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      Ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii in patients with COVID-19: Two problems, one solution?

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          Abstract

          Dear editor, In late 2019, a cluster of pneumonia cases reported from Wuhan City (Hubei Province, China) were associated with a novel betacoronavirus, first called the 2019 novel coronavirus (2019-nCov) [1]. Posteriorly, the sequence of 2019-nCov genome reveled 89% similarity and 80% identity with SARS-CoV, the causative agent of the 2002–2003 pandemic of severe and acute respiratory syndrome (SARS). Since then, the International Committee on Taxonomy of Viruses renamed the 2019-nCov as SARS-CoV-2, and the World Health Organization (WHO) defined that this pathogen causes the coronavirus disease of 2019 (COVID-19) [2], [3], [4]. The outbreak of COVID-19 started in Wuhan quickly spread worldwide, and in March 11th, 2020 the WHO declared a pandemic state. By June 20th, 2020, SARS-CoV-2 had infected 14,668,298 people and caused 609,511 deaths in almost all countries around the world [5]. The symptoms of COVID-19 can range from mild, self-limiting respiratory tract illness to severe progressive pneumonia, which can evolve to multiorgan failure and death [1]. Patients with severe COVID-19 usually need endotracheal intubation and mechanical ventilation due to airway failure. For instance, two-thirds of patients with COVID-19 who required critical care in the UK needed mechanical ventilation within 24 h of admission, following by immediately transfer to intensive care units (ICUs) [6], [7]. Importantly, patients with tracheal intubation and mechanical ventilation are at increased risk to acquire bacterial ICU-pneumonia [8]. Thus, Deng et al. [9] analyzed electronic medical records of 25 patients with COVID-19 in Renmin Hospital at Wuhan University and showed that bacterial pneumonia might be associated with the death of patients with the novel coronavirus. Likewise, Wang et al. [10] showed that the levels of procalcitonin, a bacterial infection marker, are almost four times higher in patients who died from COVID-19 than in those who recovered from the disease. Also, a study with 11 patients showed that cases of COVID-19 associated with bacterial pneumonia were considerably more severe [11]. These findings indicate that ventilator-associated pneumonia (VAP) could worsen the clinical condition of COVID-19 patients, requiring special attention by health professionals. Gram-negative bacilli have been detected in sputum and tracheal aspirates cultures of mechanically ventilated patients with severe COVID-19 [11], [12]. Lescure and collaborators (2020) identified Acinetobacter baumannii as the causative agent of VAP in a patient infected by SARS-CoV-2 [12]. A. baumannii is an aerobic Gram-negative opportunistic, glucose non-fermentative, and non-motile coccobacillus commonly found in various environments, such as soil and water. This bacterium can adhere to medical devices (including the system used for mechanical ventilation) and survive up to 33 days in dry surfaces [13], [14], [15]. Furthermore, the acquisition of multiple drug resistance, especially to carbapenems, has made this pathogen a major public health concern [16]. A. baumannii is responsible for approximately 47% of VAP cases in ICUs [17]. It is commonly resistant to disinfection, and the production of a polysaccharide capsule and formation of biofilms contribute to the high pathogenicity of this bacterium [13], [14], [15]. More importantly, patients with severe COVID-19 usually present the main risk factors observed to VAP caused by A. baumannii (i.e., hypertension, chronic obstructive pulmonary disease, chronic renal failure, length of ICU stay, presence of organ failure, and low blood oxygenation level) [18], [19], [20]. Thus, rigid application of infection control precautions should be taken to prevent infections by A. baumannii in patients with COVID-19 on mechanical ventilation. Carbapenem antibiotics are considered the last therapeutic option to treat VAP caused by multidrug-resistant A. baumannii [21]. However, since 1991, when the first carbapenem-resistant A. baumannii (CRAB) was reported, a considerable increase in the number of these resistant strains has been documented worldwide [22], [23]. In 2015 in Greece, 94.5% of A. baumannii isolates were resistant to imipenem, while in North American hospitals (2008), 58% of the strains were identified as CRAB [23]. Colistin, also known as polymyxin E, is considered one of the last therapeutic options to treat CRAB