Evolution of echocardiographic and cardiac magnetic resonance imaging abnormalities during follow-up in patients with multisystem inflammatory syndrome in children.

AIMS: Multisystem inflammatory syndrome in children (MIS-C) with cardiovascular manifestations are frequent. However, there is lacking evidence regarding cardiological follow-up of this cohort of patients. The aim of our study was to describe the early and mid-term cardiac abnormalities assessed by standard and speckle-tracking echocardiography (STE), and cardiac MRI (CMR). METHODS AND RESULTS: We enrolled 32 patients (21 male, 11 female), mean age 8.25 ± 4years, with diagnosis of MIS-C. During admission, all children underwent TTE, STE with analysis of left ventricle global longitudinal strain (GLS) and CMR. Patients underwent cardiological evaluation at 2 (T1) and 6 months (T2) after discharge. Cardiac MRI was repeated at 6 months after discharge. Mean left ventricular ejection fraction (LVEF) at baseline was 58.8 ± 10% with 10 patients (31%) below 55%. Speckle-tracking echocardiography showed reduced mean LV GLS (-17.4 ± 4%). On CMR, late gadolinium enhancement (LGE) with non-ischaemic pattern was evident in 8 of 23 patients (35%). Follow-up data showed rapid improvement of LVEF at T1 (62.5 ± 7.5 vs. 58.8 ± 10.6%, P-value 0.044) with only three patients (10%) below ≤ 55% at T1. Left ventricular (LV) GLS remained impaired at T1 (-17.2 ± 2.7 vs.-17.4 ± 4, P-value 0.71) and significantly improved at T2 (-19 ± 2.6% vs. -17.4 ± 4%, P-value 0.009). LV GLS was impaired (>-18%) in 53% of patients at baseline and T1, whereas only 13% showed persistent LV GLS reduction at T2. Follow-up CMR showed LGE persistence in 33.4% of cases. CONCLUSION: Early cardiac involvement significantly improves during follow-up of MIS-C patients. However, subclinical myocardial dysfunction seems to be still detectable after 6 months of follow-up in a not negligible proportion of them.

Left ventricle longitudinal strain alterations in asymptomatic or mildly symptomatic pediatric patients with recent SARS-CoV-2 infection

Introduction: Evidence suggests that, compared with adult patients, clinical manifestations of children's COVID-19 may be less severe. However, multiple reports have raised concern about the so called pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) which resembles other inflammatory conditions (i.e. Kawasaki disease, toxic shock). Patients affected by PIMS-TS showed cardiac involvement with myocardial injury, reduced left ventricle systolic function and coronary artery abnormalities, and in some cases, need for inotropes/ vasopressors and extracorporeal life support (ECLS). Little is known regarding cardiac involvement in pediatric patients with SARS-CoV-2 infection and none or only mild symptoms of disease. Methods: We analyzed 52 pediatric patients (29males, 56%) with diagnosis of SARS-CoV-2 infection based on either PCR analysis of nasopharingeal swab (NPS), or serological finding of IgG on blood sample and asymptomatic (23%) or only mildly symptomatic (77%) for COVID-19. Patients underwent transthoracic echocardiogram (TTE) after a median time of 3.6 months from diagnosis and negative NPS for SARS-CoV-2. Offline analysis with GE EchoPAC software to measure global longitudinal strain (GLS) of the LV using 2D speckle tracking imaging. Therefore, we compared the results with an age-matched group of 32 controls (18males, 56%). Results: Cases and controls were similar regarding age and gender. LV biplane EF was significantly lower in the cases group, although still in the normal range (62.4±4.1% vs. 65.2±5.5%, p=0.012). TAPSE and LV-GLS were comparable between the two groups. GLS analysis showed significant strain reduction of the LV midwall segments and of the basal anterior, posterior and septal inferior segments among cases compared to controls. On the other hand, apical segments showed higher deformation in cases compared to controls. Furthermore, in the case group there were 14 subjects (27%) with a strain below 16% (mean value minus 2.5 SD) in at least 2 segments. Conclusions: SARS-CoV-2 infection may affect LV deformation in asymptomatic or only mildly symptomatic children, showing a peculiar pattern with lower longitudinal strain in all mid-wall segments of LV compared to control subjects. The clinical significance of this findings is unclear and follow-up is needed to verify the reversibility of this alterations.

