García‑Salido et al. Crit Care (2020) 24:666 https://doi.org/10.1186/s13054-020-03332-4 RESEARCH Open Access Severe manifestations of SARS‑CoV‑2 in children and adolescents: from COVID‑19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain Alberto García‑Salido1†, Juan Carlos de Carlos Vicente2†, Sylvia Belda Hofheinz3, Joan Balcells Ramírez4, María Slöcker Barrio5, Inés Leóz Gordillo1, Alexandra Hernández Yuste6, Carmina Guitart Pardellans7, Maite Cuervas‑Mons Tejedor8, Beatriz Huidobro Labarga9, José Luís Vázquez Martínez10, Míriam Gutiérrez Jimeno11, Ignacio Oulego‑Erróz12, Javier Trastoy Quintela13, Carmen Medina Monzón14, Laura Medina Ramos15, María Soledad Holanda Peña16, Javier Gil‑Antón17, Clara Sorribes Ortí18, José Carlos Flores González19, Rosa María Hernández Palomo20, Inma Sánchez Ganfornina21, Emilia Fernández Romero22, María García‑Besteiro23, Jesús López‑Herce Cid5, Rafael González Cortés5* and the Spanish Pediatric Intensive Care Society working group on SARS-CoV-2 infection Abstract Background: Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admit‑ ted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia. Methods: A multicentric prospective national registry including 47 PICUs was carried out. Data from children admit‑ ted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared. Results: Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5–11.8) vs 3.4 years (IQR 0.4–9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more fre‑ quently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a *Correspondence: rafa_gonzalez_cortes@hotmail.com † Alberto García-Salido and Juan Carlos de Carlos Vicente contributed equally to this work 5 Paediatric Intensive Care Unit, Hospital General Universitario Gregorio Marañón, Calle Doctor Castelo 47, 28007 Madrid, Spain Full list of author information is available at the end of the article © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat​iveco​ mmons​.org/publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. García‑Salido et al. Crit Care (2020) 24:666 Page 2 of 13 lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lympho‑ cyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5–8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group. Conclusions: MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infec‑ tion. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients. Keywords: SARS-CoV-2, Pediatric multisystem inflammatory syndrome temporally associated with COVID-19, Kawasaki disease, Toxic shock syndrome, Children, Critical care, Shock Background Although the presence of KD symptoms has been pre- In January 2020 a novel coronavirus (SARS-CoV-2) viously described in patients with infections by other was described in Wuhan, China. This virus pro- coronaviruses [31, 32], the evidence provided on KD in duces the coronavirus disease 2019 (COVID-19), and pediatric patients with SARS-CoV-2 in the scientific lit- its rapid spread has led to the declaration of a global erature is very limited. health emergency and pandemic by the World Health The purpose of this prospective multicenter registry Organization [1, 2]. The infection affects adults more carried out in Spain, is to compare the cases of pediatric frequently than children and the clinical manifestations patients with SARS-CoV-2 infection and clinical symp- of the infection are generally less severe in pediatric toms consistent with MIS-C to those with SARS-CoV-2 patients than in adults [3–7]. infection not fulfilling MIS-C criteria. To date, the scarce literature on pediatric patients with SARS-CoV-2 infection shows that it most com- Methods monly affects short-age children in the form of respira- The Spanish Society of Pediatric Intensive Care pro- tory problems [3, 4, 6–10], although severe respiratory moted the creation of a multicentric prospective registry symptoms are significantly more frequent in adults of pediatric patients with SARS-CoV-2 infection admit- than in children [11]. Indeed, only a low proportion of ted to PICUs in Spain. The Registry was approved by the pediatric patients with SARS-CoV-2 infection require Institutional Review Board of the coordinating center intensive care [12, 13], and mortality is lower in chil- (Hospital General Universitario Gregorio Marañón). dren than in adults [12]. The Registry is fed by 47 PICUs, which account for more By the end of April 2020 and the beginning of May, than 90% of the PICUs of the Spanish health system. several scientific societies reported a new clinical pres- Researchers at each participating PICU were responsi- entation related to SARS-CoV-2 infection [14–17]. This ble for identifying those who fulfilled inclusion criteria syndrome, known as multisystem inflammatory syn- among every admitted patient during the study period. drome temporally associated with COVID-19 (MIS-C), is Written informed consent was obtained from patients or characterized by fever, abdominal pain, gastrointestinal their parents before data collection. Data about patients and cutaneous symptoms, and hemodynamic alterations. who met inclusion criteria were collected by an elec- As described in these reports, MIS-C has similar features tronic data collection form and entered into the Registry to those of Kawasaki disease (KD), toxic shock syndrome by researchers at each site. Data were collected between (TSS), bacterial sepsis, and macrophage-activation syn- the 1st of March 2020 and the 15th of June 2020. Partial drome. To date, several publications have reported clus- data from patients included in the study have been previ- ters of patients with different severity in the UK [10, ously published as case series elsewhere [29, 30]. 