key: cord-355560-vsxe97xs authors: Alves, Amanda Mandarino; Yvamoto, Erika Yuki; Marzinotto, Maira Andrade Nacimbem; Teixeira, Ana Cristina de Sá; Carrilho, Flair José title: SARS-CoV-2 leading to Acute Pancreatitis: an unusual presentation date: 2020-09-15 journal: Braz J Infect Dis DOI: 10.1016/j.bjid.2020.08.011 sha: doc_id: 355560 cord_uid: vsxe97xs During SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) pandemic, the etiologic agent of COVID-19, several studies described the involvement of other tissues besides the respiratory tract, such as the gastrointestinal tract. Angiotensin-converting enzyme-2, the functional virus host cell receptor expressed by organs and tissues, seems to have an important role in the pathophysiology and presentation of this disease. In pancreas, this receptor is expressed in both exocrine glands and islets, being a potential target for the virus and subsequent pancreatic injury. There are few articles reporting pancreatic injury in COVID-19 patients but most of them do not report acute pancreatitis. Diagnosing acute pancreatitis secondary to SARS-CoV-2 infection is challenging due to the need to rule out other etiologies as well the notable heterogeneous presentations. Herein we report the case of a patient with COVID-19 who developed severe acute pancreatitis. SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), the etiologic agent of COVID-19 pandemic, has spread rapidly worldwide since December 2019. Despite the infection primarily affecting the respiratory tract, gastrointestinal involvement has been reported in an increasing number of patients, with symptoms such as nausea, vomiting, diarrhea, abdominal pain and gastrointestinal bleeding [1] . Laboratory abnormalities such as hepatic and pancreatic J o u r n a l P r e -p r o o f injury have been evident in a subset of patients, although it remains unclear if these abnormalities have any impact on prognosis [2, 3] . The more common causes of acute pancreatitis are gallstones and alcohol abuse, however viral-induced acute pancreatitis has also been described [4] . Angiotensin-converting enzyme-2 (ACE2), the functional virus host cell receptor, expressed in both exocrine and endocrine pancreatic cells, plays a role in this disease process. The mechanisms of pancreatic injury in SARS-CoV-2 infection include direct cytopathic effects or indirect systemic inflammatory and immune-mediated cellular responses, resulting in organ damage or secondary enzyme abnormalities [1] . This case report describes a patient with COVID-19 that developed severe acute pancreatitis. A 56-year old female presented at the emergency department with dry cough, dyspnea, general malaise and epigastric pain which had persisted for a couple of days. Comorbidities included only hypertension treated with losartan and hydrochlorothiazide. The patient reported minimal alcohol intake and did not smoke. On initial examination, the patient was hemodynamically stable and presented only with tachypnea (24 breaths/min). Chest radiography showed diffuse interstitial opacities. She was admitted to an inpatient unit, but her condition worsened over the first seven days showing signs of acute respiratory distress, being transferred to the Intensive Care Unit and required mechanical ventilation for six days. She received intravenous antibiotics; however inotropic drugs were not Plasma level of triglycerides was 209 mg/dL and calcium level was normal (1.24 mg/dL). An Endoscopic Ultrasound was performed, after complete recovery from respiratory symptoms and after two negative results for RT-PCR, showing no microlithiasis. Other causes of acute pancreatitis such as drugs, trauma and hypotension were excluded, and the patient was discharged after 35 days of hospitalization without any long-term sequelae. Initially reported as a respiratory tract pathogen, SARS-CoV-2 has been identified in many other tissues, such as the cardiovascular, renal and gastrointestinal tract, similar to SARS-CoV in 2003 [5, 6] . Both viruses have ACE2 as the functional host cell receptor, enabling virus entry and replication [1, 5, 7] . However, different from SARS-CoV, SARSCoV-2 does not use other receptors such as aminopeptidase N and dipeptidyl peptidase 4 [8] , being more selective. Furthermore, SARS-CoV-2 has higher affinity to ACE2 when compared to SARS-CoV, being more pathogenic [5] and increasing the ability of community transmission [9] . ACE2 is abundantly expressed in many different tissues, justifying the involvement of different organs and extrapulmonary symptoms of those diseases [1, 5, 7] . The expression of ACE2 in the gastrointestinal tract during SARS-CoV-2 infection leads to digestive system dysregulation [1] . Symptoms like nausea, vomiting and diarrhea have commonly been described in 11% to 50% of cases [10, 11, 12] . Gastrointestinal findings are significant due to their association with adverse outcomes such a delayed hospital admission and evidence of more laboratory changes, including prolonged coagulation time [10] . In addition to gastrointestinal symptoms, some blood abnormalities were found in severe patients, such as increased pancreatic enzymes [1, 3, 7, 10] , suggesting pancreatic injury. In spite of gallstones and alcohol abuse being reported as the more common causes of acute