Difficult cases in inpatient care for COVID-19 - PowerPoint Presentation

1. Difficult cases in inpatient care for COVID-19Peter Chin-Hong, MDProfessor of MedicineUniversity of California San FranciscoSan Francisco, California

2. Financial Relationships With Ineligible Companies (Formerly Described as Commercial Interests by the ACCME) Within the Last 2 Years:Dr Chin-Hong has no financial relationships with ineligible companies to disclose. (Updated 07/19/22)

3. Learning ObjectivesAfter attending this presentation, learners will be able to: Construct combination of current antiviral and anti-inflammatory drugs for treatment of hospitalized patients with COVID-19List 3 emerging therapies for critically ill hospitalized COVID-19 patientsDescribe toxicities of commonly used COVID-19 therapeuticsDifferentiate emerging and opportunistic infections in patients hospitalized with COVID-19

4. Case 153 year-old man with idiopathic pulmonary fibrosis s/p bilateral lung transplant 2019 on maintenance immunosuppression (tacrolimus / mycophenolate / prednisone) who calls your clinic reporting a COVID-19 diagnosis

5. Case 153M s/p bilateral lung transplant 2019 (maintenance IS: tac/MMF/pred) with COVID-19. Currently being managed in the ambulatory settingHe comes to the hospital insteadWhat do you recommend?

6. Case 153 y-o M s/p bilateral lung transplant 2019 on maintenance immunosuppression (tacrolimus / mycophenolate / prednisone) with worsening cough, dyspnea. 93% RAWhat is the next best management plan?Admit for remdesivir IV, check spike protein AbAdmit for remdesivir IV, check spike protein Ab, reduce immunosuppressionAdmit for remdesivir IV, check spike protein Ab, reduce immunosuppression (MMF), start dexamethasoneAdmit for remdesivir IV, check spike protein Ab, reduce immunosuppression (MMF), start dexamethasone, start baricitinibOutpatient management with O2 monitoring, monoclonal antibodies

7. Case 153 y-o M s/p bilateral lung transplant 2019 on maintenance immunosuppression (tacrolimus / mycophenolate / prednisone) with worsening cough, dyspnea. 93% RAWhat is the next best management plan?Admit for remdesivir IV, check spike protein AbAdmit for remdesivir IV, check spike protein Ab, reduce immunosuppressionAdmit for remdesivir IV, check spike protein Ab, reduce immunosuppression (MMF), start dexamethasoneAdmit for remdesivir IV, check spike protein Ab, reduce immunosuppression (MMF), start dexamethasone, start baricitnibOutpatient management with O2 monitoring, monoclonal antibodies

8. TreatmentVirusRemdesivirPaxlovidMolupiravirMonoclonal AbInflammationDexamethasoneBaracitnibTocilizumabInfliximabAbataceptSabizabulin

9. RemdesivirImmunosuppressed (IS) patients included in ACTT-1 but no subgroup analysis. No IS patients in SOLIDARITYHigher risk of drug interactions and toxicityIS patients can have prolonged viral replicationAntivirals may have more benefit due to impaired immune responseHigh risk for viral mutation and variants76F with CLL on rituximab with COVID-19 treated with remdesivir who developed a mutation in RdRpMartinot et al, Clin Inf Dis 2020. Choi et al, NEJM 2020. IS=Immunosuppressed

10. Inpatient ManagementGeneral GuidanceImproves time to recovery & reduces symptoms. Mortality benefit limited to subset on O2Recommendations:Monotherapy if minimal O2Combination therapy (with dexamethasone +/- immunomodulator) for if ⬆️ O2, high-flow O2, non-invasive ventilation5 days rx, extend to 10 days if no substantial clinical improvementSide effects Liver: discontinue for ALT >10x upper limit Cyclodextrin can ⬆️ in renal failureCYP 34A substrateIS PatientsAppears to be safe with IS medicationsNo signal increased toxicity (liver, in setting of renal failure) Do IS patients experience more benefit from antiviral therapy?Hospitalized, no O2 requirementOutpatientShould IS patients receive longer duration of therapy?Will antiviral resistance develop in IS patients?RemdesivirAntiviral inhibiting RNA-dependent RNA polymeraseIS=Immunosuppressed