18–21], Italy [22], France [23–25], and the USA [26–28]. In Spain, 5 cases of children presenting with suspected Inclusion criteria acute abdomen and SARS-CoV-2 infection were initially All patients younger than 18 years admitted to a PICU reported in a single-center study [29]. General data of with a diagnosis of SARS-CoV-2 infection were included. patients with SARS-CoV-2 admitted to Spanish PICUs Patients who met the case definition for MIS-C accord- have been published with no differentiation of those pre- ing to the criteria of the Royal College of Paediatrics and senting with MIS-C in a previous report [30]. Child Health (RCPCH) [14] were also included, even García‑Salido et al. Crit Care (2020) 24:666 Page 3 of 13 lacking a confirmed microbiological diagnosis of SARS- the hands and feet); cervical lymphadenopathy; arterial CoV-2 infection. hypotension; renal, hematological, or hepatic involve- A case of MIS-C was defined as persistent fever (for ment; presence of Acute Respiratory Distress Syndrome longer than 4 days), laboratory data showing inflamma- (ARDS); neurological involvement, or soft tissue necro- tion (neutrophilia, lymphopenia, or elevated C-reactive sis. The presence of ARDS was defined following the protein) and evidence of organ dysfunction (as described Pediatric Acute Lung Injury Consensus Conference cri- in the variables section) with other additional symptoms teria [33]. For renal involvement, the definition employed such as cutaneous–mucosal or abdominal involvement. was an increase in creatinine levels of double the normal Patients with other infections explaining their symptoms limits for the age of the patient or twice as baseline cre- were excluded. Polymerase chain reaction (PCR) testing atinine levels. The considered definition of hematologic for SARS-CoV-2 in patients with MIS-C may be positive involvement included the presence of coagulopathy or negative [14]. (aPTT or PT above normal limits) or thrombocytopenia As cases consistent with MIS-C may have been over- (< 100,000 platelets/mcl). Liver involvement was defined looked before the definition of this entity was published, as an increase in transaminase or bilirubin levels twice researchers at every participating PICU were asked to above baseline or normal values for the age of the patient. perform a retrospective review of all admissions since Laboratory data on admission and during hospital stay the Registry’s inception. None of the participating PICUs were also collected, including hemoglobin, leukocyte and identified any patient who met the established criteria platelet counts, coagulation tests, D-dimer, creatinine, and had not been previously included in the Registry. urea, liver function markers, LDH, and ions. Inflamma- tory markers such as C reactive protein (CRP), procal- Variables collected citonin (PCT), and IL-6 were recorded. In patients with Collected data included the date of admission to and dis- hyperinflammatory symptoms, NT-ProBNP, and serum charge from PICU, demographic variables; any medical troponin levels were also included. Microbiologically history of interest; and the main reason for PICU admis- confirmed diagnosis of SARS-CoV-2 infection (PCR and sion. Other data included were clinical diagnosis within serology) was also recorded. PCR testing was performed the first 24 h of admission, severity scores (PRISM III) on nasopharyngeal swab samples. The microbiological and multi-organ failure scores (P-SOFA), and other clini- tests were carried out according to the established prac- cal and analytical parameters recorded on admission and tice at each participating center. during the hospital stay. A clinical diagnosis of shock was Besides, antibiotic, antiviral, and immunomodulatory established in the presence of arterial hypotension with therapies administered during PICU stay, respiratory mean blood pressure values below the 5th percentile of and cardiovascular support (administration of vasoac- the reference values for age, need for vasoactive therapy tive drugs and/or ECMO) or need for renal replacement to maintain normal blood pressure, or presence of signs therapy were obtained. of hypoperfusion despite adequate fluid resuscitation. Acute cardiac dysfunction was defined as the appearance of any of the following echocardiographic alterations: Statistical analysis global or segmental contractility alterations, ventricular Data were entered into a database that was analyzed dilatation, reduced ejection fraction and/or presence of using the SPPS statistical package (IBM SPSS Statistics, pericardial effusion. Version 25.0. Armonk, NY: IBM Corp). Continuous Additional data included the presence or absence of the quantitative variables were expressed as median values following symptoms: fever, cough, respiratory distress, and interquartile ranges as measures of central tendency. odynophagia, rhinorrhea, diarrhea, nausea, vomiting, Comparison of continuous quantitative variables was refusal to eat, headache, irritability, altered level of con- performed using the Wilcoxon rank-sum test. Compari- sciousness, seizures, fatigue, myalgia or abdominal pain. son of proportions between subgroups of patients was Additionally, symptoms consistent with hyperinflam- carried out by Chi-squared test and Fisher’s test when matory syndromes such as KD and TSS were recorded the first method could not be used due to the small num- in patients who met the MIS-C case definition. Possible ber of cases. Heatmap and dendrogram were performed symptoms of hyperinflammatory syndromes included using Jaccard distance and Jaccard index to describe clus- fever; persistent fever (more than 4 days of duration); ters of co-occurring symptoms. Dendrogram was built ocular manifestations such as non-exudative conjunc- using Jaccard distance as metric and complete linkage tivitis; oral mucosa lesions; cutaneous manifestations as adjustment method. Heatmap and dendrogram were (palmar