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Review
. 2020 Sep;30(5):e2130.
doi: 10.1002/rmv.2130. Epub 2020 Jul 12.

Lessons from dermatology about inflammatory responses in Covid-19

Paulo Ricardo Criado  1   2 , Carla Pagliari  3 , Francisca Regina Oliveira Carneiro  4 , Juarez Antonio Simões Quaresma  4
Affiliations
Review

Lessons from dermatology about inflammatory responses in Covid-19

Paulo Ricardo Criado et al. Rev Med Virol. 2020 Sep.

Abstract

The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. 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 infection 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 understood, 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 gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological 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 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 intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.

Keywords: Covid-19; SARS-CoV-2; innate immunity; lipoprotein a; livedoid vasculitis; skin.

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Conflict of interest statement

The authors have no competing interest.

Figures

FIGURE 1
FIGURE 1
Mast cell during degranulation process (anaphylactic type) in intimal contact with dermal dendrocyte. Mast cell resembles a ball in a baseball glove (dermal dendrocyte). Note that membrane flaps of dermal dendrocyte consistently shrouded mast cell membrane for 50% to 90% of their perimeter. This suggests the presence of functional interactions between these cells. Immunoelectron microscopy (ITM) technique (original magnification ×40 000)
FIGURE 2
FIGURE 2
Livedoid vasculopathy. A, Upper left: Livedoid macules on malleolar area of the leg. B, Typical clinical cutaneous lesion of LV demonstrates white scar lesions (Atrophie Blanche), ulcer and residual hyperpigmentation due purpura. B, Upper right: Histopathological exam of the skin biopsy showing thrombosis and fibrin deposition into dermal blood vessels in a patient with LV (Haematoxylin‐Eosin, OM ×100). C, Down left: Immunohistochemistry stain using mouse monoclonal antibody [8F6A9,8H5C5,Abcam] to Lipoprotein a (dilution 1:200), revealed by LAB‐alkaline phosphatase technique (Sigma, St. Louis, Missouri) showing immunostaining in endothelial cells of upper dermal small blood vessels in a patient with LV, confirming the lipoprotein a deposition on cutaneous blood vessels (OM, ×1000). D, Down right: Detail of dermal blood vessels under immunohistochemistry to Lipoprotein(a) (OM, ×1000). LV, livedoid vasculopathy
FIGURE 3
FIGURE 3
This Vein's diagram could explain some of the myriad of factors involved on LV. The majority of the patients have minimal or evident signs and symptoms of venous stasis on lower limbs, which predispose to slower blood flux into venous microcirculation. Risks factors for thrombophilia as inherited and/or acquired hypercoagulability or autoimmunity (antiphospholipid antibodies) may composed the clinical scenario for LV install under certain conditions (genetic background, summer season, winter and cryoglobulins). Lipoprotein a [(Lp(a)] deposited on dermal endothelial vessels and perivascular monocytes, or in the blood circulation may contribute to coagulation and impairment on fibrinolysis in microcirculation and/or microcirculation. Besides of these effects, Lp(a) enhanced the atherosclerosis process in arterial vessels on heart, brain arteries an peripheral artery. Adapted from Criado et al. LV, livedoid vasculopathy
FIGURE 4
FIGURE 4
Lipoprotein(a) structure. A core of LDL coupled with ApoB‐100 particle. This structure is disulphide linked to Apo(a). Apo(a) contains multiple Kringle IV‐like domains (KIV1‐10), one Kringle V domain and a terminal protease‐like domain (P). Negro or Afro‐descendants subjects have two to three times serum levels than other ethnic groups, due to Apo(A) shorter isoforms. In this setting, cardiovascular comorbidities, and risk of fibrinolytic disturbs during Covid‐19 could contribute to morbidity and/or mortality into this ethnical group face to viral infection. LDL, low density lipoprotein
FIGURE 5
FIGURE 5
Clinical outcomes in SARS‐CoV‐2 infected patients/Covid‐19, immune system responses, systemic and possible cutaneous manifestations.① The outcome spectrum is probably related to intrinsic host factors. Other factors are adequate type I IFN response, blood group type, high levels of proteases as plasmin(ogen) in the serum, which may cleave a newly inserted furin site in the S (Spike) protein of SARS‐CoV‐2, extracellularly and increasing its infectivity and virulence. The affinity to human ACE2 receptors and activity of TMPRSS2 protease transmembrane, which may also cleave angiotensin‐converting enzyme 2 (ACE2) for augmented viral entry. The capacity of the virus non‐structural proteins like ORF1ab, ORF7a and ORF8 and surface glycoprotein to bind with the human porphyrin, respectively, while ORF1ab, ORF10 and ORF3a proteins could co‐ordinately attack β1‐heme chain of the human red blood cells contribute to impair the normal oxygen and carbon dioxide changes between pulmonary alveoli and interstitial capillaries, producing hypoxia inducing macrophages responses. ② Most subjects when infected by a down or moderate load of SARS‐CoV‐2 produce an adequate and early synthesis of IFNγ and type I IFNs, their distinct cells of innate and acquired immune system will respond with pro‐inflammatory cytokines and oxidative metabolites causing symptoms and probably an adequate host response to conducted for a favorable clinical outcome. ③ In a selected group of patients, with moderate and severe Covid‐19, some authors proposed that a genetic background in these subjects might determinate one new immune response as ④ ‘second wave’ of cytokines production, the ‘CSS’ in response to the SARS‐CoV‐2 infection, similar to Macrophage Activation Syndrome (MAS‐like/sHLH). The CSS can be the result of rare homozygous genetic defects in perforin pathway proteins, as proposed by Cron and Chatham, due to the similarities with infants with familial HLH. ⑤There is evidence of D‐dimer level elevation in Covid‐19 pneumonia which might represent an extension of this novel virally induced hyper‐inflammatory pulmonary immunopathology to the adjacent microcirculation with extensive secondary fibrinolytic activation. The MAS that supervenes Covid‐19 pneumonia is probably related to ‘virally‐induced immunosuppression or Covid‐19 immunodeficiency status’, by the viral escape of the human immune pathways, playing a key role. ⑥ In this setting of hypercoagulability state and MAS/sLHL‐like milieu several dermatological conditions could be observed. CSS, cytokine storm syndrome; HLH, hemophagocytic lymphohistiocytosis
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