11. Corticosteroids | DexamethasoneIS patients excluded / underrepresented in trialsStandard of care in IS patientsPossible ⬇️ in SARS-CoV-2 viral clearance with steroidsBroad IS effects with increased risk of infectionBacterial: no ⬆️ risk of 2° infectionsViral: HBV, CMV, HSV reactivationFungal: possible ⬆️ fungal infections Aspergillus, mucor, cryptococcus, endemic mycosesParasitic: disseminated Strongyloides infectionLi et al, Infect Dis Ther 2020.Salmanton-García et al, Emerg Infect Dis 2021.Permpalung et al, Clin Inf Dis 2021.Marchese et al, Infection 2021.Abdolin et al, Clin Exp Med 2021.IS=Immunosuppressed

12. General GuidanceNOT in outpatients and inpatients not requiring O2For inpatients with:⬆️ O2High-flow O2 & non-invasive ventilation (+/- baricitinib or tocilizumab)Mechanical ventilation (+/- tocilizumab)Consider screening / treatment for:StrongyloidesHBVMonitor for side effects:HyperglycemiaPsychiatric effectsSecondary infectionsAvascular necrosisDexamethasoneIS PatientsCurrently, same threshold for initiation as for non-IS populationsWhat is the benefit of steroids in IS patients?Higher risk of complicationsDo these agents ⬆️ risk of infection in IS patients with COVID-19? What is the impact on mortality?Secondary infectionsOpportunistic infectionsReactivation of latent infectionInpatient ManagementIS=Immunosuppressed

13. Tocilizumab and baricitinibIS excluded from clinical trialsSmall studies in IS without adverse outcomesCase-control tocilizumab study in organ transplant recipients with no difference in mortality (41% vs 28%, p>0.2) or secondary infections (34% vs 24%, p>0.2)Theoretical but unknown degree of risk of secondary and opportunistic infections, especially when added to dexamethasonePereira et al, Am J Transplant 2020; Busani et al, Clin Infect Dis 2020.Khatib et al, Clin Case Rep 2021.Lier et al, Am J Trop Med Hyg 2021.Amundson et al, Infect Dis Clin Pract 2021.BacterialViralDisseminated tuberculosisFatal HSV-1 liver failure CMV viremiaFungalParasiticFatal cryptococcemiaDisseminated StrongyloidiasisIS=Immunosuppressed

14. Inpatient ManagementGeneral GuidancePatients with rapidly increasing O2 requirement + systemic inflammation:Add baricitinib or tocilizumab to dexamethasone +/- remdesivir Patient with mechanical ventilation and within 24hrs of ICU admissionAdd tocilizumab to dexamethasoneDo not use tocilizumab and baricitinib togetherSide effectsAvoid tocilizumab if significant IS, ALT >5x upper limit, high risk for GI perforation, uncontrolled infectionConsider prophylactic treatment for StrongyloidesIS PatientsCurrently used in IS patients with caution What is the benefit of immunomodulators in IS patients?Higher risk of complicationsDo these agents ⬆️ risk of infection in IS patients with COVID-19? With and without steroidsImpact on mortalityOther immunomodulators: tocilizumab (anti-IL-6) & baricitinib (JAK-inhibitor)IS=Immunosuppressed

15. Inpatient ManagementGeneral GuidanceNo clear role for patients with severe diseaseNot routinely recommended for inpatient or outpatient use unless part of clinical trialCCP EUA allowed for treatment of hospitalized patients with impaired immunityIS PatientsCurrent data do not suggest adverse outcomesDo IS patients experience more benefit?Potentially, based on small studiesWhat timing / disease severity to administer?Related to serostatus? Does CCP in IS patients contribute to development of resistant variants?No clear use at this timeConvalescent Plasma

16. Inpatient ManagementImmunosuppression AdjustmentIndividualized approach based on COVID-19 disease severity, underlying disease / immunocompromise, and treatment agentsSpecific agents associated with worse COVID-19 outcomes: e.g. anti-CD20 agents, mycophenolate

17. Case 153M s/p bilateral lung transplant 2019 (maintenance IS: tac/MMF/pred) hospitalized with COVID-19. Remdesivir started&MMF heldDexamethasonestartedConvalescent plasma considered & Tocilizumabstarted

