Corrigendum: The new Italian registry of infantile thrombosis (RITI): a reflection on its journey, challenges and pitfalls.

[This corrects the article DOI: 10.3389/fped.2023.1094246.].

COVID-19 and Thromboembolic Events in the Pandemic and Pre-Pandemic Era: A Pediatric Cohort.

The Coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) have been variably associated with thromboembolic events (TEs) in children. The aim of our study was to assess the prevalence of TEs in children hospitalized during a five-year period in a tertiary pediatric hospital, particularly in patients with COVID-19 and MIS-C. Overall, 38 patients were discharged with the diagnosis of TE: 20 in the pre-pandemic and 18 in the pandemic period. The prevalence of TEs was the same (0.08%) in the pre-pandemic and pandemic periods. The occurrence of TEs was higher in patients with COVID-19 or MIS-C (6/517, 1.16%) when compared to children without these conditions in the pandemic and in the pre-pandemic periods. The prevalence of TEs in children with MIS-C was significantly higher than the prevalence in patients with COVID-19. Five out of six of the patients with COVID-19 or MIS-C developing a TE had at least one predisposing factor to thrombosis. In conclusion, our study shows an increased prevalence of TEs in children hospitalized with COVID-19 or MIS-C, if compared to children without COVID-19 or MIS-C in the pandemic period and in the pre-pandemic period. The prevalence of TEs was significantly higher in patients with MIS-C.

Benign acute children myositis: 5 years experience in a tertiary care pediatric hospital.

Benign acute childhood myositis (BACM) is a self-limited childhood illness, and viral infections mainly cause it. Clinical and laboratory alterations usually normalize rapidly; generally, the only medical intervention required is supportive (hydration and analgesic medication). The low awareness about BACM often led to delayed diagnosis and unneeded ancillary investigations. This study aims to better characterize the clinical and laboratory features of BACM to improve the diagnostic process and inpatient and outpatient management. We conducted a retrospective study selecting all children admitted to Meyer's Children's Hospital-IRCCS (Florence, Italy) with a diagnosis of BACM over the last 5 years, both those visited at Emergency Department (ED) and those admitted to the Pediatric Unit. Clinical, laboratory, and instrumental data were collected from electronic clinical records and analyzed. Overall, sixty-five patients were enrolled; 49 children were visited and discharged directly from ED, whereas 16 were admitted in the Pediatric or Neurologic Wards. The median age was 6.56 years (IQR 4.9-9.1). Male gender (66.1%) and Caucasian ethnicity (70%) were prevalent. Most patients were admitted during winter, and a second peak was found in autumn. All patients had bilateral calf pain, most of them (87.7%) associated with asthenia and refuse to walk (93.8%). Prodromal symptoms were fever (75.3%), cough (32.3%), coryza (26.1%), sore throat (26.1%), and vomiting (15.3%). The median value of CPK was 1827 U/L (IQR 915.5-2462) at peak. CPK median time to normalization was 7 days (IQR 7-8.5) from the nadir. Influenza B was the virus most frequently BACM associated, followed by Influenza A; a novel association with Sars-CoV-2 has been detected. Two patients had pathogenic variants at the Next Generation Sequencing myopathies panel.    Conclusion: School-aged children admitted to the hospital with walking difficulty and myalgia, generally after an upper respiratory tract infection with a moderate CPK elevation, should remind at first of BACM. Rapid complaint resolution and biochemical markers normalization will prevent unnecessary tests and inappropriate therapies. What is Known: • BACM is a self-limited syndrome associated with acute infections. Influenza A and B viruses are the main etiological agents, but BACM may be related to many other microorganisms like Parainfluenza virus, Epstein-Barr virus, Cytomegalovirus, Human herpesvirus 6, Respiratory syncytial virus, Coxsackieviruses, Mycoplasma pneumoniae, Streptococcus pyogenes, Legionella, and Salmonella spp. • Clinical and laboratory alterations usually normalize rapidly; generally, the only medical intervention required is supportive (hydration, analgesic medication). Evolution in rhabdomyolysis and kidney damage is possible but rarely reported. What is New: • Sars-CoV-2 could be an emerging possible cause of BACM. During and after the Sars-CoV-2 outbreak, virus infection seasonality has changed, and so has BACM seasonality. • Screening tests for muscular and metabolic disorders are recommended in recurrent myositis and/or cases with marked CPK elevation (≥ 5000 U/L).

The new Italian registry of infantile thrombosis (RITI): A reflection on its journey, challenges and pitfalls.

