key: cord-0936079-ur0zble5
authors: García-Salido, Alberto; Antón, Jordi; David Martínez-Pajares, José; Garcia, Gemma Giralt; Cortés, Borja Gómez; Tagarro, Alfredo
title: Spanish consensus document on diagnosis, stabilisation and treatment of pediatric multisystem inflammatory syndrome related to SARS-CoV-2 (SIM-PedS)()
date: 2021-01-14
journal: An Pediatr (Engl Ed)
DOI: 10.1016/j.anpede.2020.09.005
sha: 3ea5e503f7fc191b9a6f0088b06dbc1fc65405b5
doc_id: 936079
cord_uid: ur0zble5

A new paediatric multisystem inflammatory syndrome, linked to SARS-CoV-2 (MIS-Paed), has been described. The clinical picture is variable and is associated with an active or recent infection due to SARS-CoV-2. A review of the existing literature by a multidisciplinary group of paediatric specialists is presented in this document. Later, they make recommendations on the stabilisation, diagnosis, and treatment of this syndrome.

Hospital Sant Joan de Déu. Institut de Recerca Sant Joan de Déu (IRSJD). 5 Sociedad Española de Pediatría Hospitalaria (SEPHO) 6 Unidad de Pediatría, Área Sanitaria Norte de Málaga. 7 Sociedad Española de Cardiología Pediátrica y Cardiopatías Congénitas (SECPCC) 8 Hospital Universitario Hospital Vall d'Hebron, 9 Sociedad Española de Urgencias de Pediatría (SEUP) 10 Hospital Universitario Cruces. 11 Sociedad Española de Infectología Pediátrica (SEIP) 12 

Introduction It is known infection by the novel coronavirus (SARS-CoV-2) in the paediatric population is usually mild. 1,2 In Spain, paediatric patients aged less than 15 years account for 0.4% of hospital admissions, 0.7% of intensive care unit admissions and 0.15‰ of deaths to date. 1 However, since the beginning of May 2020, a small number of paediatric patients have developed a hyperinflammatory syndrome with a variable presentation. 3 This syndrome is characterised by clinical and laboratory features similar to those found in Kawasaki disease (KD), toxic shock syndrome (TSS) or macrophage activation syndrome (MAS). [4] [5] [6] [7] Official health agencies, such as the Centers of Disease Prevention and Control (CDC) of the United States, the World Health Organization or the Royal College of Paediatrics and Child Health (RCPCH) have defined its general characteristics. [5] [6] [7] This novel syndrome seems to be associated with active or recent infection by SARS-CoV-2. Most affected patients have positive IgG antibody tests and elevated inflammatory markers, which suggests immune dysregulation as opposed to a direct pathogenic effect of the virus. 6, 7 In this document, we will use the term paediatric multisystem inflammatory syndrometemporally associated with SARS-CoV-2 (PIMS-TS) to refer to this condition, also known widely as multisystem inflammatory syndrome in children (MIS-C).

The definition of PIMS-TS differs slightly between these public health agencies (Table 1) . [4] [5] [6] This diagnosis should be contemplated in areas with a current or recent high incidence of cases of SARS-CoV-2 or coronavirus disease 2019 (COVID-19). 8 It has significant overlap with the different clinical forms of KD (complete KD, incomplete KD, KD shock syndrome [KDSS]). Therefore, some experts recommend considering PIMS-TS in patients meeting the diagnostic criteria for any of the forms of KD. 9 The following features are particularly relevant for suspicion of PIMS-TS: diagnostic criteria for complete or incomplete KD at any age, presence of gastrointestinal manifestations (vomiting, nausea, abdominal pain, diarrhoea), elevation of acute phase reactants, shock, hypotension, myocardial dysfunction, lymphopenia, anaemia and thrombocytopenia (Table 2) . 10 The differential diagnosis should always include the following:

-Bacterial sepsis. 

Initial care and stabilization will follow the ABCDE approach. The airway is usually patent, unless the patient presents with altered level of consciousness. Administer supplemental oxygen as needed. Monitor the oxygen saturation (SatO 2 ), along with the expired carbon dioxide (EtCO 2 ) when possible. Prepare the equipment and drugs needed for rapid sequence intubation.

