Clinical Characteristics of Pediatric Inammatory Multisystem Syndrome Associated With COVID-19

Background: Although symptoms and signs of COVID-19 (Coronavirus disease 2019) in children are milder than adults, there are reports of more severe cases which was dened as pediatric inammatory multisystem syndrome (PIMS). The purpose of this report is to describe possible association between COVID-19 and PIMS in children. Methods: From 28 March to 24 June 2020, 10 febrile children were admitted with COVID-19 infection showing characteristics of PIMS in a tertiary hospital in the north of Iran. Demographic and clinical characteristics, laboratory and imaging ndings and therapeutic modalities were recorded and analysed. Results: The mean age of patients was 5.37±3.9 years (13 months to 12 years). Six of them were boy. Kawasaki disease, myocarditis, toxic shock syndrome, appendicitis, sepsis, urosepsis, prolonged febrile seizure, acute hemorrhagic edema of infancy, and COVID-19-related pneumonia were their rst impression. All of them had increased C-reactive protein level and most of them had an elevated erythrocyte sedimentation rate, lymphopenia, anemia, and hypoalbuminemia. Some of them had thrombocytopenia. Six of them were serologically or polymerase chain reaction positive for COVID-19, and 4 of them were diagnosed as COVID-19 just by chest computed tomography scan. Most of the patients improved without a residual sequel, except one who died with multiorgan failure and another case discharged with a giant coronary aneurysm. Conclusion: Children with COVID-19 may present symptoms similar to Kawasaki disease and inammatory syndromes. PIMS should be considered in children with fever and rash, seizure, cough, tachypnea, and gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain. hydroxychloroquine 2 On but with in examination. initiation thrombocytosis (platelet count: and and clopidogrel skin erythematous around to the a suppository of diclofenac and acetaminophen for pain and fever relief. a of repaired duodenal atresia at birth. On physical exam, the was ill and febrile, had macular erythematous rashes around feet, hands, trunk and perioral, periorbital edema, erythema of oropharynx, right eardrum erythema and hypogastric tenderness. elevated ESR and CRP in addition to abnormal urine sediment. Ceftriaxone started and chest CT-scan performed with non-signicant changes for COVID-19. Urine culture of the rst day was negative. On the second day of admission, the patient got toxic and irritable with respiratory distress, low SPO2: 87%, mild abdominal distension, and anasarca edema. The patient transferred to the PICU. Serum albumin was 2.6 g/dL, while other indexes like amylase and lipase were in normal values. So, albumin started. During the last 2 days, general condition of the patient got worst, he became anemic and more toxic, so albumin, 1 gr/kg IVIG, packed cell, hydroxychloroquine, and vitamin D were administered and ceftriaxone changed to vancomycin and meropenem. A second chest CT-scan showed bilateral opacity compatible with COVID-19. COVID-19 RT-PCR was negative but COVID-19 IgG was positive which was measured a week later. Abdominal ultrasonography showed mild splenomegaly, free interloop uid, and several reactive lymph nodes. year-old with fever from 3 days ago. from epigastric pain which was shifted to the right lower quadrant (RLQ) after 2 days and was not associated with eating. He had nausea, vomiting, and normal defecation pattern. He was admitted 10 days ago for acute intravascular hemolysis due to glucose 6 phosphate dehydrogenase deciency (G6PDd) and fava bean exposure and was treated with packed cell and hydration. In the recent admission, he was ill and febrile without respiratory symptoms. On physical examination, tenderness in RLQ and rebound tenderness were noted. Ultrasonography showed reactive lymph nodes, and free interloop uid. In the CBC, leukocytosis with a shift to left was found. ESR and CRP were markedly elevated, urine and stool were unremarkable. So, the patient received ceftriaxone plus metronidazole and underwent appendectomy, but normal appendix with some exudative secretion in the peritoneal cavity was seen during the operation. After surgery, the patient's condition got worse and became toxic, developed abdominal distension and recurrent vomiting. Abdominal X-ray was normal and repeated ultrasonography reported mild interloop uid only. A chest CT-scan showed ndings compatible with COVID-19 infection. Ceftriaxone changed to meropenem and vitamin D, hydroxychloroquine, and zinc gluconate started. 3 fever and abdominal got better. Other investigations like liver transaminases, serum LDH and echocardiography were normal. After 4 days, the patient discharged. COVID-19 IgM and IgG and RT-PCR during admission were negative. 5, 7, 13, 15). Almost all our patients discharged without complication, except one case with giant aneurysms. There was only one death in our patients, which was due to a history of uncontrolled renal failure and late referral. Our study was the rst report of PIMS in Iran. We aimed to share clinical characteristics, paraclinical ndings and therapeutic experiences regarding more severe pediatric COVID-19 cases who fulll PIMS criteria. All of them were previously healthy children, except one case with CRF.