Introduction: Thrombotic events in neonates and children represent a rare although severe occurrence in view of the associated risk of mortality and sequelae. Quality evidence is limited in this field, and registry studies provide an essential base for research. The aim of this paper is to present the new Italian Registry of Infantile Thrombosis (RITI), set it into the scene of international thrombosis and stroke registries, and provide some insight on the challenges associated with registry management. Methods: We present the detailed structure and content of the new RITI registry, a brief overview of its main data, and a reflection on its features, pitfalls and the main challenges related to its management. Results: The RITI, initially started in 2007 and officially re-launched in 2017 after structural modifications, is a non-interventional retrospective and prospective registry study collecting data on neonatal and pediatric patients (0-18 years) who experienced a systemic or cerebral thrombotic event in Italy. The RITI is managed by a multidisciplinary team with expertise in pediatric thrombosis, and participation is open to all Italian physicians, on a voluntary basis. The overall aim of the registry is to acquire new evidence to better characterize the population of children with thrombotic events and improve their management and outcome. 48 Italian pediatric and intensive care units are actively involved in the RITI, including 85 medical doctors from 16 Italian regions. A total of 1,001 neonates and children affected by cerebral or systemic thrombosis have been enrolled. Discussion: The RITI is one of the largest available European registries of neonatal and pediatric thrombosis. National registries like the RITI represent a model for the study of rare conditions based on multidisciplinary and multicenter collaboration, aimed at overcoming the limitations due to small populations of patients, and creating a network of experts for patient referral and continuous education. Moreover, registry studies have a pivotal role in the research on pediatric thrombosis, due to the limited feasibility of high-quality studies. In our experience, the main critical stages, pitfalls and challenges in registry management include adequate registry designing, diffusion, data completeness and quality control.

Thrombotic Events in MIS-C Patients: A Single Case Report and Literature Review.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a systemic hyperinflammatory disorder that is associated with a hypercoagulable state and a higher risk of thrombotic events (TEs). We report the case of a 9-year-old MIS-C patient with a severe course who developed a massive pulmonary embolism that was successfully treated with heparin. A literature review of previous TEs in MIS-C patients was conducted (60 MIS-C cases from 37 studies). At least one risk factor for thrombosis was observed in 91.7% of patients. The most frequently observed risk factors were pediatric intensive care unit hospitalization (61.7%), central venous catheter (36.7%), age >12 years (36.7%), left ventricular ejection fraction <35% (28.3%), D-dimer >5 times the upper limit of normal values (71.9%), mechanical ventilation (23.3%), obesity (23.3%), and extracorporeal membrane oxygenation (15%). TEs may concurrently affect multiple vessels, including both arterial and venous. Arterial thrombosis was more frequent, mainly affecting the cerebral and pulmonary vascular systems. Despite antithrombotic prophylaxis, 40% of MIS-C patients developed TEs. Over one-third of patients presented persistent focal neurological signs, and ten patients died, half of whom died because of TEs. TEs are severe and life-threatening complications of MIS-C. In case with thrombosis risk factors, appropriate thromboprophylaxis should be promptly administered. Despite proper prophylactic therapy, TEs may occur, leading in some cases to permanent disability or death.

Anticoagulation and Thrombotic Events in the Multisystem Inflammatory Syndrome in Children: Experience of a Single-center Cohort and Review of the Literature.

The multisystem inflammatory syndrome in children (MIS-C) is a severe clinical entity affecting the coagulative system; although thromboembolic events (TEs) are not common, most patients receive anticoagulation. We retrospectively assessed patients below 18 years admitted with MIS-C at Meyer Children's Hospital (Florence, Italy). Data on baseline clinical and laboratory presentation, treatment, and outcome, including differences between patients with and without thrombotic prophylaxis, were analyzed. Thirty-two children 1 to 15 years were included. Seventeen patients (53.1%) required intensive care admission, 2 (8.7%) had obesity, 7 (30.4%) a central venous catheter, and 14 (43.8%) an impaired cardiac function. Twelve patients (37.5%) received prophylactic anticoagulation: they had more frequent cardiac involvement (91.7 vs. 50%, P =0.02) and higher ferritin levels (median 1240 vs. 501.5 ng/mL, P <0.001). No differences were found in median d -dimers between the 2 groups. Twenty-one patients (65.6%) had d -dimers >5×upper limit of normal but the indication for anticoagulation was not driven by d -dimers. No patient had hemorrhagic events and only 1 patient (3.1%) had a superficial thrombotic event (under thromboprophylaxis). Our series and the available literature data on MIS-C and thromboembolic events suggest that TEs are a rare complication of MIS-C that is frequently associated with high d -dimer values. However, also in MIS-C, the well-established risk factors of pediatric TEs (ie, older age, central venous catheter, obesity, and cancer) should guide thromboembolic risk assessment.

