SARS COV 2 CAUSING COVID 19: THE SHORT AND THE LONG OF IT!
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The J. Boyd Francis, MD Lecture
SARS‐CoV‐2 causing COVID‐19:
The Short and the Long of it!
March 25, 2022
Charles J. Schleupner, M.Sc., M.D., FACP, FIDSA, FSHEA
Professor of Internal Medicine
Virginia Tech Carilion School of Medicine
Section of Infectious Diseases
Department of Internal Medicine
Chair, Institutional Review Board
Carilion Clinic
The J. Boyd Francis, MD Lecture
SARS‐CoV‐2 causing COVID‐19:
The short and the Long of it!
March 25, 2022
No relevant Disclosures
J. Boyd Francis, MD
OBJECTIVES
Topics for Review
• Virology of SARS‐CoV‐2 related to clinical disease
• Past and current epidemiology of COVID‐19
• Prevention of SARS‐CoV‐2 infection (mitigation and PrEP)
• Immunization against SARS‐CoV‐2 infection
• The acute clinical illness caused by SARS‐CoV‐2
• Diagnostic tests for SARS‐CoV‐2 infection related to clinical illness
• Treatment (phases) of COVID‐19 illness
• Post‐acute sequelae of COVID‐19 (PASC), “The Long Haul” – Long Covid
Virology of SARS‐CoV‐2
Timeline for Coronavirus Research
2002, 2003
2012
2019‐2022
Major findings in coronavirus research (gray boxes) as well as identification of human coronaviruses (red boxes) are indicated along the timeline.
J Exp Med. 2020;217(5). doi:10.1084/jem.20200537
Structure of Coronaviruses Cleveland Clinic Journal of Medicine June 2020, 87 (6) 321‐327; DOI: https://doi.org/10.3949/ccjm.87a.20047
SARS‐CoV‐2 variants Wild type – Wuhan‐hu‐1 virus isolated in China, November/December 2019 B.1.1.7 (Alpha) ‐ UK initially, then USA in December 2020. The N501Y variant is in the same lineage (20I/501Y.V1). B.1.351 (Beta) ‐ South Africa, then USA in January 2021. The 20H/501Y.V2 is of the B.1.351 lineage. P.1 (Gamma) ‐ Brazil ‐ November 2020, then Japan ; designated Jan 11, 2021 B.1.429 (Epsilon) ‐ B.1.525 (Eta) – multiple countries B.1.526 (Iota) ‐ USA (New York) B.1.617.1 (Kappa) – India in October, 2020 B.1.617.2 (Delta) ‐ India, then USA in March 2021; designated 4/4/2021 C.37 (Lambda) – Peru in August, 2020 B.1.621 (mu) – Columbia, January 2021 B.1.1.529 (Omicron) ‐ South Africa, multiple countries, November 9, 2021
Past and current Epidemiology of COVID‐19
2019
Possible SARS-CoV-2 transmission chains Huanan Seafood Market
Wuhan, China
horseshoe
In August 2018 an epidemic of African Swine fever virus
developed in China, resulting in massive culling of swine (China
produces about 50% of global pork and is a large consumer as
well). This had great impact upon harvesting multiple wild
mammals for meat products (fresh and frozen meat) and live
animals in markets–
racoon dogs,
hedgehogs,
badgers,
red foxes,
bamboo rats,
Porcupines.
Peng Zhou, and Zheng-Li Shi . Science 2021;371:120-1223/13/2020 National Emergency declared in USA
Cumulative Cases of Covid‐19 by Country ,
March 1, 2022
USA
Johns Hopkins University DataCumulative Deaths due to Covid‐19 by Country ,
March 1, 2022
USA
Johns Hopkins University DataCoronavirus Disease (COVID‐19) in the U.S.
As of M arch 22,2022 (from CD C)
TotalCases - 79,621,004
TotalD eaths - 971,422
*includes 50 states, District of Columbia, Guam, the Northern Mariana Islands, Puerto Rico, and the U.S Virgin IslandsNumber of COVID‐19 Cases reported each day in the
U.S. since the beginning of the outbreak (3/18/2022)
Omicron
(BA.1.1,
B.1.1.529)
Mu (B.1.621)
Alpha Lambda (C.37)
(B.1.1.7) Delta
(B.1.617.2)
Wild Type D614G Gamma
(Wuhan) mutation (P.1)
D614G mutation is characterized by an aspartic acid to glycine shift at the amino acid position 614 of a protein.
CDC Data. The blue bars show daily cases. The red line is the 7‐day moving average of cases.Number of new COVID‐19 Deaths reported each day in the U.S.
since the beginning of the outbreak (3/18/2022)
Alpha Omicron
(B.1.1.7) (BA.1.1,
B.1.1.529)
Wild Type
(Wuhan) Delta
(B.1.617.2)
Mu (B.1.621)
Lambda (C.37)
D614G
mutation
Gamma
(P.1)
D614G mutation is characterized by an aspartic acid to glycine shift at the amino acid position 614 of a protein.
CDC Data. The blue bars show daily deaths. The red line is the 7‐day moving average of deaths.Provisional Mortality Data — United States, 2020
Farida B. Ahmad, Jodi A. Cisewski, Arialdi Miniño, et al.