Monitor the respiratory rate (RR). Tachypnoea without breathing difficulty is a possible feature in these patients (as compensation of the metabolic acidosis associated with shock). Rule out lung infection or cardiogenic pulmonary oedema. Measure and document the blood pressure (BP), heart rate (HR) and peripheral perfusion (capillary refill time, skin temperature and colour, perfusion index). Establish peripheral vascular access (ideally, 2 lines). In case it cannot be establish, consider a peripheral catheter (ideally, 2). If this fails, consider placement of an intraosseous catheter. Figure 1 presents the recommended algorithm for management of haemodynamic support. The level of consciousness, pupillary reflex, glycaemia and severity of pain must be assessed in every patient. It is also necessary to assess for the presence of exanthema and petechiae and measure the temperature. 11 Any patient with suspected PIMS-TS should be transferred to a hospital allowing multidisciplinary management. In severe cases, transfer to a hospital with a paediatric intensive care unit (PICU) is recommended. [4] [5] [6] 12 Diagnostic tests unrelated to SARS-CoV-2

Alternative infectious agents that could be causing the disease must be ruled out. Table 3 details the recommended diagnostic tests and the most frequent abnormalities found in patients with suspected PIMS-TS. [10] [11] [12] [13] Patients with shock may present with lymphopenia, anaemia and thrombocytopenia and increased levels of ferritin, LDH and D-dimer D (DD). 10 Patients with coronary aneurysms may present with even lower white blood cell and lymphocyte counts associated with elevation of C-reactive protein (CPR). [10] [11] [12] [13] 14 Compared to KD or TSS, PIMS-TS usually presents with a greater elevation of inflammatory markers. 10 Specifically, compared to complete KD, PIMS-TS is associated with higher levels of CRP, ferritin, inflammatory cytokines and Nterminal pro b-type natriuretic peptide (NT-proBNP) and a higher frequency of lymphopenia and thrombocytopenia, with no differences in DD levels. [14] [15] [16] [17] Another frequent feature is an increased neutrophil-lymphocyte ratio. There is a decrease in the CD4+, CD8+ and natural killer (NK) T cell counts. This phenomenon could be associated with the infiltration of the extracellular space by these innate immune system lymphocytes. 18 When it comes to the cytokines, PIMS-TS manifests with elevation of interleukin (IL)-1 in its soluble form (IL-1) and IL-6. [19] [20] [21] Diagnostic tests related to SARS-CoV-2

Most patients with PIMS-TS have positive results in one or more diagnostic tests for detection of acute or past infection by SARS-CoV-2. In every patient with suspected PIMS-TS, at least 1 respiratory sample should be obtained to perform a reverse-transcriptase polymerase chain reaction (RT-PCR) test. It is widely accepted that the samples that offer the highest sensitivity for detection of SARS-CoV-2 infection are bronchoalveolar lavage or endotracheal aspirate samples. Nasal swab, throat swab or nasal wash samples are also acceptable. 22, 23 If the RT-PCR test is negative and the clinical suspicion is high, we recommend repetition of the test in the next 24 to 48 hours. In case of clinical worsening requiring invasive mechanical ventilation, we recommend collection of an endotracheal aspirate sample. 22 We also recommend serologic testing of all patients, independently of RT-PCR test performance or results. The yield of serology is greater after a minimum of 10 days from the onset of symptoms. In patients with negative results of both RT-PCR and serology with a high clinical suspicion, we recommend repetition of serologic testing 3 to 4 weeks after admission. Previous studies have reported that 26 to 55% of patients with PIMS-TS have positive RT-PCR tests and up to 90% have positive for IgG antibody tests. [10] [11] [12] [13] [14] [15] [16] [17] Antibodies can be detected from 10 to 15 days after infection, and cumulative seroconversion peaks at about 16 to 21 days. 22, 23 Imaging tests Performance of plain chest radiograph or a lung ultrasound scan is indicated in patients with respiratory symptoms or to assess placement of indwelling devices (endotracheal tube or central lines). 24 The chest radiograph can detect abnormalities in a high percentage of cases. [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] Some of the radiographic features reported in the literature included pulmonary infiltration, patchy consolidation, ground glass opacities or interstitial changes, atelectasis and pleural effusion. The lung ultrasound scan can detect patterns compatible with pneumonia or a buildup of fluid in the lungs. Routine performance of a thoracic computed tomography (CT) scan is not recommended, except in patients with complicated pneumonia, significant worsening or who are immunocompromised.

An abdominal ultrasound or CT scan is indicated in patients with manifestations suggestive of acute abdomen to detect potential complications and assess the need of surgery. Ileocolitis has been described in some patients with PIMS-TS.

