Indian Journal of Dermatology
: 2021  |  Volume : 66  |  Issue : 3  |  Page : 231--236

Virology and etiopathogenesis of COVID-19 with special reference to cutaneous implications

Rashmi Sarkar1, Shashank Bhargava2, Vibhu Mendiratta1,  
1 From the Department of Dermatology, Lady Hardinge Medical College and Associated KSCH and SSK Hospital, New Delhi, India
2 Department of Dermatology, R.D. Gardi Medical College, Ujjain, Madhya Pradesh, India

Correspondence Address:
Shashank Bhargava
Department of Dermatology, R.D. Gardi Medical College, Ujjain, Madhya Pradesh


Severe Acute Respiratory Virus Corona Virus 2 (SARS-CoV-2) has got its name Corona from Latin meaning “crown.” It has crown-like spikes present on the surface, which encloses the RNA, genetic material of this deadly virus. The virus attacks pneumocytes after binding with the angiotensin-converting enzyme 2 (ACE2) of the cell surface, which ultimately leads to chemotaxis followed by leukocyte infiltration, increased permeability of blood vessels and alveolar walls, and decreased surfactant in the lung leading to various symptoms. Skin provides a window to the internal changes of the body and also to mechanisms that are not readily visible. Commonly observed skin manifestations include vesicular lesions, maculopapular exanthema, urticarial eruptions, livedo or necrosis, and other forms of vasculitis, chilblain-like lesions. The skin lesions are attributed to either the virus directly affecting the skin or interferon dysregulation due to viral RNA or vascular involvement associated with alteration in coagulation or drug-induced skin manifestations. Observation of skin involvement and the vasculature due to SARS-CoV-2 illustrates the need for a precise stratification and differential diagnostic valuation so that the mechanisms of this novel virus are clearer for better management of the condition in the future. Vascular skin lesions are not seen in all the patients of COVID, but certain lesions should definitely alarm us to evaluate for coagulation abnormalities, complement levels, and skin biopsy, especially in critically ill patients. This review attempts to outline the pathogen briefly and the pathomechanism behind the development of various cutaneous manifestations.

How to cite this article:
Sarkar R, Bhargava S, Mendiratta V. Virology and etiopathogenesis of COVID-19 with special reference to cutaneous implications.Indian J Dermatol 2021;66:231-236

How to cite this URL:
Sarkar R, Bhargava S, Mendiratta V. Virology and etiopathogenesis of COVID-19 with special reference to cutaneous implications. Indian J Dermatol [serial online] 2021 [cited 2021 Jul 27 ];66:231-236
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In December 2019, an outbreak of virus infection was witnessed in Wuhan, Hubei province of China. There was a sudden surge in the number of positive cases in China by January 20, 2020. Initially, the reports of spread and deaths by this virus in other countries remained very low due to quick and early restrictions imposed on traveling. But it was on 11th March when the World Health Organization declared it as a pandemic when 112 countries across the globe had positive cases.[1] This 2019-novel Corona-virus (2019-nCoV) or Severe Acute Respiratory Virus Corona Virus 2 (SARS-CoV-2) had a fatality rate of 4%–7% considering the population of the area where the outbreak has happened.[2]

 SARS-CoV-2 and COVID19

SARS-CoV-2 is one of the newest members of a large group of RNA viruses categorized under the order Nidovirales and family coronaviridae and genera beta coronavirus (group 2B).[3] Other known coronaviruses have been elaborated in [Table 1].{Table 1}

It is transmitted through respiratory droplets, contact with any infected person or animal. Vertical transmission has also been reported.[4] RNA of the virus has also been detected in anal swabs and blood samples of infected patients.[5] The virus can easily travel 6 feet distance (much lesser than for measles and varicella zoster virus) after leaving the infected individual and survive on the surfaces such as hard, shiny, steel, and plastic for up to 72 h, whereas over porous surfaces (cardboard, paper, fabric) and copper up to 24 and 4 h respectively.[6],[7] Some simple tips to reduce the coronavirus spread have been illustrated in [Figure 1].{Figure 1}

Coronavirus disease 2019 (COVID-19) is a new type of viral pneumonitis, which is caused by infection of a novel coronavirus named SARS-CoV-2. The virus attacks pneumocytes after binding to the angiotensin-converting enzyme 2 (ACE2) of the cell surface, which ultimately leads to chemotaxis followed by leukocyte infiltration, increased permeability of blood vessels and alveolar walls, and decreased surfactant in the lungs leading to various respiratory symptoms such as cough, breathlessness along with fever. ACE2 is expressed in different body organs apart from lungs such as the heart, brain, skeletal muscles, kidney, intestine, smooth muscles, and endothelial cells.[8],[9],[10] The aggravation of local inflammation causes cytokine storms, resulting in systemic inflammatory response syndrome.