Background
In January 2020, China reported a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). The world is currently in the rapid emergence of the pandemic caused by SARS-CoV-2 now which is called COVID-19 (Coronavirus disease 2019) (2). The real incidence of this infection in children is inde nite. The most common presentations of COVID-19 are fever and cough, however, the disease can have other manifestations such as myalgia, headache, dizziness, vomiting, diarrhea, and abdominal pain. Despite the lack of the full presentation of disease and outcome data in children, the most commonly reported symptoms and signs are milder than adults (3). This may be due to differences in immune responses to the virus (4).
Unusual cases of the COVID-19 with signs and symptoms similar to atypical Kawasaki disease (KD) and toxic shock syndrome (TSS) have been reported recently (5)(6)(7). In April 2020, the rst report of a child with Kawasaki disease and concurrent positive reverse transcriptase polymerase chain reaction (RT-PCR) of COVID-19 was published in the United States (8). Since this rst report, other countries have reported some cases with prolonged fever, dyspnea, irritability, diarrhea, vomiting, abdominal pain, as well as conjunctivitis, rash, and cardiogenic shock (6,7,9). According to these reports, world health organization (WHO) and center of disease control and prevention (CDC) of some countries shared a clinical guideline as Pediatric in ammatory multisystem syndrome (PIMS) (10)(11)(12).
WHO provided a preliminary case de nition criterion for PMIS in children and adolescents 0-19 years of age with fever > 3 days AND two of the following: a) Rash or bilateral non-purulent conjunctivitis or mucocutaneous in ammation signs (oral, hands or feet); b) Hypotension or shock; c) Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including Echocardiography ndings or elevated Troponin/NT-proBNP); d) Evidence of coagulopathy (by PT, PTT, and elevated d-Dimers); e) Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain) and elevated markers of in ammation such as ESR, C-reactive protein (CRP), or procalcitonin. AND Elevated markers of in ammation such as ESR, C-reactive protein, or procalcitonin.
AND No other obvious microbial cause of in ammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes. AND Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19 (11).
A possible temporal causality between COVID-19 and PIMS has been hypothesized because some of the children tested for COVID-19 infection were either positive by polymerase chain reaction (PCR) or serology (5,7). There are limited relevant evidence and no concrete working hypothesis for pathogenesis, to examine the association between exposure to COVID-19 and PIMS. Immune response to COVID-19 involves both cell-mediated immunity and antibody production. Based on previous in vitro studies, antibodies to the spike protein may improve the ability of novel strains of the coronavirus to enter cells. In COVID-19 infection, one suggestive mechanism that causes PIMS in children could be via antibody-dependent enhancement (7).
Early diagnosis and management of PIMS are very critical in order to decrease the risk of long-term complications, morbidity and mortality. We lack knowledge about COVID-19-induced presentations, mimic other diseases like status epilepticus and acute abdomen, immune responses, and how they may relate to PIMS. Therefore, the management of PIMS remains unclear and di cult. The purpose of this report is to provide a description and characterization of PIMS, increase the level of evidence about the possible association between COVID-19 and PIMS in our pediatric referral hospital in the north of Iran, focusing on the mode of novel manifestations and best practice of suspected PIMS condition and early outcome.

