What Is Known/What Is New
What Is Known
- Children infected with SARS-CoV-2 can have a delayed, severe immune response mimicking Kawasaki disease called multisystem inflammatory syndrome in children.
- Multisystem inflammatory syndrome in children can develop without prior symptoms of COVID-19.
- Pancreatitis has previously been described as a presenting symptom of acute COVID-19 in adult patients.
What Is New
- This is the first reported case of pancreatitis in a pediatric patient due to COVID-19.
- Acute pancreatitis can be the initial presentation of multisystem inflammatory syndrome in children.
- Clinicians should monitor patients with acute pancreatitis closely for clinical deterioration, even in cases with no prior history of COVID-19 symptoms.
Children presenting with COVID-19 often demonstrate prominent gastrointestinal symptoms rather than the severe respiratory syndrome typically seen in adults (1,2). Recently, clinicians in Europe and the United States have observed an increase in the incidence of symptoms of Kawasaki disease (KD) associated with COVID-19, leading to the description of a syndrome characterized by multisystem organ dysfunction and inflammation termed multisystem inflammatory syndrome in children (MIS-C) (3,4). Although gastrointestinal symptoms are common at time of MIS-C presentation, acute pancreatitis (AP) has not been described in children (5). We describe the first known case of a child who presented with AP as the initial manifestation of MIS-C.
A 10-year-old obese African American female with a history of mild intermittent asthma presented to the emergency department (ED) in early April 2020. Symptoms began 5 days before admission with diffuse abdominal pain followed by daily fevers between 39°C and 40°C, nonbloody, nonbilious emesis, watery diarrhea, and anorexia. Other pertinent symptoms included conjunctival injection, eyelid swelling, swelling of the hands and feet, and fatigue. She had no respiratory complaints. Although she had no identified sick contacts, in late February and early March she had travelled from her home in Atlanta, GA, to New York City, New Jersey, and California, all areas with increased COVID-19 infection rates (Fig. 1). Since her return, she had remained in her home, whereas both parents intermittently worked outside of the home.
On presentation, she had fever, tachycardia, and hypotension. She reported upper abdominal pain radiating to her back and right lower quadrant pain. She was diagnosed with AP based on her symptoms, hyperlipasemia, and abdominal computed tomography (Table 1), and she was admitted for management.
Hours after admission, she developed respiratory distress and worsening acute kidney injury and hypotension. She was urgently transferred to the pediatric intensive care unit for evolving multisystem organ dysfunction. Chest radiography showed pulmonary edema and mild pleural effusions, and echocardiography showed depressed biventricular function and mild pulmonary hypertension (Table 1). She required 40 L/min high-flow nasal cannula, epinephrine, and milrinone. Diarrhea continued, and she developed severe hypoalbuminemia requiring IV replacement. Fevers persisted, and an extensive infectious and rheumatologic work-up was negative, including SARS-CoV-2 polymerase chain reaction (PCR) testing from 2 separate nasopharyngeal swabs.
Given her features of incomplete KD (>5 days of fever, limbic-sparing conjunctival injection, cervical lymphadenopathy, peripheral edema, decreased cardiac function despite normal coronary arteries, elevated C-reactive protein, elevated transaminases, and hypoalbuminemia), she was treated with intravenous immunoglobulin (IVIG) and high-dose aspirin (6). Despite an initial response to IVIG, her fevers returned. She received a second dose of IVIG 2 days later, following which she remained afebrile with improved cardiac function and resolution of acute kidney injury and edema. Respiratory support was weaned, and inflammatory markers, transaminases, albumin, and lipase improved following the second dose of IVIG. She was discharged on low-dose aspirin. Two weeks after discharge, she had mild hypertension but was otherwise well. At follow-up, COVID-19 immunoglobulin G sent during admission returned positive.
Our case is the first documented case of pediatric AP related to COVID-19. Her presentation with fever, elevated inflammatory markers, and multisystem organ involvement in the setting of previous SARS-CoV-2 infection is consistent with a diagnosis of MIS-C, as recently defined by the Centers for Disease Control and Prevention (7).
Three cases of AP have been reported in adult patients with concurrent or recent diagnosis of COVID-19; all 3 tested positive for SARS-CoV-2 via PCR (8,9). A separate case series reported 9 patients admitted for COVID-19 pneumonia in a Wuhan hospital with hyperlipasemia; however, as imaging findings and concurrent symptoms were not reported, it is difficult to determine how many patients fulfilled AP criteria (10). Hyperlipasemia in COVID-19 can be due to additional factors including acidosis, renal failure, diabetes, and enhanced intestinal permeability due to systemic inflammation (11). Our patient met formal criteria for pediatric AP based on abdominal pain, hyperlipasemia, and imaging findings (12).
