COVID-19 Blog Series: Part 3

Blog part 3: Treatments 

Fighting back- As COVID-19 vaccine development and roll-out to the UK public occurs at a rapid pace. Questions now turn to how we are going to treat those currently suffering from COVID-19, and how can we limit spread of the disease in the future. In this blog we are focussing on how our treatment of pandemics has evolved over time. By looking back at lessons learned from past key pandemics, we can appreciate how we are now able to respond rapidly to COVID-19 through the development or novel treatments for COVID-19 including monoclonal antibodies to treat hospitalised patients and novel antiviral drugs that in the future, we could administer at home during the early stages of disease.  

PAST

Throughout the course of history, viruses, bacteria and parasites have trumped both wars and natural disasters in the number of deaths caused (1). Amidst the search for treatments effective in combatting the current COVID-19 pandemic, it is useful to consider how humankind has responded to past pandemics. It is no coincidence that the most devastating early pandemics coincided with imperialisation and the advent of ocean travel (2). Widespread trade routes aided the spread of epidemics such as malaria, influenza and smallpox, and growing contact with various populations of people and animals has continued to increase the likelihood of pandemics ever since(1). With each pandemic, humans have developed novel strategies to prevent the spread of disease, many of which are still applicable today.  

In the 14th century, one-third of the world population was killed by the Black Death over the course of just 4 years (3). However, this pandemic was key in humans understanding the importance of proximity in the spread of disease. The emergency public health measures introduced as the plague entered Europe foreshadow today’s practices of social distancing and quarantine – indeed, the Venetian word ‘quarantena’ (40 days) refers to the 40 days ships were required to wait in the harbour before docking (1).  

In evaluating non-pharmaceutical interventions to reduce the transmission and impact of infectious disease, it is valuable to consider historical data from the Spanish flu pandemic (H1N1 [1918–1920])(5). Claiming 100 million lives and considered the most severe pandemic in history, the virus was airborne and spread through the sneezes and coughs of those infected (1). As such, social isolation measures were invoked, containing influenza in some communities (5). However, when evaluating the use of similar strategies to tackle COVID-19, there are several differences between Spanish flu and the current pandemic important to consider. Unlike the Spanish flu, which affected the healthy and young to a similar degree as the elderly, age appears to be a key risk factor of mortality in the case of COVID-19, as well as other factors, such as obesity (1). Moreover, increased mobility of populations and the influence of civil liberties on public health policy present additional complications to implementing such strategies in the current pandemic (5)

Vigilance and communication systems have vastly improved since past pandemics, theoretically enabling faster response to modern day disease spread (2). Despite this, preparation during development of the current pandemic was arguably inadequate (6). This lesson will undoubtedly prove valuable in improving our response to future pandemics, along with the vast amount of research currently underway to develop pharmaceutical treatments.  

Present: 

Last summer, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) approved the corticosteroid dexamethasone for use in some patients hospitalised by COVID-19 and more recently, tocilizumab and sarilumab were recommended for use in these patients too. Interestingly, these anti-inflammatory drugs have been used to treat rheumatoid arthritis (a painful joint disease) for years, in fact, dexamethasone has been in use for over 60 years. This is known as ‘drug repositioning’, which is using old drugs for new purposes. This simplifies and speeds up the development of new therapies, which is ideal for building an armoury of agents to battle against a novel virus. Rather than being a ‘magic bullet’ or miraculous cure, these drugs form a crucial part of the care now offered to the sickest COVID-19 patients to give them the best chance at recovery. 

Although no less of a tongue-twister, dexamethasone and its other corticosteroid siblings are likely more familiar to you than tocilizumab and sarilumab. Corticosteroids are derived from cortisol, a hormone that we produce naturally in response to stress, which can be used to combat inflammation. From creams to soothe dry, itchy skin to inhalers that prevent fatal flare-ups of asthma, corticosteroids are a staple of modern medicine. Their mechanism in combatting any inflammatory condition is largely the same; corticosteroids suppress genes that code for substances that cause inflammation and encourage genes that code for molecules that oppose inflammation(1). Severe COVID-19 is linked to high levels of the interleukin-6 (IL-6)(2), one of the molecules of which corticosteroids reduce the expression. However, this is only one inflammatory mediator – corticosteroids alter the production of many mediators. In turn, this acts to stop inflammation in its tracks before further damage to the lungs occurs. 

As it turns out, the monoclonal antibodies, tocilizumab and sarilumab specifically inhibit the action of interleukin-6. Monoclonal antibodies resemble the antibodies that our immune systems produce naturally in response to infection, however, they are carefully selected and produced to be identical and specific to a target. In the case of tocilizumab and sarilumab, this target is the IL-6 receptor. These drugs work by binding to the IL-6 receptor so that IL-6 can no longer bind to it, preventing a cascade of inflammatory signals within the cells of somebody with COVID-19 in order to prevent inflammation(3).  