Methods
From 28 March to 24 June 2020, 10 febrile children were admitted with COVID-19 infection showing characteristics of PIMS (10)(11)(12) in a tertiary hospital in the north of Iran, Mazandaran province, Sari. Demographic and clinical characteristics, laboratory and imaging ndings and also therapeutic modalities were recorded in all of them, separately. In this manuscript, we reported the most compatible clinical syndrome as the rst impression in each case, complications and nal outcome in detail. For detection of SARS-CoV-2 infection in our patients, in addition to chest CT scan, we used COVID-19 real-time polymerase chain

Case 1
A 12 year-old boy with history of chronic renal failure and recurrent hemodialysis, admitted with fever and chills from 7 days ago, rash from 3 days ago which disappeared before admission, diarrhea, weakness, and fatigue without respiratory complaints. He was toxic at admission time and vital signs were unstable: Temperature: 39.5 o c, blood pressure: 70/50 mmHg, heart rate: 120/min and SPO2: 92% in the ambient room. He didn't have tachypnea or abnormal lung sounds. Hours later, he developed respiratory distress. Vasoactive drugs, oseltamivir, meropenem, vancomycin, hydroxychloroquine, and Kaletra were prescribed. In the chest computed tomography (CT) scan, patchy ground-glass opacity and interlobar septal thickening were found compatible with COVID-19.
In the complete blood count (CBC), lymphopenia, anemia, and thrombocytopenia were seen. Raised blood urea and creatinine, increased liver transaminases, proteinuria, hematuria, and marked acidosis in the arterial blood gas (ABG) were also noted, but creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and electrolytes were in normal values. The patient's general condition got worse and he underwent tracheal intubation. Echocardiography showed mild mitral and tricuspid regurgitation, mild diastolic dysfunction, decreased left ventricular ejection fraction on the rst day which deteriorated on the second day (Table 1). Packed red blood cell (packed cell), intravenous immunoglobulin (IVIG), and hydrocortisone prescribed. Before completion of the IVIG infusion, the patient's condition got worse and he died on the third day after hospitalization. Result of COVID-19 RT-PCR was positive for him.  A 5 year-old girl presented with a history of 3 days high-grade fever (39-40 o c), vomiting and one episode of skin rash during fever, loss of appetite, intermittent cough, otalgia, and diarrhea. On admission, she was ill and irritable without respiratory distress and SPO2 was 99% in room air. She had bilateral otitis and bilateral non-purulent conjunctivitis. Her parents had a suspicious history of COVID infection, so the chest CT-scan was performed and was normal.
Treatment with ceftriaxone and zinc gluconate started. Gradually, picture of the disease changed and preorbital edema (day 3), headache, limb pain, pharyngeal congestion with punctuated exudate and purulent conjunctivitis occurred. Due to abdominal pain and tenderness, abdomino-pelvic ultrasonography was performed which was normal, just mild to moderate free uid was seen and also, mild to moderate bilateral pleural effusion was detected. Liver transaminases, serum amylase and lipase were in normal range. Because of a family history of COVID-19 infection and new changes in the second chest CT-scan compatible with COVID-19 infection, hydroxychloroquine and azithromycin started at the 3rd day and the patient was isolated. At day 5, COVID-19 RT-PCR result was positive, she was still febrile and her condition has deteriorated. She became drowsy, tachypneic (respiratory rate: 38 /min) without retraction and dry cough and generalized edema developed. She had SPO2 = 88% on room air. So, she was transferred to the pediatric intensive care unit (PICU). On CBC, severe anemia and thrombocytopenia in addition to hypoalbuminemia were noted (Table 1). So, packed red blood cells (packed cell), 1 g/kg IVIG and albumin were transfused and antibiotics changed to meropenem. Blood urea, Cr, LDH, peripheral blood smear, prothrombin time (PT), partial thromboplastin time (PTT), bilirubin, triglyceride, and brinogen level were in the normal range and urine analysis was normal. Blood and urine cultures were negative for any organism. Echocardiography showed mild tricuspid regurgitation, trivial mitral regurgitation with normal coronary arteries. During the rst 8 days, fever subsided, but the patient was still tachypneic. Finally, the patient discharged after 13 days with a good general condition.

