key: cord-0997883-fho2kble
authors: Shishak, Mansak; Sarkar, Rashmi
title: Dermatological therapies with relevance to COVID‐19
date: 2020-06-11
journal: Dermatol Ther
DOI: 10.1111/dth.13813
sha: 928f3b059aff91350dbb51707e7219a6d7f1baa3
doc_id: 997883
cord_uid: fho2kble

SARS‐CoV‐2 is a novel single stranded RNA virus that has gripped humanity all over. It affects primarily the respiratory system, but is not limited to it, causing widespread involvement of many organ systems. The cases are still rising at an exponential rate and manifold trials are on to test different agents with the hope for potential limitation of spread and control of symptoms. Various classes of drugs have been tried; some with moderate success while many are yet to be proven to be of definite benefit. We have observed that the drugs used in dermatology practice are featured in more than a few of such studies. Here we wish to highlight the ones that we are familiar with, which has featured at some point, in the management of this very challenging pandemic. This article is protected by copyright. All rights reserved.

The end of 2019 witnessed the outbreak of the novel 120 nm coronavirus (SARS-CoV-2) resulting in a mammoth epidemic throughout China, exponentially spreading to almost every continent except Antarctica. Rapidly evolving lines of treatment and hundreds of trials to salvage complications, and contain the spread of disease at the earliest, are ongoing.

Despite the fact that it is a condition affecting primarily the respiratory system, its therapeutic trials have witnessed many of dermatology drugs that are in use.

One of the earliest drugs to find widespread usage and give potential hope was hydroxychloroquine (HCQ), with its immunomodulatory mechanism showing effective inhibition of both the entry, transport and the post-entry stages of SARS-CoV-2. 1 It was further shown to control the cytokine storm occurring latephase in critically ill SARS-CoV-2 infected patients. 2 Pasquale et al suggested the role of HCQ as a prophylactic agent for prevention of transmission, to those healthcare workers (HCW) exposed to the SARS-CoV2. 3 With reports suggesting that the addition of the macrolide antibiotic azithromycin as a possible therapeutic agent in COVID-19, a retrospective data among patients hospitalized in New York observed that treatment with hydroxychloroquine, azithromycin, or a combination of both drugs, compared with neither treatment, was not significantly associated with differences in inhospital mortality. 4 Expressing concerns on the combination of azithromycin/hydroxychloroquine on QT interval prolongation, Claudio et al suggested doxycycline (semi-synthetic derivative of tetracycline) as a safe and inexpensive alternative agent to azithromycin. Doxycycline is known to have anti-inflammatory effects at both low and high doses, ranging from 20mg/day, up to 200 mg/day, by inhibiting metalloproteases and modulating effects of pro-inflammatory cytokines (IL-6, IL-8 and tumor necrosis factor (TNF)-alpha. 5 With all of the initial attention on HCQ, it was observed that patients were irrationally scrambling to increase their HCQ stock fearing shortage of drug supply. 6 Conclusive study results for hydroxychloroquine, however, have been lacking. In a letter to the Lancet, the authors expressed apprehension in case of its widespread and indiscriminate usage as potentially contentious. 7

Another interesting agent is Ivermectin, an FDA-approved broad spectrum antiparasitic agent which was shown to inhibit SARS-Cov-2 virus in vitro, with ∼5000-fold reduction in virion activity at 48h in cell culture. 8 Ivermectin has previously been shown to be an inhibitor of interaction between different RNA viruses and the human immunodeficiency virus-1 (HIV-1) integrase protein (IN) and importin (IMP) α/β1 heterodimer responsible for IN nuclear import of viral proteins. Its broad-spectrum anti-viral activity is thought to be by sequestering IMPα/β1 on the rough endoplasmic reticulum (RER)/Golgi membrane. Translating the impact of ivermectin's effect on nuclear transport inhibitory activity in vitro, the authors have suggested a trial of ivermectin as an antiviral agent against SARS Cov-2.

