key: cord-0780700-qq631ur8
authors: Alharthy, Abdulrahman; Balhamar, Abdullah; Faqihi, Fahad; Nasim, Nasir; Noor, AlFateh; Alqahtani, Saleh A.; Memish, Ziad A.; Karakitsos, Dimitrios
title: COVID-19 presenting as acute abdomen and sepsis: a rare case-report
date: 2020-11-17
journal: New Microbes New Infect
DOI: 10.1016/j.nmni.2020.100818
sha: 4d3a41199b9cd106e4206960fdf593c741439c54
doc_id: 780700
cord_uid: qq631ur8

COVID-19 may present as acute abdomen although the pathophysiology remains obscure. A 45 year-old-man had severe COVID-19 pneumonia with associated pulmonary embolism, and presented with acute abdomen. He underwent emergency laparotomy, and resection of an ischemic area of the jejunum. Postoperatively, he had septic shock, acute-respiratory-distress-syndrome, and acute kidney injury necessitating continuous-renal-replacement-therapy (CRRT). We administered antibiotics and therapeutic anticoagulation along with two sessions of hemoadsorption by CytoSorb® filter, in conjunction to the CRRT. The patient finally survived. Bowel ischemia due to thromboembolic disease should be promptly treated. Extracorporeal blood purification may be useful in managing sepsis in severe COVID-19.

to bowel perforation on the grounds of thromboembolism. The putative role of extracorporeal blood purification therapies in the management of COVID-19 related hyperinflammation, and perioperative sepsis is also discussed.

During the COVID-19 outbreak in Saudi Arabia, a previously healthy 45 year old male of Asian origin was admitted to our emergency department due to recent (six days) onset fever (39 o real-time PCR system (Roche, Basel, Switzerland) [14, 15] . Electrocardiogram, cardiac enzymes, and echocardiography were normal. Baseline laboratory findings showed leukocytosis (20x10 3 white blood cells, normal 4-10x10 3 ) with lymphocytopenia (0.47×10 3 /L, normal: 1.1-3.2 ×10 /L), and increased C-reactive protein (99 mg/liter, normal: 0-7 mg/liter), lactate dehydrogenase (997 units/liter, normal: 100-190 units/liter), lactate (6 mmol/L, normal: 1.0 to 2.5), and D-dimers (4.1 mcg/ml, normal: 0 to 0.5 mcg/ml). Upon admission, his blood urea nitrogen was 6.1 mmol/liter (normal: 2.5-6.4 mmol/liter), and his creatinine was 119 µmol/liter (normal: 71-115 µmol/liter). The rest of his blood count, coagulation profile, and biochemistry J o u r n a l P r e -p r o o f report were within normal limits. Chest computed tomography (CT) scans revealed bilateral peripheral ground-glass opacities with associated infiltrates, and pulmonary embolism (PE) (Fig.1) . Emergency abdominal CT scans depicted thickened bowel wall, and portal vein thrombosis, but no clear picture of intestinal perforation (Fig. 2) . Duplex ultrasonography of the lower limbs excluded deep vein thrombosis.

However, the patient's clinical status did not improve, and thus he underwent emergency exploratory laparotomy. Intraoperatively, contained small intestinal perforation with associated peritonitis was found; hence resection of an ischemic area of the jejunum was performed without any complications. Histopathology examination (hematoxylin-eosin stain) of a resected small intestinal specimen revealed epithelial necrosis with hemorrhagic infarction changes, and neutrophilic inflammation with fibrin deposition within the lamina propria.

Postoperatively, the patient was admitted to our level III COVID-19 designated intensive care unit (ICU). Upon ICU admission, we administered empiric therapy with ribavirin (400 mg tablet every 12 hours), adjusted to renal function meropenem (0.5 g intravenously every 12 hours) and vancomycin (15 mg/kg intravenously loading dose), therapeutic anticoagulation with enoxaparin 75 mg subcutaneously once daily (dosing adjusted to his body weight and renal function, see below), ARDS-net ventilation (positive end-expiratory pressure of 9 cm H 2 0), administration of hydrocortisone and vasopressors, and supportive ICU care [16] . The patient developed acute kidney injury (AKI) according to the the "risk," "injury," and "failure" (RIFLE) criteria [17] . His blood urea nitrogen was 7.9 mmol/liter (normal: 2.5-6.4 mmol/liter), and creatinine was 309 µmol/liter (normal: 71-115 µmol/liter).

