Coronavirus II: Clinical Manifestations, Long COVID, Therapeutic Update (PDF)

CORONAVIRUS II: CLINICAL MANIFESTATIONS, LONG COVID, THERAPEUTIC UPDATE ISTM TRAVEL MEDICINE REVIEW AND UPDATE COURSE FEBRUARY 12, 2022 HENRY WU, MD, DTM&H EMORY TRAVELWELL CENTER Henry M. Wu, M.D. Personal/Professional Financial Relationships with Industry External Industry Relationships * Equi...

CORONAVIRUS II: CLINICAL MANIFESTATIONS, LONG COVID, THERAPEUTIC UPDATE ISTM TRAVEL MEDICINE REVIEW AND UPDATE COURSE FEBRUARY 12, 2022 HENRY WU, MD, DTM&H EMORY TRAVELWELL CENTER Henry M. Wu, M.D. Personal/Professional Financial Relationships with Industry External Industry Relationships * Equity, stock, or options in biomedical industry companies or publishers Company Name Board of Directors or officer None Royalties from Emory or from external entity None Industry funds to Emory for my research None Other Sanofi Pasteur Role None Former Principal Investigator for Stamaril vaccination clinic 2 Disclaimers • COVID-19 is a constantly changing topic • Most data is from pre-Omicron waves • Guidance for outpatients still limited • Management guidelines and available treatments vary widely around the world • This talk based on US approach to management (IDSA/NIH evidencebased guidelines) https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/ Outline • Clinical presentation • Post-COVID conditions • Outpatient treatment • Advice for travelers The rogue beginnings of the Acute Respiratory Clinic (ARC), Emory TravelWell Center February-March 2020 Emory Acute Respiratory Clinic: Patient 1 • 23 yo female student, recently returned to school from holiday. PMH asthma. Did not get flu shot. • Started to get ill on route: feeling hot, chills, SOB (wheeze), diarrhea, nausea, abd cramping, cough w/ yellow sputum. • After return illness worst on day 3 after getting back; noted one evening to be feeling very hot, looking "red" in the mirror, dizzy/vertigo, unable to get out of bed. • However, the next morning she felt much better, well enough to get up, but had dyspnea on exertion. • She did return to class, but for next 3 wks reports the sx’s come and go, including last night and this AM, when she had recurrence of chills, diarrhea, cough, wheezing, abd discomfort. ++sore throat this AM. Labs: Flu/RSV PCR: Neg. Biofire Resp Panel: Neg. Rapid strep/cx: Neg. CDC SARS-COV-2 PCR: Neg. Diagnosis: ??????? Emory Acute Respiratory Clinic: Patient 1 • Seen on Jan 26, 2020 • 23 yo student. Hometown Shenzen (southern China near Hong Kong) • Traveled to China for Xmas and New Year holidays: • 20 Dec 2019 to 19 Dec spent in Shenzen • 29 Dec 2019 to 3 Jan 2020 in Wuhan, visiting grandparents. While there noticed a lot of coughing people in public. Grandmother was coughing too, but she thinks this was a baseline illness and not CoV. She did go to a small animal market and participated in the slaughtering of a chicken. • Jan 3 returned to Shenzen • Jan 4 illness onset during travel ATL via Seoul connection. Diagnosis: ??????? Clinical stages of illness (NIH) • Asymptomatic or presymptomatic • Both can transmit! • Mild illness • Moderate illness • Evidence of LRI • Severe illness • SpO2 <94% • RR >30 • Lung infiltrates >50% • Critical illness • • • • ARDS Septic shock Multi-organ effects Thrombotic disease Cevik M, et al. BMJ 2020;371:m3862 Post-Acute timeline Nalbandian A, et al. Nature Med 2021;27:601-15. COVID-19: Asymptomatic infections • As high as 30-40% • Depends on age of population • USS Theodore Roosevelt • Mean age 27 yrs • 1331 confirmed or suspected cases (attack rate =39%) • 43% asymptomatic • 2% hospitalized • 1 death Kasper MR et al. N Engl J Med 2020; 383:2417-2426 COVID-19 Acute Illness • Incubation: Median 4-5 days (2 to 14) • Initial presentation • Nonspecific and can present in myriad of constellations • Most common: Fever, cough, fatigue • Data suggests smell, taste alterations somewhat specific CDC, WHO • Fevers or chills • Cough • Shortness of breath • Fatigue • Body aches • Headache • Loss of taste or smell • Sore throat • Congestion or runny nose • Nausea or vomiting • Diarrhea COVID-19 symptoms: Human challenge study • Intranasal inoculation with pre-alpha wild type virus (D614G variant) • 34 healthy volunteers aged 18-29, unvaccinated and without evidence of previous infection • 18 