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Defective viral RNA sensing gene OAS1 linked to severe COVID-19

Reporter: Stephen J. Williams, Ph.D.

Source: https://www.science.org/doi/10.1126/science.abm3921

Defective viral RNA sensing linked to severe COVID-19

JOHN SCHOGGINS SCIENCE•28 Oct 2021•Vol 374, Issue 6567•pp. 535-536•DOI: 10.1126/science.abm39214,824

Why do some people with COVID-19 get sicker than others? Maybe exposure to a particularly high dose of the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accounts for the difference. Perhaps deficiencies in diet, exercise, or sleep contribute to worse illness. Although many factors govern how sick people become, a key driver of the severity of COVID-19 appears to be genetic, which is common for other human viruses and infectious agents (1). On page 579 of this issue, Wickenhagen et al. (2) show that susceptibility to severe COVID-19 is associated with a single-nucleotide polymorphism (SNP) in the human gene 2′-5′-oligoadenylate synthetase 1 (OAS1).The authors reasoned that SARS-CoV-2 should be inhibited by interferon-mediated antiviral responses, which are among the first cellular defense mechanisms produced in response to a viral infection. Interferons are a group of cytokines that induce the transcription of a large cadre of genes, many of which encode proteins with the potential to directly inhibit the invading virus. Wickenhagen et al. interrogated many hundreds of these putative antiviral proteins for their ability to suppress SARS-CoV-2 in cultured cells and found that OAS1 was particularly potent against SARS-CoV-2.OAS1 is an enzyme that is activated in the presence of double-stranded RNA, which is scattered along an otherwise singlestranded SARS-CoV-2 genome because of an assortment of RNA hairpins and other secondary structures. Once activated, OAS1 catalyzes the polymerization of adenosine triphosphate (ATP) into a second messenger, 2′-5′-oligoadenylate. This then triggers the conversion of ribonuclease L (RNaseL) into its active form so that it can cleave viral RNA, effectively blunting viral replication (3). Wickenhagen et al. found that OAS1 is expressed in respiratory tissues of healthy donors and COVID-19 patients and that it interacts with a region of the SARS-CoV-2 genome that contains double-stranded RNA secondary structures (see the figure).OAS1 exists predominantly as two isoforms in humans—a longer isoform (p46) and a shorter version (p42). Genetic variation dictates which isoform will be expressed. In humans, p46 is expressed in people who have a SNP that causes alternative splicing of the OAS1 messenger RNA (mRNA). This results in the utilization of a terminal exon that is not used to translate p42. Thus, the carboxyl terminus of the p46 OAS1 protein contains a distinct four–amino acid motif that forms a prenylation site. Prenylation is a posttranslational modification that targets proteins to membranes. In cell culture experiments, Wickenhagen et al. showed that only OAS1 p46, but not p42, could inhibit SARS-CoV-2. However, when the prenylation site of p46 was engineered into p42, this chimeric p42 protein was able to inhibit SARS-CoV-2, which strongly implicates a role for OAS1 specifically at membranes.Why are membranes important? SARS-CoV-2, like all coronaviruses, co-opts cellular membranes at the endoplasmic reticulum to form double-membrane vesicles, in which the virus replicates its genome. Thus, membrane-bound OAS1 p46 may be specifically activated by RNA viruses that form membrane-bound vesicles for replication. Indeed, the unrelated cardiovirus A, which also forms vesicular membranous structures, was inhibited by OAS1. Conversely, other respiratory RNA viruses, such as human parainfluenza virus type 3 and human respiratory syncytial virus, which do not use membrane-tethered vesicles for replication, were not inhibited by p46.Wickenhagen et al. examined a cohort of 499 COVID-19 patients hospitalized in the UK. Whereas all patients expressed OAS1, 42.5% of them did not express the antiviral p46 isoform. These patients were statistically more likely to have severe COVID-19 (be admitted to the intensive care unit). This suggests that OAS1 is an important antiviral factor in the control of SARS-CoV-2 infection and that its inability to activate RNaseL results in prolonged infections and severe disease, although other factors likely contribute. The authors also examined animals known to harbor different coronaviruses. They found evidence for prenylated OAS1 proteins in mice, cows, and camels. Notably, horseshoe bats, which are considered a possible reservoir for SARS-related coronaviruses (4), lack a prenylation motif in their OAS1 because of genomic changes that eliminated the critical four-amino acid motif. A horseshoe bat (Rhinolophus ferrumequinum) OAS1 was unable to inhibit SARS-CoV-2 infection in cell culture. Conversely, the black flying fox (Pteropus alecto)—a pteropid bat that is a reservoir for the Nipah and Hendra viruses, which can also infect humans—possesses a prenylated OAS1 that can inhibit SARS-CoV-2. These findings indicate that horseshoe bats may be genetically and evolutionarily primed to be optimal reservoir hosts for certain coronaviruses, like SARS-CoV-2.Other studies have now shown that the p46 OAS1 variant, which resides in a genomic locus inherited from Neanderthals (57), correlates with protection from COVID-19 severity in various populations (89). These findings mirror previous studies indicating that outcomes with West Nile virus (10) and hepatitis C virus (11) infection, both of which also use membrane vesicles for replication, are also associated with genetic variation at the human OAS1 locus. Another elegant functional study complements the findings of Wickenhagen et al. by also demonstrating that prenylated OAS1 inhibits multiple viruses, including SARS-CoV-2, and is associated with protection from severe COVID-19 in patients (12).There is a growing body of evidence that provides critical understanding of how human genetic variation shapes the outcome of infectious diseases like COVID-19. In addition to OAS1, genetic variation in another viral RNA sensor, Toll-like receptor 7 (TLR7), is associated with severe COVID-19 (1315). The effects appear to be exclusive to males, because TLR7 is on the X chromosome, so inherited deleterious mutations in TLR7 therefore result in immune cells that fail to produce normal amounts of interferon, which correlates with more severe COVID-19. Our knowledge of the host cellular factors that control SARS-CoV-2 is rapidly increasing. These findings will undoubtedly open new avenues into SARS-CoV-2 antiviral immunity and may also be beneficial for the development of strategies to treat or prevent severe COVID-19.

References and Notes

1J. L. Casanova, Proc. Natl. Acad. Sci. U.S.A.112, E7118 (2015).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR2A. Wickenhagen et al., Science374, eabj3624 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR3H. Kristiansen, H. H. Gad, S. Eskildsen-Larsen, P. Despres, R. Hartmann, J. Interferon Cytokine Res.31, 41 (2011).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR4S. Lytras, W. Xia, J. Hughes, X. Jiang, D. L. Robertson, Science373, 968 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR5S. Zhou et al., Nat. Med.27, 659 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR6H. Zeberg, S. Pääbo, Proc. Natl. Acad. Sci. U.S.A.118, e2026309118 (2021).CROSSREFPUBMEDGOOGLE SCHOLAR7F. L. Mendez, J. C. Watkins, M. F. Hammer, Mol. Biol. Evol.30, 798 (2013).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR8A. R. Banday et al., medRxiv2021).GO TO REFERENCECROSSREFGOOGLE SCHOLAR9E. Pairo-Castineira et al., Nature591, 92 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR10J. K. Lim et al., PLOS Pathog.5, e1000321 (2009).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR11M. K. El Awady et al., J. Gastroenterol. Hepatol.26, 843 (2011).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR12F. W. Soveg et al., eLife10, e71047 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR13T. Asano et al., Sci. Immunol.6, eabl4348 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR14C. Fallerini et al., eLife10, e67569 (2021).CROSSREFPUBMEDGOOGLE SCHOLAR15C. I. van der Made et al., JAMA324, 663 (2020).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR

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The NIH-funded adjuvant improves the efficacy of India’s COVID-19 vaccine.

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID), Part of National Institute of Health (NIH) said,

Ending a global pandemic demands a global response. I am thrilled that a novel vaccine adjuvant developed in the United States with NIAID support is now included in an effective COVID-19 vaccine that is available to individuals in India.”

Adjuvants are components that are created as part of a vaccine to improve immune responses and increase the efficiency of the vaccine. COVAXIN was developed and is manufactured in India, which is currently experiencing a terrible health catastrophe as a result of COVID-19. An adjuvant designed with NIH funding has contributed to the success of the extremely effective COVAXIN-COVID-19 vaccine, which has been administered to about 25 million individuals in India and internationally.

Alhydroxiquim-II is the adjuvant utilized in COVAXIN, was discovered and validated in the laboratory by the biotech company ViroVax LLC of Lawrence, Kansas, with funding provided solely by the NIAID Adjuvant Development Program. The adjuvant is formed of a small molecule that is uniquely bonded to Alhydrogel, often known as alum and the most regularly used adjuvant in human vaccines. Alhydroxiquim-II enters lymph nodes, where it detaches from alum and triggers two cellular receptors. TLR7 and TLR8 receptors are essential in the immunological response to viruses. Alhydroxiquim-II is the first adjuvant to activate TLR7 and TLR8 in an approved vaccine against an infectious disease. Additionally, the alum in Alhydroxiquim-II activates the immune system to look for an infiltrating pathogen.

Although molecules that activate TLR receptors strongly stimulate the immune system, the adverse effects of Alhydroxiquim-II are modest. This is due to the fact that after COVAXIN is injected, the adjuvant travels directly to adjacent lymph nodes, which contain white blood cells that are crucial in recognizing pathogens and combating infections. As a result, just a minimal amount of Alhydroxiquim-II is required in each vaccination dosage, and the adjuvant does not circulate throughout the body, avoiding more widespread inflammation and unwanted side effects.

This scanning electron microscope image shows SARS-CoV-2 (round gold particles) emerging from the surface of a cell cultured in the lab. SARS-CoV-2, also known as 2019-nCoV, is the virus that causes COVID-19. Image Source: NIAID

COVAXIN is made up of a crippled version of SARS-CoV-2 that cannot replicate but yet encourages the immune system to produce antibodies against the virus. The NIH stated that COVAXIN is “safe and well tolerated,” citing the results of a phase 2 clinical investigation. COVAXIN safety results from a Phase 3 trial with 25,800 participants in India will be released later this year. Meanwhile, unpublished interim data from the Phase 3 trial show that the vaccine is 78% effective against symptomatic sickness, 100% effective against severe COVID-19, including hospitalization, and 70% effective against asymptomatic infection with SARS-CoV-2, the virus that causes COVID-19. Two tests of blood serum from persons who had received COVAXIN suggest that the vaccine creates antibodies that efficiently neutralize the SARS-CoV-2 B.1.1.7 (Alpha) and B.1.617 (Delta) variants (1) and (2), which were originally identified in the United Kingdom and India, respectively.

Since 2009, the NIAID Adjuvant Program has supported the research of ViroVax’s founder and CEO, Sunil David, M.D., Ph.D. His research has focused on the emergence of new compounds that activate innate immune receptors and their application as vaccination adjuvants.

Dr. David’s engagement with Bharat Biotech International Ltd. of Hyderabad, which manufactures COVAXIN, began during a 2019 meeting in India organized by the NIAID Office of Global Research under the auspices of the NIAID’s Indo-US Vaccine Action Program. Five NIAID-funded adjuvant investigators, including Dr. David, two representatives of the NIAID Division of Allergy, Immunology, and Transplantation, and the NIAID India representative, visited 4 top biotechnology companies to learn about their work and discuss future collaborations. The delegation also attended a consultation in New Delhi, which was co-organized by the NIAID and India’s Department of Biotechnology and hosted by the National Institute of Immunology.