or plantar erythema, edema, swelling, desqua- drawn using Datagraph for MacOS version 4.5.1 (Visual mation, erythroderma, or polymorphic erythema in Data Tools Inc. Chapel Hill, NC). When some data were García‑Salido et al. Crit Care (2020) 24:666 Page 4 of 13 missing, the number of patients whose data were avail- 55.4 ng/L (IQR 13.3–204.7 ng/L) (normal value < 19 ng/L) able for each variable is stated. [34] and NT-ProBNP was determined in 22 patients with MIS-C (48.9%) with a median value of 5,532 pg/ml (IQR Results 1582–12,783 pg/ml) (normal value < 450 pg/ml) [35]. Forty-seven PICUs, including 1st, 2nd and 3rd level of Twenty-two patients in the MIS-C group (48.9%) exhib- care, from every region of Spain participated in the Reg- ited echocardiographic signs of ventricular dysfunc- istry. Between March 1st and June 15th, 2020, a total of tion. Coronary arteries abnormalities were reported in 3 74 children admitted to the participating PICUs were patients in the MIS-C group (6.7%): two patients had a included in the Registry, with ages ranging from 15 days homogeneously dilated anterior descendent artery along to 16.5 years. Forty-five patients (61%) were male, and its entire length, and one patient had a dilated left coro- 52 (70.3%) had no previous disease. Forty-five patients nary artery with an aneurism in the anterior descendent (61%) met the case definition for MIS-C proposed by the artery. RCPCH. Support measures and antibiotic, antiviral, and immu- SARS-CoV-2 infection was confirmed microbiologi- nomodulatory therapies administered during PICU cally in 61 of 74 patients (82.4%). Viral RNA was detected hospitalization are shown in Table 3. Invasive and non- by PCR in 44 of 74 patients (59.5%). Serologic tests were invasive mechanical ventilation were less used in patients done in 37 patients (50%) being positive in 27 of them with MIS-C, whereas the use of antibiotics and vasoac- (73%). The diagnosis was not confirmed microbiologi- tive and immunomodulatory therapies was more com- cally in thirteen patients (17.6%) with high suspicion of mon in these patients. SARS-CoV-2 infection (according to clinical, epidemio- Among 18 patients requiring intubation in 11 (61.1%) logical, or radiologic findings) or meeting MIS-C criteria. the main reason for intubation was respiratory fail- Among patients not presenting with MIS-C, viral RNA ure while in 7 (38.9%) it was due to hemodynamic was detected using PCR in 26 of 29 (89.7%) while in the failure. Patients requiring invasive ventilation were MIS-C group, PCR was positive in 18 out of 45 (40%) younger (2.9 years [IQR 0.4–9.5]) than those who did (p < 0.001). Seventeen of the 27 (63%) patients with nega- not (9.1 years [IQR 4.2–11.9]), p = 0.007. They also had tive PCR testing in the MIS-C group had serological con- higher PRISM-III score (13 points [IQR 8–16]) than non- firmation of SARS-CoV-2 infection. ventilated patients (6.5 points [IQR 4–9.3]), p = 0.005, Table 1 compares the baseline characteristics, symp- and higher p-SOFA scores (6 points [IQR 4–10.5] vs 3 toms prior to admission, and clinical diagnoses estab- points [IQR 2–5]), p < 0.001. On the contrary, patients lished within the first 24 h of admission of the group of requiring ventilation had lower CRP levels (7.1 mg/dl patients meeting the case definition for MIS-C vs the [IQR 0.9–21.6]) than non-ventilated patients (20.5 mg/dl remainder of patients with SARS-CoV-2 infection admit- [IQR 10.3–27.6]), p = 0.017. Among 18 patients requiring ted to the PICU. The group of patients with MIS-C invasive ventilation, 15 (83.3%) had radiologic alterations had an older age and higher weight. The proportion of in the chest x-ray. patients with a previous medical history of interest was Radiologic alterations in the chest-x-ray were present lower in the group of patients meeting MIS-C criteria. in 20 patients (55.6%) with MIS-C features and in 27 Respiratory symptoms were less frequent in the MIS-C patients (93.1%) without (p = 0.001). The existence of an patients, whereas the incidence of gastrointestinal symp- abnormal chest-x-ray was observed in 36 of 44 patients toms and fatigue was higher in this group. The MIS-C (81.8%) with positive PCR for SARS-CoV-2 in the naso- group presented a higher prevalence of symptoms of pharyngeal swab samples and in 16 of 30 patients (53.3%) shock and acute cardiac dysfunction. Clusters of symp- of patients with negative nasopharyngeal swab SARS- toms were identified using heatmap and dendrogram CoV-2 PCR (p = 0.008). Twenty-two patients of 74 analysis (Fig. 1). Figure 2 shows the count of new SARS- (29.7%) showed normal chest-x-ray at admission. Patients CoV-2 positives admitted to the PICU every day separat- with normal chest-x-ray had higher PCT 7.9 mcg/L ing patients with MIS-C from the remainder of patients. (3.1–55.7) than patients with chest-x-ray alterations Table 2 displays the incidence of KD and TSS symptoms (1.9 mcg/L [0.3–7.4]), p = 0.006. in the 45 patients with MIS-C. Thirty-seven patients required vasoactive drugs, among Figure 3 compares the laboratory parameters of them, 15 (40%) showed conserved cardiac function. patients with and without MIS-C. Patients with MIS-C Noradrenaline and dopamine were used in more patients exhibited lower levels of lymphocytes and LDH, higher in the MIS-C group (35.5% and 25.8%) compared to the levels of CRP and PCT, neutrophils, and a higher lympho- non-MIS-C group (7.7% and 4%), p = 0.024 and p = 0.033, cyte/neutrophil ratio. Troponin-T was determined in 34 respectively. Fluid balance per kilogram during the first of the 45 MIS-C patients (75.6%) with a median value of day of admission was 9.2 ml/kg (IQR − 7.1 to 28) in the García‑Salido et al. Crit Care (2020) 24:666 Page 5 of 13 Table 1 Clinical manifestations of SARS-COV-2 in critical pediatric