infections. However, it is highly nephron- and neurotoxic [24], so that its intravenous use in critically ill patients with COVID-19 and co-infection with CRAB must be closely monitored. On the other hand, nebulized colistin increases the concentration of this drug in the infection site, decreasing kidney and nerve damage due to its limited systemic distribution [25]. Thus, we hypothesize that the use of nebulized colistin is a reasonable choice for most critically ill patients with COVID-19 co-infected with carbapenem-resistant Gram-negative pathogens. Interestingly, the use of nebulized colistin may also improve the outcomes of pulmonary infections by SARS-CoV-2. Haukenes and Bjerkestrand (1973) showed that polymyxin B, a drug from the same pharmacological class as colistin, reduced the cytopathogenic effect of the enveloped viruses Mumps and Herpes simplex [26]. We hypothesize that this antibiotic might protect the cells against the deleterious effects of the enveloped virus by negatively interacting with the lipidic component of the viral envelope. Since SARS-CoV-2 is an enveloped virus [4], it might be susceptible to this effect of polymyxins. However, to date, no evidence of their biological activity has been found. A theoretical study suggested that colistin may interact with proteins involved in the replication cycle of the novel coronavirus. This polymyxin can form hydrogen bonds with the amino acid residues Thr24, Thr25, and Thr26, which are crucial to the enzymatic activity of the main protease (Mpro) of SARS-CoV-2 (also known as 3C-like protease) [27]. Mpro, a key enzyme for coronavirus replication, is responsible for processing the viral polypeptide into structural and functional proteins [4]. The screening and treatment of bacterial co-infection, especially VAP, is essential to ensure a better clinical outcome in patients with severe COVID-19. The isolation of A. baumannii from patients with COVID-19 highlighted the importance of preventing co-infections caused by this pathogen, which depending on the regional endemicity may be associated with resistance to carbapenems. In these cases, we hypothesize that patients would benefit from the use of nebulized colistin due to its low systemic toxicity. Additionally, we encourage studies to characterize possible therapeutic benefits of the inhaled use of colistin in severe cases of COVID-19 and to determine the potential antiviral of this polymyxin in vitro against SARS-CoV-2. However, the use of this drug should be performed only when strictly necessary since colistin is an antibiotic considered the ultimate resort, and resistance to this class usually results in intractable infections. Sources of support in the form of grants None. Declaration of Competing Interest 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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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            The proximal origin of SARS-CoV-2

            To the Editor — Since the first reports of novel pneumonia (COVID-19) in Wuhan, Hubei province, China 1,2 , there has been considerable discussion on the origin of the causative virus, SARS-CoV-2 3 (also referred to as HCoV-19) 4 . Infections with SARS-CoV-2 are now widespread, and as of 11 March 2020, 121,564 cases have been confirmed in more than 110 countries, with 4,373 deaths 5 . SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERS-CoV and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms 6 . Here we review what can be deduced about the origin of SARS-CoV-2 from comparative analysis of genomic data. We offer a perspective on the notable features of the SARS-CoV-2 genome and discuss scenarios by which they could have arisen. Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus. Notable features of the SARS-CoV-2 genome Our comparison of alpha- and betacoronaviruses identifies two notable genomic features of SARS-CoV-2: (i) on the basis of structural studies 7–9 and biochemical experiments 1,9,10 , SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2; and (ii) the spike protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1–S2 boundary through the insertion of 12 nucleotides 8 , which additionally led to the predicted acquisition of three O-linked glycans around the site. 1. Mutations in the receptor-binding domain of SARS-CoV-2 The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome 1,2 . Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses 7 . With coordinates based on SARS-CoV, they are Y442, L472, N479, D480, T487 and Y4911, which correspond to L455, F486, Q493, S494, N501 and Y505 in SARS-CoV-2 7 . Five of these six residues differ between SARS-CoV-2 and SARS-CoV (Fig. 1a). On the basis of structural studies 7–9 and biochemical experiments 1,9,10 , SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from humans, ferrets, cats and other species with high receptor homology 7 . Fig. 1 Features of the spike protein in human SARS-CoV-2 and related coronaviruses. a, Mutations in contact residues of the SARS-CoV-2 spike protein. The spike protein of SARS-CoV-2 (red bar at top) was aligned against the most closely related SARS-CoV-like coronaviruses and SARS-CoV itself. Key residues in the spike protein that make contact to the ACE2 receptor are marked with blue boxes in both SARS-CoV-2 and related viruses, including SARS-CoV (Urbani strain). b, Acquisition of polybasic cleavage site and O-linked glycans. Both the polybasic cleavage site and the three adjacent predicted O-linked glycans are unique to SARS-CoV-2 and were not previously seen in lineage B betacoronaviruses. Sequences shown are from NCBI GenBank, accession codes MN908947, MN996532, AY278741, KY417146 and MK211376. The pangolin coronavirus sequences are a consensus generated from SRR10168377 and SRR10168378 (NCBI BioProject PRJNA573298) 29,30 . While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal 7 and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding 7,11 . Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation. 2. Polybasic furin cleavage site and O-linked glycans The second notable feature of SARS-CoV-2 is a polybasic cleavage site (RRAR) at the junction of S1 and S2, the two subunits of the spike 8 (Fig. 1b). This allows effective cleavage by furin and other proteases and has a role in determining viral infectivity and host range 12 . In addition, a leading proline is also inserted at this site in SARS-CoV-2; thus, the inserted sequence is PRRA (Fig. 1b). The turn created by the proline is predicted to result in the addition of O-linked glycans to S673, T678 and S686, which flank the cleavage site and are unique to SARS-CoV-2 (Fig. 1b). Polybasic cleavage sites have not been observed in related ‘lineage B’ betacoronaviruses, although other human betacoronaviruses, including HKU1 (lineage A), have those sites and predicted O-linked glycans 13 . Given the level of genetic variation in the spike, it is likely that SARS-CoV-2-like viruses with partial or full polybasic cleavage sites will be discovered in other species. The functional consequence of the polybasic cleavage site in SARS-CoV-2 is unknown, and it will be important to determine its impact on transmissibility and pathogenesis in animal models. Experiments with SARS-CoV have shown that insertion of a furin cleavage site at the S1–S2 junction enhances cell–cell fusion without affecting viral entry 14 . In addition, efficient cleavage of the MERS-CoV spike enables MERS-like coronaviruses from bats to infect human cells 15 . In avian influenza viruses, rapid replication and transmission in highly dense chicken populations selects for the acquisition of polybasic cleavage sites in the hemagglutinin (HA) protein 16 , which serves a function similar to that of the coronavirus spike protein. Acquisition of polybasic cleavage sites in HA, by insertion or recombination, converts low-pathogenicity avian influenza viruses into highly pathogenic forms 16 . The acquisition of polybasic cleavage sites by HA has also been observed after repeated passage in cell culture or through animals 17 . The function of the predicted O-linked glycans is unclear, but they could create a ‘mucin-like domain’ that shields epitopes or key residues on the SARS-CoV-2 spike protein 18 . Several viruses utilize mucin-like domains as glycan shields involved immunoevasion 18 . Although prediction of O-linked glycosylation is robust, experimental studies are needed to determine if these sites are used in SARS-CoV-2. Theories of SARS-CoV-2 origins It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus. As noted above, the RBD of SARS-CoV-2 is optimized for binding to human ACE2 with an efficient solution different from those previously predicted 7,11 . Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used 19 . However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone 20 . Instead, we propose two scenarios that can plausibly explain the origin of SARS-CoV-2: (i) natural selection in an animal host before zoonotic transfer; and (ii) natural selection in humans following zoonotic transfer. We also discuss whether selection during passage could have given rise to SARS-CoV-2. 