Case 3
He was a 13 month-old boy presented with a 4-day history of fever and 3 days of rash. Skin rash started from palms of the hands and the soles of the feet and then, erythematous patches, papule, and some target shape lesions on edematous base on the trunk, limbs and face developed without itching sensation. He also defecated loose stool 2 to 3 times and had loss of appetite and irritability without any respiratory complaints except left tympanic membrane erythema.
His parents worked in a COVID-19 referral ward. On admission day, chest CT-scan was normal and he was treated with hydroxychloroquine and ceftriaxone. On day 3, the patient's condition deteriorated, generalized edema, purulent conjunctivitis, respiratory distress with tachypnea, intercostal and subcostal retraction occurred. While SPO2 was 84% in the ambient room, the second chest CT-scan changed to typical COVID-19 ndings (bilateral pleural effusion, basilar patchy in ltration, and reverse halo sign). Anemia and hypoalbuminemia occurred while both were in the normal range at the admission day (Table 1). So, the patient transferred to the PICU, and oxygen was administered with a hood and packed cell, albumin and IVIG (1 gr/kg) transfused. Antibiotic was changed to meropenem and vancomycin. Abdominopelvic ultrasonography was normal, just mild uid in sub-hepatic, peri-splenic, and interloop space were seen. Echocardiography showed mild tricuspid and mitral regurgitation and normal coronary arteries on two occasions. The patient gradually improved, skin rashes got better, he became afebrile and without any distress. He discharged after 8 days and COVID-19 RT-PCR result was positive for him.
A 10 year-old girl presented with fever and itching skin rash from 5 days ago referred. One day before admission, her general condition worsened; she got toxic and cough, abdominal pain, and generalized edema and oliguria developed. The skin rashes were maculopapular and target shape rashes with more accumulation around neck, trunk, and axilla. Mucous membranes were intact except for bilateral conjunctivitis and cracked lips. SPO2 was 90% in room air, blood pressure: 66/44 mmHg, pulse rate: 120 /min and respiratory rate: 36 /min. In the laboratory evaluations, anemia, hypoalbuminemia, and impaired renal function tests were noted (Table 1). According to hypotension and shock state, vasoactive drugs started in addition to meropenem, clindamycin, vancomycin, IVIG, packed cell, and albumin ( Table 1). The hemodynamic status of the patient got stable after 3 days. Liver transaminases, PT, PTT, CPK, troponin, LDH, brin degradation products (FDP), C3, C4, and CH50 were in normal range. Antistreptolysin O, antiphospholipid antibody, and antinuclear antibody (ANA) were negative too. Blood and urine culture were also negative. Chest CT-scan before admission and chest roentgenogram (CXR) at admission day were normal. COVID-19 RT-PCR result was negative but COVID-19 immunoglobulin G (IgG) was positive, which was measured a week later. On day 3, the patient complicated with edema, severe pain of right lower extremity, and venous stasis due to placement of central vein catheter of right femoral vein. Color doppler ultrasonography of lower limb veins was normal. Enoxaparin was started as prophylaxis of deep vein thrombosis (DVT). Chest CT-scan at day 4 showed COVID-19 compatible changes with mild bilateral pleural effusion. The urinary system ultrasonography was normal. Echocardiography reported mild tricuspid regurgitation, mild mitral regurgitation, mild pulmonary insu ciency, and normal ejection fraction on 3 occasions. Fever subsided 4 days after admission, vitamin D, and zinc gluconate were added to the patient's drugs. The general condition improved and inotrope drugs discontinued gradually. After 11 days, the patient discharged with complete improvement.