patients Total patients (N = 74) Patients with MIS-C Patients without MIS-C p (N = 45) (N = 29) Gender (male) n/N (%) 46/74 (62.2) 39/45 (66.7) 16/29 (55.2) 0.320 Age (years) Median (IQR) 8.1 (3–11.5) 9.4 (5.5–11.8) 3.4 (0.4–9.4) 0.002 0–5 years n/N (%) 30 (40.5) 12 (26.7) 18 (62.1) 0.003 6–12 years n/N (%) 33 (44.6) 27 (60) 6 (20.7) > 13 years n/N (%) 11 (14.9) 6 (13.3) 5 (17.2) Weight (kg) Median (IQR) 29.5 (15–43.5) 36 (22.5–50) 15.5 (6.5–32.5) < 0.001 Previously healthy n/N (%) 52/74 (70.3) 37/45 (82.2) 15/29 (51.7) 0.005 PRISM III Median (IQR) 7 (4–13.5) 7 (5–14) 7 (3–13) 0.544 p-SOFA Median (IQR) 4 (2–6) 4 (3–6) 3 (1–5) 0.135 Symptoms prior to PICU admission Fever n/N (%) 61/73 (83.6) 43/45 (95.6) 18/28 (64.3) < 0.001 Cough n/N (%) 26/73 (35.6) 12/45 (26.7) 14/28 (50) 0.043 Respiratory distress n/N (%) 23/73 (31.5) 6/45 (13.3) 17/28 (60.7) < 0.001 Odynophagia n/N (%) 12/68 (17.6) 9/43 (20.9) 3/25 (12) 0.352 Rhinorrhea n/N (%) 11/71 (15.5) 2/43 (4.7) 9/28 (32.1) 0.002 Diarrhea n/N (%) 33/71 (46.5) 30/45 (66.7) 3/26 (11.5) < 0.001 Nausea n/N (%) 22/53 (41.5) 18/30 (60) 4/23 (17.4) 0.002 Vomits n/N (%) 38/71 (53.5) 32/45 (71.1) 6/26 (23.1) < 0.001 Refusal to eat n/N (%) 48/69 (69.6) 33/43 (76.7) 15/26 (57.7) 0.096 Headache n/N (%) 16/68 (23.5) 13/44 (29.5) 3/24 (12.5) 0.113 Irritability n/N (%) 15/71 (21.8) 9/45 (20) 6/26 (23.1) 0.760 Altered consciousness n/N (%) 5/72 (6.9) 2/45 (4.4) 3/27 (11.1) 0.281 Seizures n/N (%) 1/72 (1.4) 1/45 (2.2) 0/27 (0) 0.435 Fatigue n/N (%) 38/69 (55.1) 29/44 (65.9) 9/25 (36) 0.016 Myalgias n/N (%) 8/67 (11.9) 7/43 (16.3) 1/24 (4.2) 0.143 Diagnoses within the first 24 h of admission ARDS n/N (%) 11/74 (14.9) 3/45 (6.7) 8/29 (27.6) 0.014 Shock n/N (%) 42/74 (56.8) 38/45 (84.4) 4/29 (13.8) < 0.001 Acute kidney injury n/N (%) 12/74 (16.2) 9/45 (20) 3/29 (10.3) 0.271 Acute cardiac dysfunction n/N (%) 27/74 (36.5) 24/45 (53.3) 3/29 (10.3) 0.001 Acute liver dysfunction n/N (%) 14/74 (18.9) 11/45 (24.4) 3/29 (10.3) 0.131 Comparison of patients with MIS-C and without MIS-C. Quantitative values are expressed as median values and interquartile range. Qualitative variables are expressed as number of cases with respect to the total number of cases in each group and percentages IQR Interquartile rank, p-SOFA pediatric sequential organ failure, PRISM III Pediatric risk of mortality score, ARDS Acute respiratory distress syndrome. The criteria used to define diagnostic variables within the first 24 h of admission are defined in the Materials and Methods section group of patients without MIS-C and 21.8 ml/kg (IQR VA-ECMO was weaned and discharged to the ward. 0.2–29.7) p = 0.450. Three patients included in the registry died (4%), all of The administration of antiviral treatments was similar them belonged to the group of patients not presenting in the two groups, except for remdesivir, which was not with MIS-C. All deceased patients previously had seri- used in patients with MIS-C. ous illnesses: one of them had a Niemann–Pick disease, As of June 15, 2020, 65 of the 74 patients (87.8%) and the other two had received hematopoietic stem cell included in the Registry had been discharged from the transplantation due to acute lymphoblastic leukemia PICU. The length of stay in patients with MIS-C was and to severe immunodeficiency. Deceased patients 5 days (2.5–8 days) versus 6.5 days (3.3–10.8 days) in developed severe respiratory distress, one of them died the other group (p = 0.523). The patient who required while he was on VV-ECMO support due to massive pulmonary thromboembolism. García‑Salido et al. Crit Care (2020) 24:666 Page 6 of 13 Fig. 1 Heatmap and dendrogram describing clusters of co-occurring symptoms. Jaccard index was used to describe co-occurrence. Jaccard index is the ratio of the number of times two symptoms occur together divided by the number of times either of them appears. Jaccard index ranges from 0 (symptoms never appear together) to 1 (symptoms always appear together). Red square includes those symptoms clustered in patients presenting with MIS-C features. Blue square includes those symptoms co-occurring in patients presenting with respiratory disease. ARDS Acute respiratory distress syndrome Discussion societies [14–17]. This syndrome, which symptoms In general terms, the clinical manifestations of SARS- mimic those of sepsis, KD or TSS, has been described in CoV-2 infection are less severe in pediatric patients than different studies [18–29]. The information available on in adults. The study published by Dong et al. revealed the most severe manifestation of SARS-CoV-2 in chil- that only 6% of the more than 2,000 pediatric patients dren is also very limited [12, 36]. Our multicentric Regis- included, developed severe clinical symptoms [7], and try identified the differences between PICU patients with only a small proportion needed intensive care. Respira- symptoms of hyperinflammatory syndrome and those tory problems are less frequent in children than in adults with SARS-CoV-2 infection without symptoms of hyper- [3]. inflammation. To date large series of pediatric patients The occurrence of severe systemic hyperinflammatory suffering severe manifestations of SARS-CoV-2 infection symptoms probably associated with SARS-CoV-2 infec- are lacking, and our study includes an important num- tion in children has raised concerns among scientific ber of them. It is the first describing characteristics of García‑Salido et al. Crit Care (2020) 24:666 Page 7 of 13 Fig. 2 Frequency of new admissions in PICUs participating in the Registry by date of admission. Patients fulfilling MIS-C criteria and not fulfilling MIS-C criteria are marked with different colors. Black dots represent number of new daily cases of COVID-19 in Spain according to symptom onset. Strict lockdown was imposed in Spain on 15 March, 2020 