Morb Mortal Wkly Rep 2021;70:519–522. DOI: http://dx.doi.org/10.15585/mmwr.mm7014e1Prevention of SARS‐CoV‐2 infection
Delta R0 6‐7 Omicron R0 10
Delta R0 6‐7 Omicron R0 10 R0 of Delta variant = 5.08; R0 of Omicron variant = 3.19 x Delta R0
Prevention of SARS‐CoV‐2 infection in Ambulatory Setting Mitigation • masking • Physical distancing • ventilation – air exchanges per hour indoors (6‐10 per hour) • hand washing/sanitizing • Disinfection of inanimate surfaces (? needed, undocumented risk) Infusion of long‐acting monoclonal antibody ‐ Evusheld (tixagevimab co‐packaged with cilgavimab) Immunization
SARS‐CoV‐2 infection of the oral cavity and saliva
Huang, N., Pérez, P., Kato, T. et al.
Abstract: (abbreviated)
… and salivary viral burden correlated with COVID‐19 symptoms, including taste loss. Upon recovery, this asymptomatic
cohort exhibited sustained salivary IgG antibodies against SARS‐CoV‐2.
Collectively, these data show that the oral cavity is an important site for SARS‐CoV‐2 infection and implicate saliva as a
potential route of SARS‐CoV‐2 transmission.
Nat Med 27, 892–903 (2021). https://doi.org/10.1038/s41591‐021‐01296‐8A heavy cough jet travels up to 12 ft in ∼50 s
Effectiveness of Face Mask or Respirator Use in Indoor Public Settings for Prevention
of SARS‐CoV‐2 Infection — California, February–December 2021
Kristin L. Andrejko, Jake M. Pry, Jennifer F. Myers, et al.
Bandana
Fleece
Morb Mortal Wkly Rep. ePub: 4 February 2022. DOI: http://dx.doi.org/10.15585/mmwr.mm7106e1(Most Important) Issues Addressed in this Update
• Masks and Face Coverings Work as Source Control on the infected person—
and May also Protect the Wearer from an infected person;
• Universal Masking Is Associated With Fewer New Cases and Lower Mortality;
• Evidence From Randomized Controlled Trials Remains Sparse (ethically difficult
to justify with an ongoing infectious disease when observational studies clearly
demonstrate efficacy)
Ann Intern Med. 2021; 174(4):511-520. doi:10.7326/M20-6625Adjusted odds ratio (aOR) and 95% confidence intervals for community exposures associated with confirmed
COVID‐19 among symptomatic adults aged ≥18 years (N = 314) — United States, July 1–29, 2020
MMWR September 11, 2020; 69 (36): 1258‐1264Prevention of SARS‐CoV‐2 infection
Mitigation
• masking
• physical (not social) distancing
• ventilation – air exchanges per hour indoors
• hand washing/sanitizing
• Disinfection of inanimate surfaces (? needed)
Infusion of long‐acting monoclonal antibody –
Evusheld (tixagevimab co‐packaged with cilgavimab) for PrEP;
bamlanivimab plus etesevimab and casirivimab plus imdevimab
(REGEN‐CoV) for PEP.
ImmunizationFDA Authorizes New Long‐Acting Monoclonal Antibodies for
Pre‐exposure Prevention of COVID‐19 in Certain Individuals
December 8, 2021
The U.S. Food and Drug Administration issued an emergency use authorization (EUA) for AstraZeneca’s Evusheld (tixagevimab
co‐packaged with cilgavimab and administered together) for the pre‐exposure prophylaxis (prevention) of COVID‐19 in
certain adults and pediatric individuals (12 years of age and older weighing at least 40 kilograms [about 88 pounds]).
The product is only authorized for those individuals who are not currently infected with the SARS‐CoV‐2 virus and who have
not recently been exposed to an individual infected with SARS‐CoV‐2. The authorization also requires that individuals either
have:
• moderate to severely compromised immune systems due to a medical condition or due to taking
immunosuppressive medications or treatments and may not mount an adequate immune response to COVID‐19
vaccination (examples of such medical conditions or treatments can be found in the fact sheet
for health care providers) or;
• a history of severe adverse reactions to a COVID‐19 vaccine and/or component(s) of those vaccines,
therefore vaccination with an available COVID‐19 vaccine, according to the approved or authorized
schedule, is not recommended.
With an EUA revision on February 22, 2022, FDA has increased the initial authorized dose from 150mg of each
monoclonal antibody to 300 mg of tixagevimab and 300 mg of cilgavimab.
