key: cord-0837462-wn5we9ph authors: Paul, Elisabeth; Brown, Garrett W.; Dechamps, Mélanie; Kalk, Andreas; Laterre, Pierre-François; Rentier, Bernard; Ridde, Valéry; Zizi, Martin title: Covid-19: An extra-terrestrial disease? date: 2021-07-26 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.07.051 sha: 15b48cb78280c607500b4d4fa6159d81ab3496e0 doc_id: 837462 cord_uid: wn5we9ph BACKGROUND: : Since the beginning of the pandemic, Covid-19 has been regarded as an exceptional disease. Control measures have exclusively focused on “the virus”, failing to account for other biological and social factors that determine severe forms of the disease. AIM: : We argue that if it is understandable that Covid-19 was initially considered a form of exceptionalism, justifying extraordinary response measures, this situation has changed – and so should our response. MAIN ARGUMENTS: : We now know that Covid-19 shares many features of common infectious respiratory diseases, and better understand that SARS-CoV-2 has not invented new problems out of the blue. Instead, it has unveiled and exacerbated existing problems in health systems and underlying population health. Of course, Covid-19 is not an extra-terrestrial disease. It is a complex zoonotic disease, and it needs to be managed as such, following long proven principles of medicine and public health. CONCLUSION: : A complex disease cannot be solved through a simple, magic bullet cure or vaccine. The heterogeneity of population profiles susceptible to develop a severe form of Covid-19 suggests adopting varying, targeted measures, enabled to reach risk profiles in an appropriate way. The critical role of comorbidities in disease severity calls for complementing short-term virus-targeted interventions with medium-term policies aimed at reducing the burden of comorbidities, as well as mitigating the risk of “transition” from infection to disease. Complementary strategies are needed including upstream prevention, early treatment, and the consolidation of the health system. Although the threat of a pandemic had been expected for years, Covid-19 triggered frantic and uncoordinated reactions worldwide (Independent Panel for Pandemic and Preparedness and Response, 2021; Paul et al., 2020b) . Since being declared a public health emergency in January 2020, Covid-19 has been regarded as an exceptional disease, as if it came from outer space. For the first time in history, billions of people were locked down, denied the right to go to school or to earn their living, and/or to see their loved ones, while an unprecedented race for treatment and vaccine discovery was launched. The collateral damage of these response measures were largely ignored, even if they may be greater than the positive effects of the counter-measures (Hrynick et al., 2021) . The collateral damage ranged from economic recession and loss of education, to increased domestic violence, mental health problems, and the worsening of chronic conditions from a lack of access to care (Bavli et al., 2020) . They weigh particularly heavily on young people and hit the most vulnerable disproportionately, aggravating inequities (Chakrabarti et al., 2021) . In many countries, primary healthcare professionals have been denied the right to treat their patients and, without effective primary healthcare, hospitals were left with the task of treating severe cases, notwithstanding the absence of a specific recommended drug. This led to the further exacerbation of existing disparities in health systems and services, especially in low-and middle-income countries (Baral, 2021) . Despite the fact that Covid-19 could be categorised a ‗syndemic' (Horton, 2020 ) -a synergy of epidemics that ‗co-occur in time and place, interact with each other to produce complex sequelae, and share common underlying societal drivers' (Swinburn et al., 2019 )control measures were exclusively focused on -the virus‖ and delay tactics, not taking into account other biological and social factors that contribute to determining severe forms of the disease (Paul et al., 2020a) . After several inconclusive results, it is only in July 2020 that one of the two large international randomised control trials aimed at testing the efficacy of existing treatments against Covid-19 published a preliminary report showing that dexamethasone (a glucocorticoid) resulted, on average, in lower mortality rates in patients requiring supplemental oxygen or invasive mechanical ventilation (The RECOVERY Collaborative Group, 2020). The lack of evidence on more effective medical treatments, coupled with projections suggesting high disease loads and death tolls, led to a perception that this was a one-off disease, which, unfortunately, translated into largely ignoring proven, traditional medical and public health practices. For instance, the longstanding concept of -herd immunity‖ which has always stood for an objective, or an achievement, is now considered by many as a -strategy‖, yet not to be followed if acquired naturally, but only by means of vaccination (World Health Organization, 2020, p.) . In spite of all its potential risks, limitations and considerable uncertainties regarding long-term side effects, the duration of protection and its effectiveness against viral variants, vaccination quickly became the only salvation option promoted by key governments and international institutions (Paul et al., 2021) . Although it is understandable that Covid-19 was considered a form of ‗exceptionalism' in early 2020, which justified exceptional response measuresparticularly since SARS-CoV-2 can trigger a variety of symptoms, some of them extremely severe (Hu et al., 2020; Wiersinga et al., 2020) the situation has changed. So should our response (Paul et al., 2020a) . In this piece, we argue that now that we far better understand the complex functioning of Covid-19, we