key: cord-0885455-bqakfoyz
authors: Davis, Ian M.
title: SARS‐CoV: Lessons learned; opportunities missed for SARS‐CoV‐2
date: 2020-08-18
journal: Rev Med Virol
DOI: 10.1002/rmv.2152
sha: 5a3210a09c9117099ef73f916c7c6a7be0ccf5db
doc_id: 885455
cord_uid: bqakfoyz

SARS‐CoV‐2 and Covid‐19 have made a retrospective analysis of other coronavirus diseases important, so this article reviews the history of the SARS‐CoV viral disease from 2003. Standard and clinical chemistry diagnostics were developed in response to the outbreak. The response to SARS is examined to determine if there were lessons learned before it disappeared in June and July 2003. Various diagnostic approaches were developed and implemented to assist in the rapid identification of patients and treatment of their illness, yet many of the approaches required days or weeks from the onset of fever to show statistical significance. Most of the therapeutic methods used during the outbreak relied on treating symptoms of the underlying illness, such as lower respiratory infections and systemic infection, rather than effectively suppressing or curtailing replication of the virus. Retrospective studies are examined to determine how the SARS outbreak was viewed 10 years on and what the authors hoped would be instructive patterns for possible future pandemics. Implementation of some of these recommendations might have helped ease the current pandemic but were overlooked for budgetary reasons that seem short‐sighted at present.

alyzed a global effort to diagnose, treat, and cure increasing numbers of patients. 1 As of July 24, 2020, infected patients passed 15 million, while deaths headed towards 700 000. 2 While these numbers are reported from one of several official global reporting resources, it is assumed by some epidemiologists that the numbers underestimate the actual extent of the disease. Possible explanations for underreporting include limited or inadequate testing, lack of diagnosis, or deaths due to other factors while Covid-19 is a comorbidity, thus allowing tabulation of an alternative cause of death. 3, 4, 5 It is impossible to know at present how many people will be infected, how many will die, and how many will recover. It is impossible to know for how long the pandemic will be active or how significant its global financial impact will be. coronaviruses. Both fit the definition of zoonotic diseases. Both present with an initial fever, followed by other symptoms resulting in lower respiratory infection or acute respiratory distress syndrome (ARDS). Both have required a massive global effort to define, treat, and cure those who have become ill.

Among the purposes of history should be counted its capacity to inform us of how events have transpired and guide us through similar events in our present and future. This purpose is applicable in the histories of disease, diagnosis, treatment, and recovery, as well as the histories of scientific research and application of findings. A condensed history of the brief and deadly SARS pandemic follows, along with some possible lessons to be learned for current and future viral pandemics.

As the SARS coronavirus appeared and started spreading in humans in 

Examination of the report issued by Morbidity and Mortality Weekly on March 21, 2003 , shows that evidence was accumulating for a more dire outbreak than had previously been assessed. The WHO had reported 246 cases in 11 countries, with the preponderance of the cases in Hong Kong, Singapore, Vietnam, the U.S., and Canada. 8 The illness was characterized by "rapid onset of high fever, myalgia, chills, rigor, and sore throat, followed by shortness of breath, cough, and radiographic evidence of pneumonia," along with low platelets, natural killer (NK), T, and B cells and leukocytes. The WHO reported that the cell counts initially might present as typical and take 3-4 days from fever onset to show a significant decrease. 9 An additional criterion is that a suspected patient must have been in "close contact within ten days of onset of symptoms," which is "defined as having cared for, having lived with, or having had direct contact with respiratory secretions or bodily fluids of a person suspected of having SARS" within 10 days of symptom onset. 10 Diagnostic problems frustrated identification of the infection. Initial diagnosis relied substantially on self-reported symptoms (eg, fever, myalgia, chills, sore throat, shortness of breath). Consultation with a medical professional and return of hematology laboratory results and chest radiography were compatible with a range of causes.

Reporting of proximity to an infected person also required prompt, honest self-reporting and may have been complicated by a newly exposed person not knowing whether they were in the presence of a SARS-affected patient within the previous 10 days. However, even with this battery of possible symptoms, only fever presented in 100% of the cases identified later as being SARS-positive. Other symptoms occurred in between 10% and 74% of patients, further confusing diagnosis. 11 1.3 | Determining the cause CDC reported that some initial data indicating that "paramyxoviruslike particles" were being reported, a misleading clue. 7 The CDC report was remedied in the 28 March issue, which attributed blame to a "previously unrecognized coronavirus." 11 A new coronavirus-SARS-CoV-was identified as one of a family of RNA viruses that cause respiratory illnesses, including a coronavirus that causes some cases of the common cold. 12 The 4th April issue dedicated over half of its 24 pages to issues surrounding the spread of SARS, travel precautions, and reporting protocols. 16 

While the definition of biomarkers was being pursued, pharmacotherapy was being tested in a scattershot approach 10 using antibiotics (levofloxacin, amoxicillin, clarithromycin, ceftriaxone, and azithromycin) and anti-viral drugs (oseltamivir, ribavirin, and amantadine). The antibiotics were given to address the incidence of bacterial lung sequelae to the initial viral infection and immunocompromised state caused by SARS-CoV. The glucocorticoids hydrocortisone and methylprednisolone were given intravenously for 2-3 weeks in gradually decreasing doses and showed mixed results.

Peiris concluded that early use of anti-virals and steroids might be helpful, but the approach lacked consistency or large numbers of patients at the time of publication. 10 It was shown that early, accurate detection is the mainstay of determining the underlying illness and prescribing an appropriate therapeutic response. 