We recommend performance of an echocardiographic study in all patients with PIMS-TS. Echocardiographic abnormalities are not usually found in patients with mild forms. The abnormalities described in patients with more severe disease include left ventricular systolic dysfunction, right ventricular dysfunction, mitral valve insufficiency, pericardial effusion and coronary artery (CA) dilatations or aneurysms. 13 The assessment of the CAs includes calculation of CA size z-scores and classification based on the National Consensus Document on Kawasaki Disease. 26 A high proportion of patients exhibit elevation of troponin I or T (55-68%) and BNP/NT-proBNP (83-100%), with significantly higher values compared to patients with shock. 3, [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] The electrocardiographic features are generally nonspecific. Patients with PIMS-TS may exhibit abnormalities suggestive of myocardial involvement, such as low voltage, ST segment abnormalities and prolongation of the T wave or the QT interval. Different degrees of atrioventricular block and supraventricular and ventricular arrhythmias have also been reported. 9-13 Cardiovascular magnetic resonance imaging (MRI) is not indicated during the acute phase of disease. Performance of MRI should be contemplated based on the suspicion of cardiac involvement, patient safety during the test and availability of MRI in the hospital.

All patients with suspected PIMS-TS should be admitted to the ward for observation and treatment, if applicable. All efforts must be made to keep the staff that enters in contact with the patient to the minimum necessary. The staff in contact with a patient with PIMS-TS must wear, at minimum, a FFP2 mask, disposable gowns, gloves and eye protection until the patient has at least 2 negative RT-PCR test results. A high percentage of patients will have negative RT-PCR results. This is indicative of a low or no risk of transmission. In patients with J o u r n a l P r e -p r o o f potential active infection despite a negative RT-PCR test, a second RT-PCR test must be done. Figure 2 summarizes the recommendations on isolation measures, monitoring and treatment.

If admission to PICU is necessary, the patient should be placed in an isolation room, preferably one with negative pressure. 27 If performance of aerosol-generating procedures is necessary, the care staff will wear FFP3 masks, a full-face poweredair-purifying respirator, eye goggles, disposable coveralls or caps, a water-resistant disposable gown or, if the gown is not water-resistant, a water-resistant apron, and gloves. If intubation is required, use double gloves.

The patient will be accompanied by one family member or caregiver that will adhere to the isolation and hygiene measures as directed by staff and will wear, at minimum, a surgical mask, gown and gloves. If the RT-PCR is negative, modification of the required protective measures will be considered, always maintaining contact and droplet precautions.

Patients admitted to the PICU will be monitored per protocol according to their condition and disease severity. In severe cases, consider early establishment of central arterial and venous access. 28 .

Respiratory distress occurs in 70% of cases, and the need of respiratory support is usually associated with cardiovascular involvement or haemodynamic instability. 24 Administer supplemental oxygen through nasal prongs under a surgical mask to maintain the SatO 2 in the 94 to 98% range. If this is not sufficient due to the condition of the patient or the arterial blood gas values, consider high-flow oxygen therapy (HFOT) or non-invasive ventilation (NIV). Respiratory support must always be provided while maintaining isolation and protective measures.

In case of hypoxaemia in absence of hypercapnia, consider initiation of HFOT.

If HFOT is ineffective or as an alternative option, initiate NIV with continuous positive airway pressure (CPAP) with an oronasal mask, full-face mask or helmet (the latter provides the best seal). If the patient also has hypercapnia, consider bilevel positive airway pressure (BIPAP). 29 If there is no clear improvement in clinical parameters (HR, RR, respiratory distress) and oxygenation (PaO 2 /FiO 2 , SatO 2 /FiO 2 ) within a few hours, we recommend early intubation. Early intubation should also be considered in case of altered level of consciousness or fluid-refractory or catecholamine-resistant shock. 29 We recommend the following initial settings for respiratory support: tidal volume of 4 to 8 mL/kg, identification of the optimal positive end-expiratory pressure to achieve adequate alveolar recruitment, plateau pressures of less than 30 cmH 2 O and a driving pressure of less than 15 cmH 2 O. 22 If the patient develops moderate-to-severe acute respiratory distress, follow the recommendations for lung protection with permissive hypercapnia, use of the prone position and neuromuscular blockade. Nitric oxide is reserved for patients with refractory hypoxaemia, especially if it is associated with pulmonary hypertension. 30

Haemodynamic instability is usually associated with vasoplegic syndrome or heart failure. 5,31 Figure 1 summarises the recommendations for haemodynamic support and its goals. 11 In patients with heart failure administer epinephrine and consider addition of milrinone or, in case of moderate to severe heart failure, levosimendan.

