COVID-19 medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Zand, M.D.[2], Syed Hassan A. Kazmi BSc, MD [3],Sabawoon Mirwais, M.B.B.S, M.D.[4]
Overview
COVID-19 is an inflammatory hypercytokinemia disease. The aim of therapy is prevention of viral replication and controlling the inflammatory process.
Antiviral Agents
Remdesivir
- Remdesivir is a prodrug and inhibits viral RNA polymerase when intracellularly metabolized to an ATP analog.
- Remdesivir has been effective on MERS-COV,EBOLA, SARS-COV1.
- Effects of remdesivir in COVID-19 include :
- Significant reduction in viral load in bronchoaleolar lavage
- Inhibition of SARS-COV-2 replication in nasal and bronchial airway epithelial cells.
- Remdesivir Indicates only for in-hospital setting in Severe COVID-19 disease.
- The recommended dose of remdesivir in COVID-19 is:
- Adult dosing (wt > 40 kg): 200 mg IV loading dose on day 1, then 100 mg IV daily maintenance dose
- Infuse each dose over 30-120 min
- 5 day course if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days
- 10 day course for patients on mechanical ventilation/ECMO
- Pediatric dosing (wt 3.5 - 40 kg): 5 mg/kg loading dose on day 1, then 2.5 mg/kg maintenance dose
- 5 day course if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days
- 10 day course for patients on mechanical ventilation/ECMO
- Adult dosing (wt > 40 kg): 200 mg IV loading dose on day 1, then 100 mg IV daily maintenance dose
- Contraindications of remdesivir include :
- Severe renal impairment (eGFR <30 ml/min)
- Severe hepatic dysfunction or alanin transferase (ALT)ᐳ 5-times upper limit
Hydroxychloroquine and Chloroquine
- Hydroxychloroquine has been effective in graft versus host disease ,lupus erythematosus, rheumatoid arthritis, and malaria
- In the begining of COVID-19 pandemic ,hydroxychloroquine was used due to inhibition of the entry of SARS-COV-2 and prevention of the fusion of viral spike protein to ACE2 receptor and reduction of cytokine storm.
- Intracellular uptake of hydroxychloroquine was enhanced with combination with Zinc.
- Hydroxychloroquine has cardiac side effects due to QT prolongation effect.
- Efficacy of remdesivir is reduced in combination with hydroxychroroquine.
- Due to cardiac side effects, recently FDA dissapproved the emergency use authorization of hydroxychloroquine if clinical trials are unavailable.
- Hydroxychloroquine foe early treatment of adults with mild COVID-19 does not improve outcomes in modest sized unblinded randomized controlled trial.[1]
- Lopinavir-Ritonavir Inhibits the activity of the HIV-1 protease.
- In an open-label randomized controlled trial, the comparison between patients with COVID-19 received either lopinavir-ritonavir 400/100 mg, orally twice daily plus standard of care or standard care alone showed no benefit of administration of lopinavir-ritonavir
- Only one study in Korea in the initial phase of outbreak accepted using this combination.
- Side effects: Diarrhea, nausea, asthenia
Umifenovir (Arbidol)
- Umifenovir has been used in treatment of Ebola virus, human herpesvirus 8 (HHV-8), hepatitis C virus (HCV), and Tacaribe arenavirus, influenza A,B
- Mechanism of action: inhibition of the virus fusion to the cell membrane and hydrogen binding to membrance phospholipids.
- In a retrospective cohort study showed improvement in chest ct scan of COVID-19 patients received a combination of umifenovir and lopinavir-ritonavir.
- In prospective study, umifenovir had inferior outcomes in clinical recovery rate and relief of fever and cough compared with favipiravir
- Safety and efficacy in COVID-19 is under investigation in china with two randomized open trials.
Favipiravir (Avigan)
- Favipiravir has been used in 2014 in Japan for the treatment of influenza resistant to neuraminidase inhibitors and has been used in the treatment of infectious diseases caused by RNA viruses such as influenza, Ebola, and norovirus '
- Mechanism of action: after entering the infected cells and being phosphorylated, inhibits viral RNA replication.
- SARS-CoV-2 is an enveloped, positive-sense, single-strand RNA virus and studies showed the efficacy of favipiravir on SARS-COV-2.
- A randomized control trial has shown that COVID-19 patients treated with favipiravir have superior recovery rate (71.43%) than that treated with umifenovir (55.86%), and the duration of fever and cough relief time are significantly shorter in favipiravir group than in umifenovir group
- Two randomized and nonrandomized controlled trials are evaluating the safety and efficacy of favipiravir for treatment of COVID-19 disease.
Oseltamivir (Tamiflu)
- Oseltamivir has been approved for the treatment of influenza A,B viruses and inhibits neuraminidase glygoprotein which is essential for replication of influenza A and B viruses
- The study in wohan showed no positive outcomes were observed in COVID-19 patients after recieving osetamivir
- A clinical trial is investigating the efficacy of combination between Oseltamivir with chloroquine and favipiravir .
Supportive Agents
Azithromycin
- Azithromycin has been effective in the treatment of Zika and Ebola viruses and prevented severe respiratory tract infection
- Mechanism of action is binding to 50S subunit of the bacteria ribosom,then inhibition of translation of mRNA.
