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Volume 85  Number 3  March 2021 asamonitor.org

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The Emerging Threat of SARS-CoV-2 Downloaded from http://pubs.asahq.org/monitor/article-pdf/85/3/1/503608/20210300.0-00001.pdf by guest on 02 October 2021 Variants

Richard Simoneaux Steven L. Shafer, MD Editor-in-Chief

he progress of SARS-CoV-2 has For example, the SARS-CoV-2 variant been marked by the emergence of D614G substitutes glycine (G) for aspartate several different genetic variants. (D) in position 614. The D614G variant In a recent Viewpoint article in emerged last spring, simultaneously appear- JAMAT, Lauring and Hodcroft discuss the ing across several geographic regions. Rapid history and background of SARS-CoV-2 spread is strong evidence of a survival ad- variants (JAMA January 2021). vantage, such as greater infectiousness, abil- Many variants substitute one amino acid ity to evade antibodies, or reduced lethality. for another in the “spike protein” – the spike In the case of D614G, the primary benefit observed in the Netherlands and Denmark. ceptor-binding domain (RBD) of the spike on the outside of the virus that makes it look was a substantial increase in infectiousness Among the mutations noted there were protein. This variant helps the virus escape like a WWII underwater mine. These vari- (Science 2020;370:1464-8). many instances of isolated sequences hav- neutralizing antibodies (bioRxiv November ants are typically named by the substitution, In early November 2020, outbreaks of ing a Y453F mutation (tyrosine replaced by 2020). It has since spread to patients in using single letter names for the amino acids. COVID-19 associated with mink farms were phenylalanine at position 453) in the re- Continued on page 3

Exploring the Purdue Pharma Reducing Postoperative Settlement and the Opioid Epidemic Delirium with Intraoperative Gordon Glantz Processed EEG ith lawsuits piling up against fered incentives to physicians and an elec- Jacqueline M. Leung, MD, MPH Daniel J. Cole, MD, FASA drug companies believed tronic health records company for driving Wcomplicit in the opioid crisis, opioid prescriptions. ostoperative delirium is a geriat- Alzheimer’s Disease, as postoperative de- a major precedent was set in November Purdue Pharma – owned by the Sackler ric syndrome associated with pro- lirium typically occurs in patients with 2020 when Purdue Pharma was ordered family since 1952 (when it was known P longed hospital length of stay and prior cognitive impairment. to pay an $8.3 billion settlement. as Purdue-Frederick) – agreed to plead worsened functional and cognitive status Given the powerful effects of general The order from Judge Robert Drain, guilty to three felony criminal counts of after hospital discharge. Despite its preva- anesthetics on the brain and the numer- who described the ruling as a “critical wrongdoing. lence, its pathophysiology is incompletely ous medications surgical patients are ex- building block” to resolve mounting law- According to The Washington Post, understood. Delirium is a complex inter- posed to during and after surgery, some suits against the company, capped off a Purdue – with headquarters in Stamford, play between patient vulnerability and have hypothesized that anesthetics may federal investigation of programs that of- Continued on page 8 precipitating factors. Although surgery is be toxic to the brain, manifested as ad- not a prerequisite for the occurrence of verse postoperative cognitive changes, delirium, the prevalence of postoperative including delirium. Specifically, are SPECIAL SECTION delirium after major surgery in the older we often “overdosing” our patients Our Future: Deskilled or patients is high, ranging from 10%-60% and unnecessarily exposing them to (Psychiatr Clin North Am 1996;19:429- the potential adverse effects of general Super-Skilled? 23-27 48). Understanding the pathophysiology anesthetics? Guest Editor: Uday Jain, BSEE, MD, PhD, FASA of postoperative delirium may also lend Recent advances in anesthesia research insight into revealing the mechanism have focused on neurotoxicity and neu- PERIODICALS underlying neurodegeneration such as Continued on page 12 asamonitor.org 3