We speculated that the development of AKI was partially due to severe COVID-19, and the perioperative septic shock as well as the CT scans with contrast that were performed upon J o u r n a l P r e -p r o o f admission. The patient developed mild metabolic acidosis and hyperkalemia; while he remained anuric and in a shock state necessitating the administration of vasopressors (day-1 post-ICU admission). We applied promptly continuous renal replacement therapy (CRRT) as per Kidney Disease Improving Global Outcomes (KDIGO) 2019 guidelines [18] . Two sessions of CRRT were administered for two consecutive days (24 hours/day). In addition, we performed extracorporeal blood purification therapy by means of the CytoSorb ® filter (CytoSorbents Europe GmbH, Berlin, Germany) connected to the CRRT device due to persistent sepsis and to mitigate the ensuing MSOF [19] [20] [21] [22] . CytoSorb ® was used according to the manufacturer guidelines [23] . Briefly, the filter was connected post-hemofilter via a close loop circuit to the CRRT pump (Prismaflex, Baxter Deutschland, Unterschleißheim, Germany) with an optimal ultrafiltration rate of 250-400 mL/min. The filter was changed after 24 h of each use.

Fortunately, the patient had no severe coagulopathy, and transfusion was deemed necessary only once with two packs of red blood cells, while he was on CRRT (day-1). Following two sessions of CRRT with CytoSorb ® , we were able to initiate diuresis and wean off vasopressors (day-3). The patient's lactate level and all inflammatory biomarkers were normalized, and CRRT was discontinued three days post-ICU admission. No bleeding episodes were observed although he received full anticoagulation therapy due to venous thromboembolism. His oxygenation progressively improved as the PaO 2 /FiO 2 ratio exceeded 300 on day-6. The patient was extubated on day-7 post-ICU admission. His renal function was normalized approximately two weeks post-ICU admission. We administered broad spectrum antibiotics for a total of two weeks and therapeutic anticoagulation with low-molecular-weight heparin for a month. His RT-PCR for COVID-19 was negative on day-19. The work-up for autoimmune disorders included lupus anticoagulant, antiphospholipid antibodies (anticardiolipin, anti-β2-glycoprotein I antibodies), J o u r n a l P r e -p r o o f antineutrophil cytoplasmic antibodies, and thrombophilia screening (i.e., levels of proteins C and S, homocysteine, factor V Leiden), and did not reveal any abnormalities. All follow-up blood, urine, and sputum cultures for common bacteria were negative approximately 24 days after ICU admission. The patient was discharged in a good clinical condition 34 days post-ICU admission.

Oral rivaroxaban was prescribed for another two months [24, 25] , and the patient is followed-up by a multidisciplinary physician's group including our outreach team.

An increased prevalence of thromboembolic disease in critically ill patients with COVID-19 affecting their morbidity and mortality was previously reported [26, 27] . The administration of prophylactic anticoagulation in mechanically ventilated patients with severe COVID-19 is mandatory [28] [29] [30] [31] [32] . The administration of enhanced prophylactic anticoagulation and/or therapeutic anticoagulation in critically ill COVID-19 patients should outweigh the risks of bleeding complications [32] . Our COVID-19 patient with venous thromboembolic disease had increased levels of D-dimer but no risk factors for developing thromboembolism (Padua prediction score < 4). His refractory ARDS could be attributed to a "dual hit" pathology of severe lung parenchymal inflammation and the presence of PE due to COVID-19 [33] as well as the progressive development of abdominal sepsis.

