key: cord-0750285-ipv0f44e
authors: Mehler, Katrin; Jung, Norma; Oberthuer, Andre
title: Is it all MIS-C? - Unusual findings in a series of nine German patients with multi-system inflammatory syndrome in children (MIS-C) after SARS-CoV2 infection
date: 2021-04-20
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.04.044
sha: 5f3783957af66e9d1f5792d79722cf3a36a394f8
doc_id: 750285
cord_uid: ipv0f44e

Objectives Multi-system inflammatory syndrome in children (MIS-C) is a post-viral inflammatory vasculopathy of children and adolescents following Covid-19 infection. Since the incidence of SARS-CoV-infections has been increasing in Germany since October 2020, we observe an increasing number of children presenting with MIS-C. Design We present detailed clinical charactersitics of a cohort of nine children with MIS-C admitted to a tertiary PICU at the University Hospital of Cologne between March 2020 and February 2021. Results The clinical sings and sypmtoms are largerly in line with recent reports. All but one patient had positive SARS-CoV-2 antibodies. Latency form infection to MIS-C was 4-6 weeks. Two children presented with unuauals fundings: A girl had encephalomyelitis and an boy developeed MIS-C side to side with acute leukemia. Conclusion MIS-C has been increasing in Germany paralell to SARS-CoV-2 infections. Rarely, unuasual findings may be associated with MIS-C.

Multi-system inflammatory syndrome in children (MIS-C) is a post-viral inflammatory vasculopathy of children and adolescents following Covid-19 infection. Since its first description in May 2020 (Verdoni et al., 2020) , specific diagnostic criteria have been issued by the CDC (Centers for Disease Control and Prevention) and the WHO (World Health Organisation). Recently, case series have been reported from the UK (Davies et al., 2020) and Spain (Garcia-Salido et al., 2020) and a systematic review summarized numerous MIS-C cases from European, American and Asian countries (Radia et al., 2020) . In Germany, the incidence of Covid-19 infections in spring 2020 was low, showing a maximum of 6500 infections on the 2 nd of April. Furthermore, numbers were decreasing rapidly reaching <2000 on 24 th of April (https://corona.rki.de). Consequently, patients with MIS-C have been rare in Germany during the first wave of the pandemic. However, with a marked increase of children hospitalized for Covid-19 infections (a total of 1056 children up to February 2021 (https://dgpi.de/covid-19-survey-update-2021)), pediatric intensive care units (PICU) in Germany are confronted with a rising number of children with MIS-C (a total of 137 up to February 2021) (https://dgpi.de/pims-survey-07-2020).

We here present detailed clinical characteristics of a cohort of nine children with MIS-C admitted to a single tertiary PICU at the University Hospital of Cologne between March 2020 and February 2021.

Of note, only a single MIS-C case occurred prior to September 2020. To rule out that MIS-C patients might have been unrecognized, we retrospectively assessed our PICU admissions from January to September 2020 but did not identify additional patients with MIS-C. This is in line with a recent systematic review (Radia et al., 2020) , in which numerous patients from the US, France and the UK were included, but which comprised only a single German patient. Moreover, in a nation-wide MIS-C survey in Germany and Austria only 43 children with MIS-C were reported within the first 23 weeks of 2020 compared to 94 children within the following 11 weeks. As compared to 74 cases from Spain between March 1 st and June 15 th and 78 cases form the UK occurring between April 1 st and May 10 th , the German numbers were distinctively lower.

Interestingly, all but one child came from immigrating families (Turkey, Syria, Iran, India and Eastern Europe). Similar findings were reported before in a small case series on three teenagers with MIS -C (Ng et al., 2020) . Furthermore, a recent study from Norway demonstrated a higher risk for SARS-CoV-2 infection in immigrants presumably caused by social disparity (Indseth et al., 2021) .

The clinical signs and symptoms as well as the laboratory findings of our patients are largely in line with recent reports (Table 1 ): all but one child had positive SARS-CoV-2 IgA and IgG antibodies and three had positive PCR tests. Of note, in our case series, latency between Covid-19 and MIS-C was 4-6 weeks in most patients. All patients had persistent high fever and signs of hyperinflammation with markedly elevated CRP and ferritin levels but less pronounced PCT levels. Gastrointestinal symptoms were common and were the cause for hospital admission in three patients. Additionally, cardiac involvement was observed frequently, indicated by increased troponin T levels and abnormal echocardiographic findings such as pericardial effusion, impaired fractional shortening or coronary anomalies.

Two children presented with unusual findings: A girl aged 11 months was admitted after cardiac arrest at home. She had no evidence of any previous illness except for self-limited diarrhea a few days ago.

An MRI scan of her brain showed distinct signs of encephalomyelitis ( Figure 1 ) but CSF analysis was unremarkable and failed to identify a pathogen. She was discharged in a minimal conscious state and passed away a few months later. Apart from the unusual pattern of her brain MRI scan, she had frequent episodes of generalized flush that were unresponsive the any medication but were selflimiting after 10-30 minutes. Neurologic symptoms in MIS-C are wide-ranging (Lin et al., 2021) , but mostly non-specific such as headache and fatigue. Severe neurological complications such as coma, encephalopathy, ataxia and peripheral neuropathy were described in individual cases, but we did not find any reports highlighting MRI abnormalities comparable to our case. Although the majority of neurological symptoms in children were reported to improve, data on long-term neurodevelopm ent are elusive. Our case probably indicates that MIS-C might be associated with critical neurological sequelae in a small number of cases.

The second case was a 15 year old boy who developed severe MIS-C while receiving chemotherapy for newly diagnosed acute myeloid leukemia. Intriguingly, leukemia was diagnosed only a few weeks after an oligosymptomatic SARS-CoV2-infection. After two days of induction chemotherapy with cytarabine he developed sudden dyspnea and was admitted to the PICU where he was treated with broad-spectrum antibiotics for suspected septicemia. No pathogen was identified but his respiratory function deteriorated, and he required mechanical ventilation for ARDS. Following a steroid pulse, he was successfully weaned from mechanical ventilation after three days, but his pulmonary function deteriorated again after a few days of chemotherapy. This time he rapidly progressed to severe ARDS with hemorrhagic alveolitis. He was mechanically ventilated and was started on rescue ECMO therapy for 25 days and he continued on mechanical ventilation after tracheostomy. Although his respiratory function improved, he developed both cerebral and pulmonary aspergillosis treated with neurosurgery and a triple antifungal medication. Despite these efforts he passed away after two months of intensive care treatment. While there is at present no evidence that infection with the SARS-CoV2 virus could trigger leukemic malignancies, the observation that only short cytotoxic treatment was followed by severe MIS-C associated organ failure to our minds is intriguing. Clinically, it appeared that MIS-C was triggered by chemotherapy treatment, raising the question if cytotoxic dose might need to be reconsidered carefully in patients with recently past Covid-19 infections.

The authors (Katrin Mehler, Norma Jung and Andre Oberthuer) declare no conflict of interests Funding source: The study was not funded.

Ethical approval: Approval was not required.

J o u r n a l P r e -p r o o f 

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