Video at https://www.youtube.com/watch?v=2rQKMD_5po0 Part of the "Hypoxemia in the Ward Patient with COVID-19" talks in Frederick Southwick's Coursera MOOC on COVID-19, "COVID-19 - A clinical update". "Dr. Ben Geisler, Hospitalist at Massachusetts General Hospital and Harvard Medical School faculty member reviews the current treatments for COVID-19. He first discusses the management of fluid replacement and diuretics, as well as the indications for bronchodilators and antibiotics. He emphasizes the importance of DVT anticoagulation prophylaxis. He next reviews the potential role of statins, evidence with regards angiotensin converting enzyme inhibitors, and NSAIDS. He next reviews the current indications for the agents of proven efficacy: Remdesivir and Dexamethasone. Finally he discusses the dilemma of equipoise and the best resources for staying up to date with this ever changing topic." In this iteration, we have added baricitinib and tocilizumab/IL-6 inhibitors.

1. Hypoxemia in the Ward
Patient with COVID-19:
Therapeutics
Benjamin P. Geisler, MD, MPH,
FACP, MRCP (London), FHM

2. Relevant Disclosures
• All content presented is for informational and educational purposes
only. It does not constitute medical advice and is not intended to be a
substitute for independent, professional, medical judgement; advice;
diagnosis; or treatment. Medical information changes constantly, and
medical care always needs to take into account patient-specific
information. Therefore, this content should not be considered current,
complete, or exhaustive. Reliance on this content is solely at your own
risk. Patients are advised to seek the advice of your qualified healthcare
provider with any question you may have regarding your specific
medical condition.
• I do not represent Ludwig-Maximilians University Munich,
Massachusetts General Hospital, Harvard Medical School, the Mass
General Brigham COVID Innovation Center, or its affiliates in any official
capacity here. All opinions expressed are mine alone. I have no financial
conflict of interest relevant to this presentation.

3. (Inpatient) Therapeutics – Outline
• Case
• Specific Rx/benefit
• Dexamethasone
• Remdesivir
• Baricitinib
• Tocilizumab/IL-6 inhibitors
• VTE prophylaxis
• How to keep track
• Equipoise/enrolment into clinical trials
• Application to case
• Summary
• Unspecific Rx/benefit
• Bronchodilators
• Intravenous fluids/Diuretics
• Antibiotics
• Statins

4. Out of Scope
• Non-pharmaceutical therapeutics
• Therapeutics that have not shown benefit
• Therapeutics that are still under investigation (even if
promising)
• Monoclonal antibodies
• Inhaled corticosteroids
• RAAS and NSAIDs agents
• Treatments in an ICU or ICU-like setting

5. 30yo Spanish-speaking M w/o PMH who p/w
of progressive nonproductive cough, dyspnea,
and pleuritic CP x5 days.

6. 30yo Spanish-speaking M w/o PMH who p/w
of progressive nonproductive cough, dyspnea,
and pleuritic CP x5 days.
• On exam: wheezing, HR 110s, BP normal
• Labs
• Chest CTA PE protocol with multifocal groundglass
opacities, no PE, no infiltrate/airspace disease
• On the floor, SpO2 89% on RA → 94% with 3L NC
• SARS-CoV-2 PCR positive
• CRP, D-dimer, ferritin, LDH all elevated; procalcitonin nl
• WBC count mildly elevated; lymphopenic
• elevated BUN/creatinine; normal CPK, ALT/AST

7. Bronchodilators
• Short-acting beta-2 agonist +/- anti-cholinergic (or
combination)
• e.g. in the U.S. albuterol and ipratropium (Duoneb®)
• For inpts, no data/experience with LAMAs/LABAs, inhaled
glucocorticosteroids, other Rx for obstructive dz
• Indications:
• Use at home (asthma/COPD)
• Wheezing on exam → ?improve oxygenation
• Nebulizer treatment is aerosolizing, metered dose inhaler
is preferred as the routine treatment (Δrisk vs. Δbenefit)
• If newly starting on MDI, need to teach proper technique

8. Intravenous Fluids vs. Diuretics
• No standing fluids
• For nutrition, consider tube feeds instead of dextrose
• Avoid extremes
• Be cautious with intravenous fluids unless patient hypotensive –
and even then consider vasopressors early
• Be cautious with diuretics as COVID-19 patients are prone to
developed acute kidney injury
• Assess volume status as usual
• Jugular venous distention
• Crackles on auskulation of the chest (especially the bases)
• Dependent edema (lower extremities, sacrum, scrotum)
• S3/S4 on cardiac exam
• Track input/outputs and possibly daily weights

9. Antibiotics
• Avoid “routine” antibiotics
• Add only if you suspect a bacterial infection
• But have a low threshold
• Infiltrate/airspace disease on imaging
• Talk to radiologist if uncertain
• Procalcitonin controversial, but many add antibiotics if (+)
• Tailor to the infection suspected, e.g.
• Ceftriaxone 1g/day + either doxycycline 100mg BID or
azithromycin 500→250mg for 5 days for community-acquired
pneumonia
• Stop if risk for bacterial infection low unless critically ill
• If in doubt, get infectious diseases consult

10. Statins
• Theoretical benefit (mild immunosuppressants)
• “Continue home statins”
• If indication (primary/secondary MACCE prophylaxis per
guidelines) and not pregnant, consider starting a statin
(e.g., atorvastatin 40mg)
• Check medication list for potential interactions
• Anecdotally risk of statin-induced myopathy in COVID-19
patients, so do not start if not indicated
• Before starting new statin, check CPK, ALT/AST
• Worse risk/benefit if CPK ≥500U/L or ALT >3x ULN
• Daily CPK if on new statin and azithromycin