From Wuhan, in a single centre experience of 15 patients, the authors reported an efficacious response using a trial of Tocilizumab, a monoclonal antibody particularly in the subset with cytokine storm by inhibiting binding to interleukin-6 to its receptors. 9 Meanwhile, it is learned that angiotensin converting enzyme 2 is a possible receptor for SARS Cov-2. One of the mediators is AP2-associated protein kinase 1(AAK1), which is a known inhibitor of baricitinib; thus proposed in patient management of COVID-19. 10 Intravenous Immunoglobulin (IvIg) Historical therapeutic evidence with the SARS and MERS experience showed that the main pathogenesis of organ dysfunction lay in cytokine dysregulation, wherein Intravenous immunoglobulin (IVIg) therapy exhibited well tolerated clinical benefits. Given the phylogenetic relation of MERS-CoV with SARS-COV-2, IVIg given high-dose at 0.3-0.5 g per kg weight per day for five days was tried on 3 patients with severe COVID. Promising results were shown when used at an early stage of clinical deterioration. Its immunomodulatory mechanisms, including Fc-mediated and Fab-mediated approaches have been credited for the response. 11

Of caution to be exercised is the use of corticosteroids. Given its propensity to depress immunity and worsen co-morbidities such as insulin resistance, appropriate dosing at the right stage of intervention is advised, after weighing risk-benefit ratio. In a Chinese study assessing the outcomes among patients with acute respiratory distress syndrome (ARDS) and mortality, treatment with methylprednisolone proved beneficial with decreased risk of mortality, in those with ARDS. 12 However, Tang et al warned against the improper use of systemic corticosteroids, due to the heightened risk of osteonecrosis of the femoral head (ONFH). 13 Emphasis is to be made on keeping it only as a reserve drug for critical cases such as septic shock.

An NEJM study of protease inhibitors Lopinavir-Ritonavir showed no benefit and trial halted in 13% patients due to adverse effects. 14

Covid-19 and the concurrent use of biologics in psoriasis have prompted fears onto treating dermatologists by virtue of sustained immunosuppression, putting patients as vulnerable groups for contracting infections. Quelling these fears, O.Yu et al suggest ongoing treatment with PDE-4 inhibitor apremilast might, infact, play a protective role against the evolution of the infection via decreased expression of tumor necrosis factor (TNF)-α. 15 A previous report on elderly psoriatic patients receiving secukinumab (anti-IL-17) and adalimumab (anti-TNFα) was promising, with patients being unreceptive to COVID-19. 16 

We also wish to highlight reports of a new RCT of 140 patients to assess intravenous vitamin C for the treatment of severe 2019-nCoV infected pneumonia in Wuhan, China. Based on previous trials in ARDS for its antioxidant properties, intravenous vitamin C is being administered at a dose of 24 g/day for 7 days. 17 Besides Vit C, it has also been found that low average vitamin D levels in a country are associated with a relatively high number of COVID-19 cases and mortality. In light of this, Vitamin D supplementation is expected to be proven beneficial and protect against SARS-CoV2 infection. 18 

This article is protected by copyright. All rights reserved.

Curtis et al highlighted the off-target effects of the BCG vaccine. 19 It has the potential to induce metabolic and epigenetic changes, enhancing the innate immune response to infections-" trained immunity". This can reduce viraemia in COVID-19 affected patients.

Wambier et al in their exploration of the Covid pathogenesis explain in their hypothesis why males seem to be more vulnerable reporting higher mortality rates, and attribute it to androgen receptor gene polymorphisms. 20 Based on this, it was suggested that agents halting androgen activity, such as androgen receptor inhibitors, steroidogenesis inhibitors, 5-alpha reductase inhibitors may play a role in therapeutics.

Many potential drugs are being investigated in SARS-CoV-2 treatment, for safety and efficacy. The race is on for vaccine development as that could be the potential game changer in how the infection is halted. However, in the absence of robust trials with conclusive evidence of anti-viral efficacy, trials of different therapeutics based on pathogenesis and previous reports appear to be the majority approach.

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus

Is Hydroxychloroquine a possible post-exposure prophylaxis drug to limit the transmission to health care workers exposed to COVID19?

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Doxycycline, a widely used antibiotic in dermatology with a possible anti-inflammatory action against IL -6 in COVID -19 outbreak

Potential of chloroquine and hydroxychloroquine to treat COVID-19 causes fears of shortages among people with systemic lupus erythematosus

Hydroxychloroquine prophylaxis for COVID-19 contacts in India

The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro

Tocilizumab treatment in COVID-19: A single center experience

Baricitinib as a potential treatment for 2019-nCoV acute respiratory disease

High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deterioratin g Patients With Coronavirus Disease. Open Forum Infectious Diseases

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Caution against corticosteroidbased COVID-19 treatment

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Apremilast as a potential treatment option for COVID-19: no symptoms of infection in a psoriatic patient

COVID-19 pulmonary infection in erythrodermic psoriatic patient with oligodendroglioma: safety and compatibility of apremilast with critical intensive care management

A new clinical trial to test high-dose vitamin C in patients with COVID-19

Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths

Considering BCG vaccination to reduce the impact of Cocid-19

Androgen-driven COVID-19 pandemic theory