The basic and salient structural proteins of SARS-CoV-2 are mainly four in number, namely spike protein (S), membrane protein (M), an envelope protein (E), and nucleocapsid protein (N), which is helically symmetrical.[11] The shape of the virus is either pleomorphic or spherical, and it is characterized by club-shaped projections of glycoproteins on its surface [Figure 2].{Figure 2}

The S glycoprotein attaches to host receptor ACE2, the critical step for virus entry. S1 determines the host range of the virus and cellular tropism by receptor binding domain whereas S2 mediates virus-cell membrane fusion.[12] After fusion of the membrane, the RNA is released into the cytoplasm. The entered RNA translates into two polyproteins, i.e. pp1a and pp1ab, which form the replication-transcription complex (RTC) in double-membrane vesicle.[13],[14] The RTC replicates continuously and, after translation, forms numerous accessory proteins and structural proteins.[15] M protein is responsible for the transmembrane transport of nutrients and the formation of an envelope. The N and E proteins along with several other accessory proteins interfere with host immune response or numerous unknown functions. All the components ultimately assemble and form viral particle buds, which fuses with the cell membrane to release the virus.[16]

Coronaviruses (SARS-CoV, MERS-CoV, and 2019-nCoV) mainly infect animals such as pigs, cows, chickens, dogs, and cats. MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4) as its receptor to invade bats, humans, camels, horses, and rabbits. The virus causing COVID has evolved and originated from an animal reservoir (most probably bats), but it is yet to be confirmed.[17]

 Cutaneous manifestations and Their Etiopathogenesis

Skin provides a window to the internal changes of the body and also to mechanisms that are not readily visible. In various diseases, cutaneous involvement is mutually related to systemic diseases, such as papulosquamous disorders (psoriasis and lichen planus) which can increase the risk of metabolic syndrome and atherosclerosis.[18],[19],[20]

Initially, the studies from China had not reported much on dermatological symptoms. But of late, there are various dermatological manifestations published in the literature in 3–4 months. These can mimic numerous disorders encountered by dermatologists routinely. The first report was from Italy by Recalcati[21], wherein 20.4% of the hospitalized positive COVID patients had cutaneous symptoms and recently a report from Thailand found an associated skin finding in all patients.[22]

A recent article has put a doubt on the cutaneous manifestations due to the virus per se, and they have suggested to further evaluate the occurrence of various skin lesions. They have postulated that many patients worldwide are being infected with SARS-CoV-2, and many of them present with similar histories and receive the same treatment; it seems necessary to investigate the existence of any predisposition that facilitates the development of skin lesions. It has been found that lesions with apparent vascular involvement (associated with alterations in coagulation) do not differ from other types of skin lesions, with respect to the analytical parameters.[23] Another group of authors feels skin manifestations are more likely due to endogenous viral reactivation. SARS-CoV-2 infection is often associated with a strong systemic inflammatory response and altered immunological reaction. The high number of herpes zoster and pityriasis rosea cases observed in the Spanish study by Galvàn Casas et al.[24] both of the diseases being caused by viral reactivation, together with a recent report of Epstein Barr virus reactivation in a COVID-19 patient, could confirm this hypothesis.[25] Cutaneous lesions have been categorized into five groups according to one of the largest studies (375 subjects) from Spain as[24]

vesicular lesionsmaculopapular exanthemaurticarial eruptionslivedo or necrosis and other vasculitis formschilblain-like lesions.

The skin lesions are solely due to one of the following reasons.

Virus directly affecting the skin.Interferon dysregulation due to viral RNA and other structures.Vascular involvement associated with alteration in coagulation.Drug-induced skin manifestations.