In the Know: SARS-CoV-2 Variants As David Cyranoski noted in Nature: Table 1: List of Genes and Mutations in B.1.1.7 SARS-CoV-2- Variant Continued from page 1 “2021 is shaping up to be the year of Gene Nucleotide Mutation Amino Acid Mutation COVID-19 variants” (asamonitor. Denmark, accompanied by three additional ORF1ab C3267T T1001I pub/3o1Fv4X). Intense genomic surveil- mutations (del69_70, I692V, and M1229I). C5388A A1708D lance is required to identify new mutations Taken together, these variants are referred to T6954C I2230T that are spreading in the population. The as “Cluster 5” (asamonitor.pub/35XW6jW). city of Manaus, Brazil, offers a cautionary 11288-11296 deletion 3675-3677 deletion (SGF) Authorities in Denmark quickly locked tale. In October it appeared that Manaus down the area, instituted aggressive testing, Spike (S protein) 21765-21770 deletion 69-70 deletion (HV) had reached herd immunity, with 75% of and culled every mink farm in Denmark. 21991-21993 deletion Y144 deletion the population testing positive for SARS- A23063T N501Y Cluster 5 is now considered extinct. C23271A A570D CoV-2 antibodies (Science 2021;371:288- In December 2020, the U.S. Centers for C23604A P681H 92). This came with enormous loss of life, Disease Control and Prevention (CDC) is- C23709T T716I but hopefully the worst was over. Sadly, sued a statement regarding the emergence T24506G S982A no. Manaus experienced another surge of the B.1.1.7 variant in the UK and the G24914C D1118H in December, linked to a new variant B.1.351 variant in South Africa (asamoni- Orf8 C27972T Q27stop descended from B.1.1.28 (asamonitor. tor.pub/3bVBFbb).* These variants appear G28048T R52I pub/2LN9NLG). The variant might sim- to be responsible for several recent surges, A28111G Y73C ply be more infectious, reaching suscepti- and may complicate efforts to immunize the N 28280 GAT->CTA D3L ble individual previously out of reach, or it world’s population against SARS-CoV-2. C28977T S235F might have escape mutations that permit Downloaded from http://pubs.asahq.org/monitor/article-pdf/85/3/1/503608/20210300.0-00001.pdf by guest on 02 October 2021 reinfection. Either way, the horrific toll of VB.1.1.7 (U.K.) evolved as it was transmitted through mul- two, and may also represent another es- SARS-CoV-2 returned to Manaus in the The first two samples of SARS-CoV-2 that tiple hosts and arose independent of the cape mutation (bioRxiv December 2020). form of a variant. would later be termed the B.1.1.7 lineage B.1.1.7 variant. The evolution of the B.1.1.28 variant has With genomic surveillance we can were obtained in September 2020 from The B.1.351 variant also has the E484K been tracked over many months, showing identify variants and make key therapeu- Kent and greater London (asamonitor. mutation. This is an “escape mutation” that it, like the B1.351 mutation in South tic decisions. Once a variant is identified, pub/2KCxCWc). The B.1.1.7 variant has that may permit the virus to avoid detec- Africa, evolved while passing through we can test whether existing monoclonal an astonishing 17 lineage-defining muta- tion by antibodies (bioRxiv January 2021). multiple hosts. antibodies neutralize the virus. If they fail, tions (Table 1) (JAMA January 2021). The As the authors note: “Some mutations they will likely be clinically ineffective. likely mechanism by which a single strain that reduce serum antibody binding also L452R Variant (California) Clinical guidelines will need to incor- emerged with so many mutations is that reduce viral neutralization by >10 fold. A new variant, L452R, in California has porate geographic prevalence of specific it evolved within a single immunocom- The site where mutations tend to have been tied to several large outbreaks, includ- variants to guide physicians to effective promised host (Science December 2020). the largest effect on binding and neutral- ing an outbreak at the Kaiser Permanente antibody regimens. SARS-CoV-2 evolution within immuno- San Jose Medical Center where a staff A recent study suggests that the Pfizer compromised individuals has been well member in an air-powered Christmas tree and Moderna mRNA vaccines’ “activity documented (medRxiv December 2020; Get vaccinated as soon costume infected 90 individuals (asamon- against SARS-CoV-2 