Among the scientific collaborations spawned by these endeavors was a licensing deal between Bharat Biotech and Dr. David to use Alhydroxiquim-II in their candidate vaccines. During the COVID-19 outbreak, this license was expanded to cover COVAXIN, which has Emergency Use Authorization in India and more than a dozen additional countries. COVAXIN was developed by Bharat Biotech in partnership with the Indian Council of Medical Research’s National Institute of Virology. The company conducted thorough safety research on Alhydroxiquim-II and undertook the arduous process of scaling up production of the adjuvant in accordance with Good Manufacturing Practice standards. Bharat Biotech aims to generate 700 million doses of COVAXIN by the end of 2021.

NIAID conducts and supports research at the National Institutes of Health, across the United States, and across the world to better understand the causes of infectious and immune-mediated diseases and to develop better methods of preventing, detecting, and treating these illnesses. The NIAID website contains news releases, info sheets, and other NIAID-related materials.

Main Source:

https://www.miragenews.com/adjuvant-developed-with-nih-funding-enhances-587090/

References

  1. https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciab411/6271524?redirectedFrom=fulltext
  2. https://academic.oup.com/jtm/article/28/4/taab051/6193609

Other Related Articles published in this Open Access Online Scientific Journal include the following:

Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/08/comparing-covid-19-vaccine-schedule-combinations-or-com-cov-first-of-its-kind-study-will-explore-the-impact-of-using-eight-different-combinations-of-doses-and-dosing-intervals-for-diffe/

Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development

Reporter:Amandeep Kaur, B.Sc., M.Sc.

https://pharmaceuticalintelligence.com/2021/05/04/thriving-vaccines-and-research-weizmann-coronavirus-research-development/

National Public Radio interview with Dr. Anthony Fauci on his optimism on a COVID-19 vaccine by early 2021

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/07/19/national-public-radio-interview-with-dr-anthony-fauci-on-his-optimism-on-a-covid-19-vaccine-by-early-2021/

Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

https://pharmaceuticalintelligence.com/2021/04/10/cryo-em-disclosed-how-the-d614g-mutation-changes-sars-cov-2-spike-protein-structure/

Updates on the Oxford, AstraZeneca COVID-19 Vaccine

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/06/16/updates-on-the-oxford-astrazeneca-covid-19-vaccine/

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Covid-19 and its implications on pregnancy

Reporter and Curator: Mr. Srinjoy Chakraborty (Junior Research Felllow) and Dr. Sudipta Saha, Ph.D.

Coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emerged as a serious global health issue with high transmission rates affecting millions of people worldwide. The SARS-CoV-2 is known to damage cells in the respiratory system, thus causing viral pneumonia. The novel SARS-CoV-2 is a close relative to the previously identified severe acute respiratory syndrome-coronavirus (SARS-CoV) and Middle East respiratory syndrome-coronavirus (MERS-CoV) which affected several people in 2002 and 2012, respectively. Ever since the outbreak of covid-19, several reports have poured in about the impact of Covid-19 on pregnancy. A few studies have highlighted the impact of the viral infection in pregnant women and how they are more susceptible to the infection because of the various physiological changes of the cardiopulmonary and immune systems during pregnancy. It is known that SARS-CoV and MERS-CoV diseases have influenced the fatality rate among pregnant women. However, there are limited studies on the impact of the novel corona virus on the course and outcome of pregnancy.

Figure: commonly observed clinical symptoms of COVID-19 in the general population: Fever and cough, along with dyspnoea, diarrhoea, and malaise are the most commonly observed symptoms in pregnant women, which is similar to that observed in the normal population.

The WHO and the Indian Council of Medical Research (ICMR) have proposed detailed guidelines for treating pregnant women; these guidelines must be strictly followed by the pregnant individual and their families. According to the guidelines issued by the ICMR, the risk of pregnant women contracting the virus to that of the general population. However, the immune system and the body’s response to a viral infection is altered during pregnancy. This may result in the manifestation of more severe symptoms. The ICMR guidelines also state that the reported cases of COVID-19 pneumonia in pregnancy are milder and with good recovery. However, by observing the trends of the other coronavirus infection (SARS, MERS), the risks to the mother appear to increase in particular during the last trimester of pregnancy. Cases of preterm birth in women with COVID-19 have been mentioned in a few case report, but it is unclear whether the preterm birth was always iatrogenic, or whether some were spontaneous. Pregnant women with heart disease are at highest risk of acquiring the infection, which is similar to that observed in the normal population. Most importantly, the ICMR guidelines highlights the impact of the coronavirus epidemic on the mental health of pregnant women. It mentions that the since the pandemic has begun, there has been an increase in the risk of perinatal anxiety and depression, as well as domestic violence. It is critically important that support for women and families is strengthened as far as possible; that women are asked about mental health at every contact.

With the available literature available on the impact of SARS and MERS on reproductive outcome, it has been mentioned that SARS infection did increase the risk of miscarriage, preterm birth and, intrauterine foetal growth restriction. However, the same has not been demonstrated in early reports from COVID-19 infection in pregnancy. According to a study that included 8200 participants conducted by the centre for disease control and prevention, pregnant women may be at a higher risk of acquiring severe infection and need for ICU admissions as compared to their non-pregnant counterparts. However, a detailed and thorough study involving a larger proportion of the population is needed today.

References:

https://www.news-medical.net/news/20210614/COVID-19-in-pregnancy-could-be-less-severe-than-previously-thought-A-Danish-case-study.aspx

https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.14696

https://www.nature.com/articles/s41577-021-00525-y

https://www.tandfonline.com/doi/full/10.1080/14767058.2020.1759541

https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/special-populations/pregnancy-data-on-covid-19/what-cdc-is-doing.html

https://economictimes.indiatimes.com/news/india/why-is-covid-19-killing-so-many-pregnant-women-in-india/articleshow/82902194.cms?from=mdr

https://content.iospress.com/download/international-journal-of-risk-and-safety-in-medicine/jrs200060?id=international-journal-of-risk-and-safety-in-medicine%2Fjrs200060

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C.D.C. Reviewing Cases of Heart Problem in Youngsters After Getting Vaccinated and AHA Reassures that Benefits Overwhelm the Risks of Vaccination

Reporter: Amandeep Kaur, B.Sc. , M.Sc.

The latest article in New York times reported by Apoorva Mandavilli outlines the statement of officials that C.D.C. agency is investigating few cases of young adults and teenagers who might have developed myocarditis after getting vaccinated. It is not confirmed by the agency that whether this condition is caused by vaccine or not.

According to the vaccine safety group of the Centers for Disease Control and Prevention, the reports of heart problems experienced by youngsters is relatively very small in number. The group stated that these cases could be unlinked to vaccination. The condition of inflammation of heart muscle which can occur due to certain infections is known as myocarditis.

Moreover, the agency still has to determine any evidence related to vaccines causing the heart issues. The C.D.C. has posted on its website the updated guidance for doctors and clinicians, urging them to be alert to uncommon symptoms related to heart cases among teenagers who are vaccine recipients.

In New York, Dr. Celine Gounder, an infectious disease specialist at Bellevue Hospital Center stated that “It may simply be a coincidence that some people are developing myocarditis after vaccination. It’s more likely for something like that to happen by chance, because so many people are getting vaccinated right now.”

The article reported that the cases appeared mainly in young adults after about four days of their second shot of mRNA vaccines, made by Moderna and Pfizer-BioNTech. Such cases are more prevalent in males as compared to females.

The vaccine safety group stated “Most cases appear to be mild, and follow-up of cases is ongoing.” It is strongly recommended by C.D.C. that American young adults from the age of 12 and above should get vaccinated against COVID-19.

Dr. Yvonne Maldonado, chair of the American Academy of Pediatrics’s Committee on Infectious Diseases stated “We look forward to seeing more data about these cases, so we can better understand if they are related to the vaccine or if they are coincidental. Meanwhile, it’s important for pediatricians and other clinicians to report any health concerns that arise after vaccination.”

Experts affirmed that the potentially uncommon side effects of myocarditis get insignificant compared to the potential risks of SARS-CoV-2 infection, including the continuous syndrome known as “long Covid.” It is reported in the article that acute Covid can lead to myocarditis.

According to the data collected by A.A.P, about 16 thousand children were hospitalized and more than 3.9 million children were infected by coronavirus till the second week of May. In the United States, about 300 children died of SARS-CoV-2 infection, which makes it among the top 10 death causes in children since the start of pandemic.

Dr. Jeremy Faust, an emergency medicine physician at Brigham and Women’s Hospital in Boston stated that “And that’s in the context of all the mitigation measures taken.”

According to researchers, about 10 to 20 of every 1 lakh people each year develop myocarditis in the general population, facing symptoms from fatigue and chest pain to arrhythmias and cardiac arrest, whereas some have mild symptoms which remain undiagnosed.

Currently, the number of reports of myocarditis after vaccination is less than that reported normally in young adults, confirmed by C.D.C. The article reported that the members of vaccine safety group felt to communicate the information about upcoming cases of myocarditis to the providers.

The C.D.C. has not yet specified the ages of the patients involved in reporting. Since December 2020, the Pfizer-BioNTech vaccine was authorized for young people of age 16 and above. The Food and Drug Administration extended the authorization to children of age 12 to 15 years, by the starting of this month.

On 14th May, the clinicians have been alerted by C.D.C. regarding the probable link between myocarditis and vaccination. Within three days, the team started reviewing data on myocarditis, reports filed with the Vaccine Adverse Event Reporting System and others from the Department of Defense.

A report on seven cases has been submitted to the journal Pediatrics for review and State health departments in Washington, Oregon and California have notified emergency providers and cardiologists about the potential problem.

In an interview, Dr. Liam Yore, past president of the Washington State chapter of the American College of Emergency Physicians detailed a case of teenager with myocarditis after vaccination. The patient was provided treatment for mild inflammation of the inner lining of the heart and was discharged afterwards. Later, the young adult returned for care due to decrease in the heart’s output. Dr. Yore reported that still he had come across worse cases in youngsters with Covid, including in a 9-year-old child who arrived at the hospital after a cardiac arrest last winter.

He stated that “The relative risk is a lot in favor of getting the vaccine, especially considering how coronavirus vaccine have been administered.”

In the United States, more than 161 million people have received their first shot of vaccine in which about 4.5 million people were between the age 12 to 18 years.

Benefits Overwhelm Risks of COVID Vaccination, AHA Reassures

The latest statement of American Heart Association (AHA)/ American Stroke Association (ASA) on May 23rd states that the benefits of COVID-19 vaccination enormously outweigh the rare risk for myocarditis cases, which followed the C.D.C. report that the agency is tracking the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for myocarditis cases linked with mRNA vaccines against coronavirus.

The myocarditis cases in young adults are more often observed after the second dose of vaccine rather than the first one, and have more cases of males than females. The CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) observed such heart complications after 4 days of vaccination.

CDC reported that “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

The CDC team stated that “The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection, and Strongly urged all young adults and children 12 years and above to get vaccinated as soon as possible.”

