Brigham and Women's Hospitals

Therapeutics

Updated: May 23, 2020

Overview

Therapeutics summary

  1. The anti-viral and anti-inflammatory section is meant to provide a summary of the literature. The BWH Infectious Diseases COVID-19 treatment guidelines (Partners login required) and ID consultation service take precedence over the information provided in the literature review below. This table is from those treatment guidelines, which mirror our recommendations laid out in this chapter, but in a more concise format and with BWH-specific contacts.

Clinical Trials

  1. There are a variety of clinical trials for antiviral agents and host-response modifying therapies ongoing at BWH. Please reference the above ID treatment guidelines for further information (Partners login required)
  2. For clinical trial enrollment, the contact person for the trial can be paged or emailed to discuss further. Preferred methods of contact for each trial can be found here (Partners login required)
  3. Enrollment criteria for each trial can found here (Partners login required)
  4. If a patient is enrolled in a COVID-19 clinical trial, verify that other therapeutic regimens do not add harmful drug interactions with study agents

Nebulization

  1. Nebulization is considered an aerosol generating procedure and may contribute to disease transmission.
  1. Nebulization requires appropriate PPE (e.g., N95) and room (e.g., negative airflow)
  2. Laboratory studies on human patient simulators showed increased dispersion of particles during jet nebulizations at 6L/min from 0.45 to >0.8m when simulating normal lung or severe lung injury, respectively. In comparison, there was 0.4m dispersion with 5L/min nasal cannula and 0.3m with Venturi mask (40%) Hui et al. Hong Kong Medical Journal. 2020). However, a meta-analysis of aerosol-generating procedures did not find nebulizer as a risk factor for SARS transmission, unlike procedures like tracheal intubation (Tran et al. PLOS One. 2020).

Bronchodilator therapy

  1. COVID-19 clinical reports do not indicate wheeze as a common symptom, and not all patients require bronchodilators. Bronchodilators should certainly be prescribed whenever indicated but should not be ordered as a default on every patient (Zhou et al, Lancet, 2020; Yang et al, Lancet Respir Med, 2020; Guan et al, N Engl J Med, 2020; WHO, COVID-19 Interim guidance, March 2020).

Non-intubated patients

  1. If the patient is COVID-19 confirmed or Person Under Investigation (PUI):
  1. If possible, use metered dose inhalers (MDIs) + spacer rather than nebulizers. Nebulizers are an aerosol generating procedure.
  2. Because MDI supply is limited, only prescribe when needed. Ask patients / families to bring in their home inhalers if possible and check in home MDI with pharmacy.
  3. However, if the patient requires a nebulizer (e.g., difficulty using MDI), nebulizers should be used in COVID-19 confirmed or PUI patients.
  1. For Covid-19 confirmed or PUI patients, consider a breath actuated nebulizer (BAN), which may help reduce aerosol generation.
  2. Order breath actuated nebulizer (BAN) as free text in the nebulizer order.
  3. Note: The patient needs to generate flow to trigger the neb; so patients with upper airway edema/stridor, weakness or inability to cooperate may be poor candidates for a breath actuated nebulizer (BAN).
  4. If a COVID-19 confirmed or PUI patient requires nebulizers and cannot use BAN, then a regular nebulizer should be ordered.
  1. If the COVID-19 PUI patient is ruled out and considered COVID-19 negative:
  1. The patient should use their previously prescribed MDI until it runs out, then switch to nebulizers.
  1. In patients admitted WITHOUT suspicion for COVID-19:
  1. Use nebulizers even if on droplet precautions (e.g., influenza) because MDI supply is limited.

Intubated patients

  1. For intubated COVID-19 confirmed or PUI, it is approved to use nebulizers.
  1. The in-line nebulizer container is part of a closed ventilator circuit.

Airway Clearance

Secretion thinning

  1. Patients can develop thick secretions from Covid-19 itself or secondary bacterial pneumonia.
  2. Nebulized treatments may help with airway secretion management, but published evidence is not available.
  1. Options include:
  1. Normal (0.9%) saline nebulizer BID.
  2. N-acetylcysteine (“Mucomyst”) nebulizer BID or TID
  1. N-acetylcysteine can cause bronchoconstriction.
  2. Pre-treat with albuterol 2.5mg just prior to delivery.
  1. Nebulized hypertonic (3-7%) saline once daily
  1. Hypertonic saline can cause bronchoconstriction.
  2. If using, start with 3% saline to assess response and bronchoconstriction.
  3. Pre-treat with albuterol 2.5mg just prior to delivery.
  1. Dornase alfa 2.5mg nebulizer once daily
  1. Dornase can cause bronchoconstriction, mucosal bleeding, and can clog the HEPA filter, requiring intermittent replacement by RT.
  2. Avoid in the setting of bloody secretions.
  3. Pre-treat with albuterol 2.5mg just prior to delivery
  4. It would be reasonable to consider other agents, including N-acetylcysteine, first given the need to change HEPA filters. In addition, a RCT for dornase nebulizer versus saline will begin shortly at BWH. However, if persistent secretions, it is reasonable to try dornase nebulizer.
  1. Although avoided if possible since it is an aerosol generating procedure, bronchoscopy for pulmonary toilet can be performed if needed on Covid-19 confirmed or PUI patients.

