Bahrami, A.

Moazzami, B.

Rezaei, N.

Vafapour, M.

eprints Iran University of Medical Sciences

INSTRUCTIVE CASEHyperinflammatory shock related to COVID-19 in a patientpresenting with multisystem inflammatory syndrome in children:First case from IranAhmad Bahrami,1 Maryam Vafapour,2 Bobak Moazzami 3,4 and Nima Rezaei3,4,51Division of Allergy and Immunology, Ali-Asghar Hospital, Iran University of Medical Sciences, 2Ali-Asghar Hospital, Department of Pediatrics, Iran Universityof Medical Sciences, 3Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, 4Department ofImmunology, School of Medicine, Tehran University of Medical Sciences and 5Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA),Universal Scientific Education and Research Network (USERN), Tehran, IranThe novel coronavirus (SARS-CoV-2) that is responsible for coro-navirus disease (COVID-19) has emerged as a global crisis.1According to the Johns Hopkins University information site, as of4 June 2020, over 6.29 million cases have been confirmed, andabout 380 000 deaths due to COVID-19 have been reportedworld-wide. The severity of the disease has been reported torange from mild to severe and eventually death.1 Paediatricpopulations seem to comprise only a small proportion of totalaffected individuals and are less likely than adults to be severelyaffected by COVID-19. According to a recent epidemiologicalstudy, 731 cases of COVID-19 were confirmed in children, ofwhom more than 90% of patients were reported as asymptom-atic or with mild to moderate symptoms.2 The clinical presenta-tion of paediatric patients may differ from those of the adults andcan range from asymptomatic to acute upper respiratory tractinfection, gastrointestinal symptoms with shock or coagulationdysfunction in severe cases.To date, the exact pathophysiology of COVID-19 has not beenfully understood. However, emerging evidence suggests that avascular disease process may be a contributing factor in COVID-19 pathogenesis.3 These findings indicate that direct viral-mediated tissue damage and endothelial dysfunction in the set-ting of an inflammatory state could be responsible for variousadverse outcomes.A growing body of evidence from the UK, Europe and theUSA suggests that a number of paediatric patients could presentwith fever, rash and shock with concomitant COVID-19 infection.Recently, the Royal College of Paediatrics and Child Health(UK) called this phenomenon paediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2.4 Simi-larly, the Centers for Disease Control and Prevention (USA)termed this new presentation multisystem inflammatory syn-drome in children (MIS-C). The exact underlying mechanismsfor this Kawasaki disease (KD)-like condition described in thesereports are not clear; but may be due to antibody or immune-complex mediated effects in the setting of a post-infectious del-ayed inflammatory process.Herein, we describe an Iranian paediatric case of a concurrentKD-like inflammatory syndrome and COVID-19 infection whopresented with shock.Case ReportThe patient was a 5-year-old girl who presented to paediatricurgent care with 5 days of high-grade fever, vomiting, diarrhoeaand abdominal pain, which had been managed as an outpatientas a viral infection. On the third day, she developed conjunctivi-tis, blotchy rash and swelling of the hands. In the patient’s his-tory, she had experienced upper respiratory symptoms over thepast 3 weeks that had improved with supportive care. At the ini-tial clinical examination, the patient was ill and had generalisederythematous skin rash, non-purulent bilateral conjunctivitis,periorbital oedema and erythema, swelling and congestion of thelips, mild swelling of the hands and moderate dehydration due tovomiting and diarrhoea (Fig. 1). There was no evidence oflymphadenopathy. Vital signs showed a temperature of 39.5C,sinus tachycardia (165 beats/min), tachypnoea with normalKey Points1 A growing body of evidence from the United Kingdom (UK),Europe, and the United States of America (USA) suggests thata number of paediatric patients could present with Kawasaki-like symptoms such as fever, rash and shock with concomitantCOVID-19 infection which has been referred to multisysteminflammatory syndrome in children (MIS-C).2 The negative results of polymerase chain reaction (PCR) testfor COVID-19 in a patient with high levels of serum IgG couldsuggest that the virus had been cleared and the presence ofKawasaki-like manifestations may be due to delayed immune-mediated phenomenon caused by COVID-19.3 Despite the growing number of MIS-C cases around the world,many questions remain unanswered about the underlying patho-physiology of hyperinflammatory shock related to COVID-19 aswell as treatment modalities, epidemiological and clinical charac-teristics associated with MIS-C.Correspondence: Professor Nima Rezaei, School of Medicine, TehranUniversity of Medical Sciences, Children’s Medical Center Hospital,Dr. Gharib Street, Keshavarz