variants encoding N Engl J Med 2020;3838:2291-3; Cell “ itor.pub/3bTyq48; asamonitor.pub/35X- E484K or N501Y … was reduced by a small 2020;183:1901-12). as you can. Reducing AfJk). It is not known whether this but significant margin bioRxiv( January The most significant of these is the variant increases infectiousness or confers 2021). Fortunately, the protein encoded N501Y mutation, which has been associ- the number of infected resistance to antibodies. A paper in Cell in the mRNA vaccines can be changed ated with increased infectivity (medRxiv persons will reduce the last October found that the L452R variant in a few weeks by synthesizing a different January 2021). The B.1.1.7 variant is in- conferred resistance to several monoclo- mRNA incorporating the variant. With creasingly dominant in England and has emergence of variants, nal antibodies, which raises the possibility adequate genomic surveillance, we may be spread to more than 50 other countries. that it is another escape mutation (Cell able to update our mRNA vaccines almost It is projected to soon be the dominant and this may prove a 2020;182:1284-94). as quickly as SARS-CoV-2 is able to mu- strain in the United States (Science News tate, staying ahead of novel variants. January 2021). It appears that present necessary step in bringing Where does this leave us? The key to reducing mutation is to vaccines will be fairly effective against it the pandemic to an end. Relative to viruses such as influenza and reduce viral spread. We know how to do (Science December 2020; bioRxiv January ” HIV, SARS-CoV-2 mutates relatively this! Keep wearing your mask, maintain- 2021). slowly (Pathogens 2020;9:829). However, ing social distancing, avoiding crowds ization is E484, which unfortunately is a in a worldwide pandemic with more than (particularly indoors), and using proper B.1.351 (South Africa) site where mutations are present in several 100 million cases there is plenty of op- hygiene. Get vaccinated as soon as you As the B.1.1.7 variant was emerging in emerging SARS-CoV-2 lineages.” portunity for the virus to randomly test can. Reducing the number of infected England, another complex variant ap- mutations to improve survival. It is not persons will reduce the emergence of vari- peared in South Africa (medRxiv December B.1.1.28 (Brazil) coincidence that D614G, N501Y, and ants, and this may prove a necessary step 2020). The B.1.351 lineage is also charac- Numerous mutations have arisen in Brazil. E484K arose simultaneously in multiple in bringing the pandemic to an end.  terized by numerous mutations in the spike The B.1.1.28 variant has the same N501Y locations, or that they were identified in protein. Initial samples in October 2020 mutation as the B.1.1.7 (UK) and B.1.351 part because of new outbreaks associated *Variant names are confusing and uninterpretable. The displayed the previously noted D614G as (South Africa) variants. The B.1.1.28 vari- with these mutations. That is how evolu- author (SLS) has suggested following the convention for naming hurricanes and having SARS-CoV-2 variant names well as five additional mutations. By the ant also has the same E484K escape muta- tion works. assigned by the World Meteorological Organization. end of November, investigators identified tion found in the B.1.351 (South Africa) multiple additional mutations including lineage (asamonitor.pub/3o5RWwx). The the N501Y mutation that increases in- presence of the E484K mutation in the The Best Science in Anesthesiology fectiousness. Identification of multiple first documented case of reinfection in lineages implies that the B.1.351 variant Brazil is consistent with the possibility of and Critical Care the mutation evading existing humoral The respected Anesthesiology® journal brings you the latest breakthroughs Richard Simoneaux is a freelance writer with an MS in organic chemistry from Indiana University immunity (asamonitor.pub/3sL74mW). in perioperative, critical care and pain medicine. Listen to the podcast for and more than 15 years of experience covering the The B.1.1.28 variant also has a K417N highlights or read the full issue at anesthesiology.org. pharmaceutical industry and an additional seven years as a laboratory-based medicinal chemist. mutation that does not appear in the other