Mechanical airway clearance

  1. Covid-confirmed or PUI patients can utilize the below methods of mechanical airway clearance if needed. These are aerosol generating procedures (AGP) and require appropriate PPE (e.g., N95) and a negative airflow room:
  1. Oscillating positive expiratory pressure devices (Aerobika or Acapella). Encourage the patient to use the device when staff are outside of the room with the door closed.
  2. Chest PT can be performed, but is an aerosolizing procedure requiring close contact with staff, so alternate options should be considered first where possible
  3. Chest PT vests if the patient requires at home (e.g., CF patients) should be continued
  1. For Covid-confirmed or PUI patients, the use of cough assist devices (e.g., MIE: Mechanical Insufflation Exsufflation) must be approved by Respiratory Therapy leadership prior to initiation. Approval is not required for Covid-negative patients:
  1. Cough assist devices can generate significant aerosols and require staff to be present in the room
  2. However, certain situations may merit discussion of the use of cough assist device, such as a patient with ALS that use this device at home

Systemic Corticosteroids

Evidence

  1. Data on corticosteroids for COVID-19 is mixed.
  1. Many studies show negative effects of corticosteroids on similar viruses. There is no clinical evidence of net benefit from steroids in SARS-CoV, MERS-CoV or influenza infection, and observational data show increased mortality, more secondary infections, impaired viral clearance and more adverse effects in survivors (e.g., psychosis, diabetes, avascular necrosis) (Lee et al, J Clin Virol, 2004; Stockman et al, PLoS Med, 2006; Lansbury et al, Crit Care Med 2019; Arabi et al, Am J Respir Crit Care Med, 2018; WHO, COVID-19 Interim guidance, March 2020).
  2. However, a retrospective cohort analysis of patients with COVID-19 who developed ARDS (n=84) noted that methylprednisolone treatment was associated with a decreased risk of death (Wu et al, JAMA Int Med, 2020).
  3. An earlier, non-blinded randomized controlled trial of patients with ARDS (not COVID-19) suggested a benefit to dexamethasone treatment (Villar et a, Lancet Resp Med, 2020) but this has not been replicated as of yet.

Recommendations

  1. At this time, we do not recommend steroids for COVID-19 except as part of a clinical trial or if treating another indication such as asthma or COPD exacerbation. This is in line with WHO guidance (WHO COVID-19 Interim Guidance, March 2020). The Society for Critical Care Medicine makes a weak recommendation for the use of steroids in COVID+ ARDS and the American Thoracic Society makes no recommendation for or against the use of steroids, but notes that their task force came close to recommending against steroids (SCCM COVID-19 Guidelines, March 2020; ATS COVID-19 Interim Guidance, April 2020).
  2. If treating another indication, use corticosteroids at a low dose for a short duration:
  1. For asthma or COPD exacerbation, treat with 40mg prednisone PO or 30mg methylprednisolone IV, once daily x 3-5 days.
  2. For any shock with a history of chronic steroid use in excess of 10mg prednisone daily, treat with 50mg hydrocortisone IV Q6H until improvement in shock.
  3. For multipressor (>2 pressors) shock without history of chronic steroid use, treat with 50mg hydrocortisone IV Q6H until improvement in shock.

Pulmonary Vasodilators

  1. Please see the Respiratory chapter under refractory hypoxemia”.

Remdesivir

  1. If treatment of COVID-19 is being considered, remdesivir trial enrollment should be discussed with the infectious diseases study team for key inclusion and exclusion criteria in the use for moderate or severe COVID-19 disease (NCT04292730 and NCT04292899, respectively)
  2. Outside of the currently enrolling clinical trials, remdesivir is available in limited supply via emergency use authorization or for pregnant patients in severe disease through Gilead’s compassionate use protocol. Please use this link for Partners’ criteria for the use of EUA remdesivir.

Pharmacology

  1. Remdesivir is a nucleotide prodrug metabolized to an analog of adenosine triphosphate, which inhibits viral RNA-dependent RNA polymerase, causing premature termination of RNA transcription.

