The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C.

OBJECTIVES: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome. STUDY DESIGN: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1-4, 5-11, 12-16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified. RESULTS: Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes. CONCLUSIONS: The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities.

Overlapping clinical features of systemic juvenile idiopathic arthritis and SARS-CoV-2-related multisystem inflammatory syndrome in children.

Introduction: Differential diagnosis of the systemic juvenile idiopathic arthritis (sJIA) is often complicated, because of the variability in clinical presentation and the absence of specific signs. Material and methods: The PubMed/Medline and Scopus databases from the years 2013-2022 were analysed for full articles in English and the following key words were used: "juvenile idiopathic arthritis" and "MIS-C"; "juvenile idiopathic arthritis" and "Kawasaki disease". As an example of the problem the case description of a 3-year-old patient is presented. Results: In the first step 167 publications were identified; however, after exclusion of duplicated articles and those not relevant to the topic, only 13 were included in the analysis. We analysed studies that describe overlapping clinical features of sJIA and Kawasaki disease (KD) or multisystem inflammatory syndrome in children (MIS-C). The main issues we discussed were the search for the specific features that would distinguish one disease from another. Fever refractory to intravenous immunoglobulin treatment was the most frequent indicator among the features of clinical courses. Among other clinical signs prolonged, recurrent fever, rash, an incomplete KD phenotype, Caucasian race, splenomegaly, and complicated macrophage activation syndrome also supported sJIA diagnosis. Among laboratory tests, high ferritin and serum interleukin-18 levels were found to be the most useful in differentiation. The present case demonstrates that prolonged, unexplained, recurrent fever with a specific pattern should be the reason to suspect sJIA. Conclusions: Overlapping features of sJIA and SARS-CoV-2-related MIS-C complicates diagnosis in the era of the COVID-19 pandemic. Our case presentation adds symptoms of prolonged, spiking, unexplained, recurrent fever with a specific pattern for supporting systemic juvenile idiopathic arthritis diagnosis.

Autoimmunity and long COVID in children.

Numerous hypotheses regarding the pathogenetic mechanisms of long COVID have been proposed. Immune dysregulation and autoimmunity are among the leading hypotheses. In this article, we present two clinical cases of long COVID. The first case demonstrates the phenotype of long COVID with pain and musculoskeletal symptoms, which is often associated with autoimmunity and mimics systemic connective tissue diseases. In the second case, a high titer of antinuclear antibodies was observed after SARS-CoV-2 infection, but the clinical symptoms were limited to fever and headache. Only a comprehensive evaluation of clinical symptoms and thorough objective examination can confirm or exclude autoimmune diseases after a previous SARS-CoV-2 infection. A systematic search in the PubMed Medline database was carried out for studies focusing on immune dysregulation, autoimmunity, and its association with the clinical phenotype of long COVID. The question of the role of autoimmunity in the development of long COVID and the management approaches are discussed.

Serum pyridoxine, folate, cobalamin, and homocysteine levels in children presenting with vasovagal syncope.

BACKGROUND: Recent studies confirm the role of B vitamins deficiency and hyperhomocysteinaemia in the development of dysautonomia that has been considered to be the main factor in vasovagal syncope development. The aim of the study was to investigate serum pyridoxine, folate, cobalamin, and homocysteine levels in children presenting with vasovagal syncope and to analyse the correlation between them and main clinical parameters of syncope. METHODS: We studied 40 children, ages 8-17 years with a history of vasovagal syncope and 24 healthy volunteers. The serum pyridoxine, folate, cobalamin, and homocysteine levels were measured by a quantitative sandwich enzyme immunoassay technique using a commercial kit (Monobind, USA). Twenty-four-hour Holter monitoring and 24-hour ambulatory blood pressure monitoring were conducted for all participated patients. RESULTS: Serum pyridoxine (9.42 ± 4.87, 16.11 ± 5.53 µg/L) and cobalamin (307.48 ± 95.50, 447.28 ± 108.85 ng/L) levels were reasonably low (p < 0.05) in patients with vasovagal syncope. Although there was no significant change in folate levels between syncope and healthy children (4.00 ± 1.34, 4.71 ± 1.73 µg/L; p = 0.20), we detected low folate-level association with longer duration of syncope (r = -0.42) and post syncope (r = -0.43) symptoms (p < 0.05). Finally, there was increased serum homocysteine level (13.55 ± 5.03, 7.81 ± 1.71 µmol/L; p < 0.05) in patients with vasovagal syncope. It was positively correlated with the average PQ interval (r = 0.35, p < 0.05) and average QTc interval (r = 0.49, p < 0.05). CONCLUSIONS: The results suggested that pyridoxine, folate, cobalamin, and homocysteine may be involved in the pathogenesis of vasovagal syncope. This might provide a new approach for effective treatment of paediatric vasovagal syncope, requiring further study.