Boulevard, Tehran 1419733151, Iran. Fax:+9821 6692 9235; email: rezaei_nima@tums.ac.irConflict of interest: None declared.Accepted for publication 9 June 2020.doi:10.1111/jpc.15048Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)1breath sounds and an oxygen saturation of 98% and the bloodpressure was 75/55. Laboratory tests revealed lymphopaenia,thrombocytopaenia, mildly elevated C-reactive protein (CRP) of23 mg/L and erythrocyte sedimentation rate of 40 mm/h. Shehad hyponatraemia (Na: 120 mEq/L) and elevated liver functiontests (Table 1). About 4 weeks before she was admitted to ourhospital, she had a positive history of exposure to her uncle whowas diagnosed with COVID-19. Owing to this history of expo-sure, reverse transcriptase-polymerase chain reaction (RT-PCR)and serology for SARS-CoV-2 were requested. The PCR was neg-ative on two occasions; however, IgG for SARS-CoV-2 was posi-tive (IgG: 10.3 times higher than reference standard; IgM: 0.2times lower than reference standard; normal range was definedas lower than 1.1 ratio) suggesting previous SARS-CoV-2infection.Prompt treatment with fluid resuscitation was initiated due tothe patient’s dehydration and low blood pressure. After vitalsigns stabilised, the patient was evaluated for the possible diag-nosis of KD. After establishing the diagnosis, standard treatmentfor KD was started according to guidelines. She was treated witha single dose of 2 g/kg intravenous immunoglobulin (IVIG) andhigh-dose acetylsalicylic acid. The patient’s fever subsided afterthe initiation of IVIG and she was without fever for about 24 h.However, she developed high-grade fever again as well as hypo-tension the next day. In serial laboratory tests, a markedly ele-vated CRP level along with high procalcitonin and D-dimer wereobserved (Table 1). There was evidence of shock and IVIG-resistant KD. Inotropic management of the shock with epineph-rine was started for the patient. According to advice from theinfectious diseases team, broad-spectrum antibiotics includingmeropenem, vancomycin and ciprofloxacin was also adminis-tered. After the shock resolved, a second dose of the IVIG wasinitiated.There were no significant findings on chest X-ray and theechocardiogram was normal with no evidence of coronary arterydilation. Our patient suffered from severe generalised abdominalpain. On abdominal ultrasound scan, a fluid accumulation mea-suring 33 × 34 × 14 mm was localised in the right lowerFig 1 Skin rash, congestion of the lips and periorbital edema and ery-thema. Image shared with parental permission.Table 1 The laboratory data of the patient at baseline, during and after treatmentLaboratory tests Baseline† During hospitalisation‡ After treatment§WBC, ×103/mm3 5.2 (Neu: 73%, Lym: 22%, Band: 3%, EO: 2%) 7.3 6.8Hb, g/dL 11.5 9.7 8Platelet count, mg/dL 93 187 294ESR, mm/h 40 89 3CRP, mg/L 23 103–220 6D-Dimer, mg/L 2.5 1.2 0.3Procalcitonine, ng/mL NA >100 1.4AST, U/L 94 114 NAALT, U/L 111 76 NABUN, mg/dL 15 10.2 NACr, mg/dL 0.8 0.21 NANa, mEq/L 120 127 NAK, mEq/L 4.2 4.9 NACa, mg/dL 8.6 NA NA†Baseline laboratory values referred to outpatient results prior to admission.‡Referred to 1 week after admission.§Referred to 1 week post-discharge.ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate;Hb, haemoglobin; NA, not available; WBC, white blood cell.2 Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)Hyperinflammatory Shock and COVID-19 A Bahrami et al.quadrant and a volume of 9 mL was reported. After 48 h, theabdominal ultrasound scan was repeated in which a mild freefluid collection was noted in the right paracolic area and pelvis.During this time, the patient had orthostatic hypotension andlower limb mottling while standing which was due to the pres-ence of hyperinflammatory shock (Fig. 2). The symptoms andfever were present for another 48 h. All of our patient’s signs andsymptoms began to improve on the third day of hospitalisationafter starting the second dose of IVIG and antibiotics. Antibiotictreatment was continued for 1 week. The patient’s blood cultureand adenovirus-specific PCR tests were negative. At the time ofdischarge, evidence of desquamation was observed on thepatient’s fingers. The patient was discharged with instructions totake low dose aspirin (3 mg/kg daily) and plans for repeating herfollow-up echocardiogram 1 week after discharge.DiscussionSince the first reported KD-like case of a 6-month-old femaleinfant who was concurrently diagnosed with COVID-19 inStanford Children’s Hospital in USA, a growing number of MIS-Ccases have been reported world-wide.5 Recently, an Italiancohort of KD-like cases in Bergamo province, which experiencedthe highest rate of COVID-19 infection and death in Italy,reported a sudden surge of new cases of KD with an increasedincidence of nearly 30-fold over the past 5 years in that region.6Although it has been hypothesised that a delayed immuneresponse to the virus might be contributing to the clinical featureof MIS-C, the