# Inflammation Causes Exacerbation of COVID-19: How about Skin Inflammation?
## 3 Inflammation Exacerbates COVID-19 Infection  
SARS-CoV-2 infection in most patients takes a mild course similarly to common cold, but in certain populations of patients, it takes a radical course, causing severe pneumonia, and sometimes requires ventilators or extracorporeal membrane oxygenation (ECMO). It is believed that this virus in certain population evokes a cytokine storm which cannot be controlled by regular anti-inflammatory medications. This biphasic aspect of COVID-19 has been known since the early stages of the pandemic: the first phase as the viral infection phase and the latter phase as the inflammation (cytokine storm) phase [8; 9] (Figure 1). The treatments targeting these two phases should differ, with antiviral agents such as remdesivir, drugs targeting viral infection, and anti-inflammatory agents such as tocilizumab (anti-IL-6 receptor antibody) and glucocorticoidoids targeting cytokine storm. The clinical course of COVID-19 is divided into three stages. Stage 1 is a viral infection phase with mild common-cold like symptoms. In stage 2, most patients with COVID-19 recover, but a small portion of patients have sustained or even enhanced inflammatory condition and progress into stage 3. In stage 3, various inflammatory cytokines are systemically produced and patients suffer from severe respiratory distress syndrome with cytokine storm. Some patients show coagulopathy. Many epidemiological surveys revealed that patients with diabetes mellitus, high blood pressure, respiratory disease, or obesity have a poorer prognosis compared to those without these conditions [10; 11; 12]. COVID-19 patients with these comorbidities are at a higher risk of developing severer pneumonia with cytokine storm and requiring artificial respirators or ECMO. The reason why the disease exacerbates or becomes severe in certain populations has not been fully elucidated. However, inflammation seems to cause a bad prognosis because these comorbidities share common pathophysiology of low level but a persistent chronic inflammatory state. SARS-CoV-2 enters host cells by biding to its receptor angiotensin converting enzyme ACE2 with spike protein (S). Transmembrane protease, serine (TMPRSS) 2, is one of the proteases which can prime the SARV-CoV and SARS-CoV-2 spike protein capable of binding their receptor ACE2 (Figure 2). The inhibition of this enzyme is one way to inhibit SARS-CoV-2 infection to cells [13]. Upon entering cells, ACE2 is internalized, resulting in reduction in ACE2 expression. ACE2 works competitively with ACE; ACE enhances inflammation as well as increases blood pressure and myocardial contraction while ACE2 has anti-inflammatory properties, suppressing inflammation as well as decreasing blood pressure and myocardial contraction. The ACE2 gene localizes on X chromosomes with a higher expression in females, and a lower severity of ARDS caused by the viral infection in female patients has been known. Massive COVID-19 infection could exacerbate inflammation by reducing the expression level of ACE2 by internalization of this receptor [10; 14]. SARS-CoV-2 and SARS-CoV take another route to infect cells when there are abundant elastases in the surrounding environment: the cell membrane of SARS-CoV-2 fuses with that of the host cell and the viral genome is released into the host cells directly establishing the infection. This type of infection allows SARS-CoV-2 to grow and proliferate more rapidly, which could make its infection severer. Thus, an inflammatory environment, such as chronic occlusive pulmonary disease (COPD) lung with neutrophil infiltration, could be more vulnerable to severe COVID-19 pneumonitis than healthy conditions (Figure 3) [13]. Figure 1: Three stages of COVID-19 infection. Modified from reference [8]. Patients with high blood pressure are always under a higher mechanical stress because their heart and blood vessels endure a higher mechanical force. This kind of situation renders patients' cardiovascular systems vulnerable to tissue damage by inflammation provoked by mechanical force.