should adapt our response strategy in a way that responds to its heterogeneity, and embraces proven, traditional medical and public health practices. Various types of expertise are relevant to approach the complexity of the Covid-19 response. This article is based on a collaboration of clinicians, researchers and experts in public health and policies based in three continents (America, Africa, and Europe) who are concerned by the Covid-19 response strategies in their respective countries Belgium, Democratic Republic of the Congo, France, Germany, United Kingdom, United States of America and at the global level. Together, they combine expertise in intensive care practice, biophysics, public health, virology, health policies and systems. This paper adopts a reflexive analytical approachwhere reflexivity can be defined -as an intentional intellectual activity in which individuals explore or examine a situation, an issue or a particular object on the basis of their past experiences to develop new understandings that will ultimately influence their actions‖ (Tremblay et al., 2014) to critically analyse, from a multidisciplinary point of view, the Covid-19 response strategy at the global level. We now know that Covid-19 shares many features of common infectious respiratory diseases in terms of its transmission process: it is caused by a coronavirus whose transmission is airborne (Greenhalgh et al., 2021) . Its immunopathology is better understood (Cao, 2020) and may entail vascular and immune system dysfunctions, possibly leading to a cytokine storm (Garvin et al., 2020; Varga et al., 2020) . Its severity and lethality are largely related to age, social determinants and comorbidities (Williamson et al., 2020) and its infection fatality rate, which turns around 0.2-0.3% on average, is extremely low for young people (Ioannidis, 2020; O'Driscoll et al., 2020) . Overall, SARS-CoV-2 has not invented new problems out of the blue, but has rather unveiled and exacerbated existing problems in the context it finds itself. For instance, in the United States of America, it has revealed the poor health status of a large proportion of the population (two thirds of Covid-19 hospitalizations were attributable to four major cardiometabolic conditions (O'Hearn Meghan et al., 2021)), the critical role of social determinants of health (Karmakar et al., 2021) , as well as -deep underlying problems in the health care system‖ (Blumenthal et al., 2020) . In Europe, the pandemic highlighted the ageing of the population, a lack of healthcare personnel resources and the insufficiency of quality primary healthcare (OECD/European Union, 2020). In Brazil, existing socioeconomic inequalities drove epidemic outcomes more than any other risk factor (Rocha et al., 2021) . Above all, Covid-19 revealed the lack of health system preparedness to pandemics, with inept global policies, non-existent and outdated national plans, a lack of health system adaptability, equipment shortages, unreliable availability of medicines, poor communication strategies, fragmented diagnostic capabilities, and poor governance structures (Baral, 2021; Paul et al., 2020b) . Covid-19 is not an extra-terrestrial disease coming from nowhere. It is a complex zoonotic disease and it needs to be managed as such (Wernli et al., 2021) , following long proven principles of medicine and public health. A complex disease cannot be solved through a simple magic bullet cure or vaccine. This is even more true when the infectious agent is an airborne virus with not only one, but many animal reservoirs, as a known zoonosis, which can be found in numerous species around human habitats (Shi et al., 2020; Ye et al., 2020; Wardeh et al., 2021; He et al., 2021) . As a result, claims for eradication are naïve. In fact, some scientists are suggesting that -full‖ herd immunity to end this pandemic is probably impossible because of new variants arising, doubts whether the vaccines can prevent transmission, signs of waning immunity, and inequities in the global distribution of vaccines (Aschwanden, 2021) . This simple fact also renders viral control policies via the increased use of lockdowns unsustainable. According to fifty years of coronavirus research, as well as knowledge accumulated on respiratory viral infections, we should expect new waves of the virus, or of a variant, probably more regularly in Autumn and Winter, particularly in the Northern hemisphere (Estola, 1970; Moriyama et al., 2020) . This calls for shifting our policies from a -zero-risk‖ strategy, which is imposed top-down via -command-and-control‖ lockdowns, to a -risk mitigation‖ and -harm reduction‖ strategy through educating and empowering people, especially the most vulnerable (Arnold, 2021; Loewenson et al., 2021 Loewenson et al., , 2020 . The heterogeneity of population profiles susceptible to develop a severe form of Covid-19 calls for adopting varying, targeted measures, which are enabled to reach risk groups in an appropriate way. The critical role of comorbidities in disease severity calls for complementing short-term virus-targeted interventionsincluding through prophylaxis in high transmission settings (Seet et al., 2021 )with medium-term procedures aimed at reducing the burden of comorbidities, as well as SARS-CoV-2 infection to Covid-19 disease transition risks, at an early stage. The heterogeneity of Covid-19 symptoms suggests that we should not simply wait for a specific cure that works -on average‖ against SARS-CoV-2, at a late stage of the disease. With such a heterogeneity, most people's disease development profile lies far from average. Moreover, viral infections follow a well-known path from their entry point to ultimate outcomes, requiring the adaptation of treatment to each patient's stage in infection. It is better to start treating before inflammation sets in and to