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      We Asked the Experts: Covid-19 Outbreak: Is There Still a Place for Scheduled Surgery? “Reflection from Pathophysiological Data”

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          Abstract

          Introduction Covid-19 pandemic severely hits the world, and many countries need to adapt their health systems to handle a large influx of patients with pneumonia due to this new virus. This unique crisis is putting a strain on our hospitals, which have to respond to the influx of patients with Covid-19. At the same time, physicians must provide care for patients suffering from other, and sometimes urgent, conditions. In this context, the management of patients requiring major oncological or cardiac surgery within adapted (often short) timeframes is a difficult preoccupation, especially since that some pathophysiological data on this virus leads us to believe that immunosuppressive changes due to surgery may increase susceptibility to the virus. In this article, we present areas for reflection regarding the management of these patients during the Covid-19 pandemic situation, based on the little-known pathophysiological data on this virus. COVID-19 is a virus of the β-coronavirus family and is responsible for the third human epidemic of coronavirus zoonosis after SARS-Cov (2002) and MERS-Cov (2012). It is more precisely named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) because of its high sequence homology with SARS-Cov, sharing 80% genetic similarities [1] and equivalence in physiophathological mechanisms. All continents are currently affected, and the World Health Organization estimates that 179,111 cases are currently confirmed and 7426 deaths have occurred as of 17 March 2020. These figures are most probably underestimated since 80% of cases may be pauci-symptomatic and 34% asymptomatic [2]. Severe forms with respiratory failure can constitute up to 15% of cases and would be more frequent in patients with cardiovascular comorbidities, diabetes or advanced age [2], which can evolve into an Acute Respiratory Distress Syndrome (ARDS) in a rapid manner. Pathological analysis of a deceased patient revealed the presence of typical ARDS lesions with tissue edema, epithelial desquamation and hyaline membrane formations, associated with lymphocyte infiltration [3]. Due to the high similarity with SARS-Cov (angiotensin-converting enzyme 2 as receptor to penetrate into pulmonary epithelial, leukocytes or endothelial cells), we can assume that cellular damages are equivalent, with rapid viral replication within the pulmonary epithelial cells responsible for capillary leakage, cell apoptosis and a local pro-inflammatory process responsible for lymphocyte influx. In addition, Covid-19 patients present a particular immune profile with lymphopenia, mainly to the detriment of CD4+ and CD8+ T lymphocytes, but also B and NK lymphocytes [2, 4] and hyperneutrophilia with an increase in the Neutrophil/Lymphocyte (N/L) ratio. At the same time, Covid-19 patients present an unbalanced cytokine profile with a predominantly proinflammatory response (Tool Like Receptor 3 and inflammasome activation; Damaged Associated Molecular Patterns and Mitogen-Activated Protein Kinases pathway). Qin et al. [4] demonstrated in a cohort of 452 Covid-19 patients an increase in levels of interleukins IL-2R, IL-6, IL-8, IL-10 and TNFα. In particular, IL-6 levels were especially high in the most severe patients (+90% versus non-severe patients). This point is crucial because IL-6 is known to be highly associated with the severity of critically ill patients, the onset of organ failure and myocardial dysfunction during sepsis [5]. Surgical stress is associated with a change in the immune profile. Patients undergoing major surgery, particularly cardiac, thoracic or abdominal surgery, present increased levels of pro-inflammatory cytokines [6]. IL-6 levels have been described as associated with post-operative complications, with an odds-ratio of 56.4 for the highest levels in a cohort of 96 patients benefiting from thoracic surgery [7]. Moreover, surgical patients often present a modification of their leukocyte profile with a redistribution of lymphocytes from the vascular area to lymphatic tissues, responsible for lymphopenia. Patients undergoing cardiac surgery present immunoparalysis described as an alteration in the expression of monocytic