Table 2 Frequency of characteristic symptoms of other the USA and Canada [12, 36] had respiratory symptoms, hyperinflammatory syndromes as KD and TSS in patients inflammatory syndromes were more frequent in our with MIS-C series. This difference may be explained by the fact that Symptom Number of patients % Spain is in a more advanced stage of the pandemic, as no cases of this type were recorded in our Registry during Fever 43/45 95.6 the initial stages. Several studies in different regions have Arterial hypotension for the age 41/45 91.1 shown a delay between the peak of incidence of COVID- Abdominal pain 40/45 90.9 19 cases and the rise in the number of MIS-C cases [10, Cutaneous manifestations 31/45 68.9 21, 22, 27, 28]. In the same vein, the presence of previous Prolonged fever (> 4 days) 27/45 60 comorbidities was higher in the sample of Shekerdemian Hematologic alterations 26/45 68.4 et al. (above 80%), whereas previous comorbidities in our Ocular manifestations 18/45 40 sample were only identified in patients without systemic Liver involvement 14/45 31.8 inflammatory symptoms, who were prevailingly hospital- Alterations in the oral mucosa 10/45 27 ized during the first weeks of operation of the Registry. Renal involvement 8/45 17.8 Many published studies point out that most patients pre- Neurologic involvement 6/45 13.6 senting with MIS-C are previously healthy [19–21, 24, Soft tissue necrosis 2/45 5.4 26–28]. Lymphadenopathy 2/45 5.4 In total, 75% of pediatric patients with MIS-C were ARDS 2/45 4.7 older than 6 years. This finding contrasts with KD, which ARDS Acute respiratory distress syndrome. The criteria used to define the is more frequent in children less than 5 years old [37]. different variables are defined in the Materials and Methods section These findings are consistent with those observed in the studies published by Whittaker et al. and Verdoni et al. where MIS-C patients are compared with previous SARS-CoV-2 infection comparing the patients present- cohorts of KD patients showing older age [19, 22]. ing with multisystem inflammatory symptoms with those Cluster analysis has identified two big groups of without. patients in our cohort, those presenting with fever, shock, Whereas the most of COVID-19 patients in the studies acute cardiac dysfunction, and gastrointestinal symptoms performed by Shekerdemian et al. and Sachdeva et al. in (the group of patients with MIS-C features), and a second García‑Salido et al. Crit Care (2020) 24:666 Page 8 of 13 Fig. 3 Laboratory findings of patients fulfilling and not fulfilling MIS-C criteria group presenting with respiratory symptoms including a third of the patients without MIS-C do not present a ARDS that often associates also acute liver and kidney fever. Almost the totality of patients with MIS-C of our dysfunction (the group of patients with a more classical series exhibited arterial hypotension. It is worth noting presentation of COVID-19). that we only analyzed PICU patients. Therefore, there In patients with MIS-C, gastrointestinal symptoms may have been patients with milder MIS-C symptoms are more frequent than respiratory symptoms, whereas who did not develop hemodynamic alterations and did patients with SARS-CoV-2 typically show respiratory not require intensive care as described in studies that symptoms. This finding contradicts the data reported by include patients not requiring intensive care [19, 20, 22, Shekerdemian et al., who reported a very low incidence 23, 27, 28]. of gastrointestinal problems (2%) [12]. In our series, As mentioned above, the clinical-laboratory manifesta- gastrointestinal symptoms were uncommon in patients tions of MIS-C mimic those of KD and TSS, and a high without MIS-C (4% of these patients have diarrhea), proportion of patients may meet the diagnostic criteria whereas more than 60% of patients with inflammatory for both diseases [37, 38]. However, some of the typical syndromes exhibited gastrointestinal symptoms. This is symptoms of these diseases were very uncommon in our in line with the previously described MIS-C case series, series, especially the typical cervical adenopathy of KD or in which abdominal symptoms as abdominal pain, diar- the oral mucosa and lips lesions (only present in 1 out of rhea, nausea and vomiting are present in most patients 4 patients of our series) [37]. Some studies have described [10, 18–24, 26–28]. how the presence of cutaneous manifestations in children Fever is the most frequent symptom in patients with with MIS-C might vary according the age, being less fre- MIS-C, with 100% of patients developing a fever, whereas quent in older patients [27, 28]. García‑Salido et al. Crit Care (2020) 24:666 Page 9 of 13 Table 3 Support measures and pharmacological treatments administered to patients admitted for SARS-COV-2 Total patients (N = 74) Patients with MIS-C Patients without MIS-C p (N = 45) (N = 29) Support measures. n/N (%) Oxygen therapy 56/74 (79.7) 36/45 (80) 20/29 (69) 0.215 HFO 26/74 (35.1) 14/45 (31.1) 12/29 (41.4) 0.379 NIV 9/74 (12.2) 2/45 (4.4) 7/29 (24.1) 0.026 MV 18/74 (24.3) 6/45 (13.3) 12/29 (41.4) 0.005 Neuromuscular blockade 12/74 (16.2) 3/45 (6.7) 9/29 (31) 0.009 Ventilation in prone position 9/74 (12.2) 1/45 (2.2) 8/29 (27.6) 0.002 V-V-ECMO 1/74 (1.4) 0/45 (0) 1/29 (3.4) 0.394 A-V-ECMO 1/74 (1.4) 1/45 (2.2) 0/29 (0) 1 NOi 3/74 (4.1) 0/45 (0) 3/29 (10.3) 0.057 CRRT​ 0/74 (0) 0/45 (0) 0/29 (0) - Transfusion of hemoderivatives 14/74 (18.9) 5/45 (11.1) 9/29 (31) 0.034 Vasoactive drugs 37/74 (50) 30/45 (66.7) 7/29 (24.1) < 0.001 Pharmacological therapies n/N (%) Antibiotic 65/74 (87,8) 42/45 (93.3) 23/29 (79.3) 0.020 Lopinavir–ritonavir 30/74 (40.5) 18/45 (40) 12/29 (41.4) 0.857 Remdesivir 5/74 (6.8) 0/45 (0) 5/29 (17.2) 0.006 Hydroxychloroquine 43/74 (58.1) 25/45 (55.6) 18/29 (62.1) 0.550 