Our patient's clinical features closely match those of a recently reported cohort of Italian children with severe KD-like disease and SARS-CoV-2 infection. Those patients were older than expected for KD with features of incomplete KD including elevated inflammatory markers, lymphopenia, thrombocytopenia, respiratory and gastrointestinal features, cardiac dysfunction, and shock (5). Only 2 of the 10 patients in that cohort were PCR positive for SARS-CoV-2, whereas 8 were immunoglobulin G-positive, similar to our patient. These results support the suggestion that MIS-C is a later finding of COVID-19 illness due to a delayed immune response following a mild or asymptomatic primary infection. Our patient's timeline of travel exposures and eventual presentation fit this description.
The association between AP and SARS-CoV-2 is not well understood. Several potential mechanisms of injury are possible. Viral infections, including the coronavirus family, account for 10% of idiopathic AP. Angiotensin-converting enzyme 2 is the human receptor for coronaviruses, including both the 2003 SARS-CoV strain and the current SARS-CoV-2 strain (13,14). Angiotensin-converting enzyme 2 is widely expressed in epithelial tissues including the pancreas, and autopsy data from the 2003 SARS-CoV outbreak detected viral RNA polymerase in pancreatic acinar cells (15). Thus, direct viral invasion with cytopathic effect is a potential cause of pancreatic injury.
Another possible mechanism for pancreatic injury in acute COVID-19 or MIS-C is the systemic inflammatory response. Biomarkers including C-reactive protein, procalcitonin, and interleukin 6 are significantly elevated in both adult and pediatric patients with COVID-19 (16–18). Those biomarkers were significantly elevated in our patient. Many patients with COVID-19 are sedated or mechanically ventilated, precluding evaluation of pancreatitis symptoms. In one report, 7.5% of such patients had inflammatory changes in the pancreas on abdominal computed tomography, suggesting that pancreatitis may be underrecognized (19).
Viruses, including coronaviruses, are associated with KD and have been isolated from respiratory secretions of patients with KD at higher rates than healthy controls (20). AP itself, meanwhile, has been described as a rare complication of KD before the COVID- 19 pandemic (6,21). As such, AP alone does not appear to distinguish MIS-C from KD.
The progression to MIS-C can be more rapid and severe than what is typically seen in severe pancreatitis. As we learn more about SARS-CoV-2 and how it affects children, pediatric gastroenterologists must maintain a high index of clinical suspicion for its presence in patients who present with AP or other significant gastrointestinal symptoms.
1. Cheung KS, Hung IF, Chan PP, et al. Gastrointestinal manifestations of SARS-CoV-2
infection and virus load in fecal samples from the Hong Kong cohort and systematic review and meta-analysis. Gastroenterology
2020; S0016-5085:30448-0Epub ahead of print.
2. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics
3. Rivera-Figueroa EI, Santos R, Simpson S, et al. Incomplete Kawasaki disease in a child with COVID-19. Indian Pediatr
2020; S097475591600179Epub ahead of print.
4. Belhadjer Z, Méot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2
pandemic. Circulation. 2020 May 17. Epub ahead of print.
5. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2
epidemic: an observational cohort study. Lancet Lond Engl
6. Prokic D, Ristic G, Paunovic Z, et al. Pancreatitis and atypical Kawasaki disease. Pediatr Rheumatol Online J
7. U.S. Centers for Disease Control. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). 2020. https://emergency.cdc.gov/han/2020/han00432.asp
. Accessed May 20, 2020.
8. Hadi A, Werge M, Kristiansen KT, et al. Coronavirus disease-19 (COVID-19) associated with severe acute pancreatitis: case report on three family members. Pancreatology
9. Anand ER, Major C, Pickering O, et al. Acute pancreatitis in a COVID-19 patient. Br J Surg
10. Wang F, Wang H, Fan J, et al. Pancreatic injury patterns in patients with COVID-19 pneumonia. Gastroenterology
2020; S0016-5085:30409-1Epub ahead of print.
11. De Madaria E, Siau K, Cárdenas-Jaén K. Increased amylase and lipase in patients with COVID-19 pneumonia: don’t blame the pancreas just yet!. Gastroenterology
2020; S0016-5085:30561-8Epub ahead of print.
12. Morinville VD, Husain SZ, Bai H, et al. Definitions of pediatric pancreatitis and survey of present clinical practices. J Pediatr Gastroenterol Nutr
13. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature
14. Wan Y, Shang J, Graham R, et al. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol
15. Ding Y, He L, Zhang Q, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol
16. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet Lond Engl
17. Wang Y, Zhu F, Wang C, et al. Children hospitalized with severe COVID-19 in Wuhan. Pediatr Infect Dis J
2020; 39:e91-4Print information is now available and noted separately.
18. Sun D, Li H, Lu X-X, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study. World J Pediatr
19. Liu F, Long X, Zhang B, et al. ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2
infection. Clin Gastroenterol Hepatol
2020; 18:2128-30.e2Print information is now available and noted separately.
20. Chang L-Y, Lu C-Y, Shao P-L, et al. Viral infections associated with Kawasaki disease. J Formos Med Assoc Taiwan Yi Zhi
21. Botti M, Costagliola G, Consolini R. Typical Kawasaki disease presenting with pancreatitis and bilateral parotid gland involvement: a case report and literature review. Front Pediatr