surface protein HLA-DR and an inhibition of monocytic and dendritic functions associated with an increase in the length of stay in intensive care units [6]. HLA-DR is implicated in defenses against pathogens and the reduction in its expression is associated with mortality in severe infections [8] (Fig. 1). Fig. 1 Schematic representation of the main pathophysiological changes induced by both SARS-CoV-2 and surgery. DAMPs, damage associated molecular patterns; IL, interleukins; LT, lymphocytes T; LB, lymphocytes B; LNK, lymphocytes natural killers; TLR, tool like receptor; TNFα, tumor necrosis factor α All these elements allow us to suppose that adding surgical stress to a Covid-19 patient, or conversely developing this infection in an operated patient, may be deleterious in patients undergoing major surgery, particularly after cardiac surgery. This can also be transposed to patients requiring carcinological surgery. Thus, a recently published study by a Chinese team suggests an increased susceptibility to develop a severe SARS-Cov-2 infection in patients with underlying neoplasia, probably due to the underlying immunodepression. Thus, patients operated on or treated in the month prior to infection had a severe form in 75% of cases [9]. In addition, in a cohort study of 154 patients undergoing surgery for colorectal cancer, Xia et al. [10] demonstrated that patients with an N/L ratio >2.8 had an increase in postoperative complications with a 2-year Hazard-ratio for mortality of 5.36 [1.95–14.90]. Because SARS-Cov-2 infection also increases N/L ratio, it questions the legitimity to operate these patients in such setting. In the context of this epidemic, we must evaluate the risk of delaying an intervention for major surgery for more than 6–8 weeks by taking into account the characteristics of the patient and his disease. The theoretical risk of postoperative complications is high, but the evolution of the disease while waiting for the resolution of the epidemic raises questions. The possibilities of alternative therapies or monitoring must be considered on a case-by-case basis. Proposals have very recently been made by Tuech et al. [11] to best adapt the strategy according to the digestive surgical oncological situation, the co-morbidities of the patient and the risks of surgical complications. Restricted access to surgical operating theatres due to the epidemic will make it necessary to adapt the monitoring strategy and to optimize drug therapy to each patient. In the absence of alternative treatment, or waiting treatment, the patient will have to be informed of the appropriate strategy. In this context of expectation, care must be articulated around different key points as proposed by Tuech et al.: Discuss care in multidisciplinary meetings: personalized care plan best suited to the patient disease and the period of the epidemic (dematerialized meetings). Give preference to a therapeutic sequence that does not impose a strict surgical timing that cannot be achieved. Combating undernutrition and dehydration by promoting a balanced diet (nutritional supplement, hydration). Avoid significant damage to the immune system through aggressive treatments (case-by-case discussion of potential stand-by treatments). Avoid hospitalizations, visits, hospital stays that would favor contamination by the virus. Offer psychological support to patients who have to cope with the wait for major surgery (cardiac pathology, cancer) and with the management of the epidemic. In Summary, SARS-Cov-2 infection as well as major surgery induce major inflammatory stress and deregulation of immunity, suggesting an increased risk of post-operative complications and mortality in this subgroup of patients. In the current pandemic context, the surgical indication of major scheduled must take into account the need for public health priorities in terms of the provision of intensive care units and dedicated personnel, as well as the aforementioned data on increased susceptibility to COVID-19 due to immunosuppressive changes around surgery. It would seem legitimate to decide on a case-by-case basis to operate only patients absolutely requiring surgery, based on a multidisciplinary discussion, making it possible to avoid an excess risk to the patient but also to spare the currently strained health system (Fig. 2). Fig. 2 Suggestion of a decisional algorithm for surgical scheduling in epidemic period of Covid-19