Even though the analysis of myocarditis reports related to coronavirus vaccine is in progress, the AHA/ASA stated that “myocarditis is typically the result of an actual viral infection, and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF) and former acting director of the CDC stated on ABC’s Good Morning America “We’ve lost hundreds of children and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis.” He added “still, from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine.”

After COVID-19 vaccination the symptoms that occur include tiredness, muscle pain, headaches, chills, nausea and fever. The AHA/ASA stated that “typically appear within 24 to 48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All healthcare providers are suggested to be aware of the rare adverse symptoms such as myocarditis, low platelets, blood clots, and severe inflammation. The agency stated that “Healthcare professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly.”

President Mitchell S.V. Elkind, M.D., M.S., FAHA, FAAN, Immediate Past President Robert A. Harrington, M.D., FAHA, President-Elect Donald M. Lloyd-Jones, M.D., Sc.M., FAHA, Chief Science and Medical Officer Mariell Jessup, M.D., FAHA, and Chief Medical Officer for Prevention Eduardo Sanchez, M.D, M.P.H., FAAFP are science leaders of AHA/ASA and reflected their views in the following statements:

We strongly urge all adults and children ages 12 and older in the U.S. to receive a COVID vaccine as soon as they can receive it, as recently approved by the U.S. Food and Drug Administration and the CDC. The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection. According to the CDC as of May 22, 2021, over 283 million doses of COVID-19 vaccines have been administered in the U.S. since December 14, 2020, and more than 129 million Americans are fully vaccinated (i.e., they have received either two doses of the Pfizer-BioNTech or Moderna COVID-19 vaccine, or the single-dose Johnson & Johnson/Janssen COVID-19 vaccine).

We remain confident that the benefits of vaccination far exceed the very small, rare risks. The risks of vaccination are also far smaller than the risks of COVID-19 infection itself, including its potentially fatal consequences and the potential long-term health effects that are still revealing themselves, including myocarditis. The recommendation for vaccination specifically includes people with cardiovascular risk factors such as high blood pressure, obesity and type 2 diabetes, those with heart disease, and heart attack and stroke survivors, because they are at much greater risk of an adverse outcome from the COVID-19 virus than they are from the vaccine.

We commend the CDC’s continual monitoring for adverse events related to the COVID-19 vaccines through VAERS and VSD, and the consistent meetings of ACIP’s VaST Work Group, demonstrating transparent and robust attention to any and all health events possibly related to a COVID-19 vaccine. The few cases of myocarditis that have been reported after COVID-19 vaccination are being investigated. However, myocarditis is usually the result of a viral infection, and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine, especially since the COVID-19 vaccines authorized in the U.S. do not contain any live virus.

We also encourage everyone to keep in touch with their primary care professionals and seek care immediately if they have any of these symptoms in the weeks after receiving the COVID-19 vaccine: chest pain including sudden, sharp, stabbing pains; difficulty breathing/shortness of breath; abnormal heartbeat; severe headache; blurry vision; fainting or loss of consciousness; weakness or sensory changes; confusion or trouble speaking; seizures; unexplained abdominal pain; or new leg pain or swelling.

We will stay up to date with the CDC’s recommendations regarding all potential complications related to COVID-19 vaccines, including myocarditis, pericarditis, central venous sinus thrombosis (CVST) and other blood clotting events, thrombosis thrombocytopenia syndrome (TTS), and vaccine-induced immune thrombosis thrombocytopenia (VITT).

The American Heart Associationrecommends all health care professionals be aware of these very rare adverse events that may be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, or symptoms of severe inflammation. Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly. As detailed in last month’s AHA/ASA statement, all suspected CVST or blood clots associated with the COVID-19 vaccine should be treated initially using non-heparin anticoagulants. Heparin products should not be administered in any dose if TTS/VITT is suspected, until appropriate testing can be done to exclude heparin-induced antibodies. In addition, health care professionals are required to report suspected vaccine-related adverse events to the Vaccine Adverse Event Reporting System, in accordance with federal regulations.

Individuals should refer to their local and state health departments for specific information about when and where they can get vaccinated. We implore everyone ages 12 and older to get vaccinated so we can return to being together, in person – enjoying life with little to no risk of severe COVID-19 infection, hospitalization or death.

We also support the CDC recommendations last week that loosen restrictions on mask wearing and social distancing for people who are fully vaccinated. For those who are unable to be vaccinated, we reiterate the importance of handwashing, social distancing and wearing masks, particularly for people at high risk of infection and/or severe COVID-19. These simple precautions remain crucial to protecting people who are not vaccinated from the virus that causes COVID-19.

Source:

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development

Reporter: Amandeep Kaur, B.Sc., M.Sc.

https://pharmaceuticalintelligence.com/2021/05/04/thriving-vaccines-and-research-weizmann-coronavirus-research-development/

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc.

https://pharmaceuticalintelligence.com/2021/04/19/identification-of-novel-genes-in-human-that-fight-covid-19-infection/

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, B.Sc., M.Sc. 

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

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Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development

Reporter: Amandeep Kaur, B.Sc., M.Sc.

In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”

The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.

A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.

The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.

Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”

The following are few important projects with recent updates reported in the article.

Mapping a hijacker’s methods

Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.

She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.

Like chutzpah, some things don’t translate

Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.

Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.

The landscape of elimination

The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.

After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.

Gearing up ‘chain terminators’ to battle the coronavirus

Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.

Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.

Resolving borderline diagnoses

Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.

The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.

In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.

Moon shot consortium refining drug options

The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.

To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.

The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.

Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.

Source: https://www.weizmann.ac.il/WeizmannCompass/sections/features/the-vaccines-are-here-and-research-abounds

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

https://pharmaceuticalintelligence.com/2021/04/19/identification-of-novel-genes-in-human-that-fight-covid-19-infection/

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

Read Full Post »

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

Scientists have recognized human genes that fight against the SARS-CoV-2 viral infection. The information about genes and their function can help to control infection and aids the understanding of crucial factors that causes severe infection. These novel genes are related to interferons, the frontline fighter in our body’s defense system and provide options for therapeutic strategies.

The research was published in the journal Molecular Cell.

Sumit K. Chanda, Ph.D., professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys reported in the article that they focused on better understanding of the cellular response and downstream mechanism in cells to SARS-CoV-2, including the factors which causes strong or weak response to viral infection. He is the lead author of the study and explained that in this study they have gained new insights into how the human cells are exploited by invading virus and are still working towards finding any weak point of virus to develop new antivirals against SARS-CoV-2.

With the surge of pandemic, researchers and scientists found that in severe cases of COVID-19, the response of interferons to SARS-CoV-2 viral infection is low. This information led Chanda and other collaborators to search for interferon-stimulated genes (ISGs), are genes in human which are triggered by interferons and play important role in confining COVID-19 infection by controlling their viral replication in host.

The investigators have developed laboratory experiments to identify ISGs based on the previous knowledge gathered by the outbreak of SARS-CoV-1 from 2002-2004 which was similar to COVID-19 pandemic caused by SARS-CoV-2 virus.

The article reports that Chanda mentioned “we found that 65 ISGs controlled SAR-CoV-2 infection, including some that inhibited the virus’ ability to enter cells, some that suppressed manufacture of the RNA that is the virus’s lifeblood, and a cluster of genes that inhibited assembly of the virus.” They also found an interesting fact about ISGs that some of these genes revealed control over unrelated viruses, such as HIV, West Nile and seasonal flu.

Laura Martin-Sancho, Ph.D., a senior postdoctoral associate in the Chanda lab and first author of the study reported in the article that they identified 8 different ISGs that blocked the replication of both SARS-CoV-1 and CoV-2 in the subcellular compartments responsible for packaging of proteins, which provide option to exploit these vulnerable sites to restrict infection. They are further investigating whether the genetic variability within the ISGs is associated with COVID-19 severity.

The next step for researchers will be investigating and observing the biology of variants of SARS-CoV-2 that are evolving and affecting vaccine efficacy. Martin-Sancho mentioned that their lab has already started gathering all the possible variants for further investigation.

“It’s vitally important that we don’t take our foot off the pedal of basic research efforts now that vaccines are helping control the pandemic,” reported in the article by Chanda.

“We’ve come so far so fast because of investment in fundamental research at Sanford Burnham Prebys and elsewhere, and our continued efforts will be especially important when, not if, another viral outbreak occurs,” concluded Chanda.

Source: https://medicalxpress.com/news/2021-04-covid-scientists-human-genes-infection.html

Reference: Laura Martin-Sancho et al. Functional Landscape of SARS-CoV-2 Cellular Restriction, Molecular Cell (2021). DOI: 10.1016/j.molcel.2021.04.008

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Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

Mechanism of Thrombosis with AstraZeneca and J & J Vaccines: Expert Opinion by Kate Chander Chiang & Ajay Gupta, MD

Reporter & Curator: Dr. Ajay Gupta, MD

https://pharmaceuticalintelligence.com/2021/04/14/mechanism-of-thrombosis-with-astrazeneca-and-j-j-vaccines-expert-opinion-by-kate-chander-chiang-ajay-gupta-md/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

Read Full Post »

Fighting Chaos with care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, BSc, MSc (Exp. 6/2021)

According to the Global Health Security Index released by Johns Hopkins University in October 2019 in collaboration with Nuclear Threat Initiative (NTI) and The Economist Intelligence Unit (EIU), the United States was announced to be the best developed country in the world to tackle any pandemic or health emergency in future.

The table turned within in one year of outbreak of the novel coronavirus COVID-19. By the end of March 2021, the country with highest COVID-19 cases and deaths in the world was United States. According to the latest numbers provided by World Health Organization (WHO), there were more than 540,000 deaths and more than 30 million confirmed cases in the United States.

Joia Mukherjee, associate professor of global health and social medicine in the Blavatnik Institute at Harvard Medical School said,

“When we think about how to balance control of an epidemic over chaos, we have to double down on care and concern for the people and communities who are hardest hit”.

She also added that U.S. possess all the necessary building blocks required for a health system to work, but it lacks trust, leadership, engagement and care to assemble it into a working system.

Mukherjee mentioned about the issues with the Index that it undervalued the organized and integrated system which is necessary to help public meet their needs for clinical care. Another necessary element for real health safety which was underestimated was conveying clear message and social support to make effective and sustainable efforts for preventive public health measures.

Mukherjee is a chief medical officer at Partners In Health, an organization focused on strengthening community-based health care delivery. She is also a core member of HMS community members who play important role in constructing a more comprehensive response to the pandemic in all over the U.S. With years of experience, they are training global health care workers, analyzing the results and constructing an integrated health system to fight against the widespread health emergency caused by coronavirus all around the world.

Mukherjee encouraged to strengthen the consensus among the community to constrain this infectious disease epidemic. She suggested that validation of the following steps are crucial such as testing of the people with symptoms of infection with coronavirus, isolation of infected individuals by providing them with necessary resources and providing clinical treatment and care to those people who are in need. Mukherjee said, that community engagement and material support are not just idealistic goal rather these are essential components for functioning of health care system during an outburst of coronavirus.

Continued alertness such as social distancing and personal contact with infected individual is important because it is not possible to rapidly replace the old-school public health approaches with new advanced technologies like smart phone applications or biomedical improvements.

Public health specialists emphasized that the infection limitation is the only and most vital strategy for controlling the outbreak in near future, even if the population is getting vaccinated. It is crucial to slowdown the spread of disease for restricting the natural modification of more dangerous variants as that could potentially escape the immune protection mechanism developed by recently generated vaccines as well as natural immune defense systems.

Making Crucial connections

The treatment is more expensive and complicated in areas with less health facilities, said Paul Farmer, the Kolokotrones University Professor at Harvard and chair of the HMS Department of Global Health and Social Medicine. He called this situation as treatment nihilism. Due to shortage of resources, the maximum energy is focused in public health care and prevention efforts. U.S. has resources to cope up with the increasing demand of hospital space and is developing vaccines, but there is a form of containment nihilism- which means prevention and infection containment are unattainable- said by many experts.

Farmer said, integration of necessary elements such as clinical care, therapies, vaccines, preventive measures and social support into a single comprehensive plan is the best approach for a better response to COVID-19 disease. He understands the importance of community trust and integrated health care system for fighting against this pandemic, as being one of the founders of Partners In Health and have years of experience along with his colleagues from HMS and PIH in fighting epidemics of HIV, Ebola, cholera, tuberculosis, other infectious and non-infectious diseases.

PIH launched the Massachusetts Community Tracing Collaborative (CTC), which is an initiative of contact tracing statewide in partnership with several other state bodies, local boards of Health system and PIH. The CTC was setup in April 2020 in U.S. by Governor Charlie Baker, with leadership from HMS faculty, to build a unified response to COVID-19 and create a foundation for a long-term movement towards a more integrated community-based health care system.

The contact tracing involves reaching out to individuals who are COVID-19 positive, then further detect people who came in close contact with infected individuals and screen out people with coronavirus symptoms and encourage them to seek testing and take necessary precautions to break the chain of infection into the community.

In the initial phase of outbreak, the CTC group comprises of contact tracers and health care coordinators who spoke 23 different languages, including social workers, public health practitioners, nurses and staff members from local board health agencies with deep links to the communities they are helping. The CTC worked with 339 out of 351 state municipalities with local public health agencies relied completely on CTC whereas some cities and towns depend occasionally on CTC backup. According to a report, CTC members reached up to 80 percent of contact tracking in hard-hit and resource deprived communities such as New Bedford.

Putting COVID-19 in context

Based on generations of experience helping people surviving some of the deadliest epidemic and endemic outbreaks in places like Haiti, Mexico, Rwanda and Peru, the staff was alert that people with bad social and economic condition have less space to get quarantined and follow other public health safety measures and are most vulnerable people at high risk in the pandemic situation.

Infected individuals or individuals at risk of getting infected by SARS-CoV-2 had many questions regarding when to seek doctor’s help and where to get tested, reported by contact tracers. People were worried about being evicted from work for two weeks and some immigrants worried about basic supplies as they were away from their family and friends.

The CTC team received more than 7,000 requests for social support assistance in the initial three months. The staff members and contact tracers were actively connecting the resourceful individuals with the needy people and filling up the gap when there was shortage in their own resources.

Farmer said, “COVID is a misery-seeking missile that has targeted the most vulnerable.”

The reality that infected individuals concerned about lacking primary household items, food items and access to childcare, emphasizes the urgency of rudimentary social care and community support in fighting against the pandemic. Farmer said, to break the chain of infection and resume society it is mandatory to meet all the elementary needs of people.

“What kinds of help are people asking for?” Farmer said and added “it’s important to listen to what your patients are telling you.”

An outbreak of care

The launch of Massachusetts CTC with the support from PIH, started receiving requests from all around the country to assist initiating contact tracing procedures. In May, 2020 the organization announced the launch of a U.S. public health accompaniment to cope up with the asked need.

The unit has included team members in nearly 24 states and municipal health departments in the country and work in collaboration with local organizations. The technical support on things like choosing and implementing the tools and software for contact tracing was provided by PIH. To create awareness and provide new understanding more rapidly, a learning collaboration was established with more than 200 team members from more than 100 different organizations. The team worked to meet the needs of population at higher risk of infection by advocating them for a stronger and more reliable public health response.

The PIH public health team helped to train contact trackers in the Navajo nation and operate to strengthen the coordination between SARS-CoV-2 testing, efforts for precaution, clinical health care delivery and social support in vulnerable communities around the U.S.

“For us to reopen our schools, our churches, our workplaces,” Mukherjee said, “we have to know where the virus is spreading so that we don’t just continue on this path.”

SOURCE:

https://hms.harvard.edu/news/fighting-chaos-care?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_1&utm_content=HMNews04052021

Other related articles were published in this Open Access Online Scientific Journal, including the following:

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

The WHO team is expected to soon publish a 300-page final report on its investigation, after scrapping plans for an interim report on the origins of SARS-CoV-2 — the new coronavirus responsible for killing 2.7 million people globally

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/27/the-who-team-is-expected-to-soon-publish-a-300-page-final-report-on-its-investigation-after-scrapping-plans-for-an-interim-report-on-the-origins-of-sars-cov-2-the-new-coronavirus-responsibl/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

Artificial intelligence predicts the immunogenic landscape of SARS-CoV-2

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2021/02/04/artificial-intelligence-predicts-the-immunogenic-landscape-of-sars-cov-2/

Read Full Post »

Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure.

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

SARS-CoV-2, the virus that causes COVID-19, has had a major impact on human health globally; infecting a massive quantity of people around 136,046,262 (John Hopkins University); causing severe disease and associated long-term health sequelae; resulting in death and excess mortality, especially among older and prone populations; altering routine healthcare services; disruptions to travel, trade, education, and many other societal functions; and more broadly having a negative impact on peoples physical and mental health.

It’s need of the hour to answer the questions like what allows the variants of SARS-CoV-2 first detected in the UK, South Africa, and Brazil to spread so quickly? How can current COVID-19 vaccines better protect against them?

Scientists from the Harvard Medical School and the Boston Children’s Hospital help answer these urgent questions. The team reports its findings in the journal “Science a paper entitled Structural impact on SARS-CoV-2 spike protein by D614G substitution. The mutation rate of the SARS-CoV-2 virus has rapidly evolved over the past few months, especially at the Spike (S) protein region of the virus, where the maximum number of mutations have been observed by the virologists.

Bing Chen, HMS professor of pediatrics at Boston Children’s, and colleagues analyzed the changes in the structure of the spike proteins with the genetic change by D614G mutation by all three variants. Hence they assessed the structure of the coronavirus spike protein down to the atomic level and revealed the reason for the quick spreading of these variants.


This model shows the structure of the spike protein in its closed configuration, in its original D614 form (left) and its mutant form (G614). In the mutant spike protein, the 630 loop (in red) stabilizes the spike, preventing it from flipping open prematurely and rendering SARS-CoV-2 more infectious.

Fig. 1. Cryo-EM structures of the full-length SARS-CoV-2 S protein carrying G614.

(A) Three structures of the G614 S trimer, representing a closed, three RBD-down conformation, an RBD-intermediate conformation and a one RBD-up conformation, were modeled based on corresponding cryo-EM density maps at 3.1-3.5Å resolution. Three protomers (a, b, c) are colored in red, blue and green, respectively. RBD locations are indicated. (B) Top views of superposition of three structures of the G614 S in (A) in ribbon representation with the structure of the prefusion trimer of the D614 S (PDB ID: 6XR8), shown in yellow. NTD and RBD of each protomer are indicated. Side views of the superposition are shown in fig. S8.

IMAGE SOURCE: Bing Chen, Ph.D., Boston Children’s Hospital, https://science.sciencemag.org/content/early/2021/03/16/science.abf2303

The work

The mutant spikes were imaged by Cryo-Electron microscopy (cryo-EM), which has resolution down to the atomic level. They found that the D614G mutation (substitution of in a single amino acid “letter” in the genetic code for the spike protein) makes the spike more stable as compared with the original SARS-CoV-2 virus. As a result, more functional spikes are available to bind to our cells’ ACE2 receptors, making the virus more contagious.


Fig. 2. Cryo-EM revealed how the D614G mutation changes SARS-CoV-2 spike protein structure.

IMAGE SOURCE:  Zhang J, et al., Science

Say the original virus has 100 spikes,” Chen explained. “Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that is functional. So even though they don’t bind as well, the chances are greater and you will have an infection

Forthcoming directions by Bing Chen and Team

The findings suggest the current approved COVID-19 vaccines and any vaccines in the works should include the genetic code for this mutation. Chen has quoted:

Since most of the vaccines so far—including the Moderna, Pfizer–BioNTech, Johnson & Johnson, and AstraZeneca vaccines are based on the original spike protein, adding the D614G mutation could make the vaccines better able to elicit protective neutralizing antibodies against the viral variants

Chen proposes that redesigned vaccines incorporate the code for this mutant spike protein. He believes the more stable spike shape should make any vaccine based on the spike more likely to elicit protective antibodies. Chen also has his sights set on therapeutics. He and his colleagues are further applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor. That could point the way to drugs that would block the virus from gaining entry to our cells.

In January, the team showed that a structurally engineered “decoy” ACE2 protein binds to SARS-CoV-2 200 times more strongly than the body’s own ACE2. The decoy potently inhibited the virus in cell culture, suggesting it could be an anti-COVID-19 treatment. Chen is now working to advance this research into animal models.

Main Source:

Abstract

Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. We report here cryo-EM structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer, effectively increasing the number of functional spikes and enhancing infectivity, and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

https://science.sciencemag.org/content/early/2021/03/16/science.abf2303?rss=1

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Tiny biologic drug to fight COVID-19 show promise in animal models

Reporter : Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/10/11/tiny-biologic-drug-to-fight-covid-19-show-promise-in-animal-models/

Miniproteins against the COVID-19 Spike protein may be therapeutic

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/09/30/miniproteins-against-the-covid-19-spike-protein-may-be-therapeutic/

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From Cell Press:  New Insights on the D614G Strain of COVID: Will a New Mutated Strain Delay Vaccine Development?

Reporter: Stephen J. Williams, PhD

Two recent articles in Cell Press, both peer reviewed, discuss the emergence and potential dominance of a new mutated strain of COVID-19, in which the spike protein harbors a D614G mutation.

In the first article “Making Sense of Mutation: What D614G means for the COVID-19 pandemic Remains Unclear”[1] , authors Drs. Nathan Grubaugh, William Hanage, and Angela Rasmussen discuss the recent findings by Korber et al. 2020 [2] which describe the potential increases in infectivity and mortality of this new mutant compared to the parent strain of SARS-CoV2.  For completeness sake I will post this article as to not defer from their interpretations of this important paper by Korber and to offer some counter opinion to some articles which have surfaced this morning in the news.

Making sense of mutation: what D614G means for the COVID-19 pandemic remains unclear

 

Nathan D. Grubaugh1 *, William P. Hanage2 *, Angela L. Rasmussen3 * 1Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06510, USA 2Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA 3Center for Infection and Immunity, Columbia Mailman School of Public Health, New York, NY 10032, USA Correspondence: grubaughlab@gmail.com

 

Abstract: Korber et al. (2020) found that a SARS-CoV-2 variant in the spike protein, D614G, rapidly became dominant around the world. While clinical and in vitro data suggest that D614G changes the virus phenotype, the impact of the mutation on transmission, disease, and vaccine and therapeutic development are largely unknown.

Introduction: Following the emergence of SARS-CoV-2 in China in late 2019, and the rapid expansion of the COVID19 pandemic in 2020, questions about viral evolution have come tumbling after. Did SARS-CoV-2 evolve to become better adapted to humans? More infectious or transmissible? More deadly? Virus mutations can rise in frequency due to natural selection, random genetic drift, or features of recent epidemiology. As these forces can work in tandem, it’s often hard to differentiate when a virus mutation becomes common through fitness or by chance. It is even harder to determine if a single mutation will change the outcome of an infection, or a pandemic. The new study by Korber et al. (2020) sits at the heart of this debate. They present compelling data that an amino acid change in the virus’ spike protein, D614G, emerged early during the pandemic, and viruses containing G614 are now dominant in many places around the world. The crucial questions are whether this is the result of natural selection, and what it means for the COVID-19 pandemic. For viruses like SARS-CoV-2 transmission really is everything – if they don’t get into another host their lineage ends. Korber et al. (2020) hypothesized that the rapid spread of G614 was because it is more infectious than D614. In support of their hypothesis, the authors provided evidence that clinical samples from G614 infections have a higher levels of viral RNA, and produced higher titers in pseudoviruses from in vitro experiments; results that now seem to be corroborated by others [e.g. (Hu et al., 2020; Wagner et al., 2020)]. Still, these data do not prove that G614 is more infectious or transmissible than viruses containing D614. And because of that, many questions remain on the potential impacts, if any, that D614G has on the COVID-19 pandemic.

The authors note that this new G614 variant has become the predominant form over the whole world however in China the predominant form is still the D614 form.  As they state

“over the period that G614 became the global majority variant, the number of introductions from China where D614 was still dominant were declining, while those from Europe climbed. This alone might explain the apparent success of G614.”

Grubaugh et al. feel there is not enough evidence that infection with this new variant will lead to higher mortality.  Both Korber et al. and the Seattle study (Wagner et al) did not find that the higher viral load of this variant led to a difference in hospitalizations so apparently each variant might be equally as morbid.

In addition, Grubaugh et al. believe this variant would not have much affect on vaccine development as, even though the mutation lies within the spike protein, D614G is not in the receptor binding domain of the spike protein.  Korber suggest that there may be changes in glycosylation however these experiments will need to be performed.  In addition, antibodies from either D614 or G614 variant infected patients could cross neutralize.

 

Conclusions: While there has already been much breathless commentary on what this mutation means for the COVID19 pandemic, the global expansion of G614 whether through natural selection or chance means that this variant now is the pandemic. As a result its properties matter. It is clear from the in vitro and clinical data that G614 has a distinct phenotype, but whether this is the result of bonafide adaptation to human ACE2, whether it increases transmissibility, or will have a notable effect, is not clear. The work by Korber et al. (2020) provides an early base for more extensive epidemiological, in vivo experimental, and diverse clinical investigations to fill in the many critical gaps in how D614G impacts the pandemic.

The link to the Korber Cell paper is here: https://www.cell.com/cell/fulltext/S0092-8674(20)30820-5

Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus

DOI: https://doi.org/10.1016/j.cell.2020.06.043

Keypoints

  • The consistent increase of G614 at regional levels may indicate a fitness advantage

 

  • G614 is associated with lower RT PCR Ct’s, suggestive of higher viral loads in patients

 

  • The G614 variant grows to higher titers as pseudotyped virions

Summary

A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to the introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to higher titer as pseudotyped virions. In infected individuals G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, although not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus, and support continuing surveillance of Spike mutations to aid in the development of immunological interventions.

 

References

  1. Grubaugh, N.D., Hanage, W.P., Rasmussen, A.L., Making sense of mutation: what D614G means for the COVID-19 pandemic remains unclear, Cell (2020), doi: https:// doi.org/10.1016/j.cell.2020.06.040.
  2. Korber, B., Fischer, W.M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E.E., Bhattacharya, T., Foley, B., et al. (2020). Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell 182.
  3. Endo, A., Centre for the Mathematical Modelling of Infectious Diseases COVID-19 Working Group, Abbott, S., Kucharski, A.J., and Funk, S. (2020). Estimating the overdispersion in COVID-19 transmission using outbreak sizes outside China. Wellcome Open Res 5, 67.
  4. Hu, J., He, C.-L., Gao, Q.-Z., Zhang, G.-J., Cao, X.-X., Long, Q.-X., Deng, H.-J., Huang, L.-Y., Chen, J., Wang, K., et al. (2020). The D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity and decreases neutralization sensitivity to individual convalescent sera. bioRxiv 2020.06.20.161323.
  5. Wagner, C., Roychoudhury, P., Hadfield, J., Hodcroft, E.B., Lee, J., Moncla, L.H., Müller, N.F., Behrens, C., Huang, M.-L., Mathias, P., et al. (2020). Comparing viral load and clinical outcomes in Washington State across D614G mutation in spike protein of SARS-CoV-2. Https://github.com/blab/ncov-D614G.

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National Cancer Institute Director Neil Sharpless says mortality from delays in cancer screenings due to COVID19 pandemic could result in tens of thousands of extra deaths in next decade

Reporter: Stephen J Williams, PhD

UPDATED: 10/11/2021

Source: https://cancerletter.com/articles/20200619_1/

NCI Director’s Report

Sharpless: COVID-19 expected to increase mortality by at least 10,000 deaths from breast and colorectal cancers over 10 years

By Matthew Bin Han Ong

This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full list of our coverage, as well as the latest meeting cancellations, is available here.

The COVID-19 pandemic will likely cause at least 10,000 excess deaths from breast cancer and colorectal cancer over the next 10 years in the United States.

Scenarios run by NCI and affiliated modeling groups predict that delays in screening for and diagnosis of breast and colorectal cancers will lead to a 1% increase in deaths through 2030. This translates into 10,000 additional deaths, on top of the expected one million deaths resulting from these two cancers.

“For both these cancer types, we believe the pandemic will influence cancer deaths for at least a decade,” NCI Director Ned Sharpless said in a virtual joint meeting of the Board of Scientific Advisors and the National Cancer Advisory Board June 15. “I find this worrisome as cancer mortality is common. Even a 1% increase every decade is a lot of cancer suffering.

“And this analysis, frankly, is pretty conservative. We do not consider cancers other than those of breast and colon, but there is every reason to believe the pandemic will affect other types of cancer, too. We did not account for the additional non-lethal morbidity from upstaging, but this could also be significant and burdensome.”

An editorial by Sharpless on this subject appears in the journal Science.

The early analyses, conducted by the institute’s Cancer Intervention and Surveillance Modeling Network, focused on breast and colorectal cancers, because these are common, with relatively high screening rates.

CISNET modelers created four scenarios to assess long-term increases in cancer mortality rates for these two diseases:

  1. The pandemic has no effect on cancer mortality
  1. Delayed screening—with 75% reduction in mammography and, colorectal screening and adenoma surveillance for six months
  1. Delayed diagnosis—with one-third of people delaying follow-up after a positive screening or diagnostic mammogram, positive FIT or clinical symptoms for six months during a six-month period
  1. Combination of scenarios two and three

Treatment scenarios after diagnosis were not included in the model. These would be: delays in treatment, cancellation of treatment, or modified treatment.

“What we did is show the impact of the number of excess deaths per year for 10 years for each year starting in 2020 for scenario four versus scenario one,” Eric “Rocky” Feuer, chief of the NCI’s Statistical Research and Applications Branch in the Surveillance Research Program, said to The Cancer Letter.

Feuer is the overall project scientist for CISNET, a collaborative group of investigators who use simulation modeling to guide public health research and priorities.

“The results for breast cancer were somewhat larger than for colorectal,” Feuer said. “And that’s because breast cancer has a longer preclinical natural history relative to colorectal cancer.”

Modelers in oncology are creating a global modeling consortium, COVID-19 and Cancer Taskforce, to “support decision-making in cancer control both during and after the crisis.” The consortium is supported by the Union for International Cancer Control, The International Agency for Research on Cancer, The International Cancer Screening Network, the Canadian Partnership Against Cancer, and Cancer Council NSW, Australia.

A spike in cancer mortality rates threatens to reverse or slow down—at least in the medium term—the steady trend of reduction of cancer deaths. On Jan. 8, the American Cancer Society published its annual estimates of new cancer cases and deaths, declaring that the latest data—from 2016 to 2017—show the “largest ever single-year drop in overall cancer mortality of 2.2%.” Experts say that innovation in lung cancer treatment and the success of smoking cessation programs are driving the sharp decrease (The Cancer LetterFeb. 7, 2020).

The pandemic is expected to have broader impact, including increases in mortality rates for other cancer types. Also, variations in severity of COVID-19 in different regions in the U.S. will influence mortality metrics.

“There’s some other cancers that might have delays in screening—for example cervical, prostate, and lung cancer, although lung cancer screening rates are still quite low and prostate cancer screening should only be conducted on those who determine that the benefits outweigh the harms,” Feuer said. “So, those are the major screening cancers, but impacts of delays in treatment, canceling treatment or alternative treatments—could impact a larger range of cancer sites.

“This model assumes a moderate disruption which resolves after six months, and doesn’t consider non-lethal morbidities associated with the delay. One thing I think probably is occurring is regional variation in these impacts,” Feuer said. “If you’re living in New York City where things were ground zero for some of the worst impact early on, probably delays were larger than other areas of the country. But now, as we’re seeing upticks in other areas of the country, there may be in impact in these areas as well”

How can health care providers mitigate some of these harms? For example, for people who delayed screening and diagnosis, are providers able to perform triage, so that those at highest risk are prioritized?

“From a strictly cancer control point of view, let’s get those people who delayed screening, or followup to a positive test, or treatment back on schedule as soon as possible,” Feuer said. “But it’s not a simple calculus, because in every situation, we have to weigh the harms and benefits. As we come out of the pandemic, it tips more and more to, ‘Let’s get back to business with respect to cancer control.’

“Telemedicine doesn’t completely substitute for seeing patients in person, but at least people could get the advice they need, and then are triaged through their health care providers to indicate if they really should prioritize coming in. That helps the individual and the health care provider  weigh the harms and benefits, and try to strategize about what’s best for any individual.”

If the pandemic continues to disrupt routine care, cancer-related mortality rates would rise beyond the predictions in this model.

“I think this analysis begins to help us understand the costs with regard to cancer outcomes of the pandemic,” Sharpless said. “Let’s all agree we will do everything in our power to minimize these adverse effects, to protect our patients from cancer suffering.”

UPDATED: 10/11/2021

Patients with Cancer Appear More Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak

Source:

Mengyuan DaiDianbo LiuMiao LiuFuxiang ZhouGuiling LiZhen ChenZhian ZhangHua YouMeng WuQichao ZhengYong XiongHuihua XiongChun WangChangchun ChenFei XiongYan ZhangYaqin PengSiping GeBo ZhenTingting YuLing WangHua WangYu LiuYeshan ChenJunhua MeiXiaojia GaoZhuyan LiLijuan GanCan HeZhen LiYuying ShiYuwen QiJing YangDaniel G. TenenLi ChaiLorelei A. MucciMauricio Santillana and Hongbing Cai. Patients with Cancer Appear More Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak

Abstract

The novel COVID-19 outbreak has affected more than 200 countries and territories as of March 2020. Given that patients with cancer are generally more vulnerable to infections, systematic analysis of diverse cohorts of patients with cancer affected by COVID-19 is needed. We performed a multicenter study including 105 patients with cancer and 536 age-matched noncancer patients confirmed with COVID-19. Our results showed COVID-19 patients with cancer had higher risks in all severe outcomes. Patients with hematologic cancer, lung cancer, or with metastatic cancer (stage IV) had the highest frequency of severe events. Patients with nonmetastatic cancer experienced similar frequencies of severe conditions to those observed in patients without cancer. Patients who received surgery had higher risks of having severe events, whereas patients who underwent only radiotherapy did not demonstrate significant differences in severe events when compared with patients without cancer. These findings indicate that patients with cancer appear more vulnerable to SARS-CoV-2 outbreak.

Significance: Because this is the first large cohort study on this topic, our report will provide much-needed information that will benefit patients with cancer globally. As such, we believe it is extremely important that our study be disseminated widely to alert clinicians and patients.

Introduction

A new acute respiratory syndrome coronavirus, named SARS-CoV-2 by the World Health Organization (WHO), has rapidly spread around the world since its first reported case in late December 2019 from Wuhan, China (1). As of March 2020, this virus has affected more than 200 countries and territories, infecting more than 800,000 individuals and causing more than 40,000 deaths (2).

With more than 18 million new cases per year globally, cancer affects a significant portion of the population. Individuals affected by cancer are more susceptible to infections due to coexisting chronic diseases, overall poor health status, and systemic immunosuppressive states caused by both cancer and anticancer treatments (3). As a consequence, patients with cancer who are infected by the SARS-CoV-2 coronavirus may experience more difficult outcomes than other populations. Until now, there is still no systematic evaluation of the effects that the SARS-CoV-2 coronavirus has of patients with cancer in a representative population. A recent study reported a higher risk of severe events in patients with cancer when compared with patients without cancer (4); however, the small sample size of SARS-CoV-2 patients with cancer used in the study limited how representative it was of the whole population and made it difficult to conduct more insightful analyses, such as comparing clinical characteristics of patients with different types of cancer, as well as anticancer treatments (5, 6).

Using patient information collected from 14 hospitals in Hubei Province, China, the epicenter of the 2019–2020 COVID-19 outbreak, we describe the clinical characteristics and outcomes [death, intensive care unit (ICU) admission, development of severe/critical symptoms, and utilization of invasive mechanical ventilation] of patients affected by the SARS-CoV-2 coronavirus for 105 hospitalized patients with cancer and 536 patients without cancer. We document our findings for different cancer types and stages, as well as different types of cancer treatments. We believe the information and insights provided in this study will help improve our understanding of the effects of SARS-CoV-2 in patients with cancer.

Results

Patients Characteristics

In total, 105 COVID-19 patients with cancer were enrolled in our study for the time period January 1, 2020, to February 24, 2020, from 14 hospitals in Wuhan, China. COVID-19 patients without cancer matched by the same hospital, hospitalization time, and age were randomly selected as our control group. Our patient population included 339 females and 302 males. Patients with cancer [median = 64.00, interquartile range (IQR) = 14.00], when compared with those without cancer (median = 63.50, IQR = 14.00) had similar age distributions (by design), experienced more in-hospital infections [20 (19.04%) of 105 patients vs. 8 (1.49%) of 536 patients;P < 0.01], and had more smoking history [36 (34.28%) of 105 patients vs. 46 (8.58%) of 536 patients; P < 0.01], but had no significant differences in sex, other baseline symptoms, and other comorbidities (Table 1). With respect to signs and symptoms upon admission, COVID-19 patients with cancer were similar to those without cancer except for a higher prevalence of chest distress [15 (14.29%) of 105 patients vs. 36 (6.16%) of 536 patients; P = 0.02].

Table 1.

Characteristics of COVID-19 patients with and without cancer

Clinical Outcomes

Compared with COVID-19 patients without cancer, patients with cancer had higher observed death rates [OR, 2.34; 95% confidence interval (CI), (1.15–4.77); P = 0.03], higher rates of ICU admission [OR, 2.84; 95% CI (1.59–5.08); P < 0.01], higher rates of having at least one severe or critical symptom [OR, 2.79; 95% CI, (1.74–4.41); P < 0.01], and higher chances of needing invasive mechanical ventilation (Fig. 1A). We also conducted survival analysis on occurrence of any severe condition which included death, ICU admission, having severe symptoms, and utilization of invasive mechanical ventilation (see cumulative incidence curves in Fig. 1B). In general, patients with cancer deteriorated more rapidly than those without cancer. These observations are consistent with logistic regression results (Supplementary Fig. S1), after adjusting for age, sex, smoking, and comorbidities including diabetes, hypertension, and chronic obstructive pulmonary disease (COPD). According to our multivariate logistic regression results, patients with cancer still had an excess OR of 2.17 (P = 0.06) for death (Supplementary Fig. S1A), 1.99 (P < 0.01) for experiencing any severe symptoms (Supplementary Fig. S1B), 3.13 (P < 0.01) for ICU admission (Supplementary Fig. S1C), and 2.71 (P = 0.04) for utilization of invasive mechanical ventilation (Supplementary Fig. S1D; Supplementary Table S1). The consistency of observed ORs between the multivariate regression model and unadjusted calculation reassures the association between cancer and severe events even in the presence of other factors such as age differences.

Figure 1.

Severe conditions in patients with and without cancer, and patients with different types, stages, and treatments of cancer. Severe conditions include death, ICU admission, having severe/critical symptoms, and usage of invasive mechanical ventilation. Incidence and survival analysis of severe conditions among COVID-19 patients with cancer and without cancer (A and B), among patients with different types of cancer (C and D), among patients with metastatic and nonmetastatic cancers (E and F), among patients with lung cancer, other cancers than lung with lung metastasis, and other cancers than lung without lung metastasis (G and H), and patients receiving different types of cancer treatments (I and J). P values indicate differences between cancer subgroups versus patients without cancer. For ACEGI, *, P < 0.05; **, P < 0.01. OR, 95% CI, and P values between different subgroups are listed in Supplementary Table S2. For BDFHJ, HR, 95% CI, and P values are listed in Supplementary Table S3.

Cancer Types

Information regarding potential risks of severe conditions in SARS-CoV-2 associated with each type of cancer was calculated. We compared different conditions among cancer types (Table 2). Lung cancer was the most frequent cancer type [22 (20.95%) of 105 patients], followed by gastrointestinal cancer [13 (12.38%) of 105 patients], breast cancer [11 (10.48%) of 105 patients], thyroid cancer [11 (10.48%) of 105 patients], and hematologic cancer [9 (8.57%) of 105 patients]. As shown in Fig. 1C and D and Supplementary Table S2, patients with hematologic cancer including leukemia, lymphoma, and myeloma have a relatively high death rate [3 (33.33%) of 9 patients], high ICU admission rate [4 (44.44%) of 9 patients], high risks of severe/critical symptoms [6 (66.67%) of 9 patients], and high chance of utilization of invasive mechanical ventilation [2 (22.22%) of 9 patients]. Patients with lung cancer had the second-highest risk levels, with death rate [4 (18.18%) of 22 patients], ICU admission rate [6 (27.27%) of 22 patients], risks of severe/critical symptoms [11 (50.00%) of 22 patients], and the chance of utilization of invasive mechanical ventilation [4 (18.18%) of 22 patients; Table 2].

Table 2.

Severe events in 105 patients with cancer for each type of cancer

Cancer Stage

We found that patients with metastatic cancer (stage IV) had even higher risks of death [OR, 5.58; 95% CI (1.71–18.23); P = 0.01], ICU admission [OR, 6.59; 95% CI (2.32–18.72); P < 0.01], having severe conditions [OR, 5.97; 95% CI (2.24–15.91); P < 0.01], and use of invasive mechanical ventilation [OR, 55.42; 95% CI (13.21–232.47); P < 0.01]. In contrast, patients with nonmetastatic cancer did not demonstrate statistically significant differences compared with patients without cancer, with all P > 0.05 (Fig. 1E and F; Supplementary Tables S2 and S3). In addition, when compared with patients without cancer, patients with lung cancer or other cancers with lung metastasis also showed higher risks of death, ICU admission rates, higher critical symptoms, and use of invasive mechanical ventilation, with all P values below 0.01, but other cancers without lung metastasis had no statistically significant differences (all P values > 0.05; Fig. 1G and H; Supplementary Table S3) when compared with patients without cancer.

Cancer Treatments

Among the 105 COVID-19 patients with cancer in our study, 13 (12.26%) had radiotherapy, 17 (14.15%) received chemotherapy, 8 (7.62%) received surgery, 4 (3.81%) had targeted therapy, and 6 (5.71%) had immunotherapy within 40 days before the onset of COVID-19 symptoms. All of the targeted therapeutic drugs were EGFR–tyrosine kinase inhibitors for treatment of lung cancer, and all of the immunotherapy drugs were PD-1 inhibitors for the treatment of lung cancer. A patient with cancer may have more than one type of therapy. Our observation suggested that patients who received immunotherapy tended to have high rates of death [2 (33.33%) of 6 patients] and high chances of developing critical symptoms [4 (66.67%) of 6 patients]. Patients who received surgery demonstrated higher rates of death [2 (25.00%) of 8 patients], higher chances of ICU admission [3 (37.50%) of 8 patients], higher chances of having severe or critical symptoms [5 (62.50%) of 8 patients], and higher use of invasive ventilation [2 (25.00%) of 8 patients] than other treatments excluding immunotherapy. However, patients with cancer who received radiotherapy did not show statistically significant differences in having any severe events when compared with patients without cancer, with all P values > 0.10 (Fig. 1I and J). Clinical details on the cancer diagnoses and cancer treatments are summarized in Supplementary Table S4.

Timeline of Severe Events

To evaluate the time-dependent evolution of the disease, we conducted the timeline of different events for COVID-19 patients with cancer (Fig. 2A) and COVID-19 patients without cancer (Fig. 2B) with death and other severe events marked in the figure. COVID-19 patients with cancer had a mean length of stay of 27.01 days (SD 9.52) and patients without cancer had a mean length of stay of 17.75 days (SD 8.64); the difference is significant (Wilcoxon test, P < 0.01). To better clarify the contributing factors that might influence outcomes, we also included logistic regression of COVID-19 patients with cancer adjusted by immunosuppression levels in Supplementary Table S5. However, no significant association between immunosuppression and severe outcomes was observed from the analysis (with all P > 0.05).

Figure 2.

Timeline of events for COVID-19 patients. A, Timeline of events in COVID-19 patients with cancer. B, Timeline of events in COVID-19 patients without cancer. For visualization purposes, patients without timeline information are excluded and only 105 COVID-19 patients without cancer are shown.