developed infection (53%) • Symptom onset begins 2 days after inoculation • Mild-moderate symptoms in 16 (89%) • Sore throat, runny nose, stuffy sneezing common • Fever in 39% • Smell disturbance in 12 (67%) • Total anosmia in 6 (50%) • 5 (42%) with persistent disturbance at 6 mos • *Pending peer-review Killingley B, et al. Research Square, https://doi.org/10.21203/rs.3.rs-1121993/v1 Omicron (B.1.1.529) variant • Norway Christmas party outbreak • Attack rate of 74% among mostly vaccinated but unboosted attendees • Incubation 0-8 days (median 3) • 91% with at least 3 symptoms • Symptoms: • • • • • • • • • Cough (83%) Runny/stuffy nose (78%) Fatigue (74%) Sore throat (72%) Headache (68%) Fever (54%) Sneezing (43%) Reduced taste (23%) Reduced smell (12%) Brandal LT, et al. Euro Surveill 2021;26(50):pii=2101147. Iacobucci G. BMJ 2021;375:n3103. • Most common symptoms reported in ZOE COVID Study (London) • • • • • Runny nose Headache Fatigue Sneezing Sore throat Dermatologic findings • Not common but reported • • • • Exanthematous (morbilliform) rash Pernio (chilblains), “covid toes” Urticaria Other rashes including livedo reticularis, erythema multiforme Erythema multiforme https://www.aad.org/public/diseases/coronavirus/covid-toes#_ Severe or Critical COVID-19 • Typically >7 days after onset • Respiratory failure, ARDS • Cardiac • Arrhythmias, acute cardiac injury, shock • Thromboembolic • PE, CVA • Neurologic: encephalopathy • Inflammatory complications • Hyper-inflammation • Guillain-Barré syndrome • Secondary infections • Bacterial, fungal Radiographic progression of pneumonia in a 65 yo M with COVID-19 (Phan LT et al. NEJM Jan 28, 2020). Risk factors for severe illness • • • • • • Unvaccinated Increasing age Comorbid conditions Socioeconomic background Gender (men) Laboratory abnormalities • Lymphopenia, thrombocytopenia • Elevations in liver function tests, D-dimer, troponin, inflammatory markers • Acute kidney injury Severe illness in vaccinated persons Risk factors: • Age ≥65 • Comorbid conditions Protective: Previous illness 78% of persons who died had ≥4 risk factors! Caveats: • Pre-Omicron • Very few boosted persons in study Yek C, Warner S, Wiltz JL, et al. MMWR Morb Mortal Wkly Rep 2022;71:19–25. DOI: http://dx.doi.org/10.15585/mmwr.mm7101a4. Be careful with travelers who are elderly, have comorbidities…… Yek C, Warner S, Wiltz JL, et al. MMWR Morb Mortal Wkly Rep 2022;71:19–25. DOI: http://dx.doi.org/10.15585/mmwr.mm7101a4. Risk of severe illness or death during Omicron? • Studies suggest lower rates of severe illness indicators, including • Length of stay • ICU admission • Deaths • Hospitals can still be severely strained with the high case numbers! Iuliano AD, Brunkard JM, Boehmer TK, et al. Trends in Disease Severity and Health Care Utilization During the Early Omicron Variant Period Compared with Previous SARS-CoV-2 High Transmission Periods — United States, December 2020–January 2022. MMWR Morb Mortal Wkly Rep 2022;71:146–152. DOI: http://dx.doi.org/10.15585/mmwr.mm7104e4 What is driving the lower rates of severe illness from Omicron? • Vaccination + boosters! • Natural immunity from prior infections? • Decrease variant virulence might account for 25% of risk reduction (S. Africa) Johnson AG, et al. MMWR Morb Mortal Wkly Rep 2022;71:132–138. DOI: http://dx.doi.org/10.15585/mmwr.mm7104e2external icon Davies MA, et al. medRxiv 2022.01.12.22269148; doi: https://doi.org/10.1101/2022.01.12.22269148 Risks for children (pre-Omicron data!) • Study of 167,262 US cases • 10,245 (6.1%) hospitalized • 1423 (13.9%) met criteria for severe disease • 131 (1.3%) deaths • Risk factors for severe disease • • • • Male sex Black/African American race Obesity Comorbid conditions, especially cardiovascular, malignancy, respiratory, and technology dependence • Multisystem inflammatory syndrome in children (MIS-C) • Severe hyperinflammatory syndrome 2-6 weeks after acute infection • 1-2% mortality reported in literature • 707 children diagnosed MIS-C • Risk factors • • • • • Male sex Age <12 yrs Black/African American race Obesity Not having a pediatric complex condition Martin B, DeWitt PE, Russell S, et al. Characteristics, Outcomes, and Severity Risk Factors Associated With SARS-CoV-2 Infection Among Children in the US National COVID Cohort Collaborative. JAMA Netw Open. 2022;5(2):e2143151. doi:10.1001/jamanetworkopen.2021.43151 POST-COVID Lopez-Leon, S, et al. Sci Rep 11, 16144 (2021). https://doi.org/10.1038/s41598021-95565-8 “Post-COVID” conditions • AKA “long covid,” post-acute sequelae of SARS-CoV-2 infection (PASC) • Generally defined as period following acute period, >4 weeks after onset • Likely many causes, syndromes • Organ damage from acute illness (cellular damage, vascular injury, pro-coagulant state) • Persistent inflammation, immune dysregulation (e.g. autoimmune phenomena, multi-organ inflammatory syndrome) • Maladaptation of ACE2 pathway • Post-ICU syndrome (severe cases) • Ongoing viral activity? • Effects of social isolation • Range of symptoms, chronic complications • • • • • • • Cardiac, dysautonomia (POTS) Respiratory Renal Dermatologic Neurologic Psychiatric Myalgic encephalomyelitis/CFS-like conditions • Can affect young, healthy patients • Similar post-infection syndromes in SARS, MERS, dengue, mononucleosis, Ebola, etc. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/late-sequelae.html Nalbandian A, et al. Nature Med 2021;27:601-15. PASC in non-hospitalized patients? • Norway: 52% of ambulatory young adults (16-30 yrs old) with persistent symptoms at 6 mos • • • • • Loss taste/smell (28%) Fatigue (21%) Dyspnea (13%) Impaired concentration (13%) Memory problems (11%) • Prevalence of memory encoding impairment after infection (mean 7.6 months after diagnosis) • Outpatient: 16% • Patients seen in ER: 26% • Hospitalized: 37% Blomberg B, et al. Nature Med https://doi.org/10.1038/s41591-021-01433-3 Becker et al. JAMA Netw Open. 2021;4(10):e2130645. • PASC associations • • • • • • • Female gender Severe initial illness Elevated BMI Age 40-54 Preexisting conditions Black race/ethnicity ANA ≥1:160 (for sx’s at 12 mos) • COVID-19 in outpatients associated with increased new drug prescriptions and new diagnoses of dyspnea, DVT Seeßle J, et al. Clin Infect Dis. doi: 10.1093/cid/ciab611. Bliddal S, et al. Scientific Reports 2021;11:13153. Yomogida K, et al. MMWR 2021;70(37):1274-7. Lund LC, et al. Lancet 2021;21(10):1373-82. From: Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers JAMA. 2021;325(19):2015-2016. doi:10.1001/jama.2021.5612 Figure Legend: COVID-19–Related Long-term Functional ImpairmentThe percentage of seropositive (n = 323) and seronegative (n = 1072) participants reporting symptoms lasting at least 2 months and their related functional impairment in their work, social, and home life using the Sheehan Disability Scale (1-3, mild; 4-6, moderate; and 7-10, marked). Date of download: 2/10/2022 Copyright 2021 American Medical Association. All Rights Reserved. Diabetes risk? • Previous studies suggest increased diagnoses of new DM (or new insulin dependence with preexisting DM) after COVID • CDC study: Increased DM incidence among children with COVID compared to those without COVID or pre-pandemic ARI • Possible mechanisms • Attack of pancreatic cells expressing angiotensin converting enzyme 2 receptors • Stress hyperglycemia resulting from cytokine storm and altered glucose metabolism • Precipitation of prediabetes to diabetes Rubino F, et al. N Engl J Med. 2020;383(8):789. Barrett CE, et al. MMWR 2022;71(2):59-65. TREATMENT Monoclonal therapy at ARC (Nov 2020 to present) Treatment: Evolving paradigms Early infection: Neutralize virus and stop replication! • Monoclonal antibodies • Convalescent plasma • Antiviral drugs Later infection: Control inflammation! • Dexamethasone • Baricitinib (JAK inhibitor)* • Tocilizumab (IL-6 receptor blocker)* Remdesivirǂ *FDA emergency use authorization (EUA) ǂFDA approved for hospitalized AND non-hospitalized patients Monoclonal antibodies (mAbs) • Directed against receptor-binding domain of spike protein • Blocks virus binding to ACE2 receptor • Reduce viral loads in animal studies • Studied for treatment and prophylaxis • Generally appear to reduce risk of severe illness (hospitalization) by 7080% • Intravenous, but some can be given for subcutaneous • EUAs withdrawn due to variant resistance: • Bamlanivimab-etesevimab (Lilly) • Casirivimab-imdevimab (Regeneron) Taylor, P.C., Adams, A.C., Hufford, M.M. et al. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol 21, 382– 393 (2021). https://doi.org/10.1038/s41577-021-00542-x Sotrovimab for treatment • Indicated for symptomatic mild to moderate COVID-19 in patients with high risk of progression to severe disease, within 10 days of symptom onset • Not authorized for hospitalized patients or those with new O2 needs • Lowers risk of hospitalization or death 70-85% (pre-Omicron data) • Presumed efficacy against Omicron based on in-vitro studies https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/ https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/ • Nov 2020 to Feb 2021 • 305 mAb treated cases vs. with 6354 untreated cases • Treated with bamlanivimab (76.3%) or casirivimab-imdevimab (23.7%) Anderson B, et al. OFID, Volume 8, Issue 7, July 2021, ofab315, https://doi.org/10.1093/ofid/ofab315 New mAb EUA alert (Feb 11, 2022)! • Bebtelovimab (Lilly) • Given within 7 days of onset • Appears to retain activity against Omicron • No placebo controlled data in high risk individuals, but granted EUA based on similarities to other mAbs and presumed efficacy in preventing severe illness • Indicated for patients “for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate.” mAbs for Prophylaxis • Casirivimab-imdevimab • Former EUA granted for post-exposure prophylaxis of high risk individuals who are not fully vaccinated or not expected to mount an adequate response to vaccine • EUA revoked due to Omicron resistance • Tixagevimab-cilgavimab (Evusheld) • EUA for pre-exposure prophylaxis for ages ≥12 who are uninfected, without known recent exposure, AND one of the following • Have moderate to severe immune compromise and may not mount an adequate response to vaccination • Vaccination to COVID-19 is not possible due to history of severe adverse reaction to vaccine or vaccine component • Long-acting mAb, may provide protection 6 or more months • Reduces symptomatic infection within 6 mos (>80%, RR 0.18) • Likely activity against Omicron https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-18 Oral antiviral: Nirmatrelvir/ritonavir (Paxlovid) • EUA for use in mild-moderate COVID in persons aged ≥12 with risk factors for severe disease within 5 days of symptom onset • Decreases risk of hospitalizations or death by 88% • 300/100 mg q12 hr x 5 days • Dose adjustment for renal insufficiency • Not recommended in severe renal or hepatic impairment • AEs: Dysgeusia (6%), diarrhea (3%) • Many drug-drug interactions (DDIs)! • Many other DDIs—immunosuppressive medications, HIV/HCV antivirals, Ca channel blockers, and more! • See PI and online resources • www.covid19-druginteractions.org https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-18 Fact sheet for healthcare providers: Emergency use authorization for Paxlovid available at: https://www.fda.gov/media/155050/download Oral antiviral: Molnupiravir • EUA for use in mild-moderate COVID in adults with risk factors for severe disease within 5 days of symptom onset • Recommended when there are “no other treatment options” • 800 mg x 5 days, no known drug interactions • Decreases risk of hospitalization or death by 30% • AEs similar to placebo • Not for ages <18 (may affect bone and cartilage growth) • May cause fetal harm in pregnancy! • Advise against conception for men and women! https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-18 Covid-specific treatments for outpatients (as of 11 Feb 2022) Route Rx Window (from onset) Severe illness reduction (relative) Nirmatrelvir/ritonavir (Paxlovid) PO <5 days 88% • Drug interactions Yes Molnupiravir PO <5 days 30% • Pregnancy No mAb—Sotrovimab IV <10 days 85% mAb—Bebtelovimab IV <7 days unknown • Limited clinical data No Remdesivir (FDA approved) IV <7 days 87% • 3 day course Yes <50% • • • Transfusion reaction Variation in Ab titers Limited clinical data No Treatment High-titer convalescent plasma* IV <8 days Concerns Preferred Yes • Treatment indicated for persons at high risk for severe illness • Data (and theoretical considerations) suggest earlier treatment is more beneficial • Confirmed illness required according to EUA guidance • No head to head trials; ultimately the treatment that a patient can get earliest is probably a good choice. *New IDSA recommendation, 8 Feb 2022. Limited clinical data. Availability of treatments in lower income countries? • Wealthier countries have advanced purchased much of supply • WHO Access to COVID-19 Tools (ACT) Accelerator