necrolysis (TEN), exfoliative dermatitis, erythroderma, erythema multiforme (EM), erythema annulare centrifugum, lichenoid eruptions, phototoxicity, blue-grey nail and mucosal pigmentation, and alopecia.14,15
Antivirals
Lopinavir/Ritonavir
An antiretroviral protease inhibitor with Lopinavir boosted by Ritonavir in a fixed drug combination has shown in vitro inhibitory action on SARS-Cov-2 by binding to the active site of SARS-CoV 3C-like protease (SARS-CoV 3CLpro).16 However, Cao et al has shed a doubtful benefit of this therapy when compared to standard care.17
The known cutaneous side effects of Lopinavir/Ritonavir include eczemas, acne, stomatitis, alopecia, maculopapular rash, exfoliative dermatitis, and acute generalized exanthematous pustular (AGEP).18,19
Glucocorticoids
Uncontrolled immunologic response to the virus leads to a pro-inflammatory cytokine storm and inflammation, which are responsible for fatality associated with severe pneumonia caused by infection with COVID-19. Glucocorticoids are employed to manage this infection due to their anti-inflammatory role, as was previously done with SARS and MERS viruses.20 However, corticosteroids delayed viral clearance and increased rates of secondary infections. The World Health Organization has recommended against routine use of systemic glucocorticoids in COVID-19 patients.21 However, the Chinese Thoracic Society in a consensus statement has recommended using corticosteroids in pneumonia associated with COVID-19.22
A number of cutaneous adverse effects are secondary to use of corticosteroids, including acne, hypertrichosis, telangiectasia, candidiasis, poor wound healing, seborrheic dermatitis, striae, and AGEP.
Ivermectin
Oral ivermectin, an anti-parasitic drug, has shown to have broad-spectrum anti-viral activity in vitro. Caly et al have reported successful inhibition of SARS-CoV-2 with a ~5000-fold decrease in viral RNA at 48 hours utilizing a single treatment of viral cell culture.23 The addition of ivermectin to HCQ has been hypothesised to have a synergistic role in chemoprophylaxis and treatment of COVID-19.24 Oral ivermectin is widely and safely employed in mass treatment programs in Africa for onchoceriasis.25 Generalized pruritus has been reported following ivermectin intake.
Azithromycin
Azithromycin, a macrolide antibiotic used in uncomplicated skin and soft tissue infections, has shown in vitro activity against Zika and Ebola viruses and in the prevention of severe respiratory tract involvement in viral infections, probably owing to its immunomodulatory action. Antiviral action of HCQ against COVID-19 was shown to be reinforced by azithromycin with a synergistic action.13,26
Cutaneous side effects are uncommon, but include EM, urticaria, angioedema, fixed drug eruption, vasculitis, photosensitivity, vasculitis and rarely SJS.26
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
There were emerging concerns related to the use of NSAIDs in COVID-19 infection, particularly with ibuprofen, with French authorities suggesting it as detrimental. Ibuprofen leads to increased expression of ACE2 in diabetics and those being treated with angiotensin II type-I receptor blockers, which could facilitate infection with COVID-19.27 In vitro action of indomethacin possesses potent antiviral activity against canine coronavirus, thereby inhibiting virus replication.28 The further role of NSAIDs in management of COVID-19 is yet to be explored.
Morbilliform rashes, SJS, EM, urticaria, angioedema, vasculitis, phototoxic drug reaction, aggravation of systemic lupus erythematous, and pemphigoid-like reactions are known to uncommonly occur with NSAIDs.
Tetracyclines and Doxycycline
Tetracycline, in addition to being antibacterial, has antiinflammatory and immunomodulatory roles by scavenging intracellular reactive oxygen species, downregulating the NFKB pathway, and decreasing levels of inflammatory cytokines such as TNFâ€Î±, ILâ€1β, and ILâ€6. These cytokines are significantly elevated in COVID-19 infection, which could be downregulated by tetracyclines, including doxycycline. A potential therapeutic efficacy of tetracycline in treating COVID-19 has thus been hypothesised.29
Cutaneous side effects of tetracyclines are uncommon, but include maculopapular rashes, exfoliative drug rashes, onycholysis, photosensitivity, teeth and nail discoloration, urticaria, angioedema, exacerbation of systemic lupus erythematosus (SLE), serum sickness-like reaction, glossitis, black hairy tongue, and anogenital candidiasis.
Thalidomide
Thalidomide has anti-inflammatory, anti-fibrotic, antiangiogenesis, and immune regulation effects. The safety and efficacy of thalidomide as a pulmonary anti-inflammatory and anti-fibrotic agent have been evident in idiopathic pulmonary fibrosis and severe H1N1 influenza lung injury. Its role to control or relieve lung inflammation is under study in clinical trials for COVID-19 therapy.