- Effects of azithromycin in treatment of viral respiratory tract infection include:1. antibacterial coverage 2.immunomodulatory and anti-inflammatory effects.
- A trial in france reported %100 viral clearance in nasopharengeal swap after recieving hydroxychloroquine with azithromycin
- Data about benefits of azithromycin in COVID-19 disease is still inadequate and needs further evaluation.
Vitamin C (Ascorbic Acid)
- Effects of Vitamin C in viral agents include:
- Maturation of T lymphocytes and NK( natural killer) cells which are involved in the immune response to viral agents.
- Inhibition of reactive oxygen species (ROS) production
- Remodulation of the cytokine network in systemic inflammatory syndrome.
- Study in COVID-19 patients in china showed administration of high dose IV,Vitamin C (1500mg per day) in moderate and severe cases was correlated with improvement in oxygenation indexes and recovery .
Corticosteroids
- Corticosteroids are indicated only if patients are on supplemental oxygen or receiving mechanical ventilation[2]
- Due to suppression of immune system, the role of corticosteroid in COVID-19 would be evaluated by further investigation.
Methylprednisolone
- Effects of low doses of methylprednisolone in COVID-19 include:
- Controlled of hypercytokinemia
- Anti-inflammatory effect in superimposed infection in COVID-19
- Increased blood pressure when it is low
- Decreased risk of death in ARDS related COVID-19
Dexamethasone
- The recommended dose of dexamethasone for COVID-19 is 6 mg IV once daily or po x 10 days[2]
- Effects of dexamethason in ARDS related COVID-19 include:
- Decreased days of intubation
- Decreased mortality
Niclosamide and Ivermectin
- Mechanism of action is Inhibition of binding of coronavirus onto the cells.
- Niclosamid inhibits replication of MERS-COV AND SARS-COV-2.
- Ivermectin inhibits viral replication in dengue virus, flavivirus,influenza.
- FDA approved Ivermectin for treatment of SARS-COV-2. Study showed Ivermectin inhibited SARS-COV-2 replication up to 5000 fold at 48 h in vitro.
Convalescent Plasma
- Convalescent Plasma is Transfusion of plasma loaded with antibodies after improvement from COVID-19.
- Studies in Taiwan and South Korea showed clinical benefits in severe cases of SARS-COV and MERS
- Pilot study in COVID19 showed symptoms improvement including fever, cough, tightness of breath,chest pain.
- Serious side effects were not reported.
- There is no randomized trial data to assess the efficacy of convalescent plasma in COVID-19.
Anticoagulation
- In COVID-19 hypercoagulable state induces micro-macro-vascular thrombosis.
- Predictors of poor outcome in COVID-19 include: Disseminated intravascular coagulation , high level of D-dimer.
- Mortality with anticoagulant therapy was decreased in COVID-19.
- Efficacy of heparin in COVID-19 includes : 1.anti inflammatory properties,2. prevention of viral attachment via changing in covid 19 spike protein 3.anticoagulation effect.
- Efficacy of low molecular weight heparin in COVID-19 includes:
- 1.Reduction in level of IL-6 and cytokine storm.
- 2.Anticoagulation effect.
- Prophylactic anticoagulant therapy is necessary for all hospitalized COVID-19 patients.
- In patients with rapidly progressing respiratory distress and the probability of thrombosis, treatment doses of anticoagulant is considered.
Ibuprofen
- Ibuprofen is an anti-inflammatory drug (NSAID) and blocks the renin-angiotensin pathway.
- Ibuprofen is Activator of ACE2 receptor.
- There is No strong evidence between intake of NSAID and worsening COVID-19.
- Ibuprofen approved by FDA for treatment of COVID-19.
Tucilizumab (Actemra)
- Tucilizumab is a monocolonal antibody that binds to IL-6 receptor on the cells and prevents inflammatory response.
- Tucilizumab has been used for treatment of RA and juvenile ideopathic artheritis.
- Study in wohan showed significant clinical improvement in severe COVID-19 patients.
- Tucilizumab is indicated in COVID-19 patients with the following criteria:
- Hypoxia
- Lung infiltration on CXR
- High inflammatory markers(CRP>3g/dl,ferritin>400ng/dl
- Clinical deterioration
- Contraindications of tucilizumab include as followings:
- Confirmed bacterial or fungal infection
- Platelet count<100000/cc
- Neutrophil count<2000/cc
- Alanin aminotrasferase or aspartat aminotransferase >5times upper limit normal
References
- ↑ Skipper, Caleb P.; Pastick, Katelyn A.; Engen, Nicole W.; Bangdiwala, Ananta S.; Abassi, Mahsa; Lofgren, Sarah M.; Williams, Darlisha A.; Okafor, Elizabeth C.; Pullen, Matthew F.; Nicol, Melanie R.; Nascene, Alanna A.; Hullsiek, Kathy H.; Cheng, Matthew P.; Luke, Darlette; Lother, Sylvain A.; MacKenzie, Lauren J.; Drobot, Glen; Kelly, Lauren E.; Schwartz, Ilan S.; Zarychanski, Ryan; McDonald, Emily G.; Lee, Todd C.; Rajasingham, Radha; Boulware, David R. (2020). "Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19". Annals of Internal Medicine. doi:10.7326/M20-4207. ISSN 0003-4819.
- ↑ 2.0 2.1