Corticosteroids 49/74 (66.2) 36/45 (80) 13/29 (44.8) 0.003 Immunoglobulins 25/74 (33.8) 23/45 (51.1) 2/29 (6.9) < 0.001 Tocilizumab 17/74 (23) 11/45 (24.4) 6/29 (20.7) 0.871 Comparison of patients with MIS-C and without MIS-C HFO high-flow rate oxygen, NIV noninvasive ventilation, MV invasive mechanical ventilation, V-V-ECMO veno-venous extracorporeal membrane oxygenation, V-A ECMO veno-arterial extracorporeal membrane oxygenation, NOi Inhaled nitric oxygen, CRRT​ continuous renal replacement therapy Concerning the laboratory parameters, the MIS-C with hyperinflammatory features such as elevated CRP, patients presented severe inflammation, with very ele- showed lower prevalence of chest x-ray abnormalities vated levels of acute-phase reactants (CRP and PCT), and lesser need of mechanical ventilation. Our study exceeding those of SARS-CoV-2 patients without MIS- points out differences regarding hyperinflammatory C. Although absolute leukocyte counts were not very states related to SARS-CoV-2 infection in children as elevated and were similar in the two groups, patients compared to those described in adults. In adults, hyper- with MIS-C exhibited severe lymphopenia, with a high inflammation is more frequent in the context of COVID- neutrophils/lymphocyte ratio and a low platelet count. 19 bilateral pneumonia and in children in patients with Special attention needs to be paid to the fact that LDH mild or absent respiratory symptoms presenting gastro- was lower in patients with MIS-C as compared to those intestinal symptoms and shock fulfilling MIS-C criteria. without MIS-C, since elevated LDH levels may be associ- Several authors have proposed a mechanism of ated with hemolysis or myocardial damage. The clinical immune dysregulation underlying MIS-C cases. In chil- interpretation of this finding is challenging. The analyti- dren, increased antibodies against receptor binding cal findings in our series were similar to those previously domain of SARS-CoV-2 have been described in patients reported, i.e., lymphopenia without significant leukocy- with MIS-C compared with patients with COVID-19 tosis, thrombocytopenia, and high CRP and PCT [18–22, without hyperinflammatory features [41]. Activation of 27, 28]. neutrophils and monocytes has been also described in Hyperinflammatory state has been previously reported the acute phase of pediatric patients with MIS-C with in adults presenting with COVID-19. This hyperinflam- normalization in the resolution and convalescent phases matory state has been related to disease severity and the of the disease [42]. In adults with severe COVID-19, need for mechanical ventilation and has been described hyperinflammation and abnormal activation of different in the context of classic COVID-19 syndrome present- cell lineages have also been described widely [43]. How- ing with bilateral pneumonia [39, 40]. In our study, ever, it remains unclear why in children, SARS-CoV-2 contrary to the studies in adults, patients presenting related hyperinflammatory states seems to affect more García‑Salido et al. Crit Care (2020) 24:666 Page 10 of 13 frequently cardiovascular and digestive organs instead of was already decreasing. The simultaneous occurrence the lungs as seen in adults. of similar symptoms to those described in our series in With regard to the treatments administered, most other European countries [18–24] leads us to foresee MIS-C patients admitted to the PICU required vasoac- an increase in the incidence of this syndrome in more tive therapy, whereas this therapy was less frequent in advanced stages of the epidemic in countries where the patients without this MIS-C. There was a high propor- coronavirus spike occurred some weeks later than in tion of MIS-C patients requiring vasoactive drugs with Europe. This added to the fact that PCR was negative conserved cardiac function and use of noradrenaline was in more than half of MIS-C patients but serology was also higher in this group. These facts might point out an positive for SARS-CoV-2 in a high proportion of them important element of vasoplegia in MIS-C patients. suggests that MIS-C may be caused by an underlying In contrast with the use of vasoactive drugs, the need deregulation of the immune system, with the viral infec- of mechanical ventilation was higher amongst those tion triggering a hyperinflammatory response rather than patients without MIS-C. In overall terms, the use of being a direct expression of SARS-CoV-2 infection [22]. mechanical ventilation nearly reached 30%, which is As to prognosis, the course of MIS-C patients included similar to the percentage reported in studies about in our registry was generally favorable, without any mor- PICU admissions including children with SARS-CoV-2 tality. Most patients were discharged to the ward in a few related diseases [12, 36]. In our population of patients days. Other studies describe similar findings with low with MIS-C, the use of mechanical ventilation was infre- mortality in patients with MIS-C (below 3% in all series) quent (below 15%) as described by Dufort et al. in New [19, 21, 23, 24, 27, 28]. York State [28], and lower to the rates described in stud- ies from other regions as U.S.A., U.K. and France where Limitations more than 30% of patients with MIS-C needed mechani- This study has some limitations. First, it is a multicen- cal ventilation. tric study that includes most—but not all—PICUs in As to pharmacological treatments, most patients with Spain. Therefore, some patients with similar symptoms MIS-C included in the Registry received antibiotic ther- could have not been included in the study. We consider apy. The use of immunomodulatory and corticosteroid that PICUs not participating in the registry do not rep- treatments was also higher in the group of patients with resent a specific