Immunomodulatory therapy will be given with a stepwise approach, starting with intravenous immunoglobulin (IVIG) or corticosteroids as first-line treatment. [24] [25] [26] [27] [28] [29] [30] [31] [32] In severe or refractory cases, we recommend combining both. -Mild-moderate disease: intravenous methylprednisolone at 1-2 mg/kg/day for 3-5 days followed by discontinuation of methylprednisolone. In patients requiring treatment for 6 or more days or with persistent symptoms or elevation of inflammatory markers, step up to oral prednisone with tapering off over 2-3 weeks. -Severe disease (shock, especially in patients requiring high doses of inotropes/vasopressors): intravenous methylprednisolone at 1-2 mg/kg/day for 3-5 days or intravenous methylprednisolone at 30 mg/kg/day for 1-3 days (maximum of 1 g). If the patient responds well, continue treatment with oral prednisone at 1-2 mg/kg/day with tapering of the dose until the inflammatory markers normalize. -Kawasaki-like disease: combine corticosteroids and IVIG in patients at high risk of IVIG resistance (male, age < 12 months, CPR > 100 mg/L, platelet count < 300 000/mm 3 , alanine aminotransferase > 100 IU/L, neutrophil count > 80%, sodium < 133 mmol/L). 9

In t e r l e u ki n -1 inhibito r s An IL-1 receptor antagonist (anakinra) has been used successfully in patients with severe pneumonia and hyperinflammation associated with SARS-CoV-2 infection, 33 MAS and KD refractory to IVIG/corticosteroid therapy. Thus, it may be beneficial to patients with PIMS-TS. It is considered a safe drug on account of its short half-life, quick action and infrequent association with bacterial superinfections. Although it is distributed in syringes for subcutaneous administration, it has been delivered intravenously in severely ill patients. 5-10 The duration of treatment would be of 5 to 14 days depending on the clinical response (Table 4 ).

Infliximab has been proposed as an alternative treatment in patients with IVIGresistant KD, but in clinical trials, while it achieved quicker improvement of symptoms and la boratory parameters, it did not improve long-term cardiovascular outcomes. 10, 11 There are few data on its use in patients with PIMS-TS (Table 4 ).

In t e r l e u ki n -6 inhibit o r s Tocilizumab is approved for treatment of CAR T-cell-associated cytokine release syndrome and several trials are currently underway of its use in patients with SARS-CoV-2 pneumonia. It has been used in select cases of PIMS-TS, but the use of tocilizumab in patients with KD could accelerate the development of coronary aneurysms 34, 35 (Table 4 ).

At the time of this writing, there is no evidence on the efficacy or safety of any antiviral used for treatment of SARS-CoV-2 infection in children. We recommend against the use of hydroxychloroquine 36, 37 or hydroxychloroquine combined with azitromicin. 37, 38 While the role of SARS-CoV-2 in the development of PIMS-TS remains unclear, treatment with remdesivir should be contemplated in case of active infection, high suspicion of SARS-CoV-2 or severe disease (Table 5) . Remdesivir can be administered to paediatric patients in the context of a clinical trial or after obtaining authorization for expanded access. 39 An t i t h r o m b o t i c and a n t i a g g r e g a n t t h e r a p y In d i c a t i o n s f o r l o w m o l e c u l a r w e i g h t h e p a r i n Consider prophylaxis with low molecular weight heparin in the following cases 39 

Patients with PIMS-TS may be eligible for extracorporeal membrane oxygenation if they fail to respond to maximal conventional therapies, their condition is deemed reversible and they have no absolute contraindications for ECMO. 40 These patients must be referred before their condition precludes conventional transport. When the latter occurs, consider transport under ECMO with cannulation at the referring hospital performed by qualified staff.

Assess the potential risk of transmission of SARS-CoV-2 in the household. Patients with a negative RT-PCR test and a positive IgG test are not considered infectious. Also, positive detection of IgG antibodies combined with a positive RT-PCR test or seroconversion after negative PCR results is currently interpreted as detection of dead viral remnants that are not infectious. We recommend followup by a multidisciplinary team at the outpatient level, with involvement of the primary care paediatrician (Figure 2 ).