Direct impact on the skin

Papulovesicular lesions are a result of direct effect of the virus on skin as observed in herpes viruses, pox virus, measles, etc., whereas verrucous lesions are seen due to human papillomavirus. Identification of ACE2, the receptor for spike protein which is expressed in keratinocytes of the basal cell layer confirms this hypothesis. The interaction between virus and ACE2 induces acantholysis and dyskeratosis for these vesicular lesions to manifest.[8],[26]

Interferon Dysregulation

The immune response to the virus varies from one individual to another. The viral RNA can lead to interferon dysregulation and present as various cutaneous manifestations such as urticaria, erythema multiforme-like lesions, morbilliform eruptions, vasculitis, atypical Kawasaki disease, erythema nodosum, and pityriasis rosea.[27]

Morbilliform rashes may be due to immune complex deposition and activation of cytokines.[26] The urticarial lesions could be due to direct or indirect induction of mast cells and basophil activation.[28] Skin manifestations of multisystem inflammatory syndrome (atypical Kawasaki disease) could be due to exaggerated innate immunologic activation that has been proven by direct immunofluorescence by the presence of IgA and complements in the vessel walls.[29]

Vascular involvement

Numerous cutaneous manifestations have been reported, namely pseudo-chilblain-like lesions, acro-ischaemia, petechiae, retiform purpuric lesions, necrosis, and lived oreticularis. Cutaneous vascular lesions can be categorized into two groups, i.e. transient mild lesions and severe major lesions. The first category comprises pseudo-chilblain lesions and mild initial lesions of lived oreticularis, whereas the latter includes necrotic lesions, hemorrhagic bullae, and dry gangrene, which ultimately indicates systemic coagulopathic progression, thrombocytopenia, leucocytoclastic, lymphocytic, ANCA-associated or septic vascultis, complement-mediated vascular injury, and vaso-occlusion.[30],[31],[32]

The endothelium is directly attacked by the virus causing damage to the wall, which can progress to antiphospholipid syndrome, disseminated intravascular coagulation, and mimickers of vasculitis. It has been observed that the prognosis is poor if a patient has sustained ischemic cutaneous changes. The damaged endothelial cells enhance the expression of adhesive molecules and ultimately recruit inflammatory cells. It also fastens the thrombotic complications by increasing the levels of thrombin and VWF and reducing thrombomodulin, protein C, and several other anticoagulant factors.[33] Increased immune response and cytokine storm have resulted in thrombotic disorders and are also confirmed with correlation with increased levels of D-dimer in such patients.[34],[35],[36]

In a study by Magro et al.[37] the median time recorded from limb ischemia to death due to circulatory failure in five patients was 12 days. Severely ill patients have been observed to have dusky purpuric patches on the palms and soles, lived oreticularis on the chest and limbs, and retiform purpurae on the buttocks. Vascular injury followed by hypercoagulable state may play a crucial role behind high mortality following COVID infection.[38] Skin and lung biopsies have revealed deposition of C5b-9 and C4d along with thrombogenic vasculopathy. This was also accompanied by generalized activation of both lectin and alternative complement pathways, proposing thrombotic microvascular injuries involving skin, lungs, and possibly other organs in critically ill patients.[37] The vascular injury has been confirmed on histopathological examination, and it revealed dermal edema, fibrinoid necrosis, microvascular thrombosis, leukocytoclasia, infiltration of inflammatory cells such as polymorphs and lymphocytes, erythrocyte extravasation, and complement deposition in the vessel walls of skin, heart, kidneys, and lungs.[39] Another hypothesis is that the innate immune system is responsible through an early interferon type I-mediated response of the host, which relates to early SARS-CoV-2 replication and results in peripheral microangiopathy manifesting as in chilblain-like lesions.[40] Etiopathogenesis of numerous skin manifestations has been summarized in [Table 2].{Table 2}

The overall prognosis varies depending upon the severity and the morphology. Patients with pseudo-pernio-like lesions experienced a mild disease and those with morphologies following the vascular occlusion (e.g., lived oreticularis and purpura) experienced severe disease with a higher risk of intensive care admission and mortality (10%). The patients with other morphologies showed an intermediate disease severity. Hence, it becomes our priority to look for such cutaneous signs in all admitted COVID patients, because the lesions may serve as markers of impending deterioration of the patients.[41]

Drug-Induced Cutaneous Manifestations

Cutaneous drug reactions can be observed in the form of urticarial rash, maculopapular exanthema, severe cutaneous adverse drug reaction (SCAR), or drug-induced vasculitis.