region or subset of PICUS that might MIS-C. No differences were observed in the use of antivi- prevent generalizing our results to all Spanish PICUs. ral treatments, although remdesivir was not administered Secondly, the new syndrome observed led us to retro- to any of the patients with MIS-C. Remdesivir availability spectively review the potential cases that may have been was limited in Spain during this phase of the pandemic. overlooked. Although the participating PICUs reviewed The distribution of remdesivir was subject to request and their records, some patients may have not been included. authorization by the ministry of health and administra- Although it is a prospective Registry, some clinical or lab- tion in children was considered only in the context of a oratory variables were missing. Beside this, each hospital clinical trial. Remdesivir administration was requested had their own microbiological tests and thus differences in several patients in the MIS-C group but delay related on diagnostic precision regarding SARS-CoV-2 infec- to approval and favorable course in most MIS-C patients tion might be present. As only patients admitted to PICU probably determined the difference in its use between were included in the registry, we consider that probably groups. In view of the scant evidence available on the our study does not include the whole spectrum of MIS-C effectiveness of antiviral therapies in the treatment of and some patients might develop milder manifestations. SARS-CoV-2, further studies should be conducted to Finally, the long-term course of patients could not be assess the efficacy of the immunomodulators used to analyzed, given the short period of time elapsed from treat similar symptoms to those described above (such as the onset of the clinical symptoms and analysis. In this steroids and immunoglobulins) to attenuate the inflam- sense, given that KD is one of the most frequent causes matory mechanisms involved in the disease [44]. Treat- of heart disease acquired in childhood, it would be very ments used in patients with MIS-C are similar to those interesting to describe the incidence of coronary lesions described in studies from other regions [21, 27, 28]. in patients with MIS-C. The relationship observed between time and the occurrence of MIS-C cases is worthy of note. All MIS-C Conclusions patients were admitted to the PICU at least 15 days Although SARS-CoV-2 infection is less severe in chil- after the lockdown was imposed in Spain on March 15, dren than in adults, some pediatric patients may present 2020. In the stage where the first patients with MIS-C severe symptoms requiring intensive care. In Spain, most were recorded, in early April, the number of new cases pediatric patients requiring intensive care presented García‑Salido et al. Crit Care (2020) 24:666 Page 11 of 13 with hyperinflammatory syndrome instead of classic Azagra Garde, María Ángeles García Teresa (Hospital Infantil Universitario Niño Jesús), Corsino Rey Galán (Hospital Universitario Central de Asturias), Alfredo COVID-19 disease with severe respiratory involvement. Molina Cambra (Hospital Universitario y Policllinico La Fé), Manuel González- This syndrome is characterized by fever, hypotension, Ripoll Garzón (Hospital Universitario Torrecardenas), Pepe Fernández-Cantalejo gastrointestinal symptoms and cutaneous manifestations Padial (Hospital Universitario Fundación Jiménez Díaz), Ignacio Oulego-Erróz (Hospital Universitario de Leon), Laia Vega Puyal (Hospital Universitari Dexeus), with elevation of inflammatory markers together with Daniel Moreno (Hospital Universitario de A Coruña), Emilia Fernández Romero significant lymphopenia, requiring vasoactive therapy. (Hospital Universitario Virgen de la Macarena), María García Besteiro (Corpo‑ The course of this syndrome is generally favorable. The ración Sanitaria Parc Taulí), José Carlos Flores González (Hospital Universitario Puerta del Mar), Carmen Medina Monzón (Hospital General Universitario de number of cases of MIS-C was higher after the spike in Albacete), Beatriz Huidobro Labarga (Complejo Hospitalario Universitario de coronavirus cases in Spain. This, and the fact that it is Toledo), Rosa María Hernández Palomo (Hospital Universitario Quirónsalud), frequent that MIS-C patients have negative SARS-CoV-2 Cristina Calvo Monge (Hospital Universitario Donostia), Francisco Fernández (Hospital Universitario de Salamanca), Nieves González (Hospital Universitario PCR tests supports a causal link between SARS-CoV-2 de Canarias), Lorena Bermudez Barrezueta, Cesar Villa Francisco (Hospital and MIS-C in which children immune response dysreg- Clínico Universitario de Valladolid), Ana Abril Molina (Hospital Materno Infantil ulation might be involved. Larger, international, multi- Virgen de las Nieves), Mónica Valeron (Complejo Hospitalario Universitario Insular Materno Infantil), Ramón Hernández Rastrollo (Hospital Universitario centric studies are needed to characterize this syndrome de Badajoz), Sylvia Belda Hofheinz and Manuel Gijón Mediavilla (Hospital Uni‑ more accurately and establish the optimal treatment. versitario Doce de Octubre), José Luis Vázquez Martínez (Hospital Universitario Health policies regarding pediatric intensive care units Ramón y Cajal), Manuel Frias and Raúl Montero Yéboles (Hospital Universitario Reina Sofía), Juan Ignacio Muñóz Bonet (Hospital Clínico Universitario de preparedness for SARS-CoV-2 pandemic should take into Valencia), María Velázquez (Hospital Universitario La Moraleja), Inma Sánchez account that a high proportion of patients will present Ganfornina (Hospital Universitario Virgen del Rocio), Antonio Pérez Iranzo with MIS-C. Therefore, specific management protocols (Hospital General Universitario de Castellón), David Lozano (Hospital General La Mancha