Received: 2 May 2020 Revised: 14 May 2020 Accepted: 15 May 2020 DOI: 10.1002/rmv.2130 REVIEW Lessons from dermatology about inflammatory responses in Covid-19 Paulo Ricardo Criado1,2 | Carla Pagliari3 | Francisca Regina Oliveira Carneiro4 | Juarez Antonio Simões Quaresma4 1Dermatology Department, Centro Universitário Saúde ABC, Santo André, Brazil 2Dermatology Department, Faculdade de Medicina, Centro Universitário Saúde ABC, Santo André, Brazil 3Pathology Department, Faculdade de Medicina, Universidade de S~ao Paulo, S~ao Paulo, Brazil 4Center of Biological and Health Sciences, State University of Pará, Belém, Brazil Correspondence Professor Paulo Ricardo Criado MD, PhD, Summary Dermatology Department, Centro The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural pro- Universitário Saúde ABC, Rua Carneiro Leao~ 33 Vila Scarpelli, Santo André, SP 09050-430, teins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the Brazil. property to block host innate immune response and to promote cytokine expression. Email: [email protected] NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infec- tion are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully under- stood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointes- tinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a ‘cytokine storm’. These systemic conditions share poly- morphous cutaneous lesions where innate immune system is involved in the histo- pathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive- C-protein and serum A amyloid. It is described that several polymorphous cutaneous Abbreviations: AB, atrophie blanche; ACE, angiotensin-converting enzyme; aCL, anticardiolipin; AD, atopic dermatitis; Ang, angiotensin; AOSD, adult-onset Still disease; APC, activated protein C; aPL, antiphospholipid; aPTT, activated partial thromboplastin time; ARDS, acute respiratory distress syndrome; ARE, androgen receptor elements; AT1R, angiotensin type 1 receptor; CAPS, catastrophic antiphospholipid syndrome; CAPS, cryopyrin-associated autoinflammatory syndrome; CoV, coronavirus; Covid-19, coronavirus disease-19; CSVV, cutaneous small vessel vasculitis; CWA, clot waveform analysis; DAD, diffuse alveolar damage; DIC, disseminated intravascular coagulation; GCSF, granulocyte colony-stimulating factor; GPI, glycoprotein I; GTPase, guanosine triphosphatase; HAPE, high altitude pulmonary edema; HAT, human airway trypsin-like protease; HLH, hemophagocytic lymphohistiocytosis syndrome; HRV, human rhinovirus; ICU, intensive care unit; IFN, interferon; IHC, immunohistochemistry; IL, interleukin; IP, interferon-inducible protein 10; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; LMWH, low molecular weight heparin; Lp, lipoprotein; LV, livedoid vasculopathy; MAS, macrophage activation syndrome; MASR, macrophage activation syndrome receptor; MCP, monocyte chemoattractant protein; MERS, middle east respiratory syndrome; MIP1A, macrophage inflammatory protein 1a; MMP, metalloproteinase; NLRP3, NOD-,LRR and pyrin domain-containing 3; NO, nitric oxide; NSP, non- structural proteins; PAI-1, plasminogen activator inhibitor-1; PAP, plasmin-α 2-antiplasmin; PAR2, protease-activated receptor 2; PCR, reactive-C protein; pDC, plasmacytoid dendritic cell; PPE, personal protective equipment; protein S, protein spike; RAS, renin-angiotensin system; RNA, ribonucleic acid; ROS, reactive oxygen species; SAA, serum A amyloid; SARS, severe acute respiratory syndrome; SARS-CoV, severe acute respiratory syndrome-coronavirus; SAVI, STING-associated vasculopathy with onset in infancy; SIC, sepsis-induced coagulopathy; SID, systemic immune-mediated disease; SLE, systemic erythematous lupus; TLR, toll-like receptor; TMPRSS2, transmembrane protease, serine 2; TNFα, tumour necrosis factor alpha; TTPS, transmembrane serine protease; UFH, unfractionated heparin; ULN, upper limit of normal; VARI, viral acute respiratory infections; VEGF, vascular endothelial growth factor; VWF, von Willebrand factor. ‘Nothing is lost, nothing is created, everything is transformed’(Antoine Laurent de Lavoisier). Rev Med Virol. 