Jordi Antón has received research grants, speaker and consultant fees and financial support to attend medical congresses from Sobi and Roche. Esmeralda Núñez has participated in educational activities sponsored by AbbVie, Roche and Sobi. Inmaculada Calvo has participated in educational activities sponsored by Novartis, AbbVie, Sobi, Roche and GSK and collaborated in workshops offered by GSK, Novartis and Sobi. Javier Pérez-Lescure Picarzo has received fees from MSD for delivery of educational programmes. The rest of the authors have no conflicts of interest to declare. table in the case  definition) . It may include children fulfilling full or partial criteria for Kawasaki disease Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus SARS-CoV-2 PCR testing may be positive or negative BNP, B-type natriuretic peptide; COVID, coronavirus disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, interleukin 6; LDH, lactate dehydrogenase; PCT, procalcitonin; PPT, partial prothrombin time; PT, prothrombin time; RT-PCR, reverse transcription-polymerase chain reaction.

Clinical manifestations ▓Fever (in nearly 100% of cases); fever > 3 days (a shorter duration does not rule out PIMS-T S) ▓Gastrointestinal symptoms (> 50%): abdominal pain, vomiting, diarrhoea ▓Rash (scarlatiniform rash, erythroderma, erythema multiforme, livedo reticularis), non-exudative conjunctivitis, mucosal abnormalities, peripheral abnormalities (>2/3 patients) ▓Shock, tachycardia, hypotension, hypoperfusion (approximately half of patients) ▓Headache, meningism, confusion (10-20%) ▓Respiratory symptoms: cough, dyspnoea (30-60%) Laboratory findings ▓Complete blood count : leucocytosis with lymphopenia, neutrophilia and thrombocytopenia Elevated CPR (> 20 mg/L), PCT (> 0.5 µg/mL), IL-6 (> 8.5 pg/mL) and ferritin (> 120 mg/dL)

Increased fibrinogen (> 400 mg/dL) Significant D-dimer elevation D (> 500 ng/mL) Abnormal PT /PPT Blood culture

Usually negative Other Coinfections [0,1-2]▓Urine culture [0,1-2]▓PCR respiratory panel in nasal aspirate sample [0,1-2]▓Stool culture/PCR for detection of pathogens in stool CPR, C-reactive protein; IL-6, interleukin 6; PCT, procalcitonin; PPT, partial prothrombin time; PT, prothrombin time. a Suggested values, consider the reference values used at the hospital. 

Análisis de los casos de COVID-19 hasta el 10

Estudio ENE-COVID19: segunda ronda estudio nacional de seroepidemiología de la infección por SARS-CoV-2 en España

Multi-Inflammatory Syndrome in Children related to SARS-CoV-2 in Spain

Emergency Preparedness and Response Multisystem In Ammatory Syndrome in Children ( MIS-C ) Associated with Coronavirus Disease

Guidance: paediatric multisystem inflammatory syndrome temporally associated with COVID-19

Multisystem inflammatory syndrome in children and adolescents with COVID-19

Rapid risk assessment: Paediatric inflammatory multisystem syndrome and SARS -CoV-2 infection in children

Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2

Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children

Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multiinstitutional Study from New York City

Hyperinflammatory shock in children during COVID-19 pandemic

Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study

Characteristics of

Peripheral Lymphocyte Subset Alteration in COVID-19 Pneumonia

An inflammatory profile correlates with decreased frequency of cytotoxic cells in COVID-19

Severe SARS-CoV-2 Infection in Children With Suspected Acute Abdomen: A Case Series From a Tertiary Hospital in Spain

On the Alert for Cytokine Storm: Immunopathology in COVID-19

Serology characteristics of SARS-CoV-2 infection after exposure and post-symptom onset

Interpreting Diagnostic Tests for SARS-CoV-2

Screening and Severity of Coronavirus Disease 2019 (COVID-19) in Children in Madrid, Spain

Multisystem Inflammatory Syndrome in U

Personal protective equipment for preventing highly infectious diseases due to exposure to contaminated body fluids in healthcare staff

et associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study

Clinical Consensus Recommendations Regarding Non-Invasive Respiratory Support in the Adult Patient with Acute Respiratory Failure Secondary to SARS-CoV-2 infection

Paediatric Inflammatory Multisystem Syndrome: Temporally Associated with SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital

Clinical Guidance for Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19

Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic macrophage activation syndrome

Coronary-Artery Aneurysm in Tocilizumab-Treated Children with Kawasaki's Disease

Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: A systematic review and meta-analysis

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Extracorporeal Life Support Organization COVID-19 Interim Guidelines

µg/kg/min IV/IO If signs of warm shock, administer norepinephrine > 0.05 µg/kg/min

We thank all health care professionals involved in paediatric care, patients and their families.