FDA News Release. December 08, 2021Immunization against SARS‐CoV‐2 infection
X
The Race
for Coronavirus Vaccines:
Nucleic‐Acid Vaccines
translation
Nature 580, 576‐577 (2020) doi: 10.1038/d41586‐020‐01221‐yPfizer and Moderna SARS‐CoV‐2 Vaccines Pfizer‐BioNTech vaccine – Comirnaty Moderna vaccine ‐ Spikevax
Characteristics of patients with report of anaphylaxis and non‐anaphylaxis allergic reactions after receipt of
Pfizer‐BioNTech COVID‐19 vaccine — Vaccine Adverse Events Reporting System (VAERS),
United States, December 14–23, 2020
Morb Mortal Wkly Rep 2021;70:46–51. DOI: http://dx.doi.org/10.15585/mmwr.mm7002e1Interim Estimates of Vaccine Effectiveness of Pfizer‐BioNTech and Moderna COVID‐19 Vaccines Among
Health Care Personnel — 33 U.S. Sites, January–March 2021
Tamara Pilishvili, Katherine E. Fleming‐Dutra, Jennifer L. Farrar, et al.
Morb Mortal Wkly Rep 2021;70:753–758. DOI: http://dx.doi.org/10.15585/mmwr.mm7020e2Cases of Myocarditis After mRNA-Based COVID-19 Vaccination by Age at Onset of Myocarditis
Myocarditis rate per million vaccine doses* = 14.2; Myocarditis rate per million vaccine doses* = 21.1;
After dose 1 = 4.7; after dose 2 = 24.1 After dose 1 = 9.7; after dose 2 = 33.0
*from CDC/ACIP slides shown at meeting of ACIP on February 4, 2022
JAMA. 2022;327(4):331-340. doi:10.1001/jama.2021.24110J&J/ Janssen Vaccine has 69.7% Efficacy against
symptomatic infection after single dose, 74.6%
against severe COVID‐19, 82.8% against death;
Improved with booster.
The risks of Vaccine‐induced Thrombotic Thrombocytopenia (VITT) syndrome and
Guillain‐Barre Syndrome prompted ACIP on December 16, 2021 to make a
preferential recommendation for the use of mRNA COVID‐19 vaccines over the
Janssen adenoviral‐vectored COVID‐19 vaccine in all persons aged ≥18 years in the
United States.
MMWR 2022; 71: 90‐95. DOI: http://dx.doi.org/10.15585/mmwr.mm7103a4Analysis of COVID‐19 Vaccine Type and Adverse Effects Following Vaccination
Alexis L. Beatty, Noah D. Peyser, Xochitl E. Butcher, et al.
Key Points:
Question: What factors are associated with adverse effects after COVID‐19 vaccination?
Findings: In an online cohort study including 19,586 adults who received a COVID‐19 vaccination, the factors
most strongly associated with adverse effects were:
‐ full vaccination dose (2nd dose),
‐ brand of vaccine (Moderna),
‐ younger age (< 65 YO),
‐ female sex, and
‐ having had COVID‐19 before vaccination.
Allergic reaction or anaphylaxis was reported in 0.3% of participants after partial vaccination and 0.2% of
participants after full vaccination.
Meaning These findings suggest that some individuals experience more adverse effects after COVID‐19
vaccination, but serious adverse effects are rare.
JAMA Netw Open. December 22, 2021; 4(12):e2140364. doi:10.1001/jamanetworkopen.2021.40364Adverse Effects by Vaccine Brand
Line defining
reports
by 50% of
respondents
Participants could report more than 1 adverse effect.
Denominators include all participants who provided an
answer to the question.
JAMA Netw Open. December 22, 2021; 4(12):e2140364. doi:10.1001/jamanetworkopen.2021.40364Immunization schedule for persons 5 years of age and older (2/22/2022)
Intervals for primary two‐
dose series lengthened due
to lower incidence of Interval for booster in
myocarditis and higher T‐cell immunocompromised patients
and neutralizing antibody shortened from
levels; for those >65YO or 5 months to 12 weeks
immunocompromised no
change of this interval.
Booster doses have been
shown important for
broadening immunity
to include Omicron. mRNA booster Preferred
https://www.cdc.gov/vaccines/covid‐19/clinical‐considerations/covid‐19‐vaccines‐us.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fcovid‐19%2Finfo‐by‐product%2Fclinical‐considerations.htmlAcute clinical illness caused by SARS‐CoV‐2
Transmission and life‐cycle of SARS‐CoV‐2 causing COVID‐19
SARS-CoV-2 is transmitted via respiratory droplets of infected cases to oral and respiratory mucosal cells. The virus, possessing a single-stranded RNA genome wrapped in nucleocapsid (N) protein and
three major surface proteins: membrane (M), envelope (E) and Spike, replicates and passes to the lower airways potentially leading to severe pneumonia. The gateway to host cell entry (magnified view)
is via Spike-converting enzyme 2 (ACE2) interaction with cleavage of Spike in the prefusion state by proteases TMPRSS-2/furin. A simplified depiction of the life cycle of the virus is shown along with
potential immune responses elicited.
Front. Pharmacol., 19 June 2020 | https://doi.org/10.3389/fphar.2020.00937There are many more upper respiratory cells with ACE2 receptors than there are cells with both ACE2 and TMPRSS2. This potentiates Omicron replication in the upper airway and thereby infectivity since Omicron only requires an ACE2 receptor for cell infection. Omicron is an inducer of interferon by pneumocytes, in contrast to previous SARS‐CoV‐2 variants, and this limits its infection/replication in the lung.