The pathomechanism behind urticarial rashes includes mast cell activation, immune complex deposition, and complement activation.[42] The exanthema may result from cutaneous type IV (T cell-mediated) hypersensitivity reaction with lymphohistiocytic infiltrate or eosinophils.[43] Drug reaction with eosinophilia and systemic symptoms is diagnosed based on clinical symptoms and positive findings in investigations.[44] Various drugs have been implicated to cause cutaneous vasculitis, which is mediated as type III hypersensitivity reactions (immune complex deposits).[45] Finally, the authors recommend caution on using drugs in dermatology that could possibly cause coagulopathy, and should be started after assessing the patient thoroughly.

Hence, COVID-19 skin manifestations could be due to one or a combination of the components mentioned above, i.e., reaction to the virus, drug hypersensitivity reaction, or due to pre-existing immune state of the skin/immune system.


Since skin can help us to know the functioning of various internal organs to some extent, keen observation is required to diagnose cutaneous manifestations for early treatment of COVID. Vascular skin lesions are not seen in all the patients of COVID but these lesions should definitely alarm us to evaluate for coagulation parameters, complement levels, and skin biopsy, especially in critically ill patients. We think that vascular damage is the key pathomechanism of COVID-19 in several vital organs; knowledge about cutaneous manifestations shall definitely help us in early diagnosis and a more rapid therapeutic approach for such similar events in other vital organs.


[Figure 1] has been contributed by Dr Preethi B Nayak and [Figure 2] has been drawn by Mr. Darrel D'souza.

Financial Support and Sponsorship


Conflicts of Interest

There are no conflicts of interest.


