key: cord-0971244-f2imx9a6 authors: Palabiyik, Figen; Akcay, Nihal; Sevketoglu, Esra; Hatipoglu, Nevin; Sari, Emine Ergul; Inci, Ercan title: Imaging of multisystem inflammatory disease in children (MIS-C) associated with COVID-19 date: 2021-06-05 journal: Acad Radiol DOI: 10.1016/j.acra.2021.05.030 sha: 45c7abc644c5d43b0d32d548ab49719ff6896fe3 doc_id: 971244 cord_uid: f2imx9a6 RATIONALE AND OBJECTIVES: To retrospectively evaluate imaging findings in multisystem inflammatory disease in children associated with COVID-19 (MIS-C). MATERIALS AND METHODS: The radiological imaging findings of 45 pediatric patients aged between 52 days and 16 years, who were diagnosed with MIS-C according to the World Health Organization (WHO) criteria, were evaluated. All the patients underwent chest X-ray and echocardiography. The findings obtained from 25 abdominal radiographs, 24 abdominal US, 7 abdominal CT, 16 thorax CT, 21 cranial MRI and one spinal MRI, MR cholangiography (MRCP) and cardiac MRI examinations were categorized and evaluated according to the affected systems. RESULTS: While the most common findings in chest X-ray were perihilar opacity and peribronchial thickening, pleural effusion was the most finding in thorax CT . Echocardiography findings of myocarditis were observed in 31% of the cases. The most common findings in abdominal radiological evaluation were hepatomegaly and splenomegaly, edema in the gallbladder wall and periportal area, mesenteric lymph nodes in the right lower quadrant, thickening of the intestinal walls, and free fluid. Reversible splenial lesion syndrome (RESLES) was the most common neurological finding. Acute disseminated encephalomyelitis (ADEM)-like lesions, acute hemorrhagic necrotizing encephalomyelitis, and radiological findings consistent with Guillain-Barré syndrome were found in one case each. CONCLUSION: Radiological findings seen in MIS-C in pediatric cases are correlated with the affected system. According to the system involved, there is no specific finding for this disease. Radiological findings are not the primary diagnostic tool but can assist in the evaluation of the affected systems and to guide treatment. When the coronavirus disease 2019 (COVID-19) infection first occurred, it was shown that children survived this infection less often than adults in the acute disease. However, in the later stages of the pandemic, symptoms similar to severe multisystemic hyperinflammatory syndrome that did not resemble the acute form of COVID-19 began to be observed in children. Multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C) was reported for the first time in April 2020 in children from the UK and the USA, who were previously healthy but were determined to have a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription-polymerase chain reaction (RT-PCR) or serology testing for SARS-CoV-2. Fever, abdominal pain, rash and conjunctivitis, and increased acute phase reactants and cardiac markers, often accompanied by hypotensive shock and myocardial dysfunction have been identified in children diagnosed with MIS-C. In MIS-C, there is a previous COVID-19 infection in children, a family history of the disease, or a history of contact with an infected individual, and symptoms occur approximately within two to three weeks after COVID-19. Unlike acute COVID-19 infection, many systems are affected due to the inflammatory response that develops, and some radiological findings occur due to the pathologies that occur. Although radiological findings are not typical, they may be of warning findings for the diagnosis of MIS-C when correlated with clinical and laboratory findings and if other pathologies are excluded. There are few publications on the radiological imaging of MIS-C in the literature, but they report non-specific radiological findings. Sharing radiological findings from different countries on this subject will increase knowledge and awareness. The aim of this study was to retrospectively report the radiological findings of children diagnosed with MIS-C as a result of various system involvement in our pandemic hospital. Forty-five pediatric patients who presented to the pediatric department of our hospital between March 2020 and March 2021 and were diagnosed with MIS-C were retrospectively evaluated. The clinical and laboratory findings and chest X-ray, echocardiography, abdominal radiography, ultrasonography (US) , computed tomography (CT) and magnetic resonance imaging (MRI) images of all cases were evaluated. Written consent was provided by the parents of the cases after obtaining approval from the ethics committee of our hospital. The patients were diagnosed with MIS-C according to the WHO criteria for MIS-C (Table 1) . All cases underwent the RT-PCR testing of the upper respiratory tract and serology for SARS-CoV-2 antibodies using blood or cerebrospinal fluid (CSF) samples. The history of COVID-19 in the family was