A schematic description of
immune responses in
asymptomatic and mildly
symptomatic and severe cases
Shedding virus while
of COVID‐19 asymptomatic or
pre‐symptomatic
Lymphopenia
Front. Immunol. 12:693938. doi: 10.3389/fimmu.2021.693938CDC Suggested Symptom Observation ranging from mild symptoms to severe illness These sym ptom s m ay appear 2-14 days after exposure to and infection by the virus: •Fever •Cough •Shortness ofbreath or difficulty breathing •Chills •Repeated shaking w ith chills •M uscle pain •H eadache •Sore throat •N ew loss oftaste or sm ell(associated w ith anorexia)
Laboratory Biomarkers of COVID‐19 Progression
⇩ Lymphocyte count
Hematologic ⇧ Neutrophil count
Risk factors for severity: ⇩ Platelet count
BMI > 40
Age > 50 YO Biochemical ⇩ Albumin
Male gender ⇧ Creatinine
Prior organ transplant ⇧ Lactate dehydrogenase
⇧ Cardiac troponin
⇧ B‐type natriuretic peptide
⇩ Oxygen saturation
Inflammatory ⇧ C‐reactive protein
⇧ Ferritin
⇧ Procalcitonin
⇧ Interleukin‐6
Coagulation ⇧ D‐dimer
Worsening of biomarkers is predictive of disease progression and can inform decisions to initiate antiviral, anti‐inflammatory,
anticoagulant, or supportive treatment interventions.
Clin Infect Dis, 1 December 2020, 71(11):2996–3001, https://doi.org/10.1093/cid/ciaa742. Ann Intern Med. 2020; 173(10):773‐781. doi:10.7326/M20‐3742Illness duration and symptom profile in symptomatic UK school‐aged
children tested for SARS‐CoV‐2
Erika Molteni, Carole H Sudre, Liane S Canas et al.
Summary:
Interpretation: Although COVID‐19 in children is usually of short duration with low symptom burden, some
children with COVID‐19 experience prolonged illness duration. Reassuringly, symptom burden in these children
did not increase with time, and most recovered by day 56.
Some children who tested negative for SARS‐CoV‐2 also had persistent and burdensome illness. A holistic
approach for all children with persistent illness during the pandemic is appropriate.
The Lancet Child and Adolescent Health Available on‐line August 3, 2021. https://doi.org/10.1016/S2352‐4642(21)00198‐X
Hospitalization of Infants and Children Aged 0–4 Years with Laboratory‐Confirmed COVID‐19 —
COVID‐NET, 14 States, March 2020–February 2022
During Omicron variant predominance beginning in late December 2021, U.S. infants and children aged 0–4 years were hospitalized at approximately five times the
rate of the previous peak during Delta variant predominance.
Morb Mortal Wkly Rep 2022;71:429–436. DOI: http://dx.doi.org/10.15585/mmwr.mm7111e2 CJS Note: Multi‐system Inflammatory Syndrome in children (MIS‐C) , though uncommon, can occur.Survivors of COVID‐19 who spent time on a ventilator may be at risk of long‐term disability and illness Survivors' burden. Kelly Servick Science 24 Apr 2020; 368: 359
Risk for In‐Hospital Complications Associated with COVID‐19 and Influenza —
Veterans Health Administration, United States, October 1, 2018–May 31, 2020
Jordan Cates, Cynthia Lucero‐Obusan, Rebecca M. Dahl et al.
MMWR October 23, 2020; 69(42);1528–1534Variability in Resources and Testing Strategies, and in Contracting COVID‐19 After Exposure to SARS‐CoV‐2
or systemic heparinization
in non‐critically ill
patients (CJS)
J Am College Cardiology June 16, 2020; 75 (23): 2950‐2973. https://doi.org/10.1016/j.jacc.2020.04.031Association Between COVID‐19 and Myocarditis Using Hospital‐Based Administrative Data —
United States, March 2020–January 2021
Tegan K.Boehm er,Lyudm yla Kom paniyets,Am y M .Lavery,etal.
Morb Mortal Wkly Rep 2021;70:1228–1232. DOI: http://dx.doi.org/10.15585/mmwr.mm7035e5SARS‐CoV‐2 Variants in Patients with Immunosuppression
Lawrence Corey, Chris Beyrer, Myron S. Cohen, et al.
Patients with immunosuppression are at risk for prolonged infection with severe acute respiratory syndrome
coronavirus 2 (SARS‐CoV‐2). …
The findings that immunocompromised patients with persistent SARS‐CoV‐2 infection may generate
more transmissible or more pathogenic SARS‐CoV‐2 variants have a number of medical and public health
implications. Heightened precautions should be taken to avert nosocomial transmission of Covid‐19 among
immunocompromised patients.
CORRESPONDENCE
Shedding of Viable SARS‐CoV‐2 after Immunosuppressive Therapy for Cancer
Teresa Aydillo, Ana S. Gonzalez‐Reiche, Sadaf Aslam et al.
Patients with profound immunosuppression after undergoing hematopoietic stem‐cell transplantation or receiving cellular
therapies may shed viable SARS‐CoV‐2 for at least 2 months. The current guidelines for Covid‐19 isolation precautions may need
to be revised for immunocompromised patients.