1. Natural selection in an animal host before zoonotic transfer As many early cases of COVID-19 were linked to the Huanan market in Wuhan 1,2 , it is possible that an animal source was present at this location. Given the similarity of SARS-CoV-2 to bat SARS-CoV-like coronaviruses 2 , it is likely that bats serve as reservoir hosts for its progenitor. Although RaTG13, sampled from a Rhinolophus affinis bat 1 , is ~96% identical overall to SARS-CoV-2, its spike diverges in the RBD, which suggests that it may not bind efficiently to human ACE2 7 (Fig. 1a). Malayan pangolins (Manis javanica) illegally imported into Guangdong province contain coronaviruses similar to SARS-CoV-2 21 . Although the RaTG13 bat virus remains the closest to SARS-CoV-2 across the genome 1 , some pangolin coronaviruses exhibit strong similarity to SARS-CoV-2 in the RBD, including all six key RBD residues 21 (Fig. 1). This clearly shows that the SARS-CoV-2 spike protein optimized for binding to human-like ACE2 is the result of natural selection. Neither the bat betacoronaviruses nor the pangolin betacoronaviruses sampled thus far have polybasic cleavage sites. Although no animal coronavirus has been identified that is sufficiently similar to have served as the direct progenitor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled. Mutations, insertions and deletions can occur near the S1–S2 junction of coronaviruses 22 , which shows that the polybasic cleavage site can arise by a natural evolutionary process. For a precursor virus to acquire both the polybasic cleavage site and mutations in the spike protein suitable for binding to human ACE2, an animal host would probably have to have a high population density (to allow natural selection to proceed efficiently) and an ACE2-encoding gene that is similar to the human ortholog. 2. Natural selection in humans following zoonotic transfer It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system that detected it 1,2 . All SARS-CoV-2 genomes sequenced so far have the genomic features described above and are thus derived from a common ancestor that had them too. The presence in pangolins of an RBD very similar to that of SARS-CoV-2 means that we can infer this was also probably in the virus that jumped to humans. This leaves the insertion of polybasic cleavage site to occur during human-to-human transmission. Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made with current sequence data point to emergence of the virus in late November 2019 to early December 2019 23 , compatible with the earliest retrospectively confirmed cases 24 . Hence, this scenario presumes a period of unrecognized transmission in humans between the initial zoonotic event and the acquisition of the polybasic cleavage site. Sufficient opportunity could have arisen if there had been many prior zoonotic events that produced short chains of human-to-human transmission over an extended period. This is essentially the situation for MERS-CoV, for which all human cases are the result of repeated jumps of the virus from dromedary camels, producing single infections or short transmission chains that eventually resolve, with no adaptation to sustained transmission 25 . Studies of banked human samples could provide information on whether such cryptic spread has occurred. Retrospective serological studies could also be informative, and a few such studies have been conducted showing low-level exposures to SARS-CoV-like coronaviruses in certain areas of China 26 . Critically, however, these studies could not have distinguished whether exposures were due to prior infections with SARS-CoV, SARS-CoV-2 or other SARS-CoV-like coronaviruses. Further serological studies should be conducted to determine the extent of prior human exposure to SARS-CoV-2. 3. Selection during passage Basic research involving passage of bat SARS-CoV-like coronaviruses in cell culture and/or animal models has been ongoing for many years in biosafety level 2 laboratories across the world 27 , and there are documented instances of laboratory escapes of SARS-CoV 28 . We must therefore examine the possibility of an inadvertent laboratory release of SARS-CoV-2. In theory, it is possible that SARS-CoV-2 acquired RBD mutations (Fig. 1a) during adaptation to passage in cell culture, as has been observed in studies of SARS-CoV 11 . The finding of SARS-CoV-like coronaviruses from pangolins with nearly identical RBDs, however, provides a much stronger and more parsimonious explanation of how SARS-CoV-2 acquired these via recombination or mutation 19 . The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios. New polybasic cleavage sites have been observed only after prolonged passage of low-pathogenicity avian influenza virus in vitro or in vivo 17 . Furthermore, a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described. Subsequent generation of a polybasic cleavage site would have then required repeated passage in cell culture or animals with ACE2 receptors similar to those of humans, but such work has also not previously been described. Finally, the generation of the predicted O-linked glycans is also unlikely to have occurred due to cell-culture passage, as such features suggest the involvement of an immune system 18 . Conclusions In the midst of the global COVID-19 public-health emergency, it is reasonable to wonder why the origins of the pandemic matter. Detailed understanding of how an animal virus jumped species boundaries to infect humans so productively will help in the prevention of future zoonotic events. For example, if SARS-CoV-2 pre-adapted in another animal species, then there is the risk of future re-emergence events. In contrast, if the adaptive process occurred in humans, then even if repeated zoonotic transfers occur, they are unlikely to take off without the same series of mutations. In addition, identifying the closest viral relatives of SARS-CoV-2 circulating in animals will greatly assist studies of viral function. Indeed, the availability of the RaTG13 bat sequence helped reveal key RBD mutations and the polybasic cleavage site. The genomic features described here may explain in part the infectiousness and transmissibility of SARS-CoV-2 in humans. Although the evidence shows that SARS-CoV-2 is not a purposefully manipulated virus, it is currently impossible to prove or disprove the other theories of its origin described here. However, since we observed all notable SARS-CoV-2 features, including the optimized RBD and polybasic cleavage site, in related coronaviruses in nature, we do not believe that any type of laboratory-based scenario is plausible. More scientific data could swing the balance of evidence to favor one hypothesis over another. Obtaining related viral sequences from animal sources would be the most definitive way of revealing viral origins. For example, a future observation of an intermediate or fully formed polybasic cleavage site in a SARS-CoV-2-like virus from animals would lend even further support to the natural-selection hypotheses. It would also be helpful to obtain more genetic and functional data about SARS-CoV-2, including animal studies. The identification of a potential intermediate host of SARS-CoV-2, as well as sequencing of the virus from very early cases, would similarly be highly informative. Irrespective of the exact mechanisms by which SARS-CoV-2 originated via natural selection, the ongoing surveillance of pneumonia in humans and other animals is clearly of utmost importance.
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              Coronavirus Disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up

              Highlights • COVID-19 in the elderly patients was severe and highly fatal • COVID-19 progressed rapidly in patients who died • Cardiovascular disease, COPD, dyspnea, lymphocytopenia and ARDS predict mortality • The elderly patients need close monitoring and timely treatment
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                Author and article information

                Journal
                Med Hypotheses
                Med Hypotheses
                Medical Hypotheses
                Elsevier Ltd.
                0306-9877
                1532-2777
                25 July 2020
                November 2020
                25 July 2020
                : 144
                : 110139
                Affiliations
                [a ]Researcher of the Group (CNPq) for Epidemiological, Economic and Pharmacological Studies of Arboviruses (EEPIFARBO), Brazil
                [b ]Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
                [c ]Ezequiel Dias Foundation (FUNED), Belo Horizonte, MG, Brazil
                [d ]Carleton University, Ottawa, Ontario, Canada
                Author notes
                [* ]Corresponding author at: Faculdade de Farmácia, Campus Pampulha, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil.
                [1]

                ORCID: 0000-0001-8946-9363.

                Article
                S0306-9877(20)32318-5 110139
                10.1016/j.mehy.2020.110139
                7833701
                32758905
                d7c7b916-fd9f-4e38-9676-2eec8dcbb933
                © 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.

                History
                : 20 July 2020
                : 23 July 2020
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