exact link between COVID-19 and MIS-C remainsunclear.The role of respiratory viruses in the pathogenesis of KD is notfully understood. According to previous studies, the most com-mon viruses detected in KD patients were rhinovirus and entero-virus.7 Although most of the reported COVID-19 cases amongchildren experienced mild symptoms, the potential to progress toa more severe course such as with shock still exist and could leadto permanent organ damage and mortality. The observed nega-tive results of PCR in our patient along with high levels of serumIgG could suggest that the virus had been cleared and the mani-festations displayed in this patient may be due to delayedimmune-mediated phenomenon caused by COVID-19.8 How-ever, limited data exist regarding the exact immunological mech-anism of COVID-19 in predisposing individuals tohyperinflammatory shock.The patient presented in this study had severe symptomsconsistent with MIS-C and developed hyperinflammatory shockduring the admission but had a good response to standard treat-ments. The high procalcitonin and CRP levels along with symp-toms of shock in this patient suggest a serious and life-threatening medical condition. With respect to her history ofcontact with COVID-19, preceding upper respiratory tractsymptoms, positive IgG for SARS-CoV-2 and negative bloodculture; our patient’s symptoms appear to be related to COVID-19. As more cases of concurrent COVID-19 and MIS-C havebeen increasingly reported world-wide, whether this relation-ship is causation or association is not yet fully elucidated. Onthe epidemiological aspect of the current pandemic, the timingbetween positive cases of COVID-19 and identification of newcases of MIS-C in various locations, suggest that this phenome-non may be partly contributed to by a delayed immune-mediated process that is triggered by the SARS-CoV-2 infection.This observation is supported by the fact that the majority ofreported cases were PCR negative for SARS-CoV-2, while serol-ogy testing has been found to be positive in many cases.6 Nev-ertheless, it is worth noting that although vasculitis is known tobe caused by coronavirus, it is too early to conclude that KD isdue to coronavirus.Despite the growing number of reported cases, many ques-tions remain unanswered about the new coronavirus such asthe treatment modalities, epidemiological, and clinical featuresassociated with COVID-19, especially in the paediatric popula-tion. Early recognition and management of this novel phenome-non is crucial in order to minimise potential complications ofthis disease in the paediatric population. Further studies areneeded to increase our knowledge regarding MIS-C related toCOVID-19 pathogenesis.Written informed consent for publication of this patient’s clini-cal details and clinical images was obtained from the parents.Fig 2 Lower limb mottling.Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)3A Bahrami et al. Hyperinflammatory Shock and COVID-19AcknowledgementWe would like to thank both our patient and her family for let-ting us share their experience. Also, we thank all doctors andnurses who fought bravely during this pandemic.References1 Wu F, Zhao S, Yu B et al. A new coronavirus associated with humanrespiratory disease in China. Nature 2020; 579: 265–9.2 Dong Y, Mo X, Hu Y, Qi X, Jiang F, Tong S. Epidemiological characteris-tics of 2143 pediatric patients with 2019 coronavirus disease in China.Pediatrics 2020; e20200702. https://doi.org/10.1542/peds.2020-07023 Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU:Vascular dysfunction, thrombosis, and dysregulated inflammation.Intensive Care Med. 2020; 28: 1–4.4 Royal College of Paediatrics and Child Health. Guidance—PaediatricMultisystem Inflammatory Syndrome Temporally Associated withCOVID-19. UK: Royal College of Paediatrics and Child Health (RCPCH);2020. Available from: https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19 [accessed 25 May 2020].5 Jones VG, Mills M, Suarez D et al. COVID-19 and Kawasaki disease:Novel virus and novel case. Hosp. Pediatr. 2020; 10: 537–40.6 Verdoni L, Mazza A, Gervasoni A et al. An outbreak of severeKawasaki-like disease at the Italian epicentre of the SARS-CoV-2epidemic: An observational cohort study. Lancet 2020; 395:1771–8.7 Turnier JL, Anderson MS, Heizer HR, Jone PN, Glode MP,Dominguez SR. Concurrent respiratory viruses and Kawasaki disease.Pediatrics 2015; 136: e609–6.8 Giamarellos-Bourboulis EJ, Netea MG, Rovina N et al. Complex immunedysregulation in COVID-19 patients with severe respiratory failure. CellHost Microbe 2020; 27: 992–1000.e3.4 Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)Hyperinflammatory Shock and COVID-19 A Bahrami et al.

Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: First case from Iran

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Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: First case from Iran

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