Clinical and autoantibody phenotypes of juvenile dermatomyositis.

Juvenile dermatomyositis (JDM) is a heterogeneous autoimmune inflammatory myositis with symmetrical proximal muscle weakness and a characteristic rash. Juvenile dermatomyositis is characterized by variable presentation and phenotypes. Detection of myositis autoantibodies is useful in improving JDM diagnosis and predicting the prognosis. In this literature review based on case series we analyze clinical and autoantibody phenotypes of JDM in four patients who were hospitalized in one regional center in Ukraine during the last 3 years and three of them presented in the time of the COVID-19 pandemic. The reviewed literature showed the last updates for the JDM diagnosis and the role of myositis autoantibodies in the prediction of disease course, systemic involvement, and malignancy risk. The presence of anti-synthetase syndrome in all presented patients, mainly due to anti-PL-7 autoantibodies, encourages further study with more patients and with detection of other myositis-specific autoantibodies to identify or refute certain regional features.

Newborn screening for severe combined immunodeficiency: clinical and cost-effectiveness approaches.

Severe combined immunodeficiency (SCID) is a group of lifethreatening diseases, for which early diagnostics, before the development of infectious complications, is extremely important. Newborn screening for SCID with T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) assay for the identification of T- and B-lymphopenia has been implemented in a number of highly developed countries of the world. A number of studies proved the clinical and cost-effectiveness of screening for SCID by using TREC assay. However, both clinical benefits and economic costs for screening may vary depending on country and continent, requiring pilot projects to establish reference values of TREC and KREC levels for the diagnosis of SCID and other diseases associated with T- and B-lymphopenia, as well as determination of cost-effectiveness/costbenefit ratio and expediency of their further implementation. Other challenges, outlined in the article, need to be solved. The development of hematopoietic stem cell transplantation in Ukraine opens up full opportunities for the implementation of newborn screening for SCID. The expediency of conducting a pilot study to determine the most effective method (TREC or TREC/KREC) and the algorithm for SCID detection has been shown.

AWARENESS OF FOLIC ACID USE AND ITS EFFECTS AMONG MEDICAL STUDENTS IN UKRAINE.

OBJECTIVE: The aim: To evaluate the awareness of folic acid, its use and effects, general knowledge about neural tube defects among medical students in Ukraine. PATIENTS AND METHODS: Materials and methods: This cross-sectional survey was conducted by questioning 114 fourth and fifth years' students of the Faculty of Medicine. The questionnaire contained questions about folic acid, its dietary sources, effects and periconceptional uses; spina bifida and its main symptoms. RESULTS: Results: Overall, 96.5% of students knew that folic acid was a vitamin and 95.6% were aware of the one natural product which had a high folate level. However, awareness of its amount in different products was insufficient. Overall, 86.8% of surveyed knew that folic acid deficiency during pregnancy caused the congenital malformations. The knowledge of the synthetic folic acid supplementation before and during pregnancy was low (67.5% and 53.5% respectively). Only 10 % of women among medical students consumed folic acid regularly. CONCLUSION: Conclusions: Despite the high level of general knowledge about folic acid and its effects among medical students in Ukraine, there is a poor awareness of the pre-conception administration of folic acid, and the number of people who regularly take folic acid among the respondents was very low.

Impact of the J Project on progress of primary immunodeficiency care in Ukraine.

The J Project is a Central-Eastern European collaborative program in the field of physician education and clinical research aimed at improving the clinical care and diagnosis of primary immunodeficiency disorders (PIDs). Ukraine was one of the first to participate in the project, which allowed us to join the whole European PID community. Since 2004, the country has been holding annual J Project meetings with the involvement of new regions. The spread of the J Project impact has contributed to significantly improved early PID diagnosis in Ukraine. Progress has been made not only in identifying patients but also in arranging the treatment. The assistance in genetic diagnosis made it possible to detect PIDs, study their features, and improve approaches to the management. This also gave an impetus to the development of regional PID centers and participation in scientific research. Of utmost importance is the cooperation with colleagues from Poland, Hungary, and Belarus, who are active members of the J Project.

COVID-19 in patients with juvenile idiopathic arthritis: frequency and severity.