Case 5
He was a 14 month-old boy, presented with fever and irritability from 5 days and skin rash from 3 days ago. Maculopapular erythematous rashes rst presented from the trunk and upper limb and then generalized and edema of hands and feet developed. Cracked and erythematous lips, erythematous tongue, and bilateral non-purulent conjunctivitis also happened. During the rst admission day, the patient became toxic and transferred to the PICU. The CBC showed leukocytosis with signi cant neutrophil count. Elevated ESR, CRP, and liver transaminases and hypoalbuminemia were found. Urine analysis was normal.
COVID-19 RT-PCR was negative, CXR was normal and Chest CT-scan showed non-signi cant changes. So, cefotaxime, hydroxychloroquine, 2 gr/kg IVIG and 60 mg/kg aspirin, zinc, vitamin D, and albumin started. Echocardiography in the rst day showed normal coronary arteries, minimal right pleural effusion (5 mm), minimal mitral regurgitation without coronary artery abnormality. Because of prolonged PT and PTT, fresh frozen plasma (FFP), and vitamin K prescribed. Fever continued 2 days after IVIG infusion, and he was still toxic. So, the second dose of IVIG was infused in the fourth day of admission.
Echocardiography in that time showed diastolic dysfunction, mild right and left coronary artery dilatation in left anterior descending artery (LAD) and left circum ex artery without aneurysm. Liver transaminases, PT and PTT decreased to the normal level but leukocytosis continued and packed cell transfused for severe anemia, and ceftriaxone changed to vancomycin and meropenem. The second chest CT-scan showed non-signi cant changes. While fever subsided at day 7, hydroxychloroquine discontinued, but echocardiography showed progression in coronary arteries dilatation, moderate mitral and tricuspid regurgitation, decreased ejection fraction, and mild diastolic dysfunction, so 2 mg/kg/day prednisolone, vasoactive drugs and furosemide started. On day 10, the patient got hemodynamically stable, so vasoactive drugs tapered but abdominal distension occurred with non-signi cant ndings in the examination. Ultrasonography showed mild hepatosplenomegaly, mild intra-abdominal uid, and mild bilateral pleural effusion. The CBC showed leukocytosis and initiation of thrombocytosis (platelet count: 420.000/µL). Echocardiography showed progressive coronary artery aneurysm and beading and clopidogrel started.
Abdominal distension improved during the last 5 days, and the skin rash disappeared with pilling on day 14. Still afebrile, he was toxic. COVID-19 RT-PCR result was negative but COVID-19 IgM was positive. After that, marked thrombocytosis appeared in the CBC (platelet count: 1.168.000/µL), ESR and CRP normalized but coronary artery dilatation progressed to a giant aneurysm in day 17 as follows: right coronary artery (RCA): 8.3 mm, left main coronary artery (LMCA) and LAD: 6.7-7.2 mm with good left ventricular ejection fraction. So, warfarin and in iximab prescribed. The patient discharged from the hospital with aspirin and warfarin. Results of other evaluations during admission like serum vitamin D, LDH, CPK, and antiphospholipid antibodies were unremarkable. Two weeks later, the coronary diameters decreased to 6 mm in RCA and near to 5 mm in LMCA and LAD in follow-up echocardiography.
Case 6 A 6.5 year-old boy, presented with a history of 3 days fever, anorexia, and abdominal pain in periumbilical and hypogastric area with occasional vomiting (3 times), one loose defecation, and skin erythematous rash around ankles which spread to the trunk. He had no respiratory complaints and received a suppository of diclofenac and acetaminophen for pain and fever relief. He had a history of repaired duodenal atresia at birth. On physical exam, the patient was ill and febrile, had macular erythematous rashes around feet, hands, trunk and perioral, periorbital edema, erythema of oropharynx, right eardrum erythema and hypogastric tenderness. He had elevated ESR and CRP in addition to abnormal urine sediment. Ceftriaxone started and chest CT-scan performed with non-signi cant changes for COVID-19. Urine culture of the rst day was negative. On the second day of admission, the patient got toxic and irritable with respiratory distress, low SPO2: 87%, mild abdominal distension, and anasarca edema. The patient transferred to the PICU. Serum albumin was 2.6 g/dL, while other indexes like amylase and lipase were in normal values. So, albumin started. During the last 2 days, general condition of the patient got worst, he became anemic and more toxic, so albumin, 1 gr/kg IVIG, packed cell, hydroxychloroquine, and vitamin D were administered and ceftriaxone changed to vancomycin and meropenem. A second chest CT-scan showed bilateral opacity compatible with COVID-19. COVID-19 RT-PCR was negative but COVID-19 IgG was positive which was measured a week later. Abdominal ultrasonography showed mild splenomegaly, free interloop uid, and several reactive lymph nodes.
Echocardiography at 2 occasions reported normal coronary arteries. Other investigations like Wright, Widal, blood, urine, and stool culture were negative. Transaminases, PT, PTT, LDH, FDP, and D-dimer were in normal values. The patient's abdominal pain improved at day 6, and he discharged after 11 days.
A 7.5 year-old girl presented with a history of fever, irritability, myalgia, vomiting, diarrhea, abdominal pain, generalized erythematous maculopapular and patches from 4 days ago without respiratory complaints. Her parents were infected with COVID-19 nearly 2 weeks ago. She received diclofenac and azithromycin before admission. On physical exam, she was ill with no distress. Erythema of the throat and generalized erythematous maculopapular and patches were observed. At the admission day, lymphopenia and vitamin D de ciency were noted (Table 1). Chest CT-scan, abdominal ultrasonography and stool exam were normal and cultures of the urine, blood, and stool were negative. So, ceftriaxone, hydroxychloroquine, zinc, and vitamin D prescribed.
Evaluation for infection with COVID-19 with RT-PCR COVID-19 were negative. At the third admission day, facial edema, tachypnea and tachycardia developed and the patient got toxic with a gallop in heart auscultation. Due to marked hypoalbuminemia and anemia, packed cell and albumin were transfused. Blood urea and Cr raised, with normal values for serum electrolytes, PT, PTT, CPK, LDH, troponin, and liver transaminases. Anti-phospholipid antibodies were negative. Echocardiography showed low ejection fraction with dilated right and left ventricle, so, the diagnosis of myocarditis was raised; vasoactive drugs and 1 g/kg IVIG started and ceftriaxone changed to meropenem and vancomycin with magnesium sulphate for hypomagnesemia. CXR showed bilateral mild ground-glass opacity. Gradually, during last days, facial edema improved a little, but tachycardia and tachypnea was persistent at the 5th day. The second echocardiography report included mild pleural effusion, valve insu ciency, low ejection fraction, lack of tapering and brightness in RCA and LAD. So, another dose of IVIG (1 g/kg) with 60 mg/kg/day aspirin prescribed. With the improvement in the hemodynamic status, vasoactive drugs gradually tapered. On the 7th day, the patient became afebrile and discharged after 12 days with normal echocardiography and laboratory tests.