Non convulsive status epilepticus as ongoing symptom of multisystem inflammatory syndrome in children (MIS-C)

Introduction: Since April 2020, Multisystem inflammatory syndrome in children (MIS-C) has been reported worldwide and associated with a different spectrum of symptoms. Although mild neurological manifestations in SARS-Cov2 infection and MIS-C have been reported, severe involvement with brain abnormalities, is rare 1. Objectives: Describe a child with MIS-C presenting non-convulsive status epilepticus associated with abnormal cerebral magnetic resonance (MR), never previously reported. Methods: Case report. Results: A previously healthy 19-month-old girl presented to our emergency department after a prolonged febrile seizure involving the right side of her body lasting about 25 minutes. She presented with fever lasting more than 24 hours. On physical examination, abdominal distention and tenderness and altered mental status with irritability were detected. RT-PCR for SARS-CoV-2 on nasal swab was negative but her parents had SARS-CoV-2 infection four weeks earlier. Laboratory showed elevated CRP (35 mg/L), while all microbiological analyses in blood, urine and CSF were negative. Computerized tomography (TC) showed a doubtful left temporal hypointensity, and cerebral MRI displayed cytotoxic oedema in left temporal mesial area of the brain on diffusion-weighted imaging (DWI). Few day later, her clinical conditions worsened with irritability and drowsiness associated with persistent abdominal distention, diarrhoea, and high fever. The EEG revealed a pattern suggestive for non-convulsive status epilepticus responsive to benzodiazepines and loading dose of Levetiracetam. Consensually, an increase of inflammatory markers (CRP 153 mg/L, procalcitonin 114 ug/L) was observed. Chest X-ray, EKG, troponin and BNP levels were normal, whereas echocardiogram demonstrated left ventricular diastolic dysfunction and mild pericardial effusion. In the suspicion of MIS-C with abdominal, cardiac and neurological involvement, she was treated with intravenous immunoglobulin (2g/kg), methylprednisolone (2 mg/kg) and acetylsalicylic acid (5mg/kg). Serum SARS-Cov2 antibody test resulted positive for previous infection, confirming the diagnosis of MIS-C. Neuronal antibodies for immune-mediated CNS disorders tested negative. Within 36 hours from therapy start, a significant improvement in general conditions, along with stable apyrexia and decreasing in inflammatory markers were observed. She was discharged two weeks later on oral steroids, ASA and Levetiracetam;the physical examination was normal, and EEG showed a global improvement in brain electrical activity. Conclusion: Neurological symptoms secondary to SARS-Cov2 infection and MIS-C have been reported in children (1) but only a few present severe neurological complications such as status epilepticus. Non-convulsive status epilepticus has been previously described in an adult with acute COVID192 but has never been reported as presenting sign of MIS-C. The current case illustrates the need of a careful neurological evaluation in children with MIS-C, as CNS involvement can represent the main clinical presentation thus underlining the need of an appropriate diagnostic and therapeutic approach.

Left ventricle longitudinal strain alterations in asymptomatic or mildly symptomatic pediatric patients with recent sars-cov-2 infection

Background: Evidence suggests that, compared with adult patients, clinical manifestations of children's COVID-19 may be less severe. However, multiple reports have raised concern about the so called pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) which resembles other inflammatory conditions (i.e. Kawasaki disease, toxic shock). Patients affected by PIMS-TS showed cardiac involvement with myocardial injury, reduced left ventricle systolic function and coronary artery abnormalities, and in some cases, need for inotropes/vasopressors and extracorporeal life support (ECLS). Little is known regarding cardiac involvement in pediatric patients with SARS-CoV-2 infection and none or only mild symptoms of disease. Methods: We analyzed 52 pediatric patients (29males, 56%) with diagnosis of SARS-CoV-2 infection based on either PCR analysis of nasopharingeal swab (NPS), or serological finding of IgG on blood sample and asymptomatic (23%) or only mildly symptomatic (77%) for COVID-19. Patients underwent transthoracic echocardiogram (TTE) after a median time of 3.6 months from diagnosis and negative NPS for SARS-CoV-2. Offline analysis with GE EchoPAC software to measure global longitudinal strain (GLS) of the LV using 2D speckle tracking imaging. Therefore, we compared the results with an age-matched group of 32 controls (18males, 56%). Results: Cases and controls were similar regarding age and gender. LV biplane EF was significantly lower in the cases group, although still in the normal range (62.4±4.1% vs. 65.2±5.5%, p=0.012). TAPSE and LV-GLS were comparable between the two groups. GLS analysis showed significant strain reduction of the LV mid-wall segments and of the basal anterior, posterior and septal inferior segments among cases compared to controls. On the other hand, apical segments showed higher deformation in cases compared to controls. Furthermore, in the case group there were 14 subjects (27%) with a strain below 16% (mean value minus 2.5 SD) in at least 2 segments. Conclusion: SARS-CoV-2 infection may affect LV deformation in asymptomatic or only mildly symptomatic children, showing a peculiar pattern with lower longitudinal strain in all mid-wall segments of LV compared to control subjects. The clinical significance of this findings is unclear and follow-up is needed to verify the reversibility of this alterations.