Discussion

The findings in this study suggest that patients with cancer infected with SARS-CoV-2 tend to have more severe outcomes when compared with patients without cancer. Patients with hematologic cancer, lung cancer, and cancers in metastatic stages demonstrated higher rates of severe events compared with patients without cancer. In addition, patients who underwent cancer surgery showed higher death rates and higher chances of having critical symptoms.

The SARS-CoV-2 virus has spread rapidly globally; thus, many countries have not been ready to handle the large volume of people affected by this outbreak due to a lack of knowledge about how this coronavirus affects the general population. To date, reports on the general population infected with SARS-CoV-2 suggest elderly males have a higher incidence and death rate (7, 8). Limited information is known about the outcome of patients with cancer who contract this highly communicable disease. Cancer is among the top causes of death. Asia, Europe, and North America have the highest incidence of cancer in the world (9), and at the moment of the writing of this study the SARS-CoV-2 virus is mainly spreading in these three areas (referred from https://www.cdc.gov/media/releases/2020/s0226-Covid-19-spread.htmlhttps://www.nytimes.com/2020/02/27/world/coronavirusnews.html). Although COVID-19 patients with cancer may share some epidemiologic features with the general population with this disease, they may also have additional clinical characteristics. Therefore, we conducted this study on patients with cancer with coexisting COVID-19 disease to evaluate the potential effect of COVID-19 on patients with cancer.

On the basis of our analysis, COVID-19 patients with cancer tend to have more severe outcomes when compared with the noncancer population. Although COVID-19 is reported to have a relatively low death rate of 2% to 3% in the general population (10), patients with cancer and COVID-19 not only have a nearly 3-fold increase in the death rate than that of COVID-19 patients without cancer, but also tend to have much higher severity of their illness. Altogether, these findings suggest that patients with cancer are a much more vulnerable population in the current COVID-19 outbreak. Our findings are consistent with those presented in a previous study based on 18 patients with cancer (4). Because of the limited number of patients with cancer in the previous study, the authors concluded that among patients with cancer, age is the only risk factor for the severity of the illness. On the basis of our data on 105 patients with cancer, we have discovered additional risk factors, including cancer types, cancer stage, and cancer treatments, which may contribute to the severity of the disease among patients with cancer.

Our data demonstrate that the severity of SARS-CoV-2 infection in patients is significantly affected by the types of tumors. From our analysis, patients with hematologic cancer have the highest severity and death rates among all patients with cancer, and lung cancer follows second. Patients with hematologic cancer in our study include patients with leukemia, myeloma, and lymphoma, who have a more compromised immune system than patients with solid tumors (11). These patients all had a rapidly deteriorating clinical course once infected with COVID-19. Because malignant or dysfunctional plasma cells, lymphocytes, or white blood cells in general in hematologic malignancies have decreased immunologic function (12–14), this could be the main reason why patients with hematologic cancer have very high severity and death rates. All patients with hematologic cancer are prone to the complications of serious infection (12–14), which can exacerbate the condition which could have worsened in patients with COVID-19. In our study, 55.56% of patients with hematologic cancer had severe immunosuppression, which may be the main reason for deteriorated outcomes. Although the small sample size limits representativity of the observation, we believe our finding can serve as an informative starting point for further investigation when a larger cohort from a wide range of healthcare providers becomes available. Among solid tumors, lung cancer is the highest risk category disease in patients with SARS-CoV-2 infection (Fig. 1C). Decreased lung function and severe infection in patients with lung cancer could contribute to the worse outcome in this subpopulation (15, 16).

In our analysis, we classified the SARS-CoV-2 infection–related high risk factors based on death, severe or critical illness, ICU admission, and the utilization of invasive mechanical ventilation. Using these parameters, we detected a multi-fold increase in risk in the cancer population, in contrast to the noncancer population. If there were primary or metastatic tumors in the lungs, patients were more prone to a deteriorated course in a short time. Intriguingly, when patients with cancer had only early-stage disease without metastasis, we did not observe any difference between the cancer and noncancer population in terms of COVID-19–related death rate or severity (Fig. 1E). The stage of cancer diagnosis seemed to play a significant role in the severity and death rate of COVID-19.

Patients with cancer received a wide range of treatments, and we also found that different types of treatments had different influences on severity and death when these patients contracted COVID-19. Recently, immunotherapy has assumed a very important role in treating tumors, which aids in treatment of cancer by blocking the immune escape of cancer cells. But in our study, in contrast to patients with cancer with other treatments, patients with immunotherapy had the highest death rate and the highest severity of illness, a very puzzling finding. According to pathologic studies on the patients with COVID-19, there were desquamation of pneumocytes and hyaline membrane formation, implying that these patients had acute respiratory distress syndrome (ARDS; ref. 17). ARDS induced by cytokine storm is reported to be the main reason for death of SARS-CoV-2–infected patients (18). It is possible that in this setting, immunotherapy induces the release of a large amount of cytokines, which can be toxic to normal cells, including lung epithelial cells (19–21), and therefore lead to a more severe illness. However, in this study the number of patients with immunotherapy was too small; further research with a large case population needs to be conducted in the future.

In addition, COVID-19 patients with cancer who are under active treatment or not under active treatment do not show differences in their outcomes, and there is a significant difference between COVID-19 patients with cancer but not with active treatment and patients without cancer (Supplementary Table S2). These results indicate that COVID-19 patients with both active treatment and just cancer history have a higher risk of developing severe events than noncancer COVID-19 patients. The possible reasons could be due to some known cancer-related complications, for example, anemia, hypoproteinaemia, or dyspnea in early phase of COVID-19 (22). We considered that cancer had a lifetime effect on patients and that cancer survivors always need routine follow-up after primary resection. Therefore, in clinical COVID-19 patient management, equivalent attention needs to be paid to those with cancer whether they are under active therapeutics or not during the outbreak of COVID-19.

This study has several limitations. Although the cohort of COVID-19 patients with cancer is one of the largest in Hubei province, China, the epicenter of the initial outbreak, a larger cohort from the whole country or even from multiple countries will be more representative. Large-scale national and international research collaboration will be necessary to achieve this. At the initial stage of the outbreak, data collection and research activities were not a priority of the hospitals. Therefore, it was not possible to record and collect some data that are potentially informative for our analysis in a timely manner. In addition, due to the urgency of clinical treatment, medical data used in this study were largely disconnected from the patients’ historical electronic medical records, which are mostly stored with a different healthcare provider than the medical center providing COVID-19 care. This left us with limited information about each patient.

Our study is the midsize cohort study on this topic and will provide much-needed information on risk factors of this population. We hope that our findings will help countries better protect patients with cancer affected by the ongoing COVID-19 pandemic.

Methods

Study Design and Patients

We conducted a multicenter study focusing on the clinical characteristics of confirmed cases of COVID-19 patients with cancer in 14 hospitals in Hubei province, China; all of the 14 hospitals served as government-designated hospitals for patients diagnosed with COVID-19. SARS-CoV-2–infected patients without cancer matched by the same hospital and hospitalization time were randomly selected as our control group. In addition, as age is one of the major predictors of severity of respiratory diseases like COVID-19 (4), we excluded from our analysis 117 younger COVID-19 patients without cancer so that median ages of patients with cancer (median = 64.0, IRQ = 14.00) and patients without cancers (median = 63.5, IQR = 14.00) would be comparable.

End Points and Assessments

There were four primary outcomes analyzed in this study: death, admission into the ICU, development of severe or critical symptoms, and utilization of invasive mechanical ventilation. The clinical definition of severe/critical symptoms follows the 5th edition of the 2019Novel Coronavirus Disease (COVID-19) Diagnostic Criteria published by the National Health Commission in China, including septic shock, ARDS, acute kidney injury, disseminated intravascular coagulation, and rhabdomyolysis.

Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System

Source:

Vikas MehtaSanjay GoelRafi KabarritiDaniel ColeMendel GoldfingerAna Acuna-VillaordunaKith PradhanRaja ThotaStan ReissmanJoseph A. SparanoBenjamin A. GartrellRichard V. SmithNitin OhriMadhur GargAndrew D. RacineShalom KalnickiRoman Perez-SolerBalazs Halmos and Amit Verma. Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System

Abstract

Patients with cancer are presumed to be at increased risk from COVID-19 infection–related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19–positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six of 11 (55%) patients with lung cancer died from COVID-19 disease. Increased mortality was significantly associated with older age, multiple comorbidities, need for ICU support, and elevated levels of D-dimer, lactate dehydrogenase, and lactate in multivariate analysis. Age-adjusted CFRs in patients with cancer compared with noncancer patients at our institution and New York City reported a significant increase in case fatality for patients with cancer. These data suggest the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.

Significance: COVID-19 in patients with cancer is associated with a significantly increased risk of case fatality, suggesting the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.

Introduction

The novel coronavirus COVID-19, or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread rapidly throughout the world since its emergence in December 2019 (1). The virus has infected approximately 2.9 million people in more than 200 countries with more than 200,000 deaths at the time of writing (2). Most recently, the United States has become the epicenter of this pandemic, reporting an estimated 956,000 cases of COVID-19 infection, with the largest concentration in New York City (NYC) and its surrounding areas (approximately >203,000 cases or 35% of all U.S. infections; ref. 3).

Early data suggests that 14% to 19% of infected patients will develop significant sequelae with acute respiratory distress syndrome, septic shock, and/or multiorgan failure (1, 4, 5), and approximately 1% to 4% will die from the disease (2). Recent meta-analyses have demonstrated an almost 6-fold increase in the odds of mortality for patients with chronic obstructive pulmonary disease (COPD) and a 2.5-fold increase for those with diabetes, possibly due to the underlying pulmonary and immune dysfunction (6, 7). Given these findings, patients with cancer would ostensibly be at a higher risk of developing and succumbing to COVID-19 due to immunosuppression, increased coexisting medical conditions, and, in cases of lung malignancy, underlying pulmonary compromise. Patients with hematologic cancer, or those who are receiving active chemotherapy or immunotherapy, may be particularly susceptible because of increased immunosuppression and/or dysfunction.

According the NCI, there were approximately 15.5 million cancer survivors and an estimated 1,762,450 new cases of cancer diagnosed in the United States in 2019 (8). Early case series from China and Italy have suggested that patients with malignancy are more susceptible to severe infection and mortality from COVID-19 (9–12), a phenomenon that has been noted in other pandemics (13). Many of these descriptive studies have included small patient cohorts and have lacked cancer site–specific mortality data or information regarding active cancer treatment. As New York has emerged as the current epicenter of the pandemic, we sought to investigate the risk posed by COVID-19 to our cancer population with more granular data regarding cancer type and active treatment, and identify factors that placed patients with cancer at highest risk of fatality from COVID-19.

Results

Outcomes of 218 Cancer Patients with COVID-19 Show High Overall Mortality with Tumor-Specific Patterns

A total of 218 patients with cancer and COVID-19 were treated in Montefiore Health System (New York, NY) from March 18, 2020, to April 8, 2020. These included 164 (75%) patients with solid tumors and 54 (25%) with hematologic malignancies. This cohort included 127 (58%) males and 91 (42%) females. The cohort was predominantly composed of adult patients (215/218, 98.6%) with a median age of 69 years (range 10–92 years).

