Cutaneous Manifestations Related to COVID-19 Immune Dysregulation in the Pediatric Age Group

Abstract

Purpose of review: At the juncture of the COVID-19 pandemic, the world is currently in an early phase of collecting clinical data and reports of its skin manifestations, and its pathophysiology is still highly conjectural. We reviewed cutaneous manifestations associated with COVID-19 in the pediatric age group.

Recent findings: Children infected by SARS-CoV-2 usually develop milder respiratory symptoms, but cutaneous manifestations seem a little more prevalent than in adults. These skin features of infection by the coronavirus can be similar to those produced by other common viruses, but there are also reports of cases with more heterogeneous clinical pictures, which have made their classification difficult. To date, the more frequently reported skin variants featured in pediatric cases are purpuric (pseudo-chilblain, necrotic-acral ischemia, hemorrhagic macules, and/or cutaneous necrosis), morbilliform/maculopapular, erythema multiforme, urticarial, vesicular, Kawasaki-like, and miscellaneous (highly variable in both frequency and severity). Their pathophysiological mechanism is still elusive and is likely to be the result of the complex involvement of one or more mechanisms, like direct virus-induced skin damage, vasculitis-like reactions, and/or indirect injury as a consequence of a systemic inflammatory reaction. In this review, we presented and discussed clinical cases as examples of different cutaneous responses reported in some children with SARS-CoV-2 infection, differential diagnosis considerations, and a preliminary conceptual approach to some of their probable associated pathologic mechanisms.

Keywords: COVID-19, pediatric; Kawasaki-like; Pseudo-chilblain; Purpuric lesion; SARS-COV-2.

Fig 1

Hypothetic pathways involved in SARS-CoV-2 invasion into the host cell. Clathrin dependent, caveola dependent, flotillin dependent, and ACE2/TMPRSS2 dependent. Once the integrity of the cell membrane has been broken, viral RNA forms an endosome into the cell’s cytoplasm and uses the cellular machinery for viral replication and assembly

Fig. 2

On the left-hand side, a schematic representation of the SARS-CoV-2 virus spike protein bound to the host cell (epidermis) via ACE2 and TMPRSS2. The spike protein contains two subunits, S1 and S2, containing the receptor-binding domain (RBD). The RBD is part of the S1 subunit, and the S2 subunit is for membrane fusion. The serine protease TMPRSS2 cleaves the spike glycoprotein between S1 and S2, which helps the virus to integrate into the cell membrane and allow it to enter the host cell. At the molecular level, the binding includes amino acids, hydrogens bonds, and electrostatic and hydrophobic interactions. On the right-hand side, crystallographic image of ACE2 and the spike protein and RBD within the S1 subunit binding to the receptor site of ACE2

Fig. 3

Immune response to SARS-CoV-2. The first barrier to stop viral spreading comes from the innate immune system. A balance is produced between elimination and survival of the virus. The inflammatory response induced by PAMP sensors, among others TLRs, stimulating the production of pro-inflammatory cytokines, some with chemoattractant properties, is fundamental. As such, natural killer cells (NK), macrophages (M), dendritic cells (DC), CD8 T cells, and cytokines like interferons (IFNs), TNFα, monocytic chemoattractant protein 1 (MCP1), and macrophage inflammatory protein (MIP) are part of this first barrier; during this first phase, the virus uses different ways of evasion. The balance between both determines which path shall be followed: the one of viral elimination brought on by a systemic inflammatory response syndrome (SIRS) ending with healing or the one of virus permanence that subsequently produces an over-activated immune response (the so-called immune hyperactivation, or erroneously referred to as the cytokine storm) advancing into a second SIRS, with activation of complement and the coagulation cascade, which, if not stopped, evolves into a multiorgan failure syndrome and death. An opportunistic infection can appear at this stage, activating SIRS with even more fatal consequences. The adaptive immune response is the second barrier and appears later with a powerful humoral and cellular immune response: IgM is the first antibody to appear followed by IgA and IgG. Specific IgG memory can last up to 3 months or more