adapt treatments to individual needs, through primary and patient-centred care. For instance, while it has been known since the first wave that Covid-19 caused blood clots, it is only recently that a study confirmed that prophylactic anticoagulation treatment was probably -optimal therapy‖ for Covid-19 patients (Vaughn et al., 2021) . Likewise, we should not delay empirical antimicrobial therapy in case of suspected co-infection prior to the worsening of clinical conditions; the potential benefits of pre-emptive antimicrobial therapy at the time of Covid-19 symptom onset needs to be explored adequately (Contou et al., 2020; Intra et al., 2020; Rawson et al., 2020; Verroken et al., 2020) . This point was already promoted by Dr A. Fauci as a conclusion of the flu pandemics of 2008 -2009 (Morens et al., 2008 . Evidence is now emerging as for the potential effectiveness of re-purposed drugs (ivermectine (Hill et al., 2021) , amantadine (Cortés-Borra and Aranda-Abreu, 2021), cofloctol (Belouzard et al., 2021) ), nutritional supplementation (Alzaabi et al., 2021; Margolin et al., 2021) , and new molecules (e.g. Plitidepsin (Varona et al., 2021) ) at early stages of disease. More research is definitely needed at this level. Furthermore, when dealing with patients with known co-morbidities, it would be medically sound and therapeutically helpful to do some typing of the Human Leukocyte Antigen (HLA) for susceptibility, so as to identify persons who truly need swifter and deeper care (de Sousa et al., 2020; Langton et al., 2021) . Vaccines are an important part of the response strategy, but only if they correspond to the precautionary principle with continuous appraisal of the benefit-risk balance. Doing so is necessary to maintain confidence in vaccines and to avoid adverse effectslike with vaccines against dengue and the influenza H1N1 pandemic (Forcades i Vila, 2015; The Lancet Infectious Diseases, 2018)which could reinforce vaccine hesitancy on the part of people who need them most. Yet, vaccines alone will not solve the Covid-19 pandemic (The Lancet COVID-19 Commission, 2021) . Thus, additional complementary strategies are needed, including prevention, early treatment, and the consolidation of the health system (Paul et al., 2021) . Even if it is not recommended by the World Health Organization as a -strategy‖, innate and already naturally acquired immunity, including T-cell immunity (Braun et al., 2020) , must be taken into account when determining the most appropriate response policies, including the assessment of the hypothetical herd immunity threshold advanced by many governments as a precondition for lifting non-pharmaceutical interventions. Indeed, there is now mounting evidence showing that SARS-CoV-2 infection induces robust immune responses, regardless of disease severity (Nielsen et al., 2021) , and that acquired natural immunity is lasting (Hall et al., 2021; Turner et al., 2021) . This suggests that individuals previously infected by SARS-CoV-2 are unlikely to benefit from Covid-19 vaccination, so that vaccines can be safely prioritised to those who have not been infected before (Shrestha et al., 2021) . Non-pharmaceutical interventions continue to be implemented in many countries despite progress in vaccinationseven strict lockdowns like in Australia for instancein spite of lack of evidence on their overall efficiency (McCartney, 2020). For example, nearly a year and a half after the beginning of the pandemic, there is still low evidence as for the effectiveness of face mask wearing in community settings (Chou et al., 2021) . While some studies show that stay-at-home policies may have reduced virus transmission, others show that they have not impacted overall mortality (Agrawal et al., 2021) . In any case, nonpharmaceutical interventions must be proportional to overall health needs and chosen taking into account local context specificities, existing alternatives, and in view of maximising expected benefits on general health outcomes while minimising collateral damage. From this perspective, the most efficient measures probably include limiting mass gatherings, promoting outdoor activities, where transmission is very low (Bulfone et al., 2021) , implementing sentinel surveillance and smart testing policy (reference hidden for peer-review), and ventilating public indoor places (Bazant and Bush, 2021) . In terms of policy landscape, public health policies need to be decided and designed in a transparent way, in collaboration with all relevant disciplines and stakeholders including populations, social and healthcare workers, and regularly evaluated to ensure continuous adaptation and improvement (Paul et al., 2020a) .Moreover, there needs to be a normative shift in how we think about prevention and preparedness, particularly a mindset that understands long-term preventative health as an investment, not an expense. Lastly, it is crucial to move beyond current understandings of health security, which has traditionally favoured surveillance, exceptionalism, ‗countermeasures' and an overreliance on vaccine discovery, often at the expense of routine health. As an alternative, the link between health system strengthening and health security needs to be articulated more forcefully, with better multilevel governance mechanisms to coordinate efforts, intersecting community, national, regional and global levels (World Health Organization, 2021). If not, then the policy lessons from COVID-19 will have been sorely missed and we will once again find ourselves confronting the next pandemic as if it was an unexpected extra-terrestrial disease. Ethical approval was not required for this Perspective paper. No specific funding was utilised. All authors are independent from funders. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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