18. Case 1 (continued)53 y-o M s/p bilateral lung transplant 2019 on maintenance immunosuppression now extubated on remdesivir/dexamethasone/tocilizumab. Hospital day#25: gradually worsening hypoxia and reintubated. CT scan performed What is the most likely cause of decompensation?AspergillusDrug toxicitySARS CoV2SARS CoV2 & AspergillusNone of the above

19. Case 1 (continued)53 y-o M s/p bilateral lung transplant 2019 on maintenance immunosuppression now extubated on remdesivir/dexamethasone/tocilizumab. Hospital day#25: gradually worsening hypoxia and reintubated. CT scan performed What is the most likely cause of decompensation?AspergillusDrug toxicitySARS CoV2SARS CoV2 & AspergillusNone of the above

20. Day 25CT Chest with rounded consolidations on background of diffuse groundglass Tracheal aspirate culture positive for moderate aspergillus fumigatusSARS-CoV-2 PCR positive after prior negative with CT value of 27Isavuconazole for aspergillusWorsening hypoxia and reintubatedAdditional 5 days of remdesivirImproves and is discharged

21. Aspergillus and COVIDVery common with high mortalityObservational cohort studyN=823 in 2 ICU cohorts (Netherlands, Belgium, France)COVID-associated pulmonary aspergillosis incidence (CAPA) ECMM/ISHAM classification criteriaCOVID-associated pulmonary aspergillosis incidence: 10-15%Risk increased with: COPD, immunosuppression drugs (not steroids), HIV/AIDSMortality rates: 43-52%Janssen NA et al, Emerging Infectious Disease, 2021CAPA=COVID-associated pulmonary aspergillosis

22. Emerging COVID therapiesInfliximab & AbataceptACTIV-1 immune modulators clinical trialModerate-severe COVIDAll given backbone of remdesivir and dexamethasoneCenicriviroc vs placeboClosed Infliximab vs placebo (28d), N=1037Time to recovery: NSClinical improvement: ↑43.8%Mortality: 10% vs 14.5%Abatacept vs placebo (28d), N=1022Time to recovery: NSClinical improvement: ↑34.2%Mortality: 11% vs 15%https://sph.unc.edu/sph-news/immune-modulator-drugs-improved-survival-for-people-hospitalized-with-covid-19/

23. Emerging COVID therapiesSabizabulin Oral drug, microtubule disrupterModerate-severe COVIDPhase 3 RCT, N=204Interim analysis for first 150 ptsICU days: ↓43%Mechanical ventilation days: ↓ 49%Hospital days: ↓ 26%Mortality: 20.2% vs 45.1% (↓ 55.5%)↓ Adverse events in Sabizabulin groupNew York Times 7/6/22https://evidence.nejm.org/doi/10.1056/EVIDoa2200145

24. PanelVariations on the theme53 y-o M with HIV (CD4 23, VL <50) on ART (TAF/FTC/bictegravir) with worsening cough, dyspnea. 93% RA33 y-o F 31 weeks pregnant with worsening cough, dyspnea. 93% RAWhat is the potential role of the emerging therapies in the care of hospitalized COVID patients?

25. Case 244 y-o F s/p liver transplant 2019 on maintenance immunosuppression (tacrolimus / mycophenolate / prednisone) SARSCov2+ as outpatient on Paxlovid, admitted with acute kidney injury (Cr 4.0, baseline 1.1) What is the most likely cause of the acute kidney injury?BK virusCOVID-19 Multisystem inflammatory syndrome in adults (MIS-A)PaxlovidNone of the above

26. Case 244 y-o F s/p liver transplant 2019 on maintenance immunosuppression (tacrolimus / mycophenolate / prednisone) SARSCov2+ as outpatient on Paxlovid, admitted with acute kidney injury (Cr 4.0, baseline 1.1) What is the most likely cause of the acute kidney injury?BK virusCOVID-19 Multisystem inflammatory syndrome in adults (MIS-A)PaxlovidNone of the above