High and persistent neutralizing antibodies in children recovered from covid-19

Background: Recent evidences suggest that SARS-CoV-2 neutralizing antibodies (Nabs) may persist over time, however lack of knowledge still regards the pediatric population. Methods: A single-centre, prospective observational study evaluated family clusters of COVID-19 attending the Pediatric Department, University Hospital of Padua (Italy). Confirmed COVID-19 was defined by positive SARS-CoV-2 molecular detection and/or serology;patients/family symptom's and virological positivity were considered to define the infection onset (baseline). Blood samples were analyzed in pair to detect Nabs through Plaque Reduction Neutralization Test (PRNT), and IgG through chemiluminescent immuneenzymatic assay (CLIA) MAGLUMI™ 2000 Plus;IgG >1.1 kAU/L and/or PRNT≥1:10 were considered positive. SARS-CoV-2 viral load (VL) was quantified by multiplex quantitative assay based on One-Step RT-ddPCR. Geometric mean titers (GMT) and 95% Confidence Intervals of IgG/PRNT were evaluated, stratified by age and time from baseline to sample collection. Trends over time of immune-virological response were assessed. P-value <0.05 was considered statistically significant. Results: Among 213 subjects (57 families) evaluated, 155 had confirmed COVID-19 including 73 (47%) children/older siblings of 8 years median age (IQR 4-13) and 82 (53%) parents aged 42 years (IQR 34-46);93.5% had asymptomatic/mild COVID-19. From the cumulative analysis of 194 blood samples, Nabs persisted over a median period of 95 days (IQR, 67-133) from baseline. Children showed significantly higher NAbs than older subjects, with children <3 years ranging from a 4-fold difference at 1-2 months to 8.8-fold difference at 3-6 months after baseline, compared to adults (table). The longitudinal assessment of 42 subjects sampled at 60 days (SD+/-9.9) and at 150 days (SD+/-24.2) showed a 2-fold increase in NAbs in children <6 years (PRNT 144, 95% C.I. 74.42-277.94 versus 303, 95% C.I. 196.43-468.57) and a substantial stability in Nabs among older subjects. CLIA IgG significantly decreased over time for all age classes, becoming negative in 13/42 subjects (31%), compared to 1/42 subjects detected by PRNT. Among 32 individuals checked for VL within 4 days from baseline, VL directly correlated with PRNT titers in subjects >15 years (Pearson Coefficient =0.70, p=0,0349) but not in pediatric cases. Conclusion: Asymptomatic/mild COVID-19 disease triggers in children a superior and persistent humoral response compared to adults.

Left ventricle longitudinal strain alterations in asymptomatic or mildly symptomatic pe-diatric patients with recent SARS-CoV-2 infection

Background: Evidence suggests that clinical manifestations of children's COVID-19 may be less severe. However, it has been described the pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) which resembles other inflammatory conditions (i.e. Kawasaki disease). Patients affected by PIMS-TS showed cardiac involvement with myocardial injury, reduced left ventricle systolic function and coronary artery abnormalities. Little is known regarding cardiac involvement in pediatric patients with asymptomatic or mildly symptomatic SARS-CoV-2 infection. Methods: We analyzed 23 pediatric patients (13males, 56%) with diagnosis of SARS-CoV-2 infection based on PCR analysis of nasopharin-geal swab (NPS), and asymptomatic or only mildly symptomatic for COVID-19. Patients underwent standard transthoracic echocardiogram (TTE) within 2-3 month from diagnosis and after negative NPS for SARS-CoV-2. We performed offline analysis with GE EchoPAC software to measure global longitudinal strain (GLS) of the LV using 2D speckle tracking imaging. Therefore, we compared the results with a matched group of 23 controls (13males, 56%). Results: Cases and controls were similar regarding age (5.9 ± 4.1years vs. 6.4 ± 4.4 years, p = 0.63), body surface area (0.98 ± 0.3m2 vs. 0.8 ± 0.4m2, p = 0.17), LV FS (37.9 ± 5.9% vs. 36.4 ± 8.3%, p = 0.74) and LV biplane EF (63.9 ± 5.2% vs. 66.4 ± 5.3%, p = 0.11). GLS analysis showed significant strain reduction of the LV mid-wall segments and of the basal anterior, posterior and septal inferior segments among cases compared to controls. Furthermore, in the case group there were 7 subjects (30%) with a strain below 16.5% in at least 3 segments. Conclusion: SARS-CoV-2 infection may affect LV deformation in asymptomatic or only mildly symptomatic children, showing a peculiar pattern with lower longitudinal strain in all mid-wall segments of LV compared to control subjects. The clinical significance of this findings is unclear and follow-up is needed to verify the reversibility of this alterations.