Evidence

  1. Animal models have shown reduced lung viral loads when remdesivir is used for both SARS-CoV-1 and MERS-CoV (Sheahan et al, Sci Transl Med, 2017; Sheahan et al, Nat Commun, 2020; de Wit et al, Proc Nat Acad Sci, 2020)
  2. For the treatment of Ebola, remdesivir did not show favorable outcomes compared to other investigational agents (MAb114 and REGN-EB3) in a randomized controlled trial (Mulangu et al, N Engl J Med, 2020)
  3. Remdesivir has shown in vitro activity against SARS-CoV-2 (Wang et al, Cell Res, 2020)
  4. A case report was published on the use of remdesivir in a 35-year-old male who improved one day after remdesivir was initiated, but it is unclear if the use of remdesivir resulted in this improvement (Holshue et al, N Engl J Med, 2020)
  5. A case series of compassionate use remdesivir analyzed 53 patients, of whom 68% had improvement in their oxygen-support class, 47% were discharged, and 13% passed away (Grein et al, N Engl J Med, 2020)
  1. Without a control group, it is unclear if the use of remdesivir altered the natural progression of COVID-19 disease in these patients
  1. A randomized, double-blind, placebo-controlled trial evaluated remdesivir IV for 10 days versus placebo in adults with confirmed severe COVID-19 in 10 hospitals in Wuhan, China. In the intention-to-treat population of 237 participants (41% women, median age 65), remdesivir resulted in no significant difference in time to clinical improvement versus placebo (hazard ratio 1.23, 95% CI 0.87-1.75). Remdesivir was discontinued due to adverse events in 12% of patients versus 5% of patients in the placebo group. The trial was stopped early after only enrolling 52% of the target sample size due to decreasing incidence of COVID-19 in Wuhan. The authors estimated this yielded 58% power to detect a hazard ratio of 1.4 or higher. As the trial was underpowered, its findings are inconclusive (Wang et al, Lancet, 2020)
  2. The adaptive NIAID trial (ACTT-1) evaluated over 1000 patients with COVID-19 in a randomized, placebo-controlled trial. The median time to recovery in the remdesivir group (n=538) was 11 days (95% CI 9-12) vs. 15 days (95% CI 13-19) in the placebo group (n=521) (recovery rate ratio 1.32, 95% CI 1.12-1.55, p<0.001). The mortality rate by day 14 was 7.1% with remdesivir compared to 11.9% with placebo (HR 0.7, 95% CI 0.47-1.04). Serious adverse events were reported in 21.1% of remdesivir patients and 27% of placebo patients (Beigel et al, N Engl J Med, 2020)

Recommendations

  1. If eligible, patients can be enrolled in the remdesivir clinical trials for COVID-19 moderate or severe disease
  2. Outside of clinical trials, remdesivir is available in limited supply via emergency use authorization or for pregnant patients with severe disease at BWH through Gilead’s compassionate use protocol

Dosing

  1. Remdesivir is only available as an investigational agent through clinical trials or emergency use authorization
  2. 200 mg IV loading dose, followed by 100 mg IV daily for a total of 5-10 days

Monitoring and Toxicity

  1. Elevated liver function tests (AST, ALT), phlebitis, constipation, headache, nausea
  2. Remdesivir is co-formulated with sulfobutyl ether β-cyclodextrin (SBECD), so there is a theoretical risk of accumulation in renal failure promoting further renal injury, similar to intravenous voriconazole

Favipiravir

  1. If treatment of COVID-19 is being considered, favipiravir trial enrollment should be discussed with the infectious diseases study team for key inclusion and exclusion criteria (NCT04358549)

Pharmacology

  1. Favipiravir, also known as T-705 or Avigan, is a pyrazine derivative and guanine analog that acts as an inhibitor of viral RNA-dependent RNA polymerase, causing chain termination and preventing RNA elongation
  2. Favipiravir demonstrates anti-viral activity against a broad array of RNA viruses, including arenaviruses, bunyaviruses, and filoviruses (Furuta et al, Proc Jpn Acad Ser B Phys Biol Sci, 2017)
  3. In Japan, favipiravir is approved for influenza A resistant to neuraminidase inhibitors (Hayden et al, Curr Opin Infect Dis, 2019)