27. Case 2Tacrolimus level >60 (5-15 ng/ml normal range)Paxlovid stoppedRifampin givenPatient had received Paxlovid from local MD without adjustment of tacrolimus dosingPaxlovid contains ritonavir (taken as 100mg orally twice daily x 5 days with nirmatrelvir) and drug interactions may be dangerous if not consideredNBC 12/26/21

28. Example of tacrolimus protocol (UCSF)Also cyclosporin, everolimus, siroliumusDayPaxlovidTacrolimus management1First Paxlovid doseSTOP TAC after AM dose2-5Paxlovid continuesContinue HOLD TAC6-8Paxlovid completedContinue HOLD TAC9Restart TAC at regular dose11Check routine labs, with trough levels of TAC as appropriate

29. PanelHow do you best handle checking for drug interactions? Any favorite resources?How do you rank the therapeutics available for outpatients now to prevent serious disease?Who do you prioritize for Paxlovid? Would you treat everyone? What are the options for pregnant people?Can you prescribe people a course of Paxlovid to take abroad when traveling in case they get infected?

30. Case 334 y-o M with HIV (VL UD on elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) with recent syphilis treatment presents to ED with sore throat, headache, malaise, generalized rash on body including oral and genital lesions (“looks like zits but bigger”)What is the most likely diagnosis?COVID-19 BA.5MonkeypoxSyphilis – Jarisch Herxheimer reactionAny of the above

31. Case 334 y-o M with HIV (VL UD on Genvoya) with recent syphilis treatment presents to ED with sore throat, headache, malaise, generalized rash on body including oral and genital lesions (“looks like zits but bigger”)What is the most likely diagnosis?COVID-19 BA.5MonkeypoxSyphilis – Jarisch Herxheimer reactionAll of the above

32. Case 3SARS CoV2 +, Orthopox virus PCR +, CXR neg, 98% RATreated with Tecovirimat

33. Hospitalized with or for COVID?Lower proportion of hospitalized patients with serious diseaseLower ICU census & fewer mechanically ventilatedShorter staysStanford: 65% SARSCov2+ admitted for something elseUCSF: 52% SARSCov2+ admitted for something elseMercury News 7/17/22

34. Monkeypox 2022: ClinicalIncubation: 7 days (range 4⎼11)Flu-like symptoms: 82%Top 5: 1)Fatigue 2)Fever 3)Lymphadenopathy 4)Myalgia 5)Sore throatRash: 100% (94% anogenital then face/arms/trunk)Hospitalized: 10%PainCellulitisConcomitant STI: 25%NPR 6/3/22Girometti N et al, Lancet ID, 7/1/22

35. Rash pearlsFollows flu-like symptomsStarts in genital areaMay be initially missed or mistaken for HSV, syphilis, folliculitis, abscessMovement of rash is key (moves to face, arms, fewer on trunk)Rash can be umbilicatedRash can be extremely painfulPalms and soles (like syphilis, Rocky Mountain Spotted Fever)Then crusts over, scabs and falls off in 1 ⎼ 2 weekshttps://www.cdc.gov/poxvirus/monkeypox/clinicians/clinical-recognition.htmlMaculopapular →Vesicular → Pustular → Scabs

36. TecovirimatAntiviral PO/IV3 pills twice a day for 2 weeksFDA approved for smallpox 2018EA-IND (CDC) available for monkeypox Patients need informed consent and follow-upAvailable from national strategic stockpileOther drugs with activity: cidofovir, brincidofovir, vaccinia immune globulinForbes 5/24/22

37. TecovirimatWho to treat?Bad diseaseHospitalizedNot hospitalized but severe (confluent rectal lesions, severe oral ulcers, eye involvement)Bad hostSeverely immunocompromised< 8 years-oldPregnant or breastfeeding personsInflammatory bowel diseaseSevere/active dermatologic diseasePatient permission granted Day 0Day 3

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39. Thank you

40. Question and Answer Session

41. ChangesAdded formatted title, disclosure, and learning objectives slides.Added slide numbersSlide 29: Replaced Genvoya with drug names; changes “All of the above” to “Any of the above”Slides 31, 35, 36: Removed the tradename “(Tpoxx)”Note: we decided to leave the tradename, Paxlovid, in the presentation since it is a new drug

42. QueriesSlide 3: Please add 2 or 3 measurable learning objectives