1World Health Organisation. WHO Director‐General's Opening Remarks at the Media Briefing on COVID-19–11. Geneva, Switzerland: WHO; 2020. Available from:‐s-opening-remarks-at-the‐media-briefingon-covid-19-11-march-2020. [Last acessed on 2020 Jun 12].
2Vincent JL, Taccone FS. Understanding pathways to death in patients with COVID-19. Lancet Respir Med 2020;8:430-2.
3Fehr AR, Perlman S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol Biol 2015;1282:1-23.
4Alzamora M, Paredes T, Caceres D, Webb C, Valdez L, Mauricio LR. Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol 2020;37:861-5.
5Zhang W, Du RH, Li B, Zheng XS, Yang XL, Hu B, et al. Molecular and serological investigation of 2019-nCoV infected patients: Implication of multiple shedding routes. Emerg Microbes Infect 2020;9:386-9.
6Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect 2020;104:246-51.
7Guo ZD, Wang ZY, Zhang SF, Li X, Li L, Li C, et al. Aerosol and surface distribution of severe acute respiratory syndrome coronavirus 2 in hospital wards, Wuhan, China, 2020. Emerg Infect Dis 2020;26:1583-91.
8Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus—A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-7.
9Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111:2605-10.
10Black JRM, Bailey C, Przewrocka J, Dijkstra KK, Swanton C. COVID-19: The case for health-care worker screening to prevent hospital transmission. Lancet 2020;395:1418-20.
11Prajapat M, Sarma P, Shekhar N, Avti P, Sinha S, Kaur H, et al. Drug targets for corona virus: A systematic review. Indian J Pharmacol 2020;52:56-65.
12Tortorici MA, Veesler D. Structural insights into coronavirus entry. Adv Virus Res 2019;105:93-116.
13de Wilde AH, Snijder EJ, Kikkert M, van Hemert MJ. Host factors in coronavirus replication. Curr Top Microbiol Immunol 2018;419:1-42.
14Sawicki SG, Sawicki DL. Coronavirus transcription: A perspective. Curr Top Microbiol Immunol 2005;287:31-55.
15Hussain S, Pan J, Chen Y, Yang Y, Xu J, Peng Y, et al. Identification of novel subgenomic RNAs and noncanonical transcription initiation signals of severe acute respiratory syndrome coronavirus. J Virol 2005;79:5288-95.
16Perrier A, Bonnin A, Desmarets L, Danneels A, Goffard A, Rouille Y, et al. The C-terminal domain of the MERS coronavirus M protein contains a trans-Golgi network localization signal. J Biol Chem 2019;294:14406-21.
17Weiss SR, Navas-Martin S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 2005;69:635-64.
18Manchanda Y, Das S, De A. Coronavirus disease of 2019 (COVID-19) facts and figures: What every dermatologist should know at this hour of need. Indian J Dermatol 2020;65:251-8.
19Sil A, Das NK, Gangopadhyay DN. Bio-medical research in COVID-19 times. Indian J Dermatol 2020;65:337-40.
20Sarkar R, Nayak PB. Novel corona virus infection: A dermatologist's perspective. Pigment Int 2020;7:5-11.
21Recalcati S. Cutaneous manifestations in COVID-19: A first perspective. J Eur Acad Dermatol Venereol 2020;34:e212-3.
22Mungmungpuntipantip R, Wiwanitkit V. COVID-19 and cutaneous manifestations. J Eur Acad Dermatol Venereol 2020;34:e246.
23Cabrera-Hernández R, Solano-Solares E, Chica-Guzmán V, Fernández-Guarino M, Fernández-Nieto D, Ortega-Quijano D, et al. SARS-CoV-2, skin lesions and the need of a multidisciplinary approach. J Eur Acad Dermatol Venereol 2020;34:e659-62.
24Galván Casas C, Català A, Carretero Hernández G, Rodríguez-Jiménez P, Fernández-Nieto D, Rodríguez-Villa Lario A, et al. Classification of the cutaneous manifestations of COVID-19: A rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol 2020;183:71-7.
25Drago F, Ciccarese G, Rebora A, Muzic SI, Parodi A. Sars-CoV-2 infection: The same virus can cause different cutaneous manifestations. Br J Dermatol 2020;183:788.
26Rongioletti F, Ferreli C, Sena P, Caputo V, Atzori L. Clinicopathologic correlations of COVID-19-related cutaneous manifestations with special emphasis on histopathologic patterns. Clin Dermatol 2021;39:149-62.
27Sadeghzadeh-Bazargan A, Rezai M, Nobari NN, Mozafarpoor S, Goodarzi A. Skin manifestations as potential symptoms of diffuse vascular injury in critical COVID-19 patients. J Cutan Pathol 2021. doi: 10.1111/cup. 14059.
28Criado PR, Pagliari C, Carneiro FRO, Quaresma JAS. Lessons from dermatology about inflammatory responses in Covid-19. Rev Med Virol 2020;30:e2130.
29Shaigany S, Gnirke M, Guttmann A. An adult with Kawasaki-like multisystem inflammatory syndrome associated with COVID-19. Lancet 2020;396 e8-10.
30Zhang Y, Cao W, Xiao M, Li Y, Yang Y, Zhao  J, et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi 2020;41:302-7.
31Bolognia JL, Schaffer JV, Cerroni L. Dermatology. 4th ed. China: Elsevier; 2018.
32Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med 2020;382:e38.
33Sharlala H, Adebajo A. Virus-induced vasculitis. Cur Rheumatol Rep 2008;10:449-52.
34Jose RJ, Manuel A. COVID-19 cytokine storm: The interplay between inflammation and coagulation. Lancet Raspir Med 2020;8:e46-7.
35Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult in patients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.
36Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.
37Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res 2020;220:1-13.
38Elmas ÖF, Demirbaş A, Özyurt K, Atasoy M, Türsen Ü. Cutaneous manifestations of COVID-19: A review of the published literature. Dermatol Ther 2020;33:e13696.
39Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yu SC, et al. [A pathological report of three COVID-19 cases by minimally invasive autopsies]. Zhonghua Bing Li Xue Za Zhi 2020;49:411-7.
40Umapathi T, Kor AC, Venketasubramanian N, Lim CC, Pang BC, Yeo TT, et al. Large artery ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol 2004;251:1227-31.
41Jagadeesan S, Sarkar R. COVID-19 and the dermatologist: Finding calm in the chaos. Pigment Int 2020;7:1-4.
42Shipley D, Ormerod AD. Drug-induced urticaria. Recognition and treatment. Am J Clin Dermatol 2001;2:151-8.
43Rosell-Díaz AM, Mateos-Mayo A, Nieto-Benito LM, Balaguer-Franch I, Hernández de la Torre-Ruiz E, Lainez-Nuez A, et al. Exanthema and eosinophilia in Covid-19 patients: Has viral infection a role in drug induced exanthemas? J Eur Acad Dermatol Venereol 2020;34:e561-3.
44Martínez-Cabriales SA, Rodríguez-Bolaños F, Shear NH. Drug reaction with eosinophilia and systemic symptoms (DRESS): How far have we come? Am J Clin Dermatol 2019;20:217-36.
45Belizna CC, Hamidou MA, Levesque H, Guillevin L, Shoenfeld Y. Infection and vasculitis. Rheumatology (Oxford) 2009;48:475-82.