The aim of the study was to determine the frequency and the course of COVID-19 infection in children with juvenile idiopathic arthritis (JIA). The study involved 51 patients with JIA aged 2 to 18 years. Evidence of COVID-19 was found in 10 (19.6%) patients with JIA. COVID-19 infection occurred more often in patients with systemic arthritis (OR = 6.1667, 95% CI: 1.2053-31.5511, p = 0.0289). The course of COVID-19 infection in patients with JIA was generally similar to the course in the pediatric population, despite immunosuppressive therapy. In 3 out of 10 patients the infection caused an exacerbation of JIA, which required therapy escalation.

Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome.

Two variants in the ubiquitously expressed NHLRC2 gene have been reported to cause a lethal fibrotic cerebropulmonary disease termed fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome in three Finnish children. Our objective was to determine the genetic basis of disease in a new patient with clinical features of FINCA syndrome using whole-exome sequencing (WES) and confirmation by Sanger sequencing. The patient has one known and one novel variant in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P, respectively). p.H143P is extremely rare and is not present in the gnomAD database of >140,000 allele sequences from healthy humans. Both variants affect the highly conserved N-terminal thioredoxin (Trx)-like domain of NHLRC2 and are predicted to be damaging. We conclude that a compound heterozygous combination of a known and a novel variant in NHLRC2 causes FINCA syndrome in a 2-year-old Ukrainian patient, underscoring the importance of NHLRC2 as a central regulator of fibrosis.

Features of heritable disorders of connective tissue in children with acute rheumatic fever and rheumatic heart disease.

OBJECTIVES: Heritable disorders of connective tissue (HDCT) are associated with morphological and functional disorders of different organs and systems. The aim of our study was to determine the clinical signs of heritable disorders of connective tissue and oxyproline levels in children with acute rheumatic fever (ARF) and rheumatic heart disease (RHD). MATERIAL AND METHODS: A total of 155 patients aged 4 to 17 years participated in the study: 23 with ARF, 78 with RHD, and 54 healthy patients with a history of ARF. All patients underwent a standardized examination protocol, which consisted of a detailed medical history recorded by the physician, general and special laboratory tests, electrocardiogram, echocardiography, and Doppler echocardiography. Special attention was paid to the clinical signs of HDCT. The intensity of the metabolic processes in the connective tissue was evaluated by serum oxyproline levels. RESULTS: The signs of HDCT were revealed in 121 (78.1%) of the patients with ARF and RHD. Among cardiovascular manifestations, we observed mitral valve prolapse most often - in 91 (58.7%) patients. Musculoskeletal anomalies were observed in 94 (60.7%) patients. Both groups of patients with ARF and RHD had elevated mean serum oxyproline levels. CONCLUSIONS: Children with acute rheumatic fever and rheumatic heart disease presented with a number of signs characteristic of heritable connective tissue disorders. The cardiovascular and musculoskeletal system changes are the most frequent among all features of HDCT. Elevated levels of serum oxyproline in patients with ARF and RHD confirm connective tissue disorders. Children with manifestations of HDCT are at the risk of ARF and RHD development.

The Jarisch-Herxheimer reaction associated with doxycycline in a patient with Lyme arthritis.

OBJECTIVES: The objective of this article was to present the clinical peculiarity of the Jarisch-Herxheimer reaction (JHR) during antibiotic treatment of Lyme arthritis. MATERIAL AND METHODS: Case study presentation as a basis for discussion, literature search of PubMed database particularly in the subject of combination of the JHR and Lyme borreliosis using the combination of words "Jarisch-Herxheimer reaction" and "Lyme borreliosis", "Lyme arthritis", "antibiotic treatment", "generalized inflammation", "cytokine production", "children", "increasing awareness"; discussion of the problem based on a clinical case and cited articles. RESULTS: The authors present a case of Lyme arthritis in a 13-year-old boy, as well as a discussion of clinical features of this complication of Lyme disease treatment as the Jarisch-Herxheimer reaction. On the 7th day of doxycycline treatment the patient's condition deteriorated: a low-grade fever occurred, and severe arthralgias with intense hip, ankle and cervical spine pain and myalgias developed. Erythrocyte sedimentation rate and C-reactive protein were elevated. The Jarisch-Herxheimer reaction was diagnosed. This complication was characterized by severity, long duration and marked signs of inflammation. CONCLUSIONS: In the reviewed literature the Jarisch-Herxheimer reaction in patients with Lyme borreliosis is described more often in adults, with mild course and short duration of the disease. Based on the presented clinical picture this severe complication may also be associated with long duration and marked signs of inflammation. The authors suggest that informing health professionals about occurrence of the Jarisch-Herxheimer reaction should help physicians to distinguish it from allergic reactions or other conditions and improve treatment outcomes.