In this case-report, COVID-19 presented as septic shock and acute abdomen due to contained small bowel perforation on the grounds of thromboembolic disease. Scarce data exist about the presentation of COVID-19 as an acute abdomen; while in most reported cases no definitive underlying pathology was documented [6] [7] [8] [10] [11] [12] . In other studies, the underlying mechanism was not attributed to bowel pathology, but rather to extra-intestinal causes such as pancreatitis or cholecystitis [9, 34] . However, bowel ischemia due to arterial thromboembolism was recently J o u r n a l P r e -p r o o f described in patients with severe COVID-19 [35, 36] . Hence, the presentation of COVID-19 as an acute abdomen cannot be underestimated, and should be promptly diagnosed irrespective of the work-up challenges [10] [11] [12] . In our patient, although imaging studies were inconclusive the clinical picture was indicative of a surgical emergency, which was thereafter confirmed intraoperatively. Prompt surgical intervention was a vital management step despite the fact that the application of strict insulation measures for COVID-19 patients, intraoperatively, is a challenging process [13] . Postoperatively, the patient developed AKI necessitating CRRT due to sepsis and ensuing MSOF. Extracorporeal hemoadsorption by means of CytoSorb ® filter was used to complement CRRT. This combination therapy aimed on restoring patient's homeostasis and counteracting sepsis. Extracorporeal blood purification therapies using a variety of cartridges for septic patients were previously reported with variable results [20] [21] [22] . In our case, following two sessions of CRRT with CytoSorb ® filter, inflammatory biomarkers and lactate levels were normalized. Moreover, renal function was restored and oxygenation gradually improved.

Notwithstanding, the prompt surgical intervention, and the rest of the administered empiric treatment including antibiotics, anticoagulation therapy, and ICU supportive care could have also contributed to the patient's clinical recovery. However, given the severity of his clinical picture, we speculate that the prompt application of CRRT with hemoadsorption might have helped.

Presumably, the early application of hemoadsorption mitigated a full blown picture of COVID-19 related hyperinflammation and/or the development of refractory septic shock. The patient had an uneventful recovery without any bleeding episodes despite full anticoagulation therapy, and was finally discharged from the hospital. However, the patient's long-term rehabilitation challenges, and his pulmonary function after COVID-19 pneumonia with associated PE remain to be further elucidated.

Our patient had typical features of COVID-19 along with severe gastrointestinal manifestations.

Also, he had thromboembolic disease and a laboratory profile, which was characterized by increased inflammatory biomarkers and D-dimers. Hypercoagulability, vascular dysfunction, and cytokine storm may be the underlying mechanisms enabling the development of thromboembolic disease in severe COVID-19. No clear evidence of diffuse intravascular coagulation was observed in this case, which presumably reflects to versatile underlying pathophysiology in the development of thromboinflammation in COVID-19 [3] [4] [5] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] . SARS-CoV-2 can bind to the ACE-2 receptor, and by gaining direct cell entry may promote endotheliiitis [4, 27, 33, [37] [38] [39] , which can be further exacerbated by dysregulated responses of the renin-angiotensin-aldosterone and immune systems [4, [37] [38] [39] . The detrimental effects of thromboembolic disease on survival in severe COVID-19 were previously documented by clinical and histopathology studies [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [39] [40] [41] [42] [43] . Also, following hospital discharge, some COVID-19 patients may require additional prophylaxis for venous thromboembolism. Our critically ill patient with severe thromboembolic disease was mechanically ventilated and hospitalized for prolonged time; hence rivaroxaban was prescribed on hospital discharge as outpatient venous thromboembolism prophylaxis [24, 25, 43] . Moreover, we should consider the fact that the natural course of SARS-CoV-2 viremia, and host's natural immunity remain obscure; while, reinfections and/or recurrently positive RT-PCR results were reported [44] [45] [46] [47] [48] .

Albeit the inherent limitations of this case-report that prevent its generalizability, we documented that COVID-19 can present with severe gastrointestinal manifestations, which could be further linked to underlying thromboinflammation. Further study of such cases may enable us in tailoring cost-effective diagnostic and therapeutic strategies for the management of COVID-19 patients that present with an acute abdomen. Apart from extra-intestinal causes, bowel ischemia due to venous and/or arterial thromboembolic disease should be promptly diagnosed and treated.

The application of CRRT and extracorporeal blood purification techniques could be a useful tool in the management of perioperative sepsis, AKI, and cytokine storm, which are all poor prognostic factors in critically ill patients with COVID-19. Future larger prospective studies are needed to confirm or refute the present findings. 

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We acknowledge all health-care workers involved in the diagnosis and treatment of COVID-19 patients in Riyadh, Saudi Arabia.