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      COVID-19 pandemic: A multifaceted challenge for science and healthcare

      editorial
      , 1 2
      Trends in Anaesthesia & Critical Care
      Elsevier Ltd.

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          Abstract

          The last days of December 2019 marked an historical event in recent history, with the outbreak of the coronavirus infection in Wuhan, China and the declaration of a pandemic by the World Health Organization on March 11, 2020 [1]. The SARS-CoV-2 became an overwhelming challenge to health care systems worldwide, due to easy and fast infection, as marked by the virus reproduction time and the severity of illness resulting especially in frailer individuals [2]. Suddenly severe pulmonary and systemic complications [3] were seen, with all the implications for healthcare professionals protection and infection risks [4,5], the choice of best personal protective equipment (PPE) [6,7] and issues related to PPE shortage, correct use and training [8]. The debate on airborne transmission [9] and operational limitations because of the pandemic challenged healthcare systems that already faced a surge of critically ill patients, which immediately appeared to be beyond the system capacity [2]. Society beyond health care systems were confronted with implications on ethics [10], on professionalism, on ongoing medical training [11], on healthcare providers’ burnout and stress [12], on “avoidable deaths”, and on a global crisis on needed resources, supplies, devices, PPE, and human workforces. 1 The COVID-19 challenge and the quality of research With the new disease, a sudden unprecedented worldwide cooperation of researchers led to open-access of interdisciplinary and international data sharing, which revealed fast sequencing of virus genome and diffusion of clinical experience. Travel restrictions and cancellations of face-to-face meetings triggered a large series of virtual meetings to share experience of whom was fighting the pandemic with those who were expecting to start their battles. Sometimes the “scientific hurry” resulted in misleading studies, in poorly-sustained researches, igniting confusion, fear and, probably medical errors [13,14]. However, this evolving framework of understanding the underlying COVID-19 pathophysiology started as pure devastating pneumonia, with atypical pattern and the specific and unique clinical picture of “silent hypoxia” [15]. It was understood that SARS-CoV-2 did not lead to a “single” pneumonia, rather different phenotypes requiring different approaches were proposed based on different risk factors and co-existing diseases [3]. The choice of alveolar recruitment, selection of best PEEP, and prone positioning of patients was controversial in the early phases of the pandemic but reconsidered the more we understood of the disease. In this issue of TACC, Fernandez-Sarmmiento and Colleagues [16] present a comprehensive review of SARS-CoV-2 infection, analyzing epidemiology, pathophysiology, clinical scenario and management options, with special emphasis on a checklist and protocol for airway management and a comprehensive overview on mechanical ventilation and respiratory support options. Alves Bersot and the Brazilian group [17] discuss also in this issue the physiology of prone positioning and the use of this approach for COVID-19 pneumonia. The authors propose interesting suggestions for focused and planned pronation cycles i.e. after urgent surgery in COVID-19 critical patients. In the same perspective, Song and Colleagues [18] underline the importance of preparing adequate critical care resources, concentrating on critically ill patients in predesignated hospitals and triaging. This paper also discusses the role of cytokine storm and they propose an elegant algorithm for respiratory support, including Extracorporeal Membrane Oxygenation (ECMO), for severe COVID-19 patients. Frazer and Colleagues [19] discuss in their a review-style approach coagulation disorders in COVID-19 patients, unveiling a “missing” piece of the puzzle, which was completely underestimated or misunderstood in the initial phases of pandemic and which probably contributed to change the therapeutic approach, with implications on outcome, at the later stage. The issue is largely debated and partly still unclear but out of any doubt it represents one of the most important pathophysiological and therapeutic mechanism in the frame of severe SARs-CoV2 infection [20]. 