Case 8
A 20 month-old boy presented with intermittent fever from last week. Gradually, coryza, vomiting, and severe diarrhea, abdominal pain, irritability during urination, and loss of appetite appeared. Before admission, he received metronidazole, ce xime, nalidixic acid, diclofenac, and acetaminophen without improvement. He also had an erythematous papule with 2 centimeter diameter in the forehead and erythema of oropharynx. CBC at admission showed marked leukocytosis, thrombocytosis, anemia, and increased levels of ESR and CRP ( Table 1). The stool exam had 4-5 white blood cells and 2-3 red blood cells. PT, PTT were normal and blood levels of creatinine, urea, LDH, and CPK were in normal values. Urine analysis was unremarkable and cultures of blood, urine, and stool were negative. Abdominal ultrasonography was normal but Chest CT-scan showed bilateral ground-glass opacity compatible with COVID-19. So, the patient isolated and ceftriaxone, hydroxychloroquine, vitamin D, and zinc gluconate started. Hours after admission, he got tachypnea and SPO2 was 90% without supplementary oxygen. Unilateral tongue swelling and drooling with discrete ulcers under the tongue were seen. So, he transferred to the PICU and ceftriaxone changed to clindamycin and meropenem. Echocardiography found a lack of tapering in RCA and LAD, mild dilatation of left atrium, and diastolic dysfunction. Before starting 2 g/kg IVIG and 80 mg/kg/day aspirin, fever subsided but he was still toxic. Seven days after admission, the patient's condition improved and the second echocardiography after one week was normal. Results of COVID-19 RT-PCR, IgM, and IgG in the rst week of admission were negative.