Thromboembolic complications in children with COVID-19 and MIS-C: A narrative review.

COVID-19 and multisystem inflammatory syndrome in children (MIS-C) have been associated with a higher incidence of hypercoagulability and thromboembolic events (TEs), even in children, leading to relevant morbidity, and mortality. However, our understanding of such complications in childhood is limited. To better understand the incidence, clinical manifestations, risk factors, and management of COVID-19 and MIS-C-related TEs in children, a review of the current literature and a brief update on pathophysiology are given. Sixty-two studies, describing 138 patients with TEs associated with COVID-19 or MIS-C, were included. The overall number of TEs was 157, as 16 patients developed multiple TEs: venous TEs represented the majority (54%), followed by arterial thrombosis (38%, mainly represented by arterial ischemic stroke-AIS), and intracardiac thrombosis (ICT) (8%). Within the venous TEs group, pulmonary embolism (PE) was the most frequent, followed by deep venous thrombosis, central venous sinus thrombosis, and splanchnic venous thrombosis. Notably, 10 patients had multiple types of venous TEs, and four had both venous and arterial thrombosis including a newborn. Most of them (79 cases,57%) had at least one predisposing condition, being obesity the most frequent (21%), especially in patients with PE, followed by malignancy (9%). In 35% of cases, no data about the outcome were available About one-third of cases recovered, 12% improved at discharge or follow-up, and 6% had persistent neurological sequelae. The mortality rate was 12%, with death due to comorbidities in most cases. Most fatalities occurred in patients with arterial thrombosis. Pediatricians should be aware of this life-threatening possibility facing children with SARS-CoV-2 infection or its multisystemic inflammatory complication, who abruptly develop neurological or respiratory impairment. A prompt intensive care is essential to avoid severe sequelae or even exitus.

Systemic Catheter-Related Venous Thromboembolism in Children: Data From the Italian Registry of Pediatric Thrombosis.

Background: Central venous catheters (CVCs) represent one of the main risk factors for venous thrombotic events (VTEs) in children. Methods: We studied the Italian Registry of Pediatric Thrombosis (RITI) with regard to systemic radiologically confirmed CVC-related VTEs (CVC-VTEs) occurred during 6.5 years in children aged 29 days to 18 years. Results: A total of 78 CVC-VTEs were included, which occurred in 76 patients (40/76, 53% males). CVC-VTEs comprised 67 non-cardiac VTEs (86%) and 11 intracardiac thrombotic events (ICTEs) (14%); the median age at onset was 19 and 17 months, respectively. The most frequent reason for CVC insertion was supportive therapy. The catheters were placed percutaneously in 85% of cases (56/66) and surgically in the remaining 15% (10/66). Peripherally inserted central catheters (PICCs) were used in 47% (31/66) cases, partially implanted catheters in 42% (28/66), non-implantable catheters in 7% (5/66), and totally implanted catheters (Port) in 2% (1/66). CVC-VTEs were symptomatic in 77% of cases (60/78), while in the remaining 23%, they were incidentally detected on the imaging performed for the underlying condition. The median time between CVC insertion and the onset of symptoms was 10 days in non-cardiac VTEs and 39 days in ICTEs. Doppler ultrasound was the diagnostic technique most frequently used. The venous compartment most frequently affected was the veins of the lower extremities (52%, 43/73). Anti-thrombotic treatment was administered in 96% of CVC-VTEs (75/78). About 2.6% (2/76) of patients experienced a second thrombotic event. At discharge, post-thrombotic syndrome was reported in 13.5% (5/37) events with available data, CVC replacement in 10.8% (4/47), and ischemic necrosis with toe finger amputation in 2.7% (1/37). Three patients died due to an underlying condition; no CVC-VTE-related deaths were reported. Conclusions: We have carried out a registry-based study on CVC-VTEs in the children in Italy, providing the data that may help improve the detection and management of this CVC-related complication.

Otogenic Lateral Sinovenous Thrombosis in Children: A Case Series from a Single Centre and Narrative Review.