2 The MacGyver effect: using better what we have and invent what we don't The overwhelming request of qualified personnel, respirators, medical resource, PPEs and critical care beds deeply influenced the “routine” concept of critical care and patients’ triaging during the pandemic which unveiled the fragility of the health care system, and the fragility of the exhausted personnel as human beings. A crucial priority was and is proper and available PPE [21,22]. People started to invent their own 3D printed PPEs [23] or reused them [24,25]. If such approaches make sense the need to be assessed by rigorous and methodologically correct research. It is understandable that during the emergency solution were found but its validity, efficacy and benefit still needs to be scientifically addressed. COVID-19 forced the critical care personnel for safe airway management strategies [2,[26], [27], [28], [29], [30]] by changing the paradigm. Health care workers’ safety before medical needed interventions, like airway management, given the risk of infection during aerosol generation procedures. Simulation as an educational tool to handle such situations was proposed earlier [31]. In this issue of TACC, Ansari and Colleagues [32] provide the reader with an elegant in-situ simulation study exploring the effect of PPE on airway management, recalling the need for dedicated procedures, teamwork and training. With these premises, and as a response to PPE shortage, aerosol boxes, plastic covers and many other original artifacts were introduced in the clinical practice, with fast diffusion of their use but unparalleled proof of their efficacy. That created emerging concerns for their real effectiveness and the risk of such barrier device in airway management [33] and of “secondary aerosolization” upon removal [34]. With these in mind, we recommend reading the interesting reports by Kumar and Colleagues in this issue of TACC [35,36]. The Authors describe and discuss a low-cost and effective humidification/filtration assembly to be used in the operating room, an elegant solution for an incentive spirometry and an interesting low-cost apparatus to provide non-invasive ventilation in COVID-19 patients using a negative pressure isolation bed system. These initiatives are to be applauded and encouraged, but promoting parallel high-profile scientific research to validate the new devices, to avoid the risks of false safety or unexpected side effects, despite the brilliant MacGyver approach [37]. We probably need to revise our knowledge and to rely on and use better what we have: this is the message from the study by Chekol and Colleagues [38], offering useful information and checklists for adequate preparation for elective or emergent surgical care of COVID-19 patients, including well-proven techniques and devices and proposals of “emergency situation” solutions. Approaches for safe airway management [39], and how to organize dedicated airway teams during the pandemic were also described earlier [40]. Similar examples of “adapting” well-known techniques using ultrasound. Ultrasound machines are easy to transport, they can work bedside, they are easy to clean and many anaesthesiologists and critical care physicians are familiar with the important role for lung evaluation and decision making [41]. Extended protocols have been proposed for a holistic approach of COVID-19 patients [42]. In this issue of TACC, Dixit and Colleagues [43] propose a revised US-based protocol for central venous catheterization, combining the well-recognized benefits of US for this application with requested protocols and behaviors to grant operator's safety and reducing cross-infection risks. 3 Still a lot to understand COVID-19 and the SARS-CoV-2 are still partly unknown, but rigorous research and clinical experience will reveal the best approach to treat our patients [44] A better understanding of the disease's pathophysiology and mechanism of systemic injury is needed to understand the entire “syndrome”[3]. The involvement of the immune system [45] and the best therapeutic approach needs also to be evaluated as many manifestations of COVID-19 were described, including neurological [46] or cardiological [47] symptoms, cutaneous localization [48], and limb ischemia [49]. In this issue of TACC, Leopard and Colleagues [50] describe atypical vocal cords complications, highlighting the specific tropism of SARS-CoV-2 for upper and lower airway mucosa. Severely symptomatic patients exhibit a viral load up to 60 times the mild ones [51,52], with implications on airway mucosal inflammation and higher risk of airway lesions, including a seemingly higher incidence of bougie-related trauma [53], of pneumothorax and pneumomediastinum [54] and thoracic complications [55]. 4 The next future COVID-19 pandemic is an unprecedented event in the recent history of modern medicine. It still represents a worldwide challenge affecting any aspect of our daily life and the way we practice medicine. Implications and consequences on the different healthcare systems, on medical practice and scientific research are unique, multiple and probably partly unexplored. The pandemic ignited a paradox: while imposing social distances and isolation, it succeeded to put together researchers and physicians from all around the world independently of races, religion, geography and politics. This worldwide cooperation has led to a prompt and fast response at every level, with production of a huge body of research and daily proposals of novel techniques, devices and therapeutic approaches, which are spread worldwide on the wings of social media and scientific journals. This is probably the very important lesson we should learn from SARS-CoV-2: through challenging times, proper science, good sense of the doable and teamwork remain one of the most powerful tools also against a merciless and insidious enemy.