pancreatitis, infectious agents, especially virus, are responsible for approximately 10% of cases [5] , such as mumps, cytomegalovirus and influenza [13, 14] . Therefore, it is likely to consider SARS-COV-2 as a potential cause of pancreatitis. Curiously, in a recent study published by Schepis et al., SARS-CoV-2 RNA was detected in a pancreatic pseudocyst sample endorsing pancreatic involvement in COVID-19 [15] . Furthermore, the mRNA level of ACE2 in pancreas was shown to be higher than in lung and expressed in both the exocrine glands and islets, being potential targets of SARS-CoV-2, resulting in pancreatic injury [7] . Although the density of ACE2 in pancreatic tissue is still controversial [6, 7, 16] and has individual variation [7] , higher mRNA ACE density, during those virus infections, may signal greater predisposition to trigger acute pancreatitis [16] . ACE2 receptor is highly expressed in pancreatic islet cells [16] , therefore SARS-CoV-2 infection can theoretically cause islet damage resulting in acute diabetes [7] . The patient in this case presented increased blood glucose levels, as found in six of nine patients with pancreatic injury in another study [3] . Dysglycemias were already observed with SARS-CoV [16] and may alter disease prognosis, since diabetes and ambient hyperglycemia were independent predictors for death and morbidity in SARS patients [16, 17] . Fortunately, a minority of these patients progressed to diabetes three years after hospital discharge [16] . findings, as well as to report the presence of pancreatitis symptoms, making it difficult to establish an acute pancreatitis diagnosis. According to the current guidelines [18] , diagnosis of acute pancreatitis requires at least two of the three following signs: 1) abdominal pain, 2) amylase or lipase >3 times the upper normal limit, and 3) characteristic findings on diagnostic imaging. In the first study, conducted by Wang, et al., nine out of 52 patients (17%) had pancreatic enzyme abnormalities, with any change above the upper limit of normality being considered, and six of them (66%) also had hyperglycemia. No imaging tests were described, nor whether any of the patients had criteria for acute pancreatitis. Patients with pancreatic injury had a higher incidence of gastrointestinal symptoms, such as diarrhea and anorexia, in addition to severe disease on admission. When compared with patients without pancreatic injury, there was no difference regarding mechanical ventilation or viral clearance [3] . Regarding tomographic changes, 7.46% had some pancreatic finding. However, this article also did not describe whether any of these patients had criteria for acute pancreatitis, nor did report if serum values of amylase and lipase from those patients were associated with imaging changes [7] . Those articles demonstrated how asymptomatic or mildly gastrointestinal symptomatic patients with COVID-19 and pancreatic enzymes abnormalities could be overlooked and acute pancreatitis underdiagnosed. Herein we presented a patient with acute pancreatitis suspected due to altered pancreatic enzymes, with little or no gastrointestinal symptoms, and with subsequent diagnosis confirmed by CT scans. Similar to this case, Anand et al. diagnosed acute pancreatitis in a COVID-19 patient by examining the CT scan, which was ordered due to suspected bowel obstruction [19] . The notable heterogeneous presentation and the need to rule out other main etiologies, due to this rare association, are some of the challenges in the diagnosis. SARS-CoV-2 seems to have some tropism for pancreatic (exocrine and endocrine) cells, causing acute pancreatitis. Physicians should be aware that asymptomatic or mildly gastrointestinal symptomatic patients with COVID-19 require pancreatic enzymes and even abdomen imaging to diagnose pancreatitis. This diagnosis is important for adequate treatment and better management of systemic repercussions, such as SIRS, decreasing SARS-CoV-2 mortality. This study was a case report study, patient identity remained anonymous, and the informed consent was obtained. be published, and agree to be accountable for all aspects of the work. No funding. The authors declare no conflicts of interest. Gastrointestinal, hepatobiliary, and pancreatic manifestations of COVID-19 Review article: COVID-19 and liver disease-what we know on 1st Pancreatic Injury Patterns in Patients With Coronavirus Disease 19 Pneumonia Acute pancreatitis SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19) Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor ACE2 Expression in Pancreas May Cause Pancreatic Damage After SARS-CoV-2 Infection A pneumonia outbreak associated with a new coronavirus of probable bat origin Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Infectious causes of acute pancreatitis Influenza A viruses grow in human pancreatic cells and cause pancreatitis and diabetes in an animal model SARS-CoV2 RNA detection in a pancreatic pseudocyst sample Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis-2012: revision of the Atlanta classification and definitions by international consensus We thank Dr. Sergio Matuguma for performing the Ecoendoscopy exam. We thank Dr.Joao Marcos Wolf Maciel for providing the radiographic images. We thank Mr. Timothy Finian Coyne for reviewing the English version.