Alongside these approved pharmacological treatments which have undergone rigorous clinical trials, patients also receive an array of supportive care. In addition to intensive nursing, there is a simple procedure known as ‘proning’ that can improve COVID-19 symptoms and reduce the risk of needing to be intubated (which is an invasive procedure involving a tube being passed down the windpipe in order to improve the amount of air reaching the lungs). When someone is lay on their back, the heart puts pressure on the lungs so that they cannot inflate as much. By proning someone (turning them over to lie on their stomach), there is less pressure on the lungs, meaning that they can inflate to a greater volume(4)

Respiratory infections (AKA ‘chest’ infections) caused by viruses are known to alter the immune system in ways that leave the lungs susceptible to further infections, often by bacteria(5). Research shows that around a third of critically ill COVID-19 patients experience a secondary infection; an infection other than COVID-19 at the same time. Over 90% of these infections are caused by bacteria and can therefore be treated using antibiotics(6)

Antivirals – the way forward in COVID-19 

COVID-19 vaccines are being rolled out in a mass vaccination program in the UK and worldwide. The eradication of COVID-19 however is unrealistic, and as we look to the future for ways to prevent another global COVID-19 pandemic it is apparent that there needs to be a   long-term control strategy that must include effective antiviral drugs. The greatest hurdle for antiviral drug development, specifically for respiratory viruses, is the emergence of viral mutations. Several different viruses can cause acute respiratory infections that have identical clinical symptoms and therefore, make diagnosis incredibly difficult for physicians. 

Antivirals generated against COVID-19, the novel coronavirus called severe acute respiratory syndrome coronavirus (SARS-CoV-2) typically aim to limit virus replication in patients and reverse the progression of the virus in individuals. Although vaccination provides us with enhanced protection against COVID-19, not all vaccines are able to prevent virus shedding, and this is where antiviral treatment has a role in protecting the spread of virus within our population. The field of antiviral drug treatment is constantly changing as new drug interventions and assessment of disease severity from clinical trials are being published. One antiviral drug is considered the current gold standard for treatment with COVID-19 (Remdesivir1,2), while others are being continuously evaluated for their efficacy (Lopinavir / Ritonavir2).  Here we will discuss potential candidates for antiviral treatment for COVID-19; including an exciting new treatment which is still in early stages of research. 

The Current Standard for Treatment: Remdesivir. This is a broad-spectrum antiviral that was developed to be effective against the emerging RNA viruses and was originally trialled against the Ebola virus, but has been proven to be ineffective in controlling the disease (1). Remdesivir functions to limit viral load within host cells by blocking enzymes required by the virus for replication. During the COVID-19 outbreak, as Remdesivir was known to inhibit replication of coronaviruses, scientists evaluated the clinical use of Remdesivir as an effective treatment against the COVID-19 virus1,2.  To date, Remdesivir is the only approved antiviral treatment for COVID-19 in hospitals, and there are numerous clinical trials on-going that are assessing when to administer the drug, the correct dosage, duration of treatment and the clinical outcomes of this drug2

No Longer Recommended for Use: Lopinavir / Ritonavir. This oral drug is commonly used to the treat and manage HIV/AIDS. Due to the similarity in viral antigen sites with the HIV virus, at the start of the pandemic researchers examined Lopinavir/Ritonavir as a potential candidate to use against COVID-19. Lopinavir/Ritonavir limits virus replication by blocking coronavirus protease activity and was found to be effective against the SARS outbreak in 2002-20043. However, there is little clinical evidence that suggests we can take adequate doses to inhibit viral proteases, and that this antiviral reduces the rate of mortality, mechanical ventilation or viral shedding (within the first 7 days) associated with COVID-19, leading to a strong recommendation against future use of Lopinavir / Ritonavir treatment in COVID-19 patients2

New Candidate (research on-going): Thapsigargin; identified for COVID use was led by researchers at the University of Nottingham, UK and colleagues 4. As an alternative approach to the antiviral drugs currently in use for COVID, Thapsigarin functions to regulate a generic component of the host immune response that interacts with the virus during the early stages of infection. By changing the host environment, the virus is unable to replicate for at least 48 hours after it is ingested4. Thapsigarin is a plant based derived drug.  In small doses it can induce a highly effective broad-spectrum antiviral innate immune response against three major types of respiratory viruses including COVID-19 in mouse models4. Importantly, this drug is not sensitive to changes in viral mutation, and it can be taken orally, it does not require hospital administration (by injection) and therefore shows promise as a human drug that limits viral spread at early time points of the disease4

Our current situation with the COVID-19 pandemic highlights the need for vaccines and antiviral treatments to limit viral-shedding from infected patients. Research in this field has moved at a lighting pace, and through massive vaccination programs, in parallel with the use of broad-spectrum antivirals that are safe, easy to use and effective we have the possibility of preventing (or at least controlling) another COVID pandemic in our foreseeable future. Lessons we have learned from past pandemics aid in understanding effective treatments that are used today and, in the future, to limit the spread and infectious nature of COVID-19. 