11. Dexamethasone/steroids
• Steroids have been used in many patients early on in the
pandemic in China
• Others were reluctant to use them given there were negative
signals in SARS and MERS and mortality can be increased
influenza
• Randomized controlled trial has shown mortality benefit
in severe COVID-19, except if no O2 requirement
• Dosing in trial: dexamethasone 6 mg po daily ≤10 days
• Can also give i.v. if suspect gut edema or backordered
• Other alternatives: prednisone, hydrocortisone,
methylprednisolone
The RECOVERY Collaborative Group NEJM 2021; doi: 10.1056/NEJMoa2021436

12. Remdesivir (Veklury®)
• Antiviral effect: probably blocks viral RNA synthesis
• Randomized controlled trial showed shortened duration
of illness; mortality Δ did not reach statistical significance
• Emergency use authorization by the FDA
• Indicated for adults (incl. pregnant)/children ≥3.5kg with
severe disease, e.g.
• Hospitalized
• SpO2 ≤94% on room air
• Supplemental oxygen/mechanical ventilation/extracorporeal
membrane oxygenation (ECMO)
• Do not start (and stop) if ALT is ≥5x ULN
• Difficult to access in many places
• Start early if patient qualifies
Beigel JH NEJM 2020 online early; doi: 10.1056/NEJMoa2007764

13. Baricitinib (Olumiant®)
• Janus kinase inhibitor; ?antiviral effect: ↓viral entry
• FDA EUA in combination with remdesivir for any O2 req.
• RCT: modestly improve time to recovery; no mortality ↓
• Mortality benefit only in observational study
• Benefit for dexamethasone much clearer
• Potential use for barticitinib: patients on remdesivir (no
use w/o) with absolute contraindications to steroids, e.g.
• severe other infections including fungemia
• need for intrathecal meds
• cerebral malaria
• Benefit greater in patients on high flow or NIV
Kalil et al. NEJM 2021 10.1056/NEJMoa2031994; Stebil et al. Sci Adv 2021 10.1126/sciadv.abe4724

14. Tocilizumab (Actemra®)/IL-6 inhibit.
• Smaller, earlier trials of IL-6 inhibitors didn’t show benefit
• Two larger, later trials with different inclusion criteria
• RECOVERY: SpO2<92% RA & CRP ≥75mg/dl
• REMAP-CAP: 24 hours “after starting organ support”
both showed a mortality benefit (~12% RECOVERY; ~25%
REMAP-CAP)
• Primary endpoint in REMAP-CAP was organ support-free days
(median -11 days)
• Both studies had significant limitations (open-label, not all
patients on dex/steroids, RECOVERY not yet peer-
reviewed)
RECOVERY Collaborative Group medrXiv preprint 10.1101/2021.02.11.21249258; REMAP-CAP Investigators NEJM 2021

15. VTE prophylaxis vs. therap. AC
• Unless contraindicated, all patients should receive
pharmacologic VTE prophylaxis
• Lowers mortality
• Mechanical VTE prophylaxis only prevents lower extremity DVT
whereas in COVID-19 there might be thrombosis elsewhere
• Lower molecular weight heparin might be preferred
• E.g., enoxaparin, dalteparin
• “Prophylactic” dose
• Pregnant → unfractionated subcutaneous heparin (SqH)
• Unless there is a bleeding risk (no prophylaxis vs. SqH)
Grandone et al. J Thrombosis Thrombolysis 2021; Paolisso et al. Frontiers Pharmacology 2021

16. Siddiqi HK, Mehra MR J Heart Lung Transplant 39(5):405-407

17. How to Keep Track
www.CovidDrugs.org

18. Equipoise
• “Genuine uncertainty among experts whether a
treatment will be beneficial”
• In most other situations, we would tend to all agree that
patients should be enrolled in high-quality randomized
controlled trials
• On the other hand, in other situations doctors and other
providers are generally allowed to prescribe therapeutics
approved for other indications (“off-label use”)
• Ethical dilemma:
• Only high-level randomized controlled trials can provide
certainty whether a treatment works (“efficacy”) or not
• What if all (or almost all) cases are happening right now and
future knowledge will be less useful than treating now?

19. 30yo Spanish-speaking M w/o PMH who p/w
of progressive nonproductive cough, dyspnea,
and pleuritic CP x5 days.
• On exam, wheezing, HR 110s, BP normal
• Labs
• Chest CTA: no PE, multifocal groundglass opacities,
no airspace disease/pneumonitic infiltrate
• On the floor, SpO2 89% on RA → 94% with 3L NC
• SARS-CoV-2 PCR positive
• CRP, D-dimer, ferritin, LDH all elevated; procalcitonin nl
• WBC count mildly elevated; lymphopenic
• elevated BUN/creatinine; normal CPK, ALT/AST

20. Therapeutics Summary
• Stacked inhaled bronchodilators if bronchospastic
• Limit IVF as able; consider diuresis
• Antibiotics if e/o bacterial infection (infiltrate/+procal)
• Statin therapy if indicated anyways
• Remdesivir and dexamethasone for SpO2 <92% RA
• Baricitinib and Tocilizumab have no clear role yet
• DVT prophylaxis (eg, LMWH) for everyone
• Evidence will change!
• Keep track via IDSA’s apps, NIH guidelines, MGH FLARE,
nytimes.com’s tracker, and our own living systematic review at
www.coviddrugs.org

21. THANK YOU,
AND STAY SAFE
OUT THERE!