engaging pharmaceutical industry, Medical Patent Pool (MPP) to promote worldwide access 27 GENERIC MANUFACTURERS SIGN AGREEMENTS WITH MPP TO PRODUCE LOW-COST VERSIONS OF COVID-19 ANTIVIRAL MEDICATION MOLNUPIRAVIR FOR SUPPLY IN 105 LOWAND-MIDDLE-INCOME COUNTRIES (20 JANUARY 2022) https://medicinespatentpool.org/news-publications-post/27-generic-manufacturers-sign-agreements-with-mpp-to-producemolnupiravir Can we prescribe oral COVID antivirals for travelers for self-treatment? • Rationale • Early treatment is critical • Availability of treatments overseas limited, unpredictable • Avoidance of using local treatment resources • Precedent: Some providers consider providing oseltamivir for self-treatment of confirmed or suspected influenza in high-risk travelers • Early treatment also important in flu • Oseltamivir is relatively safe, inexpensive, and has relatively few major DDIs • Concerns: Misdiagnosis of influenza; overuse, inappropriate antiviral use; promotion of resistance • Unresolved barriers and questions for prescribing COVID-19 self-treatments • Limited supply of oral antivirals—prescribe only active confirmed illness • Major drug-drug interactions (Paxlovid), or pregnancy (molnupiravir) considerations • Wide range of COVID presentations with large overlap with influenza • Not yet! But stay tuned!! Other drugs for ambulatory acute COVID-19 treatment • Not approved/recommended, further study needed • • • • Ivermectin Fluvoxamine Nitazoxanide Vitamin C, D, zinc • Not recommended • Hydroxychloroquine/chloroquine • Lopinavir/ritonavir • Colchicine • Use if indicated for other reasons • • • • Systemic corticosteroids Inhaled corticosteroids Bronchodilators Antibiotics (azithromycin) • Routine anticoagulation not recommended (some experts consider for patients at high risk for thrombosis) Dexamethasone, systemic corticosteroids SYSTEMIC CORTICOSTEROIDS • RCT support use in critical and severe hospitalized patients • Not recommended for non-severe hospitalized patients (no oxygen requirement) • Outpatients? • Use only in situations it is otherwise indicated (asthma exacerbation) • Might consider in situations where patient requires supplemental O2/admission, but will be discharged from ED due to scarce resources (dexamethasone 6 mg daily for duration of supplemental oxygen for up to 10 days) Be careful: • • • But: • Immunosuppressi on might delay viral clearance? Adverse events Harm in acute illness when viral replication is high?? https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/ https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/ • Helpful during hyperinflammatory states Indicated in hospitalized, severe illness Other therapeutic considerations • NSAIDS • Current evidence does not support increased risk of adverse outcomes when used in COVID-19 • Use of acetaminophen generally preferred in most persons due to known NSAID adverse events (renal, GI, etc.) • ACE inhibitors, angiotensin receptor blockers (ARBs) • Observational studies do not suggest these affect risk of infection, developing severe disease or death • Continue use in COVID-19 patients if otherwise indicated Key points for travelers I • Despite its presence worldwide, COVID19 remains a potentially serious and common health risk for travelers! • Vaccinate vaccinate vaccinate! • Advise medically high risk travelers (due to age, comorbid conditions, poor vaccine response etc.) of potential pitfalls of travel to low resource countries • COVID risk may be higher at destination • Possible new variants • At this time availability of treatments are limited, even in the US • Confirmed illness overseas will prevent travelers from returning home for treatment (unless you charter an air ambulance!) Key points for travelers II • All treatments are better when given EARLY • Advise patients to monitor themselves closely when exposed • Advise high risk patients to seek testing ASAP when symptom begin • Self-test kits should be a part of a traveler health kit • At this time oral antiviral drugs only available in US for confirmed infections • Prescription of oral antivirals for travelers with risk factors for severe disease for self-treatment might be possible, but will need to navigate numerous serious drug-drug interactions (Paxlovid) Thank you! Questions? [email protected] My pandemic pup Suzie!