Clinical variability of the systemic juvenile idiopathic arthritis course: literature review based on case series.

Systemic juvenile idiopathic arthritis (sJIA) is a heterogeneous category of arthritis that frequently leads to disability and severe complications. The clinical cause of sJIA is very variable, which results in difficulties of disease recognition. In this literature review based on case series we outline the main challenges in diagnostic of sJIA and macrophage activation syndrome (MAS). Using the 2016 criteria for MAS diagnostic allowed to consider MAS in the diagnostically challenging cases, that confirms their sensitivity in pediatric patients. The reviewed literature showed last updates for the improvement of classification, diagnostic of sJIA and its complication. The modification of JIA criteria, initiated by Paediatric Rheumatology International Trials Organisation, will allow to improve detection and treatment of JIA. The presentation of this clinical cases and the discussion may be useful for understanding the disease cause and will help to differentiate sJIA and MAS from other disorders, and to improve treatment outcomes.

Streptococcus gordonii-associated infective endocarditis in a girl with Barlow's mitral valve disease.

We present a case of infective endocarditis caused by Streptococcus gordonii in an 11-year-old girl with Barlow's mitral valve disease. The differential diagnosis of rheumatic carditis and infective endocarditis was difficult as the patient fulfilled the Jones criteria. Vegetation on the mitral valve which became evident later in course of the disease and positive blood culture allowed diagnosing "definite" infective endocarditis.

Clinical variability of chromosome 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2 DS) is a disorder that has multiple symptoms and affects various organs and systems. Despite the great variability of clinical manifestations, common 22q11.2 DS includes congenital heart defect, immunodeficiency, characteristic facial features, palatal defects, developmental and/or learning disabilities, and hypocalcaemia. We present the cases of three patients with 22q11.2 DS that we have observed. Heart defects were revealed in all cases, and tetralogy of Fallot in one of them. Immune system disorders in these cases were highly variable and did not correlate with aplasia or hypoplasia of the thymus. Cleft palate was diagnosed only in one case. Characteristic facial features were presented in all cases but they were not significant and varied from subtle to mild. Developmental disability was presented by motor delays in two cases. Hypocalcaemia was revealed in one patient, and seizures were absent. Only one case completely fit CATCH-22 syndrome (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcaemia caused by22q11.2 deletion). The other cases had three out of the five main features, with some other, less significant signs also presented. In some cases, even just a few signs should be the reason for further examination to exclude 22q11.2 deletion syndrome. Currently, immunological disorders are not a significant determinant in the diagnosis of this syndrome, and timely correction of heart defects can reduce the number of recurrent respiratory infections. A multidisciplinary approach to the management of these patients and providing timely, complex medical care will prevent serious complications.

Coagulation profile in hospitalized children with COVID-19: pediatric age dependency and its impact on long COVID development.

Introduction: Pulmonary endotheliopathy and microvascular immunothrombosis play a key role in acute COVID-19. Moreover, persistent endotheliopathy and heightened coagulability frequently occur in individuals recovering from COVID-19, suggesting the intriguing possibility of their role in the development of long COVID. The aim of our study was to investigate the coagulation profile in patients with COVID-19 based on age and their role in the development of long COVID. Methods: We conducted a prospective single-center cohort study from September 2022 to August 2023. The study involved 190 patients younger than 18 years who were hospitalized at the Ternopil City Children's Hospital, Ukraine due to COVID-19. Patients underwent determination of coagulation profile in addition to the general clinical examination. After discharge from the hospital, patients were monitored for the presence of long COVID symptoms. Among the 157 participants who consented for follow-up, 62 patients (39.5%) had long COVID symptoms according to the WHO definition, while the rest (95 patients) did not have symptoms of long COVID (fully recovered). Results: The study revealed the normal count of platelets in the majority of patients (86.8%), whereas abnormalities in the coagulation profile were revealed in 94.5% of children with COVID-19, and these changes were age-dependent. The patients were mostly presented with increased activated partial thromboplastin time (69.1%), prothrombin time (PT) (39.8%) and D-dimer (45.0%). There was no significant difference between the median of platelet levels and coagulation profile indicators between the groups with long COVID and recovered. Among children who developed persistent long COVID symptoms there was a statistically higher percentage of abnormal PT values (53% versus 36.1%, p=0.0432), with no significant differences in other coagulation profile indicators. Abnormal PT along with female gender, comorbidities, especially allergic pathology, nutritional disorder, including obesity, were determined as potential risk factors of the long COVID development (Odds ratio - 2.0611; 95% 1.0179-4.1737, p=0.0445). Conclusions: The study highlights the need for more extensive research into the coagulation profiles of pediatric populations, considering age-specific factors. This could enhance our understanding of thromboinflammation in COVID-19 and its potential contribution to the development of persistent symptoms.