N Engl J Med 2021; 385:562‐566. DOI: 10.1056/NEJMsb2104756. N Engl J Med 2020; 383:2586‐2588; DOI: 10.1056/NEJMc2031670Diagnostic tests for SARS‐CoV‐2 infection
Estimated Variation Over Time in Diagnostic Tests for Detection of SARS-CoV-2 Infection Relative to Symptom Onset
IgG
Virus Isolation
Note timing of rt‐PCR
IgM versus virus isolation
BAL
Virus in Stool rt‐PCR
by PCR
NP
JAMA. 2020;323(22):2249-2251. doi:10.1001/jama.2020.8259. doi:10.1001/jama.2020.8259Antibody Assay Utility for COVID‐19
• No intention to identify active COVID‐19 infection – “a complete
misuse” of the test.
• Presence of antibody can in retrospect confirm suspected and/or
unsuspected (asymptomatic) infections.
• If defined with an antibody response, a person is then likely immune
to re‐infection.
JAMA. Published online April 17, 2020. doi:10.1001/jama.2020.6170Mass Testing for rt‐PCR Assay
Nasopharyngeal (NP‐left) and Mid‐turbinate (right) swabs
The Sensitivity and Costs of Testing for SARS‐CoV‐2 Infection With Saliva Versus Nasopharyngeal Swabs
A Systematic Review and Meta‐analysis
Mayara Lisboa Bastos, Sara Perlman‐Arrow, Dick Menzies, et al.
Abstract:
Conclusion: Saliva sampling seems to be a similarly sensitive and less costly alternative that
could replace nasopharyngeal swabs for collection of clinical samples for SARS‐CoV‐2 testing.
CJS Comment: Collection of saliva samples by patients themselves negates the need for direct interaction of
health care workers with patients and thereby reduces risk to HCW and the use of PPE.
Ann Intern Med. 2021; 174(4):501‐510. doi:10.7326/M20‐6569(rt‐PCR)
$10 ‐ $40 2 tests
per test $20‐25
Robert F. Service Science 2020;369:608-609Test results and performance characteristics of the Abbott BinaxNOW COVID‐19 Ag Card Point of Care Diagnostic Test
(BinaxNOW antigen test) compared with real‐time reverse transcription–polymerase chain reaction (RT‐PCR) for testing
received among asymptomatic and symptomatic persons at two community‐based testing sites — Pima County, Arizona,
November 2020
BinaxNOW antigen test performance, % (95% CI)
All participants (N = 3,149)
Sensitivity 52.5 (46.7–58.3) (false negative – 47.5%)
Specificity 99.9 (99.7–100.0) (false positive – 0.1%)
PPV 97.5 (93.8–99.3)
NPV 95.6 (94.9–96.3)
Symptomatic (n = 827)
Sensitivity 64.2 (56.7–71.3) (false negative – 35.8%)
Specificity 100.0 (99.4–100.0) (false positive 0%)
PPV 100.0 (96.8–100.0)
NPV 91.2 (88.8–93.1)
Asymptomatic (n = 2,592)
Sensitivity 35.8 (27.3–44.9) (false negative – 64.2%)
Specificity 99.8 (99.6–100.0) (false positive – 0.2%)
PPV 91.7 (80.0–97.7)
NPV 96.9 (96.1–97.5)
Morb Mortal Wkly Rep 2021;70:100–105. DOI: http://dx.doi.org/10.15585/mmwr.mm7003e3Antigen Test Algorithm for Community Settings https://www.cdc.gov/coronavirus/2019‐ncov/lab/resources/antigen‐tests‐guidelines.html; January 20, 2022
Persons with COVID‐19 who have had symptoms and cared for themselves
at home – conditions for discontinuing isolation
• Children and adults with mild, symptomatic COVID‐19:
‐ Isolation can end at least 5 days after symptom onset and after fever ends for 24
hours (without the use of fever‐reducing medication) and symptoms are
improving, if these people can continue to properly wear a well‐fitted mask
around others for 5 more days after the 5‐day isolation period. Day 0 is the first
day of symptoms.
• People who have moderate, symptomatic COVID‐19 illness: Isolate for 10 days.
• People who are infected but asymptomatic (never develop symptoms):
‐ same as for mildly symptomatic above with the positive test day as reference.
CDC Guidance, January 14, 2022Persons who are moderately or severely immunocompromised might have a longer infectious
period – conditions for discontinuing isolation
• People who are moderately or severely immunocompromised might
have a longer infectious period:
‐ Extend isolation to 20 or more days (day 0 is the first day of
symptoms or a positive viral test). Use a test‐based strategy and
consult with an infectious disease specialist to determine the
appropriate duration of isolation and precautions.
CDC Guidance, January 14, 2022Treatment (phases) of COVID‐19 illness • Outpatients: with mild to moderate illness • Inpatients: with moderate to severe illness
Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients
Robert L. Gottlieb, Carlos E. Vaca, Roger Paredes, et al.
Abstract:
CONCLUSIONS
Among non‐hospitalized patients who were at high risk for Covid‐19 progression, a 3‐day course of remdesivir had an acceptable
safety profile and resulted in an 87% lower risk of hospitalization or death than placebo.