Past references:  

1.      Lessons Learned from a Global History of Pandemics [Internet]. European Medical Journal. 2020 [cited 2021 Feb 18]. Available from: https://www.emjreviews.com/microbiology-infectious-diseases/article/lessons-learned-from-a-global-history-of-pandemics/  

2.       EBailey. Why haven’t we learned from past pandemics? [Internet]. Evidence-Based Nursing blog. 2020 [cited 2021 Feb 18]. Available from: https://blogs.bmj.com/ebn/2020/07/13/why-havent-we-learned-from-past-pandemics/  

3.      Pandemics: Past, present, and future [Internet]. 2020 [cited 2021 Feb 18]. Available from: https://www.medicalnewstoday.com/articles/148945  

4.      Roos D. How 5 of History’s Worst Pandemics Finally Ended [Internet]. HISTORY. [cited 2021 Feb 18]. Available from: https://www.history.com/news/pandemics-end-plague-cholera-black-death-smallpox  

5.      Ethical and Legal Considerations in Mitigating Pandemic Disease: Workshop Summary [Internet]. Washington, D.C.: National Academies Press; 2007 [cited 2021 Feb 18]. Available from: http://www.nap.edu/catalog/11917  

6.      McMullan L, Blight G, Gutiérrez P, Levett C, McMullan L, Blight G, et al. How humans have reacted to pandemics through history – a visual guide. The Guardian [Internet]. [cited 2021 Feb 18]; Available from: https://www.theguardian.com/society/ng-interactive/2020/apr/29/how-humans-have-reacted-to-pandemics-through-history-a-visual-guide 

 Present references: 

1. Barnes PJ. Glucocorticosteroids: current and future directions. British Journal of Pharmacology [Internet]. 2011 [cited 2021 22 February]; 163(1):[29-43 pp.]. Available from: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1476-5381.2010.01199.x.  

2. Mann ER, Menon M, Knight SB, Konkel JE, Jagger C, Shaw TN, et al. Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Science Immunology [Internet]. 2020 [cited 2021 22 February]; 5(51):[eabd6197 p.]. Available from: https://immunology.sciencemag.org/content/immunology/5/51/eabd6197.full.pdf.  

3. Tanaka T, Kishimoto T. The Biology and Medical Implications of Interleukin-6. Cancer Immunology Research [Internet]. 2014 [cited 2021 22 February]; 2(4):[288-94 pp.]. Available from: https://cancerimmunolres.aacrjournals.org/content/canimm/2/4/288.full.pdf.  

4. Ng Z, Tay WC, Ho CHB. Awake prone positioning for non-intubated oxygen dependent COVID-19 pneumonia patients. European Respiratory Journal [Internet]. 2020 [cited 2021 22 February]; 56(1):[2001198 p.]. Available from: https://erj.ersjournals.com/content/erj/56/1/2001198.full.pdf.  

5. Hendaus MA, Jomha FA, Alhammadi AH. Virus-induced secondary bacterial infection: a concise review. Ther Clin Risk Manag [Internet]. 2015 [cited 2021 22 February]; 11:[1265-71 pp.]. Available from: https://pubmed.ncbi.nlm.nih.gov/26345407 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554399/.  

6. Vaillancourt M, Jorth P. The Unrecognized Threat of Secondary Bacterial Infections with COVID-19. mBio [Internet]. 2020 [cited 2021 22 February]; 11(4):[e01806-20 pp.]. Available from: https://mbio.asm.org/content/mbio/11/4/e01806-20.full.pdf

Future references: 

1.  Pardo, J., Shukla, A., Chamarthi, G., & Gupte, A. (2020). The journey of remdesivir: from Ebola to COVID 19. Drugs In Context, 9, 1-9. doi: 10.7573/dic.2020-4-14  

2. Siemieniuk, R., Rochwerg, B., Agoritsas, T., Lamontagne, F., Leo, Y., & Macdonald, H. et al. (2020). A living WHO guideline on drugs for covid-19. BMJ, m3379. doi: 10.1136/bmj.m3379  

3. Parasher, A. (2020). COVID-19: Current understanding of its pathophysiology, clinical presentation and treatment. Postgraduate Medical Journal, postgradmedj-2020-138577. doi: 10.1136/postgradmedj-2020-138577  

4. Al-Beltagi, S., Preda, C., Goulding, L., James, J., Pu, J., & Skinner, P. et al. (2021). Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus. Viruses, 13(2), 234. doi: 10.3390/v13020234