent and treat malaria. Hydroxychloroquine is also known to have anti-inflammatory action and is often prescribed for the treatment of inflammatory conditions like lupus and rheumatoid arthritis (13,14).
Why is it in trial?
Both drugs have been included in the Solidarity trial as there is a wealth of evidence demonstrating both antiviral and anti-inflammatory properties. Following the SARS epidemic in 2002, pre-clinical research demonstrated that chloroquine inhibited the replication of SARS-CoV in cells (15). More recent work has shown there may be a multitude of mechanisms through which SARS-CoV-2 infection in cells can be prevented (16). Although already approved, they must be tested for safety and efficacy in a COVID-19 setting. There are a number of reported side effects and concerns regarding potential toxicity must be carefully assessed and considered before regarding it as a viable treatment option (15).
Where are we now?
The available data from clinical trials is very mixed. A number of early trials have a small sample size and poor study design (17). One paper available on the preprint server MedRxiv found that patients critically ill with COVID-19 benefitted from administration of hydroxychloroquine. Those that received the drug had a significantly lower mortality rate and level of inflammation. However, the drug treatment group included only a small number of people and inflammation levels were reported to be twice as high as the control group at the beginning of the study (18).
In contrast, an American group found no evidence that use of hydroxychloroquine reduced the risk of need for mechanical ventilation. The authors of this study do also discuss its limitations, in that the study cohort only included men over 65 and the patients were not allocated different treatments at random (19).
It is important to remember these articles are still in preprint and have not yet been accepted for publication. Evidently the answer is not clear cut and the ongoing work is essential to better understand the treatments and outcomes.
What is it?
Lopinavir and ritonavir are antiretroviral drugs that have been approved and are prescribed to treat human immunodeficiency virus (HIV). They are often used in combination as ritonavir helps to boost the efficacy of lopinavir. Although HIV and coronaviruses are very different, the known mechanism of action against HIV has propelled the combination into the Solidarity trial. It is accepted that lopinavir/ritonavir work by blocking essential proteins to prevent replication of the virus (20).
Why is it in trial?
In vitro research has demonstrated that lopinavir has an antiviral effect against several coronaviruses in cells, whilst additional in vitro studies have confirmed the same effect against SARS-CoV-2 (21,22). More advanced pre-clinical study evaluating treatment of MERS in primates, revealed improved clinical outcome when lopinavir/ritonavir was combined with interferon-β1b – more on this next (23).
Where are we now?
Studies conducted early in the epidemic demonstrated no benefit to patients that received lopinavir/ritonavir, compared to those receiving the standard of care. Although less than 200 patients participated, there was no improvement in recovery time or mortality rate (24). Other studies have provided similar evidence, whereby there is no difference in ‘viral clearance’ – the time it takes for the virus to no longer be detectable in a patient (25). Alongside having no benefit, side effects involving the gastrointestinal tract and liver have also been reported in several of these trials (25,26).
At present there just isn’t enough evidence to say if this combination is effective in humans, the current clinical trials will present more data to answer this question in the future.
What is it?
Don’t panic! Interferon-β1a is a subclass of chemical messengers that belongs to a family called type I interferons, broadly speaking they help to regulate the immune system. This β1 subclass refers to specialised signals that are produced by cells in response to infection, particularly viral. Once the signals have been released, they are intercepted and interpreted by other cells, which allows them to increase their antiviral activity. Interferons are naturally produced by the body but have also been manufactured for use in a medical setting. Some of the β1 class, like interferon- β1a, are used as a treatment for the autoimmune condition multiple sclerosis (27).
Why is it in trial?
Interferons have proved promising in in vitro and pre-clinical tests against other coronaviruses. One pre-clinical study demonstrated that administration of interferon-β1b significantly reduced viral load in the lung and severity of disease in MERS (23). There is an ongoing human trial in Saudi Arabia, assessing the utility of interferon-1 and lopinavir/ritonavir against MERS however, no clinical data has yet been published (28). The Solidarity trial is testing interferon-β1a in conjunction with the antiviral drugs lopinavir/ritonavir to see if the combination offers any advantage to patient outcome.
Where are we now?
Interferons are being used in combination with a variety of other antiviral drugs in different trials across the world. There is limited data available to say whether or not this strategy is paying off. In China interferon-B1b is being trialled in an inhaled format for direct administration to the lungs (29). One study has shown that inclusion of interferon therapy accelerated viral clearance compared to treatments that did not include interferon. However, the paper has not yet been accepted for publication and is limited by poor design, a small sample size and disproportionate male-female representation (30).
Ongoing trials will aim to assess a much larger and more balanced sample population, so we should hope to draw more firm conclusions about this treatment option in the future.
Are there any other therapeutic options?
What is it?
There is some exciting research into the usefulness of convalescent plasma. This may sound complicated but the basic premise centres around the plasma of a ‘convalescent’ or recovered individual. Plasma is the liquid part of blood which contains important proteins, salts and crucially, antibodies. It may be isolated through a process called plasmapheresis and for a person donating plasma, it is not dissimilar to giving blood [figure 3]. Instead of donating whole blood, a machine separates it into blood cells and plasma. This allows the plasma to be removed and so returns your blood cells and often a saline solution to replace the lost volume. For patients receiving convalescent plasma, their own will be removed and replaced with the antibody rich plasma of a recovered individual, so conferring passive immunity. This strategy works on the basis that the person donating plasma is now immune and has generated antibodies – which should be around 28 days after recovery. REF.
Why is it in trials?
The concept of convalescent plasma is not new. Use of convalescent blood has been documented as early as 1918 in the prevention and treatment of the Spanish Flu (31). More recent application in several case studies have demonstrated it may be useful against SARS, MERS and even Ebola (32). A study utilising convalescent plasma as a treatment option for SARS reported a clinically significant reduction in mortality rate in those that received it. Early treatment, less than 14 days after symptom onset, also enabled a more positive outcome (33).
Where are we now?
NHS Blood and Transplant is leading a programme to investigate convalescent plasma in clinical trial. The trial will aim to assess if its use can improve patient survival and recovery time. The programme has only just begun but previous case studies are encouraging. A number of these report convalescent plasma use only in severely ill patients but describe clinical improvement and an increase in antibodies against SARS-CoV-2. If you want to more about the convalescent plasma trials and if you could help, click here.
All in all, there is no definite treatment at the moment but there are many options and trials working to gather concrete evidence to make a better judgement.
We hope you enjoyed our first long read! If you need help clarifying some of the jargon or want to know more about the concepts discussed, DM us and we’ll get back to you.
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