N Engl J Med January 27, 2022; 386:305‐315. DOI: 10.1056/NEJMoa2116846
FDA Takes Actions to Expand Use of Treatment for Outpatients with Mild‐to‐Moderate COVID‐19
January 21, 2022
The U.S. Food and Drug Administration took two actions to expand the use of the antiviral drug Veklury (remdesivir) to certain
non-hospitalized adults and pediatric patients for the treatment of mild-to-moderate COVID-19 disease. This provides another
treatment option to reduce the risk of hospitalization in high-risk patients. Previously, the use of Veklury was limited to patients
requiring hospitalization.
The agency also revised the Emergency Use Authorization (EUA) for Veklury to additionally authorize the drug for treatment
of pediatric patients weighing 3.5 kilograms to less than 40 kilograms or pediatric patients less than 12 years of age
weighing at least 3.5 kilograms, with positive results of direct SARS-CoV-2 viral testing, and who are not hospitalized and have
mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization of death.
Based on today’s actions, these high-risk non-hospitalized patients may receive Veklury via intravenous infusion for a total of
three days for the treatment of mild-to-moderate COVID-19 disease.
FDA News Release. January 21, 2022Two drugs, two targets
As SARS-CoV-2 infects cells, reproduces itself, and
spreads, the coronavirus relies on dozens of viral
and host proteins to complete its life cycle.
Pfizer's new oral pill inhibits the main viral
protease used to create other proteins for the virus.
(nirmatrelvir tablets and ritonavir tablets - Paxlovid)
And Merck’s drug inserts a defective RNA building
block when the virus uses an enzyme known as a
polymerase to copy its genome.
(molnupiravir)
! " # $ !% &'*+/ ' +&'&&35 '8;$;The Current NIH COVID‐19 Treatment Guidelines for High‐Risk, Non‐hospitalized Patients
With Mild to Moderate COVID‐19 (March 2, 2022)
The NIH Panel recommends using one of the following therapies (listed in order of preference):
• Nirmatrelvir 300 mg with ritonavir 100 mg (Paxlovid) orally twice daily for 5 days, initiated
as soon as possible and within 5 days of symptom onset in those aged ≥12 years and
weighing ≥40 kg; (89% risk reduction of hospitalization or death by day 28; EUA on December
22, 2021)
• Sotrovimab 500 mg as a single intravenous (IV) infusion, administered as soon as possible
and within 7 days of symptom onset in those aged ≥12 years and weighing ≥40 kg; (85% risk
reduction of hospitalization or death by day 29; EUA on May 26, 2021)
• Remdesivir 200 mg IV on Day 1, followed by remdesivir 100 mg IV once daily on Days 2
and 3, initiated as soon as possible and within 7 days of symptom onset in those aged ≥12
years and weighing ≥40 kg; (87% risk reduction of hospitalization or death by day 28; expanded
EUA on January 21, 2022)
https://www.covid19treatmentguidelines.nih.gov/therapies/statement‐on‐bebtelovimab/The Current NIH COVID‐19 Treatment Guidelines for High‐Risk, Non‐hospitalized Patients
With Mild to Moderate COVID‐19 (cont’d.) (March 2, 2022)
Alternative Therapies
If none of the preferred therapies for high-risk, non-hospitalized patients is available, feasible to
deliver, or clinically appropriate (e.g., due to drug-drug interactions, concerns related to renal or
hepatic function), the Panel recommends using one of the following therapies (listed in alphabetical
order):
• Bebtelovimab 175 mg as a single IV infusion, administered as soon as possible and within 7 days of
symptom onset in those aged ≥12 years and weighing ≥40 kg, ONLY if none of the preferred therapies is
available, feasible to deliver, or clinically appropriate; (EUA from FDA on February 11, 2022)
• Molnupiravir 800 mg orally twice daily for 5 days, initiated as soon as possible and within 5 days of
symptom onset in those aged ≥18 years, ONLY if none of the preferred therapies are available, feasible to
deliver, or clinically appropriate. (30% risk reduction of hospitalization or death by day 29; Use in pregnancy
is not recommended due to possible mutagenicity. EUA on December 23, 2021)
https://www.covid19treatmentguidelines.nih.gov/therapies/statement‐on‐bebtelovimab/Treatment (phases) of COVID‐19 illness Inpatient illness: moderate to severe, W/O or with supplemental O2, on ventilator or ECMO • High‐titer COVID‐19 convalescent plasma • Dexamethasone • remdesivir (Veklury) • anti‐IL‐6 (receptor) monoclonal antibodies (tocilizumab, sarilumab) • Janus Kinase (JAK) inhibitors (baricitinib, tofacitinib)
Use of Convalescent Plasma
The August 23, 2020 EUA for convalescent plasma for the treatment of hospitalized patients with COVID‐19 was revised on
February 4, 2021 to limit the authorization to high‐titer COVID‐19 convalescent plasma and only for the treatment of
hospitalized patients with COVID‐19 early in their disease course or hospitalized patients who have impaired humoral
immunity.