investigated by determining whether the cases had previously tested positive for the disease or had a history of contact with an infected individual. Only cases with RT-PCR and serology positivity according to the WHO criteria were accepted as MIS-C and included in the study. The picture archiving and communication system (PACS) of hospital was scanned to review all imaging studies performed on children with MIS-C associated with COVID-19. Chest and abdominal radiography, echocardiography, abdominal US, thorax and abdominal CT, cranial and spinal MRI, MR angiography, MRCP and cardiac MRI examinations were evaluated by a pediatric radiologist with 11 years of experience. Chest X-ray and thorax CT were evaluated in terms of interstitial and alveolar opacities, distribution (unilateral or bilateral, central or peripheral), zonal distribution (upper, middle or upper zone) and focality (single, multifocal or diffuse). While parenchymal pathologies were examined in terms of peribronchial thickening, ground glass appearance, consolidation, atelectasis and pulmonary edema, the presence of pleural effusion, mediastinal and hilar lymphadenopathy, and pulmonary embolism was also investigated. Heart size, right and left ventricular function, and pericardial effusion were evaluated using echocardiography. Abdominal radiographs were evaluated in terms of ileus and obstruction, and enlargement in the intestinal loops and wall thickening. In abdominal US and abdominal CT, liver, spleen and kidney dimensions, parenchymal anomalies observed in solid organs (echogenicity and density differences and heterogeneity), periportal edema in the liver and and pericholecystic wall edema were evaluated. In addition, the presence of distension, wall thickness in visceral organs (gall bladder, stomach, bowel loops, and bladder) was investigated. If the wall thickness was over 3 mm, it was considered as thickening. Intraabdominal free fluid and abdominal lymphadenopathy were explored. The lymph nodes were considered enlarged if they were over 5 mm in the short axis. Cranial MRI was used to reveal pathological signal changes and distributions observed in cerebral and cerebellar parenchyma and brainstem, distribution of lesions, and areas of involvement (deep white matter, subcortical white matter, cortex, and basal ganglion), and contrast enhancement of lesions, diffusion characteristics, thrombus and infarction, and bleeding. In MR angiography, venous structures were evaluated in terms of thrombus, arterial structures in terms of thrombus, and aneurysmal dilatation. Of the 45 child cases, 27 were boys (60%) and 18 were girls (40%), aged 52 days to 16 years, with a median age of 7.68 years. Six cases (13%) had a history of previous COVID-19 disease 2-3 weeks ago and 18 (40%) had a family history of COVID-19. In other cases (46%), previous COVID-19 infection, family history of COVID-19, and history of contact with an infected individual were not detected. RT-PCR and serology positivity was detected in two patients (4%) while PCR was negative in 43 cases (96%) with a positive serology test. CSF serology was evaluated as positive in two cases. One patient with severe multisystem involvement and three with neurological involvement were discharged from the hospital with neurological sequelae. More than one system involvement was observed in all patients admitted to the intensive care unit (69%) and in three patients (7%) hospitalized in the pediatric service. Thirty-one patients (69%) were followed up in the intensive care unit, and 14 (31%) in the pediatric service. None of the patients had a history of chronic disease. Mortality was not observed. Eight patients (17.7%) were intubated. The most frequently reported general and gastrointestinal symptoms were fever and vomiting, abdominal pain, and diarrhea, rash, conjunctivitis and weakness. Respiratory symptoms were cough and respiratory distress while neurological symptoms included seizure, neck stiffness, and inability to walk ( Table 2 ). In all cases, the white blood cell count, C-reactive protein (CRP), ferritin, D-dimer, troponin and fibrinogen values were high, and the albumin values were low. The amylase and lipase levels were found to be high in seven cases. Ventricular dysfunction and signs of myocarditis were detected in 14 cases. The clinical, laboratory and radiological findings of the patients with a diagnosis of MIS-C are summarized in Tables 2 and 3 . Chest X-ray was performed in all cases. No lung findings were observed in 35 cases (78%). The most common findings were perihilar opacity and peribronchial thickening seen in chest X-ray ( Figure 1a) . The most common finding on thorax CT was pleural effusion. (Figure 1b ). Diffuse lung opacity in chest X-ray and diffuse ground glass appearance and consolidation in thorax CT were observed in one patient (Figure 1c -d). Echocardiography was performed in all cases diagnosed