Evidence

  1. Favipiravir is effective in protecting mice against Ebola virus, although the EC50 is relatively high at 67 μM (Oestereich et al, Antiviral Res, 2014)
  2. Favipiravir inhibits SARS-CoV-2 in vitro (Wang et al, Cell Res, 2020)
  3. A non-placebo, open-label, single-center trial of 80 patients in Shenzhen, China of oral favipiravir compared with a historical cohort of patients receiving lopinavir/ritonavir for 14 days demonstrated reduced median viral shedding time (primary endpoint) in the favipiravir group (4 vs. 11 days; p < 0.001). Radiographic improvement was seen in 91% of favipiravir treated subjects vs. 62% of those on lopinavir/ritonavir (p < 0.004). Of note, all patients also received inhaled interferon. The trial excluded patients with severe disease or ICU admission. (Cai et al, Engineering, 2020)
  4. A prospective, multicenter, open-label, randomized trial of 236 patients in China comparing favipiravir and umifenovir demonstrated a higher clinical recovery rate at day 7 in moderately ill patients receiving favipiravir (71.4% vs. 55.9%, p = 0.0199), but not among severely or critically ill patients. Clinical recovery was defined as three or more days of improvement in respiratory rate, oxygenation, cough, and fever. There was no placebo group for comparison and this study has not been peer reviewed (Chen et al, MedRxiv, 2020, unpublished report).

Recommendations

  1. If eligible, patients can be enrolled in the favipiravir clinical trial for COVID-19 (NCT04358549)

Dosing

  1. Favipiravir is only available as an investigational agent through clinical trials and is being studied at a dose of 1800 mg BID loading dose on day 1, followed by 1000 mg BID for the next 13 days

Monitoring and Toxicity

  1. Teratogenicity
  2. Increased serum uric acid (Chen et al, MedRxiv, 2020, unpublished report).
  3. In monkeys, toxicities observed have been mild hepatic and hematologic effects
  1. Elevations in AST, ALT, total bilirubin, and alkaline phosphatase
  2. Anemia

Umifenovir (Arbidol)

Pharmacology

  1. Broad spectrum of activity against enveloped and non-enveloped RNA and DNA viruses
  2. Blocks multiple stages of viral life cycle, including fusion (Kadam, Proc Natl Acad Sci USA, 2017; Blaising et al, Antiviral Res, 2014) and exocytosis (Blaising et al, Antiviral Res, 2013)
  3. Umifenovir has been licensed for use as treatment of and prophylaxis against influenza in China since 2006 and Russia since the 1990’s (Blaising et al, Antiviral Res, 2014).
  4. Demonstrates in vitro activity against HBV, HCV, and, HHV-8 (Pécheur et al, J of Virol, 2016), Coxsackievirus B (Herod et al, J Gen Virol, 2019), Ebola and Lassa viruses (Hulseberg, J Gen Virol, 2019), and Influenza (Blaising et al, Antiviral Res, 2014)

Evidence

  1. There is in vitro evidence that umifenovir suppresses reproduction of the SARS-CoV-1 virus (Khamitov et al, Vapr Virusol, 2008)
  2. In one case series of four patients, three out of four demonstrated clinical improvement with the use of lopinavir/ritonavir, umifenovir, and a traditional Chinese medicine (Wang et al, BioSci Trends, 2020)
  3. A single-center, retrospective cohort study of 33 patients in Guangzhou, China compared lopinavir/ritonavir combined with umifenovir vs. lopinavir/ritonavir alone for 7-14 days. The combination therapy was found to be more strongly associated with the primary endpoint of negative COVID-19 PCR testing at day 7 (75% vs 35%, p < 0.05) and day 14 (94% vs 53%, p < 0.05) (Deng et al, J Infect, 2020)
  4. A multicenter retrospective study of 50 patients with COVID-19 demonstrated that seven days of umifenovir monotherapy was associated with higher rates of negative SARS-CoV-2 PCR testing at 7 and 14 days after hospital admission than lopinavir/ritonavir (Zhu et al, J Infect, 2020)
  5. In another retrospective, observational study at multiple hospitals in Wuhan, China, 36 patients treated with umifenovir had higher rates of hospital discharge (33% vs 19%) and lower rates of mortality (0% vs 16%) than patients who did not receive umifenovir. These findings were not statistically significant. There was no randomization and the other treatments received (e.g., antimicrobials, steroids) were not accounted for in the comparison between umifenovir-treated and umifenovir-untreated groups (Wang et al, Clin Infect Dis, 2020)
  6. A retrospective study of 81 non-ICU patients in Wuhan, China with moderate to severe COVID-19 demonstrated no difference in the primary outcome of rate of negative nasopharyngeal PCR test at day 7 (73% vs 78%, p=0.19). Additionally, the median time from onset of symptoms to negative PCR was 18 days for patients treated with umifenovir and 16 days in the control group (p=0.42) (Lian et al, Clin Microbiol Infect, 2020)
  7. A prospective, multicenter, open-label, randomized trial of 236 patients in China comparing umifenovir and favipiravir demonstrated a lower clinical recovery rate at day 7 in moderately ill patients receiving umifenovir (55.9% vs. 71.4% p = 0.0199), but not among severely or critically ill patients. Clinical recovery was defined as three or more days of improvement in respiratory rate, oxygenation, cough, and fever. There was no placebo group for comparison and this study has not been peer reviewed (