On December 16, 2021 The NIH COVID-19 Treatment Guidelines Panel recommended against the use of COVID-19
convalescent plasma for the treatment of COVID-19 in hospitalized patients without impaired humoral immunity. The exception
remained for high tittered convalescent plasma for those with impaired immunity.
https://www.fda.gov/news‐events/fda‐brief/fda‐brief‐fda‐updates‐emergency‐use‐authorization‐covid‐19‐convalescent‐plasma‐reflect‐new‐dataTherapeutic Management of Adults
Hospitalized for COVID‐19
Based on Disease Severity
NIH Guidelines, February 24, 2022
Discussion:
Personalized therapy is an independent risk factor
for survival.
Tocilizumab ‐ Actemra; Baricitinib ‐ Olumiant
Clin Infect Dis, 1 January 2022, 74(1): 127–132. https://doi.org/10.1093/cid/ciaa964The FDA‐approved drug ivermectin inhibits the replication of SARS‐CoV‐2 in vitro
LeonCaly, Julian D.Druce, Mike G.Catton et al.
Highlights
Ivermectin is an inhibitor of the COVID‐19 causative virus (SARS‐CoV‐2) in vitro.
A single treatment able to effect ~5000‐fold reduction in virus at 48 h in cell culture.
Ivermectin is FDA‐approved for parasitic infections, and therefore has a potential for repurposing.
Ivermectin is widely available, due to its inclusion on the WHO model list of essential medicines.
Antiviral Research June 2020; 178: 10478. https://doi.org/10.1016/j.antiviral.2020.104787Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID‐19
A Randomized Clinical Trial
Eduardo López‐Medina, Pío López, Isabel C. Hurtado, et al.
Abstract:
Objective: To determine whether ivermectin is an efficacious treatment for mild COVID‐19.
Conclusion and Relevance: Among adults with mild COVID‐19, a 5‐day course of ivermectin, compared with placebo,
did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for
treatment of mild COVID‐19, although larger trials may be needed to understand the effects of ivermectin on other clinically
relevant outcomes.
JAMA. March 4, 2021;325(14):1426‐1435. doi:10.1001/jama.2021.3071Rapid Increase in Ivermectin Prescriptions and Reports of Severe Illness Associated
with Use of Products Containing Ivermectin to Prevent or Treat COVID‐19
D istributed via the CD C H ealth AlertN etw ork
Summary:
During the COVID‐19 pandemic, ivermectin dispensing by retail pharmacies has increased, as has
use of veterinary formulations available over the counter but not intended for human use.
Adverse effects associated with ivermectin misuse and overdose are increasing, as shown by a rise in calls to poison control
centers reporting overdoses and more people experiencing adverse effects.
Distributed via the CDC Health Alert Network, August 26, 2021, HAN00449Post‐acute Sequelae of COVID‐19 (PASC)
“The Long Haul” – Long CovidSurvivor Corps is a grassroots solution‐based movement to mobilize the sharply increasing number of people affected by COVID‐
19 to come together, support and participate in the medical and scientific research community efforts and take a more active
role in trying to mitigate this pandemic.
THE LONG COVID ALLIANCE
THE LONG COVID ALLIANCE is a network of patient‐advocates, scientists, disease experts, and drug developers who have
joined together to leverage their collective knowledge and resources to educate policy makers and accelerate research to
transform our understanding of post‐viral illness.
RECOVER, a research initiative from the National Institutes of Health (NIH), seeks to understand, prevent, and treat PASC,
including Long COVID. PASC stands for post‐acute sequelae of SARS‐CoV‐2 and is a term scientists are using to study the
potential consequences of a SARS‐CoV‐2 infection.NEWS FEATURE
The four most urgent questions about long COVID
Michael Marshall
• How many people get long COVID and who is most at risk?
• What is the underlying biology of long COVID? (hypotheses only at present)
• What is the relationship between long COVID and other post‐infection
syndromes?
• What can be done to help people with long COVID?
Nature 594, 168‐170 (June 9, 2021). doi: https://doi.org/10.1038/d41586‐021‐01511‐zThe symptomatology of coronavirus disease 2019 (COVID‐19)
PASC
(Post‐Acute Sequelae of COVID‐19)
Long COVID
(The Long Haul)
The CDC defines PASC as symptoms lasting beyond 4 or more weeks after initial infection; WHO defines this interval as beyond 3 months.
Front. Immunol. 12:693938. doi: 10.3389/fimmu.2021.693938. Science 11 March, 2022; 375: 1122‐1127. DOI: 10.1126/science.abm8108Approach to patients with Long COVID
35% of ambulatory
managed patients,
87% of those admitted;
female : male 2:1.
More common > 35YO,
> 2 co‐morbidities
Auto‐antibodies
RNA
Elevated CSF
cytokine levels
Worsening of
symptoms related to
co‐morbidities
Diabetes Metab Syndr 2021 May‐June; 15(3): 869–875. Published online 2021 Apr 20. doi: 10.1016/j.dsx.2021.04.007More than 50 long‐term effects of COVID‐19: a systematic review and meta‐analysis
Sandra Lopez‐Leon, Talia Wegman‐Ostrosky, Carol Perelman et al.
Abstract:
It was estimated that 80% of the infected patients with SARS‐CoV‐2 developed one or more long‐term symptoms.
The five most common symptoms were:
fatigue (58%),
headache (44%),
attention disorder (“brain fog” ‐ 27%),
hair loss (25%),
dyspnea (24%). (possibly with chest pain, palpitations and orthostatic intolerance)
Multi‐disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management
strategies with whole‐patient perspectives designed to address long COVID‐19 care.
Sci Rep 11, article number 16144 (published August 9, 2021). https://doi.org/10.1038/s41598‐021‐95565‐8. Diabetes Metab Syndr 2021 May‐June; 15(3): 869–875. Published online 2021 Apr 20. doi: 10.1016/j.dsx.2021.04.007Post‐acute COVID‐19 syndrome Interdisciplinary management in COVID‐19 clinics • Primary care • Pulmonary clinic • Cardiovascular clinics • Neuropsychiatric care clinics • Hematology clinic • Renal clinic Nat Med 27, 601–615 (published March 22, 2021). https://doi.org/10.1038/s41591‐021‐01283‐z
Preliminary evidence on long COVID in children
Danilo Buonsenso, Daniel Munblit,Cristina De Rose et al.
This cross‐sectional study included all children ≤18 year old diagnosed with microbiologically confirmed (PCR analysis on nasopharyngeal swab) COVID‐19 (through
a nasopharyngeal swab from March 2020 to October 2020) in Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy). Only children with a SARS‐CoV‐2
infection diagnosed 30 days before the assessment were included. …
During the acute COVID‐19, 33 children (25.6%) were asymptomatic, and 96 (74.4%) had symptoms. Overall, 6 (4.7%) children were hospitalized, and 3 (2.3%)
needed pediatric intensive care unit admission.
persistence of symptoms according to severity and length of follow‐up.
Insomnia (18.6%),
respiratory symptoms (including pain and chest tightness) (14.7%),
nasal congestion (12.4%),
fatigue (10.8%),
muscle (10.1%) and joint pain (6.9%), and
concentration difficulties (10.1%).
These were the most frequently reported symptoms. These symptoms, described both in children with symptomatic and asymptomatic acute COVID‐19, were
particularly frequent in those assessed >60 days after the initial diagnosis. …
Twenty out of 30 children (66.6%) assessed between 60 and 120 days after initial COVID‐19 had at least one persisting symptom
Acta Paediatrica July 2021 110(7): 2208‐2211. https://doi.org/10.1111/apa.15870Frequency of most reported symptoms among the uninfected, the vaccinated and the unvaccinated
All individuals over the age of 18
who were tested for SARS‐CoV‐2
infection by RT‐PCR between
15th March 2020 and 15th November
2021 in the three major government
hospitals in Northern Israel were
surveyed:
Uninfected:
N= 2,437
Infected, unimmunized:
N= 314
Infected, immunized:
N= 637
Conclusion: COVID‐19 vaccination with two doses may have a protective effect against long COVID
medRxiv, posted January 17, 2022. doi: https://doi.org/10.1101/2022.01.05.22268800The heartbreak of COVID‐19 Science, February 18, 2022; 375: 706‐707. doi: 10.1126/science.ada1117. Nat Med (2022). https://doi.org/10.1038/s41591‐022‐01689‐3: Published 07 February 2022
My wife Heidi Ferrer had Long Covid and killed herself (by Nick Güthe)
Nick Güthe Jeff Goldblum
The Guardian. Opinion. Wed 12 Jan 2022 06.17 ESTEmergency Department Visits for Suspected Suicide Attempts Among Persons Aged 12–25 Years Before
and During the COVID‐19 Pandemic — United States, January 2019–May 2021
Ellen Yard, PhD1; Lakshmi Radhakrishnan, MPH2; Michael F. Ballesteros, et al.
Morb Mortal Wkly Rep 2021;70:888–894. DOI: http://dx.doi.org/10.15585/mmwr.mm7024e1external iconChange in symptom scores comparing before and after immunization by those completing
the survey who had Long COVID prior to immunization
Survey performed in UK where AZ vaccine was given >>> Janssen/J&J as the AdV vaccine.
go.nature.com/3yfqem2 (2021). https://3ca26cd7‐266e‐4609‐b25f‐6f3d1497c4cf.filesusr.com/ugd/8bd4fe_a338597f76bf4279a851a7a4cb0e0a74.pdfLong COVID is contributing to America's labor shortage
Long COVID is likely keeping a lot of Americans out of the workforce, experts say, — and that could continue for years as people
struggle with persistent health problems.
1.6 million workers could be missing from the labor market right now because of long COVID, accounting for upwards of 15% of
unfilled jobs, …
Studies have estimated long COVID prevalence falls anywhere from 5% to 60% of COVID cases. Splitting the difference at
30%, more than 22 million Americans may be suffering from long COVID symptoms, according to the American Academy of
Physical Medicine and Rehabilitation.
"Many of the patients we're seeing are in the 40‐year‐old range. They're people who are still working ...
Axios, February 3, 2022There are too many simple questions
but not enough simple answers!
Thank you for helping me to honor Boyd’s memory!
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