The COVID-19 pandemic is a continuous challenge of medical systems world-wide but it has also proven an opportunity for scientific research, particularly in the field of immunology, as understanding the systemic inflammatory response is critical for the diagnosis and proper management of this altogether systemic infection  . Apart from the intrinsic morbidity and mortality, COVID-19 has negatively impacted the prognosis of patients with chronic diseases, such as HCV chronic infection .
There are biological and clinical similarities between HCV and COVID-19. Most of the current information comes from extrapolation of the results obtained in studying the SARS-CoV and the MERS pandemic . Important similarities are the induction of channelopathies as a pathologic mechanism, the involvement of T helper lymphocytes (in the carcinogenesis of HCV and in the cytokine dysregulation associated to the early stage of SARS-CoV infection) and the response to interferon therapy. From a clinical point of view, both viruses trigger inflammatory responses in multiple organs, leading to systemic disease by direct or indirect mechanisms. It is well known that HCV infection causes multiple extrahepatic manifestations  and HCV cure is associated with a favorable outcome of the liver disease and also on HCV- induced comorbidities, such as cryoglobulinemia and lymphoma .
Symptoms of HCV chronic infection are non-specific, regardless of the stage of liver disease, with a recent study pointing to 40-50% of patients with gastro-intestinal complaints . A recent review, including a total of over 18,000 patients, found that COVID-19 frequently manifests with digestive symptoms (11.5% of patients and as many as 30% in some studies), the most common symptoms being diarrhea (11.5%), nausea and vomiting (6.3%) and abdominal pain (2.3%); cases of intestinal bleeding were also reported . In our study, we found a higher prevalence of overall gastro-intestinal symptoms (36%) as well as diarrhea (32%), nausea (24%) and abdominal pain (28%). None of the patients in our study group presented intestinal bleeding. The higher prevalence of gastrointestinal symptoms can be explained by the selective addressability of patients; as our Clinic focuses primarily on gastroenterology and hepatology, patients with digestive symptoms are more likely to appeal to us. We did not include ageusia and anosmia as gastrointestinal symptoms of COVID-19 as these are more likely to be receptor and neuronal dysfunctions [32, 33].
Inflammation is a key factor in both HCV and COVID-19 infection. HCV infection promotes a chronic inflammatory process in the liver, involving IL-1 β production and secretion by liver macrophages, increased production of TNF -α and activation of Toll-like receptors . In addition, chronic HCV infection is associated with intestinal bacterial overgrowth, leading to endotoxemia, liver and systemic inflammation . This is one possible explanatory mechanism for the increased concentration of serum and fecal calprotectin in patients with active infection, compared to those with cured infection, as described in our study. Furthermore, the exclusion of patients with advanced liver disease (compensated or decompensated cirrhosis) means that there is significant inflammation due to the infection per se and not due to the degree of liver fibrosis. Inflammation in HCV infection is maintained by a vicious circle, as HCV is an inductor of liver steatosis (which induces oxidative stress and the activation of stellate cells  and insulin resistance and diabetes mellitus (via TNF- α pathways ). This may contribute to the pro-inflammatory state that is the HCV chronic infection and may explain our findings of increases CRP and ferritin levels in patients without other causes of systemic inflammation. Studies have found that increased ferritin levels in chronic HCV hepatitis are associated with insulin resistance  and diabetes . On the other hand, it has been shown that ferritin levels decrease at 24 weeks after HCV cure by direct acting antiviral therapy .
COVID-19 affects the digestive system directly, by infecting the gastro-intestinal cells via ACE2 receptors (100 fold more frequent in the small intestine and the colon than in the lungs) and indirectly, by triggering a systemic inflammatory response, a “cytokine storm”, leading to multiple organ dysfunction, including the digestive tract . The presence of ACE2 receptors in the absorptive enterocytes and consecutive COVID-19 infection may explain the presence of diarrhea as a common symptom of infection . In our study, 32% of COVID-19 patients presented diarrhea, and this was the most frequent gastrointestinal symptom. Furthermore, COVID-19 may reduce the absorption of tryptophan at an enteric level, inducing intestinal inflammation and colitis . Intestinal dysbiosis, with decreased concentration of Lactobacillus and Bifidobacterium species may also explain the digestive symptoms associated with COVID-19 . Inflammatory markers are essential in establishing the severity of COVID-19 infection as well as prognosis and management . Elevate CRP levels are associated with increased disease severity, but not increased mortality, as opposed to high levels of ferritin, which mark a poor prognosis. However, cutoff values differ significantly between studies (from 3mg/L to over 100mg/L for CRP). The role and importance of ferritin in COVID-19 infection is still under debate. It appears to be related to the development of secondary hemophagocytic lymphohystiocytosis leading to multiple organ dysfunction . In our study, we found significantly higher levels of CRP and ferritin in COVID-19 patients, compared to HCV infected patients and to the control group. Despite this, none of the patients presented a poor outcome or intensive care requirements. The use of calprotectin as a marker for inflammatory bowel disease has known a setback since the beginning of the COVID-19 outbreak, as many studies have associated increased concentrations of fecal calprotectin to the presence and severity to the COVID-19 digestive symptoms . The evolution of fecal calprotectin in COVID-19 infected patients with inflammatory bowel diseases needs to be further investigated. In our study, we have shown that both fecal and serum calprotectin have increased concentrations during COVID-19 infection, and these concentrations correlate with the severity of digestive symptoms.