The single, highly predictive diagnostic for SARS seemed to be the onset of fever, caused by the induction of endogenous pyrogens, such as IL-1, TNF-α, IL-6, or other cytokines. 24 SARS showed mixed results for common cytokine biomarkers even when measured several days after onset of fever.

All clinical tests, however simple or complicated, either 1) required several days or weeks for a biomarker to show a statistically significant difference from the control group, 2) were present in varying percentages of patients tested, 3) were ambiguous when examined across studies, or 4) all of the above. In 2004, Oxford et al. Similarly, there was no incentive to further develop SARS-CoV vaccines in the absence of an overt threat to human health. Funding agencies and peer reviewers were probably short-sighted in this respect, but many virologists also failed to take seriously the threat of the re-emergence of SARS or of a SARS-like virus. 30 

We may have learned much from the SARS outbreak, but we did not implement the massive local and global controls that were suggested.

Fast forward to 2020. Healthcare systems the world over have been overwhelmed. Healthcare workers again are exposed, are suffering and dying due to the lack of available PPE. It is, of course, not the fault of these investigators that they did not explicitly foresee the disastrous scope of Covid-19. It is fair to say that some virologists and epidemiologists knew it was a possibility but were incapable of convincing governments and institutions around the world to take the exhaustive, pervasive, and persistent measures necessary to control a massive global pandemic adequately. Humanity remained ill-prepared.

SARS-CoV-2 is wreaking devastation around the world, but some lessons that might have been learned during SARS-CoV are not making the broad and deep impact necessary to truncate the pandemic.

At present, there are scores of drug therapy candidates, and over 160 vaccines progressing through clinical trials. It will take months, if not years, to bring these therapies to global patients. The novel antiviral remdesivir has been approved through an emergency use authorization (EUA) that allows the unapproved drug to be used "in adults and children hospitalized with severe disease." 31 Dexamethasone and interferon-beta have demonstrated efficacy in randomized clinical trials. 32, 33 Some monoclonal antibody therapies known to serve as interleukin-6 inhibitors have shown efficacy in some trials. 34 We are told that any vaccine is, variously, a few months away to as much as 5 years away. 35 As of July 21, 2020, the WHO lists 24 vaccines being tested in 40 phase 1, 2, or 3 clinical trials, as well as 142 vaccines in preclinical evaluation. 36 Patient testing for the SARS-COV-2 or Covid-19 is a patchwork across the globe and generally is seen as incapable of meeting the testing needs in various populations. Any therapies and ultrasensitive methods must be available to all healthcare workers and patients within 1-3 days of fever onset, rather than later. Identification of crucial eicosanoid biomarkers, implicated in fever and inflammation onset, might aid in the rapid identification of an underlying illness. 37 The more time that elapses from fever onset, the less likely the outcome will favor patient recovery.

The humanitarian and economic impact of a global pandemic is mind-boggling. It is unknown what the eventual cost of the outbreak will be-in lives lost and diminished, emergency budgets allocated, businesses closed, supply chains interrupted, depressed gross domestic product, and other health and economic metrics. Those costs might have been lessened considerably if a less parsimonious approach had been taken to preparing a broad range of anti-virals and related drug therapies, researching shared weaknesses amongst viruses and bacteria, driving testing technologies to new sensitivities and early disease biomarkers, developing flexible capacity in hospital beds capable of responding to pandemics, and warehousing ready-to-use PPE to prepare for a worst-case scenario. Research into finding universally applicable, genuinely effective anti-viral therapies is not an easy or inexpensive task, but it is one that should be joined by research groups across the globe. It is a task being modeled by the work done by the Coalition for Epidemic Preparedness Innovations (CEPI). 38 If remedies are found, they should be made available to any affected person in any country at virtually no cost to the patient. Therapies that benefit the economically gifted while leaving most patients to suffer provides little benefit to the population at large and may result in pandemic flare-ups.

Most fundamentally, a dire need exists for discovery and development of an anti-viral that arrests viral respiratory diseases without causing any significant side effects in a broadly defined target population, that is, everyone, regardless of comorbidities. Such an anti-viral could be dosed in response to illnesses ranging from the common cold to influenza, viral pneumonia, ARDS, and SARS-like illnesses. Development of a safe and effective anti-viral for use in a wide range of viral diseases is not an easy target to achieve and might be impossible;

identification of drugs that are efficacious and safe is one of the more challenging enterprises engaged by humankind. The benefits of achieving the target, however, are overwhelmingly positive. The common cold might be a matter of a day's inconvenience rather than days out of work with their concomitant economic losses. The global population could live with a sense of calm when other viral outbreaks occur, knowing that securing the well-studied, safe, and efficacious anti-viral remedy is as close as a trip to the local pharmacy or physician's office. Achieving this kind of drug development goal is critical; it simply needs the funding and commitment of the global healthcare community.

Covid-19 proves that we must take the lessons of medical history as prescriptive for the future. If this lesson is not attended, it is possible that humanity will suffer similar tragedies. We must learn from what has happened and prepare for the possible.

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How to cite this article: Davis IM. SARS-CoV: Lessons learned; opportunities missed for SARS-CoV-2

The author has no competing interest.

The author thank Professor Claudia Cavadas of the Center for Neurosciences and Cell Biology, the University of Coimbra for suggesting the basis for this article. This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors.

Data sharing not applicable -no new data generated.

https://orcid.org/0000-0002-6522-8036