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          Most cited references51

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          A novel coronavirus outbreak of global health concern

          In December, 2019, Wuhan, Hubei province, China, became the centre of an outbreak of pneumonia of unknown cause, which raised intense attention not only within China but internationally. Chinese health authorities did an immediate investigation to characterise and control the disease, including isolation of people suspected to have the disease, close monitoring of contacts, epidemiological and clinical data collection from patients, and development of diagnostic and treatment procedures. By Jan 7, 2020, Chinese scientists had isolated a novel coronavirus (CoV) from patients in Wuhan. The genetic sequence of the 2019 novel coronavirus (2019-nCoV) enabled the rapid development of point-of-care real-time RT-PCR diagnostic tests specific for 2019-nCoV (based on full genome sequence data on the Global Initiative on Sharing All Influenza Data [GISAID] platform). Cases of 2019-nCoV are no longer limited to Wuhan. Nine exported cases of 2019-nCoV infection have been reported in Thailand, Japan, Korea, the USA, Vietnam, and Singapore to date, and further dissemination through air travel is likely.1, 2, 3, 4, 5 As of Jan 23, 2020, confirmed cases were consecutively reported in 32 provinces, municipalities, and special administrative regions in China, including Hong Kong, Macau, and Taiwan. 3 These cases detected outside Wuhan, together with the detection of infection in at least one household cluster—reported by Jasper Fuk-Woo Chan and colleagues 6 in The Lancet—and the recently documented infections in health-care workers caring for patients with 2019-nCoV indicate human-to-human transmission and thus the risk of much wider spread of the disease. As of Jan 23, 2020, a total of 835 cases with laboratory-confirmed 2019-nCoV infection have been detected in China, of whom 25 have died and 93% remain in hospital (figure ). 3 Figure Timeline of early stages of 2019-nCoV outbreak 2019-nCoV=2019 novel coronavirus. In The Lancet, Chaolin Huang and colleagues 7 report clinical features of the first 41 patients admitted to the designated hospital in Wuhan who were confirmed to be infected with 2019-nCoV by Jan 2, 2020. The study findings provide first-hand data about severity of the emerging 2019-nCoV infection. Symptoms resulting from 2019-nCoV infection at the prodromal phase, including fever, dry cough, and malaise, are non-specific. Unlike human coronavirus infections, upper respiratory symptoms are notably infrequent. Intestinal presentations observed with SARS also appear to be uncommon, although two of six cases reported by Chan and colleagues had diarrhoea. 6 Common laboratory findings on admission to hospital include lymphopenia and bilateral ground-glass opacity or consolidation in chest CT scans. These clinical presentations confounded early detection of infected cases, especially against a background of ongoing influenza and circulation of other respiratory viruses. Exposure history to the Huanan Seafood Wholesale market served as an important clue at the early stage, yet its value has decreased as more secondary and tertiary cases have appeared. Of the 41 patients in this cohort, 22 (55%) developed severe dyspnoea and 13 (32%) required admission to an intensive care unit, and six died. 7 Hence, the case-fatality proportion in this cohort is approximately 14·6%, and the overall case fatality proportion appears to be closer to 3% (table ). However, both of these estimates should be treated with great caution because not all patients have concluded their illness (ie, recovered or died) and the true number of infections and full disease spectrum are unknown. Importantly, in emerging viral infection outbreaks the case-fatality ratio is often overestimated in the early stages because case detection is highly biased towards the more severe cases. As further data on the spectrum of mild or asymptomatic infection becomes available, one case of which was documented by Chan and colleagues, 6 the case-fatality ratio is likely to decrease. Nevertheless, the 1918 influenza pandemic is estimated to have had a case-fatality ratio of less than 5% 13 but had an enormous impact due to widespread transmission, so there is no room for complacency. Table Characteristics of patients who have been infected with 2019-nCoV, MERS-CoV, and SARS-CoV7, 8, 10, 11, 12 2019-nCoV * MERS-CoV SARS-CoV Demographic Date December, 2019 June, 2012 November, 2002 Location of first detection Wuhan, China Jeddah, Saudi Arabia Guangdong, China Age, years (range) 49 (21–76) 56 (14–94) 39·9 (1–91) Male:female sex ratio 2·7:1 3·3:1 1:1·25 Confirmed cases 835† 2494 8096 Mortality 25† (2·9%) 858 (37%) 744 (10%) Health-care workers 16‡ 9·8% 23·1% Symptoms Fever 40 (98%) 98% 99–100% Dry cough 31 (76%) 47% 29–75% Dyspnoea 22 (55%) 72% 40–42% Diarrhoea 1 (3%) 26% 20–25% Sore throat 0 21% 13–25% Ventilatory support 9·8% 80% 14–20% Data are n, age (range), or n (%) unless otherwise stated. 2019-nCoV=2019 novel coronavirus. MERS-CoV=Middle East respiratory syndrome coronavirus. SARS-CoV=severe acute respiratory syndrome coronavirus. * Demographics and symptoms for 2019-nCoV infection are based on data from the first 41 patients reported by Chaolin Huang and colleagues (admitted before Jan 2, 2020). 8 Case numbers and mortalities are updated up to Jan 21, 2020) as disclosed by the Chinese Health Commission. † Data as of Jan 23, 2020. ‡ Data as of Jan 21, 2020. 9 As an RNA virus, 2019-nCoV still has the inherent feature of a high mutation rate, although like other coronaviruses the mutation rate might be somewhat lower than other RNA viruses because of its genome-encoded exonuclease. This aspect provides the possibility for this newly introduced zoonotic viral pathogen to adapt to become more efficiently transmitted from person to person and possibly become more virulent. Two previous coronavirus outbreaks had been reported in the 21st century. The clinical features of 2019-nCoV, in comparison with SARS-CoV and Middle East respiratory syndrome (MERS)-CoV, are summarised in the table. The ongoing 2019-nCoV outbreak has undoubtedly caused the memories of the SARS-CoV outbreak starting 17 years ago to resurface in many people. In November, 2002, clusters of pneumonia of unknown cause were reported in Guangdong province, China, now known as the SARS-CoV outbreak. The number of cases of SARS increased substantially in the next year in China and later spread globally, 14 infecting at least 8096 people and causing 774 deaths. 12 The international spread of SARS-CoV in 2003 was attributed to its strong transmission ability under specific circumstances and the insufficient preparedness and implementation of infection control practices. Chinese public health and scientific capabilities have been greatly transformed since 2003. An efficient system is ready for monitoring and responding to infectious disease outbreaks and the 2019-nCoV pneumonia has been quickly added to the Notifiable Communicable Disease List and given the highest priority by Chinese health authorities. The increasing number of cases and widening geographical spread of the disease raise grave concerns about the future trajectory of the outbreak, especially with the Chinese Lunar New Year quickly approaching. Under normal circumstances, an estimated 3 billion trips would be made in the Spring Festival travel rush this year, with 15 million trips happening in Wuhan. The virus might further spread to other places during this festival period and cause epidemics, especially if it has acquired the ability to efficiently transmit from person to person. Consequently, the 2019-nCoV outbreak has led to implementation of extraordinary public health measures to reduce further spread of the virus within China and elsewhere. Although WHO has not recommended any international travelling restrictions so far, 15 the local government in Wuhan announced on Jan 23, 2020, the suspension of public transportation, with closure of airports, railway stations, and highways in the city, to prevent further disease transmission. 16 Further efforts in travel restriction might follow. Active surveillance for new cases and close monitoring of their contacts are being implemented. To improve detection efficiency, front-line clinics, apart from local centres for disease control and prevention, should be armed with validated point-of-care diagnostic kits. Rapid information disclosure is a top priority for disease control and prevention. A daily press release system has been established in China to ensure effective and efficient disclosure of epidemic information. Education campaigns should be launched to promote precautions for travellers, including frequent hand-washing, cough etiquette, and use of personal protection equipment (eg, masks) when visiting public places. Also, the general public should be motivated to report fever and other risk factors for coronavirus infection, including travel history to affected area and close contacts with confirmed or suspected cases. Considering that substantial numbers of patients with SARS and MERS were infected in health-care settings, precautions need to be taken to prevent nosocomial spread of the virus. Unfortunately, 16 health-care workers, some of whom were working in the same ward, have been confirmed to be infected with 2019-nCoV to date, although the routes of transmission and the possible role of so-called super-spreaders remain to be clarified. 9 Epidemiological studies need to be done to assess risk factors for infection in health-care personnel and quantify potential subclinical or asymptomatic infections. Notably, the transmission of SARS-CoV was eventually halted by public health measures including elimination of nosocomial infections. We need to be wary of the current outbreak turning into a sustained epidemic or even a pandemic. The availability of the virus' genetic sequence and initial data on the epidemiology and clinical consequences of the 2019-nCoV infections are only the first steps to understanding the threat posed by this pathogen. Many important questions remain unanswered, including its origin, extent, and duration of transmission in humans, ability to infect other animal hosts, and the spectrum and pathogenesis of human infections. Characterising viral isolates from successive generations of human infections will be key to updating diagnostics and assessing viral evolution. Beyond supportive care, 17 no specific coronavirus antivirals or vaccines of proven efficacy in humans exist, although clinical trials of both are ongoing for MERS-CoV and one controlled trial of ritonavir-boosted lopinavir monotherapy has been launched for 2019-nCoV (ChiCTR2000029308). Future animal model and clinical studies should focus on assessing the effectiveness and safety of promising antiviral drugs, monoclonal and polyclonal neutralising antibody products, and therapeutics directed against immunopathologic host responses. We have to be aware of the challenge and concerns brought by 2019-nCoV to our community. Every effort should be given to understand and control the disease, and the time to act is now. This online publication has been corrected. The corrected version first appeared at thelancet.com on January 29, 2020
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            Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review

