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Severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) is the cause of coronavirus disease 2019 (Covid-19).
Abbreviation: US FDA: United States Food and Drug Administration, CDC: Centers for Disease Control, EMA: European Medicines Agency, BMJ: British Medical Journal, WHO: World Health Organization, NICE: National Institute for Health and Care Excellence, PHE: Public Health England, UNMD: United Nations Medical Directors, ICU: Intensive Care Unit, ARDS: Acute Respiratory Distress Syndrome, RCT: Randomized Controlled Trial.
Western Governments are prepared to spend billions of dollars on therapies for Covid-19. Doctors have a moral obligation to protect society from wasteful treatments. In the modern era, ineffective ‘cures’, on occasion supported by the media of the day, have been a recurrent feature of pandemics. Expert regulatory agencies, national and international, do not appear to have impacted significantly on this phenomenon.
1918 The Spanish flu and ‘Dr Pierce’s Pleasant Pellets’
Dr Pierce’s pleasant pellets’ were sugar coated tablets containing various plant extracts. The pellets were Initially produced in the 19th century and marketed as a purgative. The ‘pleasant pellets’ were promoted as beneficial in ‘fighting’ the Spanish flu during the 1918 pandemic.
An advertising barn (Oregon, USA). In 1918, at the height of the Spanish flu pandemic, the article by ‘Dr L. W. Bowers’ (inset) appeared in local newspapers in many different regions of the USA and Canada. In all of the publications that I have seen, the piece is presented in a manner such that it appears indistinguishable from a regular newspaper article.
Young people dying for the want of ventilators; the nightmare scenario many of us imagined in the weeks preparing for the arrival of Sars-CoV-2 on our shores, was a reality for doctors working during the polio epidemics of the early to mid-20th century. The desperation of those involved in the management of polio cases, understandably, lead to the introduction of treatments based on scientific speculation without data to support their use. The treatments given were diverse in nature and included cobra venom (1) intramuscular injection of strychnine, lumbar puncture and administration of various intrathecal agents (2). The efforts made were often heroic but there were reports of deaths resulting from some of these interventions (2).
The birthplace of the modern ICU. Medical students mechanically ventilate children with polio at Bleghams Hospital, Copenhagen, 1953. Credit: Medical Museion, University of Copenhagen.
My team and I regularly prescribed oseltamivir (Tamiflu) during the 2009 ‘swine flu’, pandemic. Since that time, concerns have been raised about the accuracy of the reporting of safety data in initial trials on the use of this agent in patients with influenza. In addition, there are major issues surrounding the efficacy of the agent in influenza infection. Problems with a meta-analysis of data from drug-company (Roche) sponsored trials were not spotted by the major national and international agencies the US FDA, the CDC, the European Medicines Agency (EMA), NICE and the WHO before these and other organisations authorized/supported the use of oseltamivir in influenza infection (3). In response to the 2009 swine flu pandemic, the UK and Australian governments commissioned an updated Cochrane review of the role of antivirals in influenza treatment. Japan had experienced considerable controversy with regard to possible side effects of Tamiflu in the years before the swine flu pandemic (4). A paediatrician based in Japan, Dr Keijia Hayashi, identified limitations affecting the initial trials used to justify the use of Tamiflu in influenza infection and brought the problem to the attention of the Cochrane review team carrying out the update. Analysis of more complete data, eventually released by the manufacturer to the Cochrane review team, demonstrated that the agent had no effect on patient outcome in influenza infection (5). An Initial claim that the agent ‘shortened disease duration’ was found to be limited to a reduction in symptom duration of less than one day (5). The findings of the review have been challenged by experts connected to the major agencies authorizing/supporting oseltamivir use in influenza infection (6). To date, the UK government has spent in the region of five hundred million pounds stockpiling antivirals (including oseltamivir), the US government, well in excess of one billion dollars (7, 8).
During the 2009 pandemic, it became standard practice to prescribe oseltamivir at ‘high dose’ to any patient requiring admission with swine flu . Thinking about it, at least on my part, this practice was largely based on ‘word of mouth’ in our hospital. The opinion of people around us, exerts significant influence on our actions. In fact, the ‘high dose’ approach followed a recommendation by the CDC based on speculation that severe disease might be related to heightened viral replication (9). There was no trial data to support an effect of high dose oseltamivir on outcome and the value of this approach remains, at best, unproven (10,11).