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          Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

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            A new coronavirus associated with human respiratory disease in China

            Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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              Pathological findings of COVID-19 associated with acute respiratory distress syndrome

              Since late December, 2019, an outbreak of a novel coronavirus disease (COVID-19; previously known as 2019-nCoV)1, 2 was reported in Wuhan, China, 2 which has subsequently affected 26 countries worldwide. In general, COVID-19 is an acute resolved disease but it can also be deadly, with a 2% case fatality rate. Severe disease onset might result in death due to massive alveolar damage and progressive respiratory failure.2, 3 As of Feb 15, about 66 580 cases have been confirmed and over 1524 deaths. However, no pathology has been reported due to barely accessible autopsy or biopsy.2, 3 Here, we investigated the pathological characteristics of a patient who died from severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by postmortem biopsies. This study is in accordance with regulations issued by the National Health Commission of China and the Helsinki Declaration. Our findings will facilitate understanding of the pathogenesis of COVID-19 and improve clinical strategies against the disease. A 50-year-old man was admitted to a fever clinic on Jan 21, 2020, with symptoms of fever, chills, cough, fatigue and shortness of breath. He reported a travel history to Wuhan Jan 8–12, and that he had initial symptoms of mild chills and dry cough on Jan 14 (day 1 of illness) but did not see a doctor and kept working until Jan 21 (figure 1 ). Chest x-ray showed multiple patchy shadows in both lungs (appendix p 2), and a throat swab sample was taken. On Jan 22 (day 9 of illness), the Beijing Centers for Disease Control (CDC) confirmed by reverse real-time PCR assay that the patient had COVID-19. Figure 1 Timeline of disease course according to days from initial presentation of illness and days from hospital admission, from Jan 8–27, 2020 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. He was immediately admitted to the isolation ward and received supplemental oxygen through a face mask. He was given interferon alfa-2b (5 million units twice daily, atomisation inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy, and moxifloxacin (0·4 g once daily, intravenously) to prevent secondary infection. Given the serious shortness of breath and hypoxaemia, methylprednisolone (80 mg twice daily, intravenously) was administered to attenuate lung inflammation. Laboratory tests results are listed in the appendix (p 4). After receiving medication, his body temperature reduced from 39·0 to 36·4 °C. However, his cough, dyspnoea, and fatigue did not improve. On day 12 of illness, after initial presentation, chest x-ray showed progressive infiltrate and diffuse gridding shadow in both lungs. He refused ventilator support in the intensive care unit repeatedly because he suffered from claustrophobia; therefore, he received high-flow nasal cannula (HFNC) oxygen therapy (60% concentration, flow rate 40 L/min). On day 13 of illness, the patient's symptoms had still not improved, but oxygen saturation remained above 95%. In the afternoon of day 14 of illness, his hypoxaemia and shortness of breath worsened. Despite receiving HFNC oxygen therapy (100% concentration, flow rate 40 L/min), oxygen saturation values decreased to 60%, and the patient had sudden cardiac arrest. He was immediately given invasive ventilation, chest compression, and adrenaline injection. Unfortunately, the rescue was not successful, and he died at 18:31 (Beijing time). Biopsy samples were taken from lung, liver, and heart tissue of the patient. Histological examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates (figure 2A, B ). The right lung showed evident desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome (ARDS; figure 2A). The left lung tissue displayed pulmonary oedema with hyaline membrane formation, suggestive of early-phase ARDS (figure 2B). Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells with atypical enlarged pneumocytes characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing viral cytopathic-like changes. No obvious intranuclear or intracytoplasmic viral inclusions were identified. Figure 2 Pathological manifestations of right (A) and left (B) lung tissue, liver tissue (C), and heart tissue (D) in a patient with severe pneumonia caused by SARS-CoV-2 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. The pathological features of COVID-19 greatly resemble those seen in SARS and Middle Eastern respiratory syndrome (MERS) coronavirus infection.4, 5 In addition, the liver biopsy specimens of the patient with COVID-19 showed moderate microvesicular steatosis and mild lobular and portal activity (figure 2C), indicating the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury. There were a few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue (figure 2D). Peripheral blood was prepared for flow cytometric analysis. We found that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38 (CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells (appendix p 3). Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules, in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive, and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury in this patient. X-ray images showed rapid progression of pneumonia and some differences between the left and right lung. In addition, the liver tissue showed moderate microvesicular steatosis and mild lobular activity, but there was no conclusive evidence to support SARS-CoV-2 infection or drug-induced liver injury as the cause. There were no obvious histological changes seen in heart tissue, suggesting that SARS-CoV-2 infection might not directly impair the heart. Although corticosteroid treatment is not routinely recommended to be used for SARS-CoV-2 pneumonia, 1 according to our pathological findings of pulmonary oedema and hyaline membrane formation, timely and appropriate use of corticosteroids together with ventilator support should be considered for the severe patients to prevent ARDS development. Lymphopenia is a common feature in the patients with COVID-19 and might be a critical factor associated with disease severity and mortality. 3 Our clinical and pathological findings in this severe case of COVID-19 can not only help to identify a cause of death, but also provide new insights into the pathogenesis of SARS-CoV-2-related pneumonia, which might help physicians to formulate a timely therapeutic strategy for similar severe patients and reduce mortality. This online publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on February 25, 2020
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                Author and article information

                Contributors
                emmanuel.besnier@chu-rouen.fr
                Journal
                World J Surg
                World J Surg
                World Journal of Surgery
                Springer International Publishing (Cham )
                0364-2313
                1432-2323
                3 April 2020
                : 1-4
                Affiliations
                [1 ]GRID grid.460771.3, ISNI 0000 0004 1785 9671, Normandie Univ, UNIROUEN, Inserm U1096, FHU- REMOD-VHF, ; 76000 Rouen, France
                [2 ]GRID grid.41724.34, Department of Anesthesiology and Critical Care, Hôpital Charles Nicolle, , Rouen University Hospital, ; 1 Rue de Germont, 76031 Rouen Cedex, France
                [3 ]GRID grid.41724.34, Department of Digestive Surgery, , Rouen University Hospital, ; 1 Rue de Germont, 76031 Rouen Cedex, France
                [4 ]GRID grid.41724.34, Department of Genomic and Personalized Medicine in Cancer and Neurological Disorders, , Normandie Univ, UNIROUEN, UMR 1245 INSERM, Rouen University Hospital, ; 76000 Rouen, France
                Article
                5501
                10.1007/s00268-020-05501-6
                7124188
                31720792
                e2673cdd-0a6f-4398-a227-dbc85688c20f
                © Société Internationale de Chirurgie 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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