Kawasaki disease complicated by macrophage activation syndrome and parvovirus b19 infection: Which relationship?

Introduction: Macrophage activation syndrome (MAS) is characterized by massive production of cytokines leading to macrophage activation and haemophagocytosis presenting with prolonged fever, rash, hepatosplenomegaly, pancytopenia, liver dysfunction, hypertriglyceridemia, hyperferritinemia and coagulopathy that can complicate rheumatic conditions such as Systemic Juvenile Idiopathic Arthritis (sJIA) and Systemic Lupus Erythematosus (SLE). Incidence of MAS in Kawasaki Disease (KD) has been estimated in about 1.1% patients but subclinical MAS may be detected in 30-40% of KD. Objectives: Case description Methods: A previously healthy 10 years-old girl presented high grade fever for 4 days, pharyngitis and vomiting. After 24 hours, she developed diffuse maculo-papular rash and oedema on extremities. She presented progressive worsening of general conditions and bilateral bulbar conjunctivitis, mucositis with strawberry-like tongue and left cervical lymph nodes enlargement. On admission remarkable laboratory tests were increased C reactive protein (CRP), neutrophilic leucocytosis, low sodium and albumin, increased gGT and gallbladder hydrops on abdominal ultrasound. Suspecting Kawasaki disease 2 gr/kg IVIG were administered with salicylic acid (50 mg/kg/day). Nevertheless, she presented persistent remitting fever, low consciousness, diffuse vasculitic rash, worsening of mucositis and pericardial and pleural effusion. Lab tests showed low haemoglobin, platelets and fibrinogen (9,3 g/L, 65.000/ml and 1.05 g/L, respectively), ferritin 16.492 g/L, SGOT 487 U/L, SGT 351 U/L, triglycerides 345 mg/dl, Ddimers 10.353 microgr/L and soluble interleukin-2 receptor (sIL-2R), 6464 kU/L. Active haemophagocytosis was retrieved in bone marrow and cerebrospinal fluid (CSF) so MAS was diagnosed. Three consecutive iv methylprednisolone pulses (30 mg/kg) were administered followed by dexamethasone 10 mg/m2/day and cyclosporin A 2 mg/kg/day as well as plasma infusions and oxygen supplementation (6 l/min) for 48 hours. Parvovirus B19 (HPVB19) DNA was found in peripheral blood, bone marrow and CSF, while other microbiological analysis (EBV, CMV, HHV6, VZV, Influenza A-B, Measles, Adenovirus, HSV) were negative. The patient progressively improved with reduction of fever, oedema of extremities and skin rash and after 6 days presented extensive desquamation on hands, feet and limbs. Lab tests slowly improved and normal values were achieved on day 23. Echocardiogram did not show any coronary aneurism or dilatation, cerebral MRI was normal and neurological impairment gradually disappeared. Primary HLH mutations for UNC13D, STXBP2, STX11, RAB27a, SH2D1A, XIAP were not found. Corticosteroids and Ciclosporin were gradually tapered and discontinued after 7 and 12 months respectively, whilst acetylsalicylic acid was stopped after 2 months. Results: MAS is a relatively infrequent complication in KD and may be associated with severe course and poor outcome. Several potential infectious agents have been suggested as trigger factors of both MAS and KD, such as Epstein Barr virus, Influenza virus etc. and, more recently, the SARS-COV-2 epidemic has been associated with severe forms of systemic inflammatory syndrome resembling KD and MAS. Conclusion: To the best of our knowledge, this is the first case in which demonstration of HPVB19 DNA in peripheral blood, bone marrow and CSF during acute phase strongly suggests a direct role of the virus in triggering both KD and MAS rather than an antibody or immune-complex mediated mechanism.