JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES COVID-19 GRAND ROUNDS April 14, 2020 Michael Melia, MD Natasha Chida, MD, MSPH Annie Antar, MD, PhD With NATASHA CHIDA, MD, MSPH MICHAEL MELIA, MD
ABOUT COVID-19 GRAND ROUNDS Hosted by Drs. Michael Melia and Natasha Chida, COVID-19 Grand Rounds utilizes clinical cases, in-depth literature reviews, and clinical expertise within the Johns Hopkins School of Medicine to provide clinicians with relevant and timely information about the care of patients with COVID-19. All case presentations in this program have been standardized and quality assured in selection, presentation and discussion. Our goal is to publish and build a library of cases that will aid providers treating patients with COVID-19 in a rapidly changing landscape. COVID-19 Grand Rounds is intended solely as an educational resource specifically for healthcare providers, and is not be construed as medical guidance for patients on disease prevention, diagnosis, or treatment. Patients should consult their healthcare providers for clinical guidance related to their care. COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
OBJECTIVES 1. Describe in vitro data of Remdesivir as a SARS-CoV-2 therapeutic agent 2. State current clinical trials of Remdesivir 3. Describe in vitro data of Lopinavir/ritonavir as a SARS-CoV-2 therapeutic agent 4. Discuss clinical trial data of Lopinavir/ritonavir as a SARS-CoV-2 therapeutic agent 5. State the biologic plausibility for Chloroquine/Hydroxychloroquine as SARS- CoV-2 therapeutic agents 6. Describe in vitro data of Chloroquine/Hydroxychloroquine as a SARS-CoV-2 therapeutic agent 7. Discuss clinical trial data of Chloroquine/Hydroxychloroquine as a SARS-CoV- 2 therapeutic agent COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
CASE PRESENTATION • 52 year old man with worsening dyspnea . • HPI: • D1 – symptoms begin – slight cough • D2 – fevers, chills, myalgias • D6 – symptoms peaked so presented to urgent care. Tested for COVID-19. • D7 – symptoms improving, but appetite is gone. Lost all sense of smell/taste. • D10 – test resulted – COVID-19 positive • D11 – awoke with severe SOB and chest tightness. Couldn’t lay flat. JHH ED. • PMH/PSH : HTN on losartan 25mg, HLD on rosuvastatin 5mg, OSA on CPAP. • Social History : Never tobacco/drugs/alcohol. Married. Works in law enforcement. No recent travel COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
PRESENTATION TO JHH • Vitals: T emp 39.4 o C, BP 148/63, HR 106, O2 sat 91% on room air • Exam: BMI 30.6. Mild respiratory distress. No rhinitis. Tachycardic, Coughing. Crackles and rhonchi in posterior lungs • Lab work: UA 1+ protein, urine legionella & strep pneumo Ags negative, D-dimer 1.02, PT normal, CRP 13.3, CK 625, LDH 384, ferritin 917 COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
AP CXR COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
CLINICAL COURSE • D11 – Given CTX/azithro and admitted. 2L O2. • D12 – Requiring 3-4L O2. 1x fever. Tachycardic and tachypneic. Started on hydroxychloroquine. Satting 93% on 4L by end of day, proning helps. Consulted MICU. Recommended continued proning • D13 – Requiring 2-2.5L O2. Afebrile. Normal heart rate. RR 18-25. Abs lymph 1K. Ferritin peak at 1296. AST/ALT peak at 80/39. CRP peak at 18.7. • D14 –In AM satting 90% on 6L – re-consulted MICU. Proning helps. Continuous pulse ox, proned, weaned down to 4L by end of day. • D15 – Requiring 3L O2. ESR 23. LDH declined to 344. CRP decline to 5.1. • D18 – Requiring 0-1L. Discharged. • D20 – Follow-up phone call – feeling good except occasional dry cough. COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
CLINICAL PEARS FROM THE FLOOR 1. HCQ has an antipyretic effect 2. People seem to desaturate with walking more than you might expect 3. Many patients didn’t bring a cell phone charger and cannot contact family (don’t have numbers memorized; phone dies) nor can family bring charger to them. This is a real hardship for patients who are already afraid and isolated during severe disease. COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