AIM: We aimed to describe otogenic lateral sinovenous thrombosis (OLST), a rare, potentially life-threatening complication of otomastoiditis. METHODS: Children diagnosed with OLST in a tertiary-care Hospital from 2014 to 2019 was retrospectively selected. Clinical and radiological features, timing of diagnosis, treatment and outcome are reported. RESULTS: Seven children (5 males) were studied. Fever and neurological symptoms (headache, lethargy, diplopia, dizziness and papilledema) were always present. Otalgia and/or otorrhea were found in 6 children; none had signs of mastoiditis. Diagnosis was reached after 7 days (median) from clinical onset. Brain CT-scan was performed in 5 children being diagnostic for 3. Venography-MRI detected OLST and mastoiditis in all cases without parenchymal lesions. Treatment was based on intravenous rehydration, antibiotic and low-molecular weight heparin; acetazolamide was added in 3 children. Mastoidectomy and ventriculoperitoneal-shunting were selectively performed. Patients were discharged after 26 days (median). Follow-up neuroimaging showed sinus recanalization after a median time of 6 months. CONCLUSION: A multidisciplinary approach is needed to optimize diagnostic-therapeutic protocols of pediatric OLST.

Kawasaki disease in infants less than one year of age: an Italian cohort from a single center.

BACKGROUND AND AIMS: Few data are currently available for Kawasaki disease (KD) below 12 months especially in Caucasians. This study aims to analyze clinical and laboratory features of KD among an Italian cohort of infants. METHODS: A retrospective chart review of KD children aged less than 1 year at time of disease onset between January 2008-December 2017 was performed. Clinical data, laboratory parameters, instrumental findings, treatment and outcome were collected in a customized database. RESULTS: Among 113 KD patients, 32 (28.3%) were younger than 1 year. Nineteen patients aged below 6 months, and three below 3 months. The median age was 5.7 ± 2.7 months. The mean time to diagnosis was 7 ± 3 days and was longer in the incomplete forms (8 ± 4 vs 6 ± 1 days). Conjunctival injection was present in 26 patients (81.2%); rash in 25 (78.1%); extremity changes in 18 (56.2%); mucosal changes in 13 (40.6%,) and lymphadenopathy only in 7 (21.8%). Mucosal changes were the least common features in incomplete forms (18.2%). Twenty-two patients (68.7%) had incomplete KD. Nineteen (59.4%) had cardiac involvement, of whom 13 (59.0%) had incomplete form. ESR, PCR and platelet values were higher in complete KD; especially, ESR resulted significantly higher in complete forms (80 ± 25.7 mm/h vs 50 ± 28.6 mm/h; p = 0.01). Conversely, AST level was statistically significant higher in patients with incomplete forms (95.4 ± 132.7 UI/L vs 29.8 ± 13.2 UI/L; p = 0.03). All patients received IVIG. Response was reported in 26/32 patients; 6 cases needed a second dose of IVIG and one required a dose of anakinra. CONCLUSION: In our cohort, incomplete disease was commonly found, resulting in delayed diagnoses and poor cardiac prognosis. Infants with incomplete KD seem to have a more severe disease and a greater predilection for coronary involvement than those with complete KD. AST was significantly higher in incomplete forms, thus AST levels might be a new finding in incomplete forms' diagnosis. Eventually, we highlight a higher resistance to IVIG treatment. To our knowledge this is the first study involving an Italian cohort of patients with KD below 12 months.

Pediatric Scurvy: When Contemporary Eating Habits Bring Back the Past.

Vitamin C deficiency is anecdotal in developed countries, mainly associated with underling clinical morbidities as autism or neurological impairment. Chronic insufficient dietary supply is responsible for vascular fragility and impaired bone formation, resulting in gingival bleeding, petechial lesions, articular and bone pain or limb swelling. Children may present anorexia, irritability, failure to thrive, limping or refusal to walk. Accordingly, pediatric scurvy is frequently misdiagnosed with osteomyelitis, septic arthritis, bone and soft tissue tumor, leukemia, bleeding disorders, and rheumatologic conditions. We report the case of a 3-years old child developing scurvy as consequence of strict selective diet; extensive and invasive investigations were undertaken before the correct diagnosis was considered. Despite being considered a rare condition, scurvy still exists nowadays, even in children with no apparent risk factors living in wealthy families. The increasing popularity of dietary restriction for children, especially those with allergies, may potentially enhance the occurrence of scurvy in apparently healthy children. Appropriate dietary anamnesis is fundamental in order to highlight potential nutritional deficit and to avoid unnecessary invasive diagnostic procedures. Patients without considerable risk factors may benefit from psychological support in order to investigate possible eating disorders.

Paediatric venous thromboembolism: a report from the Italian Registry of Thrombosis in Children (RITI).