At the present time, I am not clear where ‘we’ (the medical profession) stand on the use of oseltamivir in influenza infection and I am not sure that where ‘we’ stand actually matters. Both the CDC (12) and Public Health England (PHE) (13) continue to recommend the use of oseltamivir in influenza infection. The most recent UK government ‘influenza pandemic preparedness plan’, advocates the stockpiling of antivirals in anticipation of future influenza pandemics (14). Will ‘we’ use oseltamivir in the next influenza pandemic? If the major agencies in the leading nations maintain their current recommendations, it will not be possible for us to avoid doing so. You can review aspects of the debate on oseltamivir in these references (15,16,17,18,19,20).
Something which struck me while researching this piece is indicated by the long list of abbreviations at the start of the article. I regularly had to add to the list of abbreviations after coming across important-sounding organizations publishing recommendations on the treatments to be employed during future influenza pandemics eg the ‘United Nations Medical Directors’ (UNMD) (21). You begin to wonder, who, if anybody, is actually calling the shots?
The reported efficacy of the steroid, dexamethasone, in critically ill patients with Covid-19 (22) came as a surprise to many of us. Previous controlled trials had not shown any benefit of steroid administration in ARDS (23). It has been argued that compared to other viral causes of ARDS, lung damage in Covid-19 differs in its underlying mechanisms (22). This is a reasonable contention. Furthermore, there is reassuringly little financial incentive to promote the widespread use of dexamethasone, a drug available in generic form. The RECOVERY trial reported that dexamethasone treatment given to patients with Covid-19 infection who demonstrate an oxygen requirement, results in a fall in 28 day mortality from 25.7% (in those not given dexamethasone) to 22.9% (in those given the drug). The reduction in mortality is reported to be greater in the subgroup of patients who are on mechanical ventilation. The reported 28 day mortality in mechanically ventilated patient’s given dexamethasone was 29.3% versus 41.4% in those not receiving the steroid. (22). The impact on mortality reported in the RECOVERY trial has been reproduced in other trials of steroid therapy in Covid-19 (24, 25). Many expensive biological agents (monoclonal antibodies etc) with effects on the immune system are now being, or are likely to be, tested for a beneficial effect on the outcome of Covid-19 viral pneumonitis. Going forward, It is important for us to keep in mind that the RECOVERY trial (22) which demonstrated benefit from dexamethasone administration in Covid-19 had limitations in design (26). Any RCT trial design concerning the application of biologicals in Covid-19 will have to be watertight in terms of design and all data must be peer-reviewed and made fully available to regulatory authorities. However, even then, we will be left with one fundamental problem:
While writing this piece, I received my usual weekly e-mail from the BMJ. One free access article caught my eye.
Tocilizumab is a monoclonal antibody inhibiting the actions of interleukin 6, a cytokine known to play a role in controlling viral infections. The article cited above reported that a randomized controlled trial of intravenous administration of tocilizumab to patients with Covid-19, undertaken in Brazil, had to be stopped due to a higher death rate in the group receiving the monoclonal antibody (28%) compared to patients on standard treatment (20%).
Five days later I received an e-mail from Medscape (an accredited educator). One article caught my eye.
Roche’s Tocilizumab Cuts Deaths in Hospitalized COVID-19 Patients: Study
This article, based on a non-peer-reviewed release on a ‘preprint server’, informed me that treatment of Covid-19 with tocilizumab in the RECOVERY trial reduced the death rate from the 33% mortality observed in the standard treatment group to 29% in those receiving the monoclonal antibody in addition to standard treatment. According to the article, the result translated to one life saved for every 25 people treated with tocilizumab. It was argued that, the data "clearly show the benefits of tocilizumab and dexamethasone in tackling the worst consequences of Covid-19 – improving survival, shortening hospital stay, and reducing the need for mechanical ventilators.” I look forward to reading the peer-reviewed publication.
Trust is the bedrock of humane medical practice. As doctors, we need people to trust us in order to function effectively but who can we trust to be our guide? Who is both untouchable and actually knows what he or she is talking about? At the present time, I have absolutely no idea.
Dr John Seery MB BChir PhD (Acadoodle CMO)
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