Centro), Clara Sorribes Ortí (Hospital Universitario Joan XXIII), María should be elaborated, and resource acquisition and distri- Soledad Holanda Peña (Hospital Universitario Marqués de Valdecilla), Miriam bution should consider the previously described patients Gutiérrez Jimeno (Clínica Universidad de Navarra). characteristics and therapeutic needs. Authors’ contributions AGS, JCCV, MSB, ABA, JLHC and RGC designed the study and database. Span‑ ish pediatric intensive care society working group on SARS-CoV-2 infection Abbreviations were responsible of patient recruitment and data collection. RGC and MSB MIS-C: Multisystem inflammatory syndrome temporally associated with were responsible of data collection and analysis. Manuscript draft was elabo‑ COVID-19; PICUs: Pediatric intensive care units; KD: Kawasaki disease; TSS: Toxic rated by AGS, JCCV, SBH, MSB, JLHC and RGC. All authors read and approved shock syndrome; RCPCH: Royal College of Paediatrics and Child Health; IQR: the final version of the manuscript. Interquartile range; PCR: Polymerase chain reaction; ARDS: Acute respiratory distress syndrome; CRP: C reactive protein; PCT: Procalcitonin; HFO: High-flow Funding rate oxygen; NIV: Noninvasive ventilation; MV: Mechanical ventilation.; VV- This study has been founded by the Carlos III Health Institute (ISCIII) through ECMO: Veno-venous extracorporeal membrane oxygenation; VA ECMO: Veno- the COVID-19 found. Ref. COV20-00944. The founder had no role in study arterial extracorporeal membrane oxygenation; NOi: Inhaled nitric oxygen; design, data collection, analysis and interpretation. CRRT​: Continuous renal replacement therapy. Availability of data and materials Acknowledgements The datasets used during the current study are available from the correspond‑ We would like to show our respect and gratitude to all the healthcare workers ing author on reasonable request. that are assisting the patients affected by COVID-19. They will probably not appear in the scientific publications derived from their hard work, but they are Ethics approval and consent to participate mainly the ones who are at the bedside caring of patients who are suffering The Registry was approved by the Institutional Review Board of the coor‑ this terrible disease. We would like to show our deepest respect and solidarity dinating center (Hospital General Universitario Gregorio Marañón). Written with all the patients and families suffering COVID-19, specially with those who informed consent was obtained from patients or from their parents before have passed away all around the world. We would like to thank to all members data collection. of the Spanish Society of Pediatric Intensive Care Study group on SARS-CoV-2 in critically ill pediatric patients which should be considered as co-authors of Consent for publication the manuscript. Members of the SECIP Study group on SARS-CoV-2 in critically Non applicable. ill pediatric patients are: María Slöcker Barrio, Amaya Bustinza Arriortua, Jesús López-Herce Cid and Rafael González Cortés (Hospital General Universitario Competing interests Gregorio Marañón), Juan Carlos de Carlos Vicente (Hospital Universitari Son The authors declare that they have no competing interests. Espases), Maite Cuervas-Mons Tejedor and Pedro Pablo Oyágüez Ugidos (Complejo Asistencial Universitario de Burgos), Iolanda Jordan and Carmina Author details Guitart Pardellans (Hospital Sant Joan de Déu), Sonia Sanchiz Cárdenas 1 Hospital Infantil Universitario Niño Jesús, Madrid, Spain. 2 Hospital Universi‑ (Hospital Clínico Universitario Virgen de la Arrixaca), Javier Gil Antón (Hospital tario Son Espases, Palma, Spain. 3 Hospital Universitario 12 de Octubre, Madrid, Universitario de Cruces), Belén Joyanes (Hospital Clínico Universitario San Spain. 4 Hospital Universitario Vall D’Hebron, Barcelona, Spain. 5 Paediatric Carlos), Ainhoa Jiménez Olmos (Hospital Universitario Miguel Servet), Antonio Intensive Care Unit, Hospital General Universitario Gregorio Marañón, Calle Rodríguez Núñez, Javier Trastoy Quintela (Complejo Hospitalario Universitario Doctor Castelo 47, 28007 Madrid, Spain. 6 Hospital Regional Universitario de de Santiago), Alexandra Hernández Yuste (Hospital Materno Infantil Univer‑ Málaga, Málaga, Spain. 7 Hospital Universitario Sant Joan de Deu, Esplugues de sitario de Málaga), Laura Díaz Munilla (Complejo Hospitalario de Navarra), Llobregat, Spain. 8 Hospital Universitario de Burgos, Burgos, Spain. 9 Hospi‑ Carlos Solís Reyes (Hospital Universitario Nuestra Señora de Candelaria), Laura tal Universitario Virgen de La Salud, Toledo, Spain. 10 Hospital Universitario Medina Ramos (Hospital General Universitario de Alicante), David Roca Pascual Ramón Y Cajal, Madrid, Spain. 11 Clínica Universidad de Navarra, Pamplona, and Joan Balcels Ramírez (Campus Hospitalario Vall d’Hebron de Barcelona), Spain. 12 Complejo Asistencial Universitario de León, León, Spain. 13 Complejo Mario Sánchez Fernández (Hospital Universitari Dr. Josep Trueta), Alberto Hospitalario Universitario de Santiago, Santiago de Compostela, Spain. 14 Hos‑ García-Salido, Inés Leóz Gordillo, Montserrat Nieto Moro, Amelia Martínez de pital General Universitario de Albacete, Albacete, Spain. 15 Hospital General García‑Salido et al. 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An inflammatory cytokine signature predicts COVID-19 Publisher’s Note severity and survival. Nat Med. 2020. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 41. Rostad CA, Chahroudi A, Mantus G, Lapp SA, Teherani M, Macoy L, et al. lished maps and institutional affiliations. Quantitative SARS-CoV-2 serology in children with multisystem inflam‑ matory syndrome (MIS-C). Pediatrics. 2020. Ready to submit your research ? Choose BMC and benefit from: • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions