Section 7: Treatments for SARS-CoV-2 Infection (from DOI: 10.1007/s11886-020-01292-3)
From publication: "Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response" published as Curr Cardiol Rep; 2020 04 21 ; 22 (5) 32. DOI: https://doi.org/10.1007/s11886-020-01292-3
Section 7: Treatments for SARS-CoV-2 Infection
Various therapies have emerged to treat the various aspects of viral pathogenesis and subsequent immune response, and an understanding of which aspect of disease pathogenesis they target may aide the clinician in knowing when to use them. Treatments which target steps early in the infection process ("respiratory phase" in Fig. 1) are meant to suppress viral replication and aid the host immune response to fight the virus. When the immune response becomes hyperactive ("sepsis/shock" phase in Fig. 1) with cytokine storm, immunomodulators that target various harmful inflammatory cytokines may help mitigate end-organ toxicity. Unfortunately, there are currently no FDA-approved therapies for SARS-CoV-2, and no substantial randomized trial data to support any therapy thus far. However, several promising therapies are actively being test in patients including the recently announced multi-center, randomized SOLIDARITY trial (remdesivir, hydroxychloroquine) sponsored by the World Health Organization.
Anti-microbial agents which target the early (pre-systemic) phase of infection include remdesivir, hydroxychloroquine, and azithromycin. Remdesivir is a drug which targets the RNA polymerase, suppresses viral replication, and has strong in vitro evidence of efficacy against SARS-CoV-2. Although randomized trial data are still pending, there have been anecdotal reports of improvement after compassionate use of remdesivir. Lopinavir-ritonavir is another RNA polymerase inhibitor which showed initial promise, but a recently published study from Beijing showed no significant difference in the treatment versus control group, suggesting that the effect, if present, was insufficient to cause a significant clinical response. Chloroquine has traditionally been used as an anti-malaria drug, but has shown reasonable efficacy against SARS-CoV-2 in vitro. A single arm study of 20 COVID-19-positive patients treated in France demonstrated some efficacy for the combination of azithromycin and hydroxychloroquine, a safer variation of chloroquine, in SARS-CoV-2. Another small non-randomized study showed similar results However, these were small, non-randomized studies in whose definition of efficacy was based on viral clearance rather than mortality benefit. A subsequent pilot randomized trial in Shanghai comparing hydroxychloroquine and placebo has shown no difference in virologic clearance. Azithromycin is an antimicrobial agent generally used for antibacterial purposes; however, it also has been shown to inhibit zika virus tropism in the human brain and has been suggested as an adjunct for treatment of intra-cellular microbes in the past. Since both chloroquine/hydroxychloroquine and azithromycin lead to corrected QT (QTC) prolongation, their use either alone or in combination should be monitored for this potential cardiotoxic side effect.
The second group of therapies is immunomodulators, used to target immune hyperactivity and the cytokine storm that occurs in the later stages of COVID-19 infection. Monoclonal antibodies have shown some promise in early studies. The IL-6 inhibitors tocilizumab and sarilumab have shown early benefit and are being studied in ongoing randomized trials. Other therapies including meplazumab (anti-CD147), eculizumab (targets complement), adalimumab (TNF-alpha inhibitor), and IVIG (saturation of Fc receptors on macrophages, suppression of chemokines/cytokines) are also intended toward reduction of deleterious immune effects. Interestingly, immune stimulatory agents aimed at enhancing beneficial aspects of the immune response are also being tested:including IFN- beta1a, PD-1 inhibitors, and donor convalescent plasma. There are conflicting data to support the use of glucocorticoids in COVID-19 related ARDS, and even potential evidence of harm in the form of decreased viral clearance in SARS and MERS and increased mortality in SARS-CoV2. Without evidence of acute lymphocytic myocarditis in cardiovascular injury, we do not currently advocate for the routine administration of glucocorticoids for elevated troponin in COVID-19 patients. Randomized trials on both glucocorticoids and IVIG in severe cases of COVID-19 are ongoing.