with MIS-C. Echocardiography was normal in 31 cases. In 14 cases (31%), varying degrees of decrease in systolic functions and ejection fraction consistent with myocarditis were detected. In the severe case with multiple system involvement, dilated cardiomyopathy was observed along with myocarditis and pericardial effusion findings. Cardiac MRI showed a marked decrease in pericardial effusion and systolic functions and an increase in cardiac dimensions. The most common finding on abdominal radiography was air-fluid level observed in four cases. The most common US findings were hepatomegaly and hepatosplenomegaly . Periportal and pericholecystic wall edema, multiple mesenteric lymph nodes in the right lower quadrant , free fluid in the abdomen, temporary invagination, and echogenic kidneys were seen (Figure 2a -c). Abdominal CT was performed in five cases that could not be clinically distinguished from acute appendicitis. While the appendix was evaluated as normal in these cases, periportal and pericholecystic wall edema, thickening of the intestinal walls, presence of free fluid in the abdomen, multiple lymph nodes in the right lower quadrant, and prominence of mesenteric vascular structures were observed. Appendicitis could not be clearly differentiated with this ultrasound these patients. All other abdominal findings observed were similar to ultrasound findings. In a severe case, the CT examination was undertaken following the detection of an increase in the amylase and lipase values, heterogeneity in the pancreas, and multiple hypoechoic areas in the parenchyma. During the treatment, amylase and lipase levels of the patients increased for the second time. The repeated abdominal CT examination revealed that the pancreatic dimensions decreased and the hypodense areas observed in the pancreatic parenchyma turned into necrotic areas ( Figure 2d ). In the same case, intrahepatic bile ducts and pancreatic canal were found to be enlarged in abdominal US and MRCP (Figure 2e-f) due to cholestasis that developed during treatment. In one case, a thrombus was observed in the inferior vena cava. Various cranial neurological findings (headache, epilepsy, hallucination, neck stiffness, and inability to walk) were observed in the clinical examination of 14 cases (31%). The most common cranial MRI finding was RESLES. In six of these cases, diffusion restriction was MIS-C cases present with a wide range of clinical symptoms according to the system affected. The most frequently reported general and gastrointestinal symptoms were fever, rash, conjunctivitis and weakness and vomiting, abdominal pain and diarrhea. Neurological symptoms were seizure, neck stiffness, and inability to walk while respiratory symptoms included cough and respiratory distress. In addition to chest X-ray and echocardiography being routinely performed in every patient admitted to our hospital and considered to have MIS-C, direct abdominal radiography and US are also undertaken in those with abdominal complaints, abdominal CT if necessary, thorax CT in the presence of respiratory complaints, and cranial and spinal MRI for those with neurological complaints if required. In our study, the radiological imaging findings found were consistent with the clinical findings of patients with MIS-C previously reported by Blumfield et al. (6) . In our study, some cases presented with the involvement of a single system while others had multisystem involvement and related radiological findings. Unlike acute infection, lung involvement is rare in MIS-C. Typical lung findings observed in acute COVID-19 infection, such as peripherally located multiple ground glass and consolidation areas are not seen in MIS-C (14-16). The most common findings observed on chest radiography are perihilar prominence and peribronchial thickening, which may be due to airway inflammation (7, 8) . In our series, lung involvement was detected in only 29% of the cases, while peribronchial thickening and perihilar prominence were the most common findings on chest X-ray. Blumfield et al (6) . frequently reported cardiomegaly and pleural effusion in their series. In our series, consolidation and associated pleural effusion were observed in the lower lobes in five cases, and diffuse ground glass appearance and consolidation were present in one case. Fenlon et al (8) . suggested that this might be due to cardiogenic or non-cardiogenic edema/acute respiratory distress syndrome due to cardiac dysfunction and multiple organ failure caused by hyperinflammation or it might be a result of causes. Pulmonary embolism did not develop in any of our patients with pulmonary involvement. The most common finding observed in MIS-C is acute myocardial dysfunction. Left ventricular systolic dysfunction and decreased ejection fractions are reported in the literature. In addition, coronary artery dilatation and aneurysm and pericarditis have been reported (11) (12) (13) . Echocardiography is usually sufficient for the diagnosis. In the echocardiography of our cases, we observed that myocardium was affected in 14 (31%). In all cases, there was a decrease in left ventricular systolic function and varying degrees of ejection fraction. The use of cardiac MRI for the diagnosis of myocarditis in MIS-C cases has been previously reported. Diffuse edema findings in the myocardial muscle are observed in cardiac MRI (14) . MRI findings suggestive of fibrosis and necrosis were not detected in our cases. We performed cardiac MRI in one of our patients with multisystem involvement, but the findings were the same as echocardiography findings. Abdominal complaints were the most common in our cases; therefore, abdominal imaging was performed. In these cases, the most common findings were edema and wall thickening around the gallbladder, multiple mesenteric lymph nodes over 5 mm in the short axis in the right lower quadrant, thickening of the ileal intestinal walls, and free fluid, which is in agreement with other studies (6) (7) (8) . Since the findings in five cases suggested acute appendicitis, abdominal US and then CT examinations were also performed. The appendix was evaluated to be normal in these examinations. Hameed (7), Fenlon (8) and Tullie (9) There are no similar radiological findings reported in the acute period in children. The most common findings in our study were hepatomegaly and hepatosplenomegaly. In addition, in eight cases in our study, although there was an increase in pancreatic and hepatic enzymes, no remarkable radiological finding was detected. Radiological findings showing pancreatic and liver involvement were observed in one patient. In one of our patients, a thrombus was detected in the vena cava inferior, which we considered to be due to coagulation disorder, while pancreatic involvement and related atrophy and necrosis were detected in the pancreas of another case. In addition, the latter had cholestasis in the intrahepatic biliary tracts due to liver involvement, which we visualized radiologically. Although the etiology of similar lesions in adults is not clearly explained, it has been linked to the direct damage of cells, inflammatory process, or hepatotoxic effect of drugs (10) . We consider that these findings may be due to vasculitis caused by inflammation in pediatric cases. Although we conducted the study in a single center, we had a higher number of cases with neurological and neuroradiological findings compared to previous case series. In adult cases, infection due to COVID-19, venous sinus thrombus, encephalomyelitis, Guillain-Barré syndrome, Miller Fisher syndrome, myelitis, and PRES have been described in the literature (17, 18) . The neurological findings of COVID 19 and MIS-C in children have been attributed to direct neuronal damage, vascular endothelial damage, and inflammatory and autoimmune damage (19) . The neuroradiological findings reported in MIS-C cases in the literature are from a multicenter study (20) and case reports (21-23) and remain limited. Orman et al. found neuroradiological findings in only 10% of the cases diagnosed with COVID-19 who underwent a neuroradiological examination (24) . These findings were reported as PRES and hippocampal signal changes. Different neurological findings were observed in 31% of our MIS-C cases, and we observed radiological findings in 64% of these patients. While only two of our cases had other system involvement, the others presented with only neurological findings. The most common finding was RESLES, which is also frequently reported in the (20) . Similar findings to our case have been reported in adults and patients with acute hemorrhagic necrotizing encephalomyelitis, which is rarely described on a case-by-case basis in the literature (17, 18, 25) . Guillain-Barré syndrome is another pathology reported in MIS-C cases (26) . We did not observe myelitis in our cases, in contrast to Kaur et al. (27) . It is considered that all the findings observed in MIS-C cases are primarily due to parainfectious inflammation due to the immune response involving the brain, spinal cord, cranial nerve, and nerve roots (20) . The limitations of our study include the single-center and retrospective design of the study and the small number of cases. Although the number of MIS-C cases is increasing, radiological imaging findings that can be demonstrated remain limited. As the number of cases is reported from different centers, our knowledge in this area will further increase; therefore, there is a need for multicenter multidisciplinary studies. The radiological findings seen in MIS-C associated with COVID-19 in pediatric cases are correlated with the affected system. According to the system involved, there is no specific finding for the disease. Radiological imaging is not the primary method for diagnosis. 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