Sixty-one (28%) patients expired as a result of COVID-19disease at the time of analysis (Table 1). The mortality was 25% among all patients with solid tumors and was seen to occur at higher rates in patients with lung cancers (55%), gastrointestinal (GI) cancers [colorectal (38%), pancreatic (67%), upper GI (38%)], and gynecologic malignancies (38%). Genitourinary (15%) and breast (14%) cancers were associated with relatively lower mortality with COVID-19 infection.

Table 1.

Outcomes in patients with cancer and COVID-19

Hematologic malignancies were associated with higher rate of mortality with COVID-19 (37%). Myeloid malignancies [myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML)/myeloproliferative neoplasm (MPN)] showed a trend for higher mortality compared with lymphoid neoplasms [non-Hodgkin lymphoma (NHL)/chronic lymphoid leukemia (CLL)/acute lymphoblastic leukemia (ALL)/multiple myeloma (MM)/Hodgkin lymphoma; Table 1]. Rates of ICU admission and ventilator use were slightly higher for hematologic malignancies than solid tumors (26% vs. 19% and 11% vs. 10%, respectively), but this did not achieve statistical significance.

Disease Characteristics of Cancer Patients with COVID-19 Demonstrate the Effect of Age, Comorbidities, and Laboratory Biomarkers on Mortality

Analysis of patient characteristics with mortality did not show any gender bias (Table 2). Older age was significantly associated with increased mortality, with median age of deceased cohort at 76 years when compared with 66 years for the nondeceased group (P = 0.0006; Cochran-Armitage test). No significant associations between race and mortality were seen.

Table 2.

Disease characteristics of patients with cancer with COVID-19 and association with mortality

COVID-19 disease severity, as evident from patients who needed ICU care and ventilator support, was significantly associated with increased mortality. Interestingly, active disease (<1 year) and advanced metastatic disease showed a trend for increased mortality, but the association did not achieve statistical significance (P = 0.09 and 0.06, respectively). Active chemotherapy and radiotherapy treatment were not associated with increased case fatality. Very few patients in this cohort were on immunotherapy, and this did not show any associations with mortality.

Analysis of comorbidities demonstrated increased risk of dying from COVID-19 in patients with cancer with concomitant heart disease [hypertension (HTN), coronary artery disease (CAD), and congestive heart failure (CHF)] and chronic lung disease (Table 2). Diabetes and chronic kidney disease were not associated with increased mortality in univariate analysis (Table 2).

We also analyzed laboratory values obtained prior to diagnosis of COVID-19 and during the time of nadir after COVID-19 positivity in our cancer cohort. Relative anemia pre–COVID-19 was associated with increased mortality, whereas pre-COVID platelet and lymphocyte counts were not (Table 3).Post–COVID-19 infection, lower hemoglobin levels, higher total white blood cell (WBC) counts, and higher absolute neutrophil counts were associated with increased mortality (Table 3). Analysis of other serologic biomarkers demonstrated that elevated D-dimer, lactate, and lactate dehydrogenase (LDH) in patients were significantly correlated with dying (Table 3).

Table 3.

Laboratory values of cancer patients with COVID-19 and association with mortality

Next, we conducted multivariate analyses and used variables that showed a significant association with mortality in univariate analysis (P < 0.05 in univariate was seen with age, ICU admission, hypertension, chronic lung disease, CAD, CHF, baseline hemoglobin, nadir hemoglobin, WBC counts, D-dimer, lactate, and LDH). Gender was forced in the model and we used a composite score of comorbidities from the sum of indicators for diabetes mellitus (DM), HTN, chronic lung disease, chronic kidney disease, CAD, and CHF capped at a maximum of 3. In the multivariate model (Supplementary Table S1), we observed that older age [age < 65; OR, 0.23; 95% confidence interval (CI), 0.07–0.6], higher composite comorbidity score (OR, 1.52; 95% CI, 1.02–2.33), ICU admission (OR, 4.83; 95% CI, 1.46–17.15), and elevated inflammatory markers (D-dimer, lactate, and LDH) were significantly associated with mortality after multivariate comparison in patients with cancer and COVID-19.

Interaction with the Healthcare Environment was a Prominent Source of Exposure for Patients with Cancer

A detailed analysis of deceased patients (N = 61; Supplementary Table S2) demonstrated that many were either nursing-home or shelter (n = 22) residents, and/or admitted as an inpatient or presented to the emergency room within the 30 days prior to their COVID-19 positive test (21/61). Altogether, 37/61 (61%) of the deceased cohort were exposed to the healthcare environment at the outset of the COVID-19 epidemic. Few of the patients in the cohort were on active oncologic therapy. The vast majority had a poor Eastern Cooperative Oncology Group performance status (ECOG PS; 51/61 with an ECOG PS of 2 or higher) and carried multiple comorbidities.

Patients with Cancer Demonstrate a Markedly Increased COVID-19 Mortality Rate Compared with Noncancer and All NYC COVID-19 Patients

An age- and sex-matched cohort of 1,090 patients at a 5:1 ratio of noncancer to cancer COVID-19 patients from the same time period and from the same hospital system was also obtained after propensity matching and used as control to estimate the increased risk posed to our cancer population (Table 4). We observed case fatality rates (CFR) were elevated in all age cohorts in patients with cancer and achieved statistical significance in the age groups 45–64 and in patients older than 75 years of age.

Table 4.

Comparison of cancer and COVID-19 mortality with all NYC cases (official NYC numbers up to 5 p.m., April 12, 2020) and a control group from the same healthcare facility

To also compare our CFRs with a larger dataset from the greater NYC region, we obtained official case numbers from New York State (current up to April 12, 2020; ref. 3). In all cohorts, the percentage of deceased patients was found to rise sharply with increasing age (Table 4). Strikingly, CFRs in cancer patients with COVID-19 were significantly, many-fold higher in all age groups when compared with all NYC cases (Table 4).

Discussion

To our knowledge, this is the first large report of COVID-19 CFRs among patients with cancer in the United States. The overall case fatality among COVID-19–infected patients with cancer in an academic center located within the current epicenter of the global pandemic exceeded 25%. In addition, striking tumor-specific discrepancies were seen, with marked increased susceptibility for those with hematologic malignancies and lung cancer. CFRs were 2 to 3 times the age-specific percentages seen in our noncancer population and the greater NYC area for all COVID-19 patients.

Our results seem to mirror the typical prognosis of the various cancer types. Among the most common malignancies within the U.S. population (lung, breast, prostate, and colorectal), there was 55% mortality among patients with lung cancer, 14% for breast cancer, 20% for prostate cancer, and 38% for colorectal cancer. This pattern reflects the overall known lethality of these cancers. The percent annual mortality (ratio of annual deaths/new diagnosis) is 59.3% for lung cancer, 15.2% for breast cancer, 17.4% for prostate cancer, and 36% for colorectal cancer (8). This suggests that COVID-19 infection amplifies the risk of death regardless of the cancer type.

Patients with hematologic malignancies demonstrate a higher mortality than those with solid tumors. These patients tend to be treated with more myelosuppressive therapy, and are often severely immunocompromised because of underlying disease. There is accumulating evidence that one major mechanism of injury may be a cytokine-storm syndrome secondary to hyperinflammation, which results in pulmonary damage. Patients with hematologic malignancy may potentially be more susceptible to cytokine-mediated inflammation due to perturbations in myeloid and lymphocyte cell compartments (14).

Many of the predictive risk factors for mortality in our cancer cohort were similar to published data among all COVID-19 patients. A recent meta-analysis highlighted the association of chronic diseases including hypertension (OR, 2.29), diabetes (OR, 2.47), COPD (OR, 5.97), cardiovascular disease (OR, 2.93), and cerebrovascular disease (OR, 3.89) with a risk for developing severe COVID-19 infection among all patients (15). In our cancer patient dataset, a large proportion of patients had at least one of these concurrent risk factors. In a univariate model, we observed significant associations of death from COVID-19 infection in patients with hypertension, chronic lung disease, coronary heart disease, and congestive heart failure. Serologic predictors in our dataset predictive for mortality included anemia at time of infection, and elevated LDH, D-dimer, and lactic acid, which correlate with available data from all COVID-19 patients.

Rapidly accumulating reports suggest that age and race may play a role in the severity of COVID-19 infection. In our cancer cohort, the median age of the patients succumbing to COVID-19 was 76 years, which was 10 years older than patients who have remained alive. The CDC has reported a disproportionate number of African Americans are affected by COVID-19 in the United States, accounting for 33% of all hospitalized patients while constituting only 13% of the U.S. population (15). However, the racial breakdown of our patients was proportional to the Bronx population as a whole, and race was not a significant predictor of mortality in our univariate or multivariate models. Our data might argue that the increased mortality noted in the larger NYC populations might also likely be driven by socioeconomic and health disparities in addition to underlying biological factors. Overall mortality with COVID-19 has been higher in the Bronx, which is a socioeconomically disadvantaged community with a mean per capita income of $19,721 (16, 17). Our patients with cancer were predominantly from the Bronx and potentially had increased mortality in part due to socioeconomic factors and comorbidities. Even after accounting for the increased mortality seen in COVID-19 in the Bronx, the many-fold magnitude increase in death rates within our cancer cohort can potentially be attributed to the vulnerability of oncology patients. This was evident in the comparison with a control group from the same hospital system that demonstrated a significant association of cancer with mortality in patients between 45 and 64 years of age and older than 75 years of age.

Interaction with the healthcare environment prior to widespread knowledge of the epidemic within NYC was a prominent source of exposure for our patients with cancer. Many of those who succumbed to COVID-19 infection were older and frail with significant impairment of pulmonary and/or immunologic function. These findings could be utilized to risk-stratify patients with cancer during this pandemic, or in future viral airborne outbreaks, and inform mitigation practices for high-risk individuals. These strategies could include early and aggressive social distancing, resource allocation toward more outpatient-based care and telemedicine, testing of asymptomatic high-risk patients, and institution of strict infection-control measures. Indeed, such strategies were implemented early in the pandemic at our center, possibly explaining the relatively low number of infected patients on active therapy.

There were several limitations to our study. Data regarding do not resuscitate or intubate orders were not included in the analysis and could have significantly affected the decision-making and mortality surrounding these patients. Although an attempt was made to control for those receiving active cancer treatment or with additional comorbidities, we could not fully account for the patients’ preexisting health conditions prior to COVID-19 infection. Differential treatment paradigms for COVID-19 infection and sequelae were not controlled for in our analysis. Because of the limited follow-up, the full clinical course of these patients may not be included. Future comparative studies to noncancer patients will be needed to fully ascertain the risk posed to oncology patients. Finally, though our data does include those who were tested and discharged within our health system, we cannot fully account for those who were tested in nonaffiliated outpatient settings, which may potentially bias our study to more severe cases. We also acknowledge that the mortality rate is highly dependent on the breadth of testing, and therefore understand that more widespread detection of viral infection would likely alter the results.

Our data suggest significant risk posed to patients with cancer infected with COVID-19, with an observed significant increase in mortality. The highest susceptibility appears to be in hematologic or lung malignancies, suggesting that proactive strategies to reduce likelihood of infection and improve early identification of COVID-19 positivity in the cancer patient population are clearly warranted. Overall, we hope and expect that our data from the current epicenter of the COVID-19 epidemic will help inform other healthcare systems, patients with cancer, and the public about the particular vulnerability of patients with cancer to this disease.

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