CLINICAL QUESTIONS FROM THIS CASE • HCQ started on Day 12 • Improved 6 days later • Did HCQ facilitate clinical improvement? • What is the evidence in support other antiviral therapeutic agents that have been used/studied in COVID-19? COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
ANTIVIRAL AGENTS FOR COVID-19 COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
SAMPLE OF COVID-19 THERAPEUTIC LANDSCAPE Antivirals Immune Modulators Other Baloxavir Anakinra ACEI/ARB Chloroquine/Hydroxychloroquine Convalescent Plasma Ascorbic Acid DAS-181 Corticosteroids Azithromycin Favipiravir IVIG Epoprostenol Interferon Lenzilumab Indomethacin Lopinavir/Ritonavir Ruxolitinib Ivermectin Neuraminidase inhibitors Sarilumab Niclosamide Remdesivir Sirolimus Nitazoxanide Ribavarin Tocilizumab Statins Umifenovir COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
SARS-CoV-2 DAS181 HCQ/CQ Lopinavir/ritonavir HCQ/CQ Remdesivir Liu C, et al. ACS Cent Sci. doi: 10.1021/acscentsci.0c00272 (2020). Jiang S, Hillyer C, Du L. Trends Immunol doi: 10.1016/j.it.2020.03.007 (2020). COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
REMDESIVIR • 2013 Ebola outbreak • CDC/USAMRIDD/Gilead Sciences identified nucleoside lead à prodrug, RDV • Metabolized to active form, adenosine nucleoside analog • Interferes with RNA polymerase Remdesivir • Evades viral exoribonuclease proofreading • Decrease in RNA production • In cell/animal models efficacious in MERS-CoV, Warren TK, et al. Nature. 2016;531(7594):381-5. Sheahan TP , et al. SARS-CoV, Marburg, Nipah, more Sci Transl Med. 2017;9(396). • IV formulation COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
REMDESIVIR ACCESS • Clinical trials • Compassionate use: pregnant women/children • Expanded access protocol COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
CLINICAL TRIALS Name /Sponsor Pertinent Characteristics Estimated Completion China-Japan Friendship 1. Hospitalized, severe April 2020 Hospital/Capital medical University 2. Hospitalized, mild-moderate April 2020 Gilead Sciences 3. Hospitalized, severe May 2020 4. Hospitalized, mild-moderate May 2020 5. Expanded access protocol, ventilated N/A NIAID 6. Adaptive, hospitalized April 2023 JHU U.S. Army Medical Research and 7. Expanded access, DOD personnel, mod- N/A Development Command severe SOLIDARITY/WHO 8. Hospitalized March 2020-2022 DISCOVERY/INSERM 9. Hospitalized March 2020-2023 No civilian studies in non-hospitalized COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
CLINICAL DATA • Report of patients Jan-March-61 patients à 53 • 40 (75%) received the full 10- day course of Remdesivir • 34 (64%) ventilated at baseline • Median duration of ventilation prior to Remdesivir 2 days [IQR 1-8] Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020). COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
CLINICAL DATA • 18 days • 36 (68%) showed improvement in oxygen support • 57% ventilated patients extubated • Most recent follow up • 25 (47%) discharged • 7 (13%) died • 6 (18%) of those ventilated, 1(5%) not ventilated Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020). COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
CLINICAL DATA • 23% serious adverse events • Summary: • Essentially a case series • Open label • No comparator • Mortality is a range • Can’t draw conclusions Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020). COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
LOPINAVIR/RITONAVIR • In-vitro activity against SARs-CoV, MERS-CoV • Hypothesis: inhibition of SARs/MERS protease • Benefit in retrospective studies in SARs-CoV • Some in vitro data SARS-CoV-2, but EC50 much higher than levels reached in HIV dosing Lopinavir/ritonavir • HIV protease different protease family • Optimized to fit in a specific part of the catalytic site of HIV protease, absent in coronaviruses • Some benefit in animal studies MERS-CoV Li G, De Clercq E. Nat Rev Drug Discov. 2020;19(3):149- 150., Yao TT, et al. J Med Virol. doi: 10.1002/jmv.2572 • Widely used in China (2020)., Jiang S, Hillyer C, Du L. Trends Immunol doi: 10.1016/j.it.2020.03.007 (2020)., Choy KT et al. Antiviral • Numerous retrospective studies Res. doi: 10.1016/j.antiviral.2020.104786 (2020). COVID-19 GRAND ROUNDS JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES
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