Nijmegen breakage syndrome: 25-year experience of diagnosis and treatment in Ukraine.

Introduction: Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder, characterized by microcephaly, immunodeficiency, and impaired DNA repair. NBS is most prevalent among Slavic populations, including Ukraine. Our study aimed to comprehensively assess the prevalence, diagnosis, clinical data, immunological parameters, and treatment of NBS patients in Ukraine. Methods: We conducted a retrospective review that included 84 NBS patients from different regions of Ukraine who were diagnosed in 1999-2023. Data from the Ukrainian Registry of NBS and information from treating physicians, obtained using a developed questionnaire, were utilized for analysis. Results: Among 84 NBS patients, 55 (65.5%) were alive, 25 (29.8%) deceased, and 4 were lost to follow-up. The median age of patients was 11 years, ranging from 1 to 34 years. Most patients originate from western regions of Ukraine (57.8%), although in recent years, there has been an increase in diagnoses from central and southeastern regions, expanding our knowledge of NBS prevalence. The number of diagnosed patients per year averaged 3.4 and increased from 2.7 to 4.8 in recent years. The median age of NBS diagnosis was 4.0 years (range 0.1-16) in 1999-2007 and decreased to 2.7 in the past 6 years. Delayed physical development was observed in the majority of children up to the age of ten years. All children experienced infections, and 41.3% of them had recurrent infections. Severe infections were the cause of death in 12%. The second most common clinical manifestation of NBS was malignancies (37.5%), with the prevalence of lymphomas (63.3%). Malignancies have been the most common cause of death in NBS patients (72% of cases). Decreased levels of CD4+ and CD19+ were observed in 89.6%, followed by a reduction of CD3+ (81.8%) and CD8+ (62.5%). The level of NK cells was elevated at 62.5%. IgG concentration was decreased in 72.9%, and IgA - in 56.3%. Immunoglobulin replacement therapy was administered to 58.7% of patients. Regular immunoglobulin replacement therapy has helped reduce the frequency and severity of severe respiratory tract infections. Conclusion: Improvements in diagnosis, including prenatal screening, newborn screening, monitoring, and expanding treatment options, will lead to better outcomes for NBS patients.

Serum Vitamin D Levels in Children and Adolescents with Vasovagal Syncope, Syncope Due to Orthostatic Hypotension, and Cardiac Syncope.

OBJECTIVE: The study aimed to compare vitamin D levels between children and adolescents with vasovagal syncope, syncope due to orthostatic hypotension, cardiac syncope, and healthy individuals and to investigate the correlations of 25(OH)D with main clinical parameters of syncope. MATERIALS AND METHODS: This study involved 83 children aged 8-17 years with syncope: 40 with vasovagal syncope, 24 with syncope due to orthostatic hypotension, and 19 with cardiac syncope. There were 24 healthy volunteers in the control group. Data concerning active standing test, electrocardiography, echocardiography, electroencephalography, and 24-hour Holter monitoring findings were collected. Serum vitamin D was evaluated by an enzyme-linked immunoassay technique test. RESULTS: The mean levels of serum 25(OH)D were decreased in children with vasovagal syncope (18.8 ± 5.9 ng/mL), syncope due to orthostatic hypotension (19.9 ± 6.7 ng/mL), and cardiac syncope (20.6 ± 7.3 ng/mL) in comparing with the control group (30.9 ± 5.9 ng/mL; P < .001). In patients with syncope due to orthostatic hypotension, vitamin D deficiency was associated with a reduction in systolic blood pressure (r = 0.43) and diastolic blood pressure (r = 0.38) within the first minute, lower systolic blood pressure (r = 0.44) within the third minute of active orthostasis (P < .05). There were significant correlations of vitamin D deficiency with parameters of cardiac autonomic activity pNN50 (r = 0.49), total power (r = 0.39), and low frequency index (r = 0.35) in children with cardiac syncope (P < .05), while heart rate variability was not affected in patients with vasovagal syncope and syncope due to orthostatic hypotension (P > .05). CONCLUSION: Children and adolescents with vasovagal syncope, syncope due to orthostatic hypotension, as well as cardiac syncope had higher frequency of vitamin D deficiency than healthy pediatric controls. This provides a new approach to syncope management in pediatric population, requiring further studies.