2020;e2130. wileyonlinelibrary.com/journal/rmv © 2020 John Wiley & Sons, Ltd 1of18 https://doi.org/10.1002/rmv.2130 2of18 CRIADO ET AL. lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related inter- triginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects. KEYWORDS Covid-19, innate immunity, lipoprotein a, livedoid vasculitis, SARS-CoV-2, skin 1 | INTRODUCTION We would like to highlight some interesting aspects of SARS- CoV-2 infections for allergists and dermatologists and their possible Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a relation with the skin: new worldwide public health crisis, that rapidly spread from its origin in Wuhan City of Hubei Province of China, on December 2019 to the 1 The SARS-CoV-2 is composed of 16 non-structural proteins (NSP rest of the world.1 At the time of writing, 13 May 2020, the Coronavi- 1-16) with specific roles in the replication of coronaviruses rus Resource Center of Johns Hopkins University (United States) (CoVs).21 NSP3 prevents host innate immune response and pro- reported 4 327 288 coronavirus disease 2019 (Covid-19) cases motes cytokine expression, NSP5 can inhibit interferon (IFN) signal- around the world, with deaths, in 188 countries/regions.2 ling and NSP16 prevents MDA5 recognition, depressing innate Up to now, cutaneous manifestations of Covid-19 reports publi- immunity.21 Four proteins are structural and essential for viral shed in periodicals indexed in PubMed using the terms ‘cutaneous’ or assembly and infection: homotrimers of S proteins (spikes on the ‘skin’ refer to economic impact, protective measures for the integu- viral surface), M protein (three transmembrane domains), E protein mentary system during Covid-19 exposure, dermatological medical (involved in viral pathogenesis) and N protein.22 education and care during this pandemic disease, the use of 2 Aerosolized uptake of SARS-CoV-2 leads to infection of target cells immunomodulators,1 immunosuppressors and immunobiological expressing angiotensin-converting enzyme (ACE) type II (ACE2) agents in dermatology in rheumatology skin conditions, and skin dam- such as alveolar type 2 (that produce lung surfactant) or other age among healthcare workers during the pandemic.3-19 unknown target cells.23 3 Dendritic cells, monocytes, and macrophages are the first line cell lineage against viral infections. Antiviral proteins that are at the 2 | WHAT WAS REPORTED ABOUT front lines of immune defence are the main targets of virus- CUTANEOUS LESIONS IN COVID-19 encoded antagonists. Protein suppressors, or others involved in up- PATIENTS UP TO NOW? regulation of the innate response, restore the antiviral response and provide an advantage to the host immune defence against a Some authors described cutaneous lesions under distinct dermatologi- specific viral infection.24 cal terms: (a) erythematous rash,3 widespread urticaria, chickenpox- 4 Immunopathogenesis is associated with an uncontrolled immune vesicles; (b) ‘mottling’4; (c) pneumonia with urticaria and pneumonia response, which may result in pulmonary tissue damage, functional with AD,5 and (d) acro-ischemia on finger/toe with cyanosis, and dry impairment and reduced lung capacity. Chemotactic factors are gangrene in seven patients, four of them diagnosed as disseminated essential to the immune responses in viral infections and spectral intravascular coagulation (DIC),6 besides other two reports, in China changes in such factors may lead to severely maladjusted immune and Italy resembling acral characteristics of DIC, and severe perniosis responses, increased viral replication and tissue damage.25 In a sub- (acute across-ischemia in the child), respectively.7,8 set of patients, the disease can progress to pneumonia, respiratory Probably due to the lack of adequate personal protective equip- failure and death related to an extreme rise in inflammatory cyto- ment (PPE) for frontline health care workers, dermatologists have not kines including interleukin (IL)2, IL6, IL7, IL10, GCSF, IP10, MCP1, registered adequately the cutaneous findings in Covid-19 patients.20 MIPI A and TNFα.1 The increase in pro-inflammatory cytokines is Viral infections can produce specific clinical and non-specific manifes- associated with severe pneumonia and it can have deleterious tations, due to the direct action in infected cells or as a phenomenon effects on the adaptative immune system.26,27 In a subset of of immune system hyperactivity.