            The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19.
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              Viral dynamics in mild and severe cases of COVID-19

              Coronavirus disease 2019 (COVID-19) is a new pandemic disease. We previously reported that the viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peaks within the first week of disease onset.1, 2 Findings from Feb, 2020, indicated that the clinical spectrum of this disease can be very heterogeneous. 3 Here, we report the viral RNA shedding patterns observed in patients with mild and severe COVID-19. 76 patients admitted to the First Affiliated Hospital of Nanchang University (Nanchang, China) from Jan 21 to Feb 4, 2020, were included in the study. All patients were confirmed to have COVID-19 at the time of admission by RT-PCR. The viral loads of their nasopharyngeal swab samples were estimated with the DCt method (Ctsample – Ctref). Patients who had any of the following features at the time of, or after, admission were classified as severe cases: (1) respiratory distress (≥30 breaths per min); (2) oxygen saturation at rest ≤93%; (3) ratio of partial pressure of arterial oxygen to fractional concentration of oxygen inspired air ≤300 mm Hg; or (4) severe disease complications (eg, respiratory failure, requirement of mechanical ventilation, septic shock, or non-respiratory organ failure). 46 (61%) individuals were classified as mild cases and 30 (39%) were classified as severe cases. The basic demographic data and initial clinical symptoms of these patients are shown in the appendix. Parameters did not differ significantly between the groups, except that patients in the severe group were significantly older than those in the mild group, as expected. 4 No patient died from the infection. 23 (77%) of 30 severe cases received intensive care unit (ICU) treatment, whereas none of the mild cases required ICU treatment. We noted that the DCt values of severe cases were significantly lower than those of mild cases at the time of admission (appendix). Nasopharyngeal swabs from both the left and right nasal cavities of the same patient were kept in a sample collection tube containing 3 mL of standard viral transport medium. All samples were collected according to WHO guidelines. 5 The mean viral load of severe cases was around 60 times higher than that of mild cases, suggesting that higher viral loads might be associated with severe clinical outcomes. We further stratified these data according to the day of disease onset at the time of sampling. The DCt values of severe cases remained significantly lower for the first 12 days after onset than those of corresponding mild cases (figure A ). We also studied serial samples from 21 mild and ten severe cases (figure B). Mild cases were found to have an early viral clearance, with 90% of these patients repeatedly testing negative on RT-PCR by day 10 post-onset. By contrast, all severe cases still tested positive at or beyond day 10 post-onset. Overall, our data indicate that, similar to SARS in 2002–03, 6 patients with severe COVID-19 tend to have a high viral load and a long virus-shedding period. This finding suggests that the viral load of SARS-CoV-2 might be a useful marker for assessing disease severity and prognosis. Figure Viral dynamics in patients with mild and severe COVID-19 (A) DCT values (Ctsample-Ctref) from patients with mild and severe COVID-19 at different stages of disease onset. Median, quartile 1, and quartile 3 are shown. (B) DCT values of serial samples from patients with mild and severe COVID-19. COVID-19=coronavirus disease 2019. *p<0·005.
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                Author and article information

                Contributors
                Role: Consultant
                Role: Professor of Anaesthesiology
                Journal
                Trends in Anaesthesia & Critical Care
                Elsevier Ltd.
                2210-8440
                2210-8467
                20 September 2020
                October 2020
                20 September 2020
                : 34
                : 1-3
                Affiliations
                [1]Anaesthesia and Intensive Care, Policlinico San Marco University Hospital, Catania, Italy
                [2]Department of Anaesthesiology and Pain Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
                [3]Medical Education, School of Medicine, Sigmund Freud University Vienna, Vienna, Austria
                Author notes
                []Corresponding author. Department of Emergency Medicine, Anaesthesia and Intensive Care, Policlinico Vittorio Emanuele San Marco University Hospital, Viale C.A. Ciampi, 95100, Catania, Italy.
                [1]

                European Society of Anaesthesiologists SC11-Respiration and Airway Management chair; European Airway Management Society (EAMS) President Elect.

                [2]

                European Airway Management Society (EAMS) Past President.

                Article
                S2210-8440(20)30228-8
                10.1016/j.tacc.2020.08.009
                7502251
                6f170dcc-6fdd-49d4-83ea-9b5925bd2bbd
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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