Case 9
He was a 7 year-old boy with fever from 3 days ago. He also suffered from epigastric pain which was shifted to the right lower quadrant (RLQ) after 2 days and was not associated with eating. He had nausea, vomiting, and normal defecation pattern. He was admitted 10 days ago for acute intravascular hemolysis due to glucose 6 phosphate dehydrogenase de ciency (G6PDd) and fava bean exposure and was treated with packed cell and hydration. In the recent admission, he was ill and febrile without respiratory symptoms. On physical examination, tenderness in RLQ and rebound tenderness were noted.
Ultrasonography showed reactive lymph nodes, and free interloop uid. In the CBC, leukocytosis with a shift to left was found. ESR and CRP were markedly elevated, urine and stool were unremarkable. So, the patient received ceftriaxone plus metronidazole and underwent appendectomy, but normal appendix with some exudative secretion in the peritoneal cavity was seen during the operation. After surgery, the patient's condition got worse and became toxic, developed abdominal distension and recurrent vomiting. Abdominal X-ray was normal and repeated ultrasonography reported mild interloop uid only. A chest CT-scan showed ndings compatible with COVID-19 infection. Ceftriaxone changed to meropenem and vitamin D, hydroxychloroquine, and zinc gluconate started. Three 3 days following admission, his fever subsided and abdominal complaints got better. Other investigations like liver transaminases, serum LDH and echocardiography were normal. After 4 days, the patient discharged. COVID-19 IgM and IgG and RT-PCR during admission were negative.

Case 10
An 18 month-old girl referred for a prolonged febrile seizure. The fever started from 4 days ago and seizure was generalized tonic colonic accompanied with loss of consciousness, upward gaze, and foaming, which lasted for 40 minutes, controlled with diazepam and phenobarbital in another hospital. The family was passenger from another province of Iran. She had an epileptic sister. In physical exam, she was lethargic and febrile without abnormal ndings. In the CBC, there was lymphopenia. Cerebrospinal uid (CSF) analysis and electrolytes were normal and CSF, blood, and urine culture were negative. Serum albumin level was decreased. Meropenem, clindamycin, phenobarbital, hydroxychloroquine, and vitamin D were prescribed. Brain CT-scan and CXR had no pathologic nding and chest CT-scan showed bilateral nonspeci c opacity in inferior lobes. She was ill and lethargic during the rst two days, so albumin, 1 g/kg/day IVIG, and zinc gluconate prescribed. On the third admission day, fever continued and maculopapular rashes appeared in the trunk. So, phenobarbital discontinued and echocardiography was done which was normal. On this day, the patient got tachypnea, ABG was normal and second chest CT-scan in the 4th day had the same features of the rst. COVID-19 RT-PCR result was positive. On the 5th admission day, fever subsided and tachypnea improved within 4 days. After 3 days, the patient discharged with good general condition.

