**4. Results**

From the 25 original patients, 21 (84%) showed increased FC, with median values of 116 (87.5; 243.5) mg/kg despite being asymptomatic for GI symptoms, and a median D-Dimer of 1.32 (0.82; 2) mg/<sup>L</sup> (normal value < 0.5 mg/L). Their clinical characteristics, possible risk factors, and biochemical parameters are reported in Table 1. We did not detect any significant correlation between FC and the C reactive protein (CRP), white blood cell count (WBC), platelet count, ferritin, lactate dehydrogenase (LDH) or albumin. However, we found a strong positive correlation between FC and D-Dimer (r = 0.745, *p* < 0.0001).


**Table 1.** Patients' Characteristics and Laboratory Parameters. Continuous Variables are Reported as the Median (Quartile1; Quartile3). CRP: C Reactive Protein; LDH: Lactate Dehydrogenase.

### *4.1. Intestinal Perforation*

Two of the enrolled patients developed intestinal perforation. They were admitted to the emergency department for high-grade fever, cough and dyspnea. Both resulted positive to SARS-CoV-2 in nasopharyngeal swabs, and according to their comorbidities, they were admitted to the hospital.

The first patient, a 68-year-old female with an FC of 216 mg/kg, WBC of 17,940 cells/mm3, CRP of 94 mg/<sup>L</sup> and D-Dimer of 1.28 mg/LFEU developed severe abdominal pain 20 days after hospital admission. The contrast-enhanced abdominal computed tomography (CT) showed rectal wall and sigmoid colon thickening surrounded by extraluminal free air; a small-sized fluid collection and a smoothly thickened peritoneum were noted. The patient was treated conservatively.

The second patient, an 84-year-old female with an FC of 290 mg/kg, WBC of 5990 cells/mm3, CRP of 290 mg/dL and D-Dimer of 2.1 mg/LFEU developed severe abdominal pain the day after admission and septic shock. The contrast-enhanced abdominal CT showed rectal wall thickening, with free air organized circumferentially around the mesorectum, suggestive for retroperitoneal perforation; an inflammatory stranding of perivisceral fat tissue was also identified. The patient died the next day.

#### *4.2. A Hypothesis on the Role of Thrombosis*

In contrast to E ffenberger et al. [5], we detected an increase in FC concentration in 88.2% of patients without GI symptoms. Besides, our findings also represent the first report of a significant positive correlation between FC and D-Dimer. This particular discovery may change our current understanding of COVID-19 intestinal-disease pathogenesis, shedding new light on the potential role of thrombosis and the consequent hypoxic intestinal damage. Indeed, FC is mainly expressed by neutrophils [11], whose functions are severely a ffected by intestinal ischemia [12]. The two patients that developed bowel perforation showed on the CT rectal and sigmoid colon wall thickening. In non-COVID-19 patients, left flexure and sigmoid colon segments have the highest risk of ischemic colitis, while distal rectum is usually spared due to its dual blood supply; at variance, in COVID-19 patients colon/rectal

thickening was previously reported in seven cases [13] in agreemen<sup>t</sup> with our data, supporting a relationship between intestinal damage and COVID-19 infection. Notably, D-Dimer was found to increase in up to 47% of patients with COVID-19 at hospital admission [14], which resulted in higher mortality rates despite not presenting pulmonary embolism or deep vein thrombosis. Was the gu<sup>t</sup> being responsible for these patients' death? Unfortunately, this question has no definitive answer, but according to a recent study, bowel abnormalities were a common finding (31%) during abdominal imaging of individuals with COVID-19. Patients who underwent laparotomy often showed histological ischemia due to small vessel thrombosis [13].

That being said, our data should be taken with caution due to the relatively small sample size and the possible limitations related to selection bias. While waiting for the additional validation, and data on gu<sup>t</sup> histopathology (autoptic reports or in vivo endoscopic biopsies) in COVID-19 patients, we firmly believe that the correlation between FC and D-Dimer may yield the secrets behind the COVID-19 Pandora's box.

**Author Contributions:** S.D.B., G.S., V.Z., M.C., A.A.O., A.P., A.C., F.M., R.L. and L.S.C. wrote the manuscript. M.G., S.D.B., V.Z., F.C., R.L., M.C., A.A.O. and L.S.C. were involved in patient care and contributed to the preparation of the manuscript. G.S., V.Z., A.P. and A.C., given their expertise in the field, were involved in the discussion of the gu<sup>t</sup> damage etiology. All authors have read and agreed to the published version of the manuscript.

**Funding:** The authors did not receive funding for the current work.

**Conflicts of Interest:** The authors declare no conflict of interest.

**Ethics Approval:** The study protocol was approved by the institutional ethics commission (Comitato Etico Unico Regionale, CEUR) with the following number 2020-OS-072.