Antivirals
Lopinavir/Ritonavir
An antiretroviral protease inhibitor with Lopinavir boosted by Ritonavir in a fixed drug combination has shown in vitro inhibitory action on SARS-Cov-2 by binding to the active site of SARS-CoV 3C-like protease (SARS-CoV 3CLpro).16 However, Cao et al has shed a doubtful benefit of this therapy when compared to standard care.17
The known cutaneous side effects of Lopinavir/Ritonavir include eczemas, acne, stomatitis, alopecia, maculopapular rash, exfoliative dermatitis, and acute generalized exanthematous pustular (AGEP).18,19
Glucocorticoids
Uncontrolled immunologic response to the virus leads to a pro-inflammatory cytokine storm and inflammation, which are responsible for fatality associated with severe pneumonia caused by infection with COVID-19. Glucocorticoids are employed to manage this infection due to their anti-inflammatory role, as was previously done with SARS and MERS viruses.20 However, corticosteroids delayed viral clearance and increased rates of secondary infections. The World Health Organization has recommended against routine use of systemic glucocorticoids in COVID-19 patients.21 However, the Chinese Thoracic Society in a consensus statement has recommended using corticosteroids in pneumonia associated with COVID-19.22
A number of cutaneous adverse effects are secondary to use of corticosteroids, including acne, hypertrichosis, telangiectasia, candidiasis, poor wound healing, seborrheic dermatitis, striae, and AGEP.
Ivermectin
Oral ivermectin, an anti-parasitic drug, has shown to have broad-spectrum anti-viral activity in vitro. Caly et al have reported successful inhibition of SARS-CoV-2 with a ~5000-fold decrease in viral RNA at 48 hours utilizing a single treatment of viral cell culture.23 The addition of ivermectin to HCQ has been hypothesised to have a synergistic role in chemoprophylaxis and treatment of COVID-19.24 Oral ivermectin is widely and safely employed in mass treatment programs in Africa for onchoceriasis.25 Generalized pruritus has been reported following ivermectin intake.
Azithromycin
Azithromycin, a macrolide antibiotic used in uncomplicated skin and soft tissue infections, has shown in vitro activity against Zika and Ebola viruses and in the prevention of severe respiratory tract involvement in viral infections, probably owing to its immunomodulatory action. Antiviral action of HCQ against COVID-19 was shown to be reinforced by azithromycin with a synergistic action.13,26
Cutaneous side effects are uncommon, but include EM, urticaria, angioedema, fixed drug eruption, vasculitis, photosensitivity, vasculitis and rarely SJS.26
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
There were emerging concerns related to the use of NSAIDs in COVID-19 infection, particularly with ibuprofen, with French authorities suggesting it as detrimental. Ibuprofen leads to increased expression of ACE2 in diabetics and those being treated with angiotensin II type-I receptor blockers, which could facilitate infection with COVID-19.27 In vitro action of indomethacin possesses potent antiviral activity against canine coronavirus, thereby inhibiting virus replication.28 The further role of NSAIDs in management of COVID-19 is yet to be explored.
Morbilliform rashes, SJS, EM, urticaria, angioedema, vasculitis, phototoxic drug reaction, aggravation of systemic lupus erythematous, and pemphigoid-like reactions are known to uncommonly occur with NSAIDs.
Tetracyclines and Doxycycline
Tetracycline, in addition to being antibacterial, has antiinflammatory and immunomodulatory roles by scavenging intracellular reactive oxygen species, downregulating the NFKB pathway, and decreasing levels of inflammatory cytokines such as TNFâ€Î±, ILâ€1β, and ILâ€6. These cytokines are significantly elevated in COVID-19 infection, which could be downregulated by tetracyclines, including doxycycline. A potential therapeutic efficacy of tetracycline in treating COVID-19 has thus been hypothesised.29
Cutaneous side effects of tetracyclines are uncommon, but include maculopapular rashes, exfoliative drug rashes, onycholysis, photosensitivity, teeth and nail discoloration, urticaria, angioedema, exacerbation of systemic lupus erythematosus (SLE), serum sickness-like reaction, glossitis, black hairy tongue, and anogenital candidiasis.
Thalidomide
Thalidomide has anti-inflammatory, anti-fibrotic, antiangiogenesis, and immune regulation effects. The safety and efficacy of thalidomide as a pulmonary anti-inflammatory and anti-fibrotic agent have been evident in idiopathic pulmonary fibrosis and severe H1N1 influenza lung injury. Its role to control or relieve lung inflammation is under study in clinical trials for COVID-19 therapy.