Discussion
In this case series study, 10 patients with COVID-19 associated PIMS who started the disease with unusual symptoms and signs like status epilepticus, appendicitis, TSS, KD and KD shock syndrome were reported. Due to the similarity with other diseases, these patients may be admitted to a ward that does not have respiratory isolation and may spread the disease to other patients and health care workers. Given that standard treatment for the disease has not been identi ed, this report provides our experience in management of these patients. Although children with COVID-19 are more likely to present fever and respiratory or gastrointestinal symptoms (13)(14)(15), but the most common presentation of our cases (8 cases of 10) at the time of onset was fever and rash with no respiratory symptoms, like the report of Whittaker et al. (7) and only 3 of our cases had cough or any other respiratory complaints. On the other hand, 2 of our patients didn't show any respiratory complaints.
However, three to four days after hospitalization, almost all patients developed respiratory symptoms like Shekerdemian et al.'s report (13). One of these patients had uncontrollable seizures and fever, with no other serious symptoms at the time of admission. The onset of the disease with unusual symptoms can delay the diagnosis and have irreparable consequences for the patient, or it can be confused with other diseases and management based on that disease can be performed.
The primary diagnosis of our patients were KD, TSS, prolonged febrile seizure, appendicitis, and suspected sepsis or COVID-19. In the case series reported by Whittaker et al. (7), the primary diagnosis was almost the same as this report, although one of our patients had prolonged febrile seizure, which could be the rst report.
Sixty percent of our patients had positive laboratory evidence for COVID-19, and all of them had a history of contact. Like report of Chiotos et al. (15), most of them had anemia, lymphopenia, hypoalbuminemia and increased ESR and CRP (all of them). It is notable that the laboratory abnormalities may not be prominent in the admission time, but the deterioration in such measures became more sever when the general condition of the patient get worse. In two patients, PT and PTT decreased. Interestingly, regarding more severe conditions, LDH was normal in all cases in contrast to Chiotos et al. (15). Laboratory tests showed acute kidney injury and hepatic dysfunction in 3 and 2 patients, respectively. These ndings have had different results in the studies of Verdoni et al. (5), Whittaker et al. (7), Shekerdemian et al. (13) and Chiotos et al. (15). The increase in ESR and CRP, anemia, and leukopenia were similar to our case series.
In this report, chest CT-scan was normal at the time of hospitalization in 8 patients. However, 3 days after hospitalization, like the report of Whittaker et al. (7), 5 patients had concurrent ndings compatible with COVID-19 on chest CT-scan at the same time as the respiratory symptoms. The most common chest CTscan ndings included patchy in ltration and ground glass opacity with halo or reverse halo sign in the lower lobes of the lungs and pleural effusion. In echocardiography, ejection fraction reduced in three cases, and in two cases, ectasia and in one patient aneurysm were reported. As reported by Verdoni et al.  (13), and Chiotos et al. (15), almost all these patients were admitted to PICU ward. In addition to supportive care like hydration, albumin infusion, packed cell transfusion, appropriate antibiotics, and chloroquine, IVIG was given to 6 patients at a dose of 1 g/kg and in three patients at a dose of 2 g/kg. Corticosteroids were prescribed for two patients with resistant Kawasaki disease with giant aneurism and multiorgan failure. As with other studies, the prognosis of most patients was good (4,5,7,13,15). Almost all our patients discharged without complication, except one case with giant aneurysms. There was only one death in our patients, which was due to a history of uncontrolled renal failure and late referral.
Our study was the rst report of PIMS in Iran. We aimed to share clinical characteristics, paraclinical ndings and therapeutic experiences regarding more severe pediatric COVID-19 cases who ful ll PIMS criteria. All of them were previously healthy children, except one case with CRF.

Conclusion
Although clinical manifestations and in ammatory biomarkers in most of the children are nonspeci c and milder than that in adults (16)

Availability of data and material
All data generated or analyzed during this study are included in this published article.

Consent for publication
The patients of this manuscript have not been reported in any other submission by us or anyone else. Also, written informed consent was obtained from all parents of the patients prior to manuscript submission for their personal or clinical details in addition to any identifying images to be published in this study.

Competing interests
None to be declared.

Funding
None.
Authors' contributions MS R contributed to the conception and design of the work, patients' management and supervision and revision of the study. L SH, MR N and A A drafted the manuscript. FH edited the manuscript. All authors approved the submitted version.