BACKGROUND: The Italian Registry of Thrombosis in Children (RITI) was established by a multidisciplinary team with the aims of improving knowledge about neonatal and paediatric thrombotic events in Italy and providing a preliminary source of data for the future development of specific clinical trials and diagnostic-therapeutic protocols. MATERIALS AND METHODS: We analysed the subset of RITI data concerning paediatric systemic venous thromboembolic events that occurred between January 2007 and June 2013. RESULTS: Eighty-five deep venous thromboses and seven pulmonary emboli were registered in the RITI. A prevalence peak was observed in children aged 10 to 18 years and, unexpectedly, in children aged 1 to 5 years. A central venous line was the main risk factor (55% of venous thromboembolic events); surgery (not cardiac) (25%), concomitant infections (23%) and malignancy (22%) were the clinical conditions most often associated with the onset of venous thromboembolism. There was a diagnostic delay of more than 24 hours in 37% of the venous thromboembolic events. Doppler ultrasound was the most widely used test for the objective diagnosis of deep venous thrombosis (87%). Antithrombotic therapy was administered in 96% of venous thromboembolic events, mainly low molecular weight heparin (60%). In 2% of cases recurrences occurred, while post-thrombotic syndrome developed in 8.5% of cases. DISCUSSION: Although the data from the RITI are largely in agreement with published data, peaks of prevalence of thrombosis, risk factors and objective tests used for the diagnosis showed some peculiarities which may deserve attention.

Paediatric arterial ischaemic stroke and cerebral sinovenous thrombosis. First report from the Italian Registry of Pediatric Thrombosis (R. I. T. I., Registro Italiano Trombosi Infantili).

Data from large case series of children with cerebral thrombotic events are pivotal to improve prevention, early recognition and treatment of these conditions. The Italian Registry of Pediatric Thrombosis (R. I. T. I.) was established in 2007 by a multidisciplinary team, aiming for a better understanding of neonatal and paediatric thrombotic events in Italy and providing a preliminary source of data for the future development of specific clinical trials and diagnostic-therapeutic protocols. We analysed data relative to the paediatric cerebral thrombotic events of the R. I. T. I. which occurred between January 2007 and June 2012. In the study period, 79 arterial ischaemic stroke (AIS) events (49 in males) and 91 cerebral sinovenous thrombosis (CSVT) events (65 in males) were enrolled in the R. I. T. I. Mean age at onset was 4.5 years in AIS, and 7.1 years in CSVT. Most common modes of presentation were hemiparesis, seizures and speech disturbances in AIS, and headache, seizures and lethargy in CSVT. Most common etiologies were underlying chronic diseases, vasculopathy and cardiopathy in AIS, and underlying chronic diseases and infection in CSVT. Time to diagnosis exceeded 24 hours in 46 % AIS and 59 % CSVT. Overall data from the Italian Registry are in substantial agreement with those from the literature, despite small differences. Among these, a longer time to diagnosis compared to other registries and case series poses the accent to the need of an earlier recognition of paediatric cerebrovascular events in Italy, in order to enable prompt and effective treatment strategies.

Severe rhabdomyolysis with myocarditis in a 2-year-old child.

Rhabdomyolysis in children is frequently a complication of a viral infection and typically has a benign course: calf pain and difficulty walking that usually resolve in a few days. Elevated levels of creatine kinase are an indicator of muscle injury. There are few reports of severe rhabdomyolysis in children without underlying metabolic or rheumatologic disease. We describe a case of acute rhabdomyolysis after a viral infection in a previously healthy child. The muscular involvement was so severe that the patient had a respiratory arrest on the second hospital day. The patient also developed cardiac involvement with mild myocardial dysfunction and myoglobinuria, without reduction of renal function.

The use of B-type natriuretic peptide in paediatric patients: a review of literature.

OBJECTIVE: Plasma levels of brain natriuretic peptide (BNP) and its inactive fragment N-terminal pro-BNP are recognized as reliable markers of ventricular dysfunction in adults. We aimed to verify BNP applications in children. METHODS: A review of the literature on this subject was carried out. RESULTS: When dealing with paediatric patients, age and sex-related normal values must be considered. Higher BNP plasma levels are reported in children with chronic heart failure; they are related with the type of dysfunction and with prognosis. Moreover, increased BNP levels have been reported in asymptomatic children and adolescents pretreated with anthracyclines, who are at risk for ventricular dysfunction. CONCLUSION: BNP and pro-BNP also seem to be effective markers of ventricular dysfunction in paediatric patients. Clinical use may be extended not only for the characterization of heart dysfunction, but also for monitoring asymptomatic patients at specific risk. To this purpose, wider application in clinical trials appears warranted.