Case Report: Recurrent pericardial tamponade in a child with COVID-19.

Background: Pericarditis is rare in Coronavirus disease 2019 (Covid-19) infection and only a few cases were reported in children. Case presentation: We present the case of a 15-year-old boy with symptoms of high fever and worsening chest pain during COVID-19 infection. Chest computer tomography (CT) and echocardiography confirmed pericardial tamponade requiring urgent drainage. Despite antiviral drug treatment, after 18 days severe attack developed requiring repeated pericardiocentesis. High dose ibuprofen, colchicin and the interleukin-1 antagonist, anakinra were given. Clinical symptoms and laboratory parameters improved after seven days of treatment. Autoinflammatory diseases were also suspected in the background the severe pericarditis, but genetic analysis ruled out any mutations. Conclusion: Pericarditis associated with COVID-19 infection may present in the acute phase or later as MIS-C. Though pericardial tamponade related to ongoing Covid-19 infection is rare in children, even biological treatment with interleukin-1 antagonist may be needed to control the inflammation.

Diagnosis and treatment of paediatric multisystem inflammatory syndrome / A gyermekkori koronavírus-fertozést követo sokszervi gyulladás diagnosztikája és kezelése.

Összefoglaló. A SARS-CoV-2-fertozés ritka gyermekkori szövodménye a sokszervi gyulladás, angol terminológiával paediatric inflammatory multisystem syndrome (PIMS). Két vagy több szerv érintettségével járó, súlyos tünetekkel induló betegségrol van szó, amelynek tünetei átfedést mutatnak a Kawasaki-betegséggel, a toxikus sokk szindrómával és a makrofágaktivációs szindrómával. A PIMS-betegek intenzív terápiás osztályon vagy intenzív terápiás háttérrel rendelkezo intézményben kezelendok, ahol biztosítottak a kardiológiai ellátás feltételei is. A szükséges immunterápia a klinikai prezentációtól függ. A jelen közleményben a szerzok a releváns nemzetközi irodalom áttekintését követoen ajánlást tesznek a PIMS diagnosztikai és terápiás algoritmusára. Orv Hetil. 2021; 162(17): 652-667. Summary. Pediatric inflammatory multisystem syndrome (PIMS) is a rare complication of SARS-CoV-2 infection in children. PIMS is a severe condition, involving two or more organ systems. The symptoms overlap with Kawasaki disease, toxic shock syndrome and macrophage activation syndrome. PIMS patients should be treated in an intensive care unit or in an institution with an intensive care background, where cardiological care is also provided. The required specific immunotherapy depends on the clinical presentation. In this paper, after reviewing the relevant international literature, the authors make a recommendation for the diagnostic and therapeutic algorithm for PIMS. Orv Hetil. 2021; 162(17): 652-667.

Peripheral Blood Lymphocyte Analysis in Oligo- and Polyarticular Juvenile Idiopathic Arthritis Patients Receiving Methotrexate or Adalimumab Therapy: A Cross-Sectional Study.

Juvenile idiopathic arthritis (JIA) is an umbrella term for seven distinct chronic immune-mediated diseases. Disease-modifying anti-rheumatic drugs (DMARD) are used to treat the underlying joint inflammation as well as extra-articular manifestations. Immunosuppression is a considerable side effect of the drugs. The main goal of this study was to investigate the effect of different JIA therapies on leukocyte subpopulations, which play a role in immune-defense. Three study groups were established. The first group consisted of JIA patients treated with methotrexate solely, the second one received a combination of methotrexate (MTX) and adalimumab (ADA). The control group was made up of the patients' healthy siblings. A total of 63 children were recruited. Fourty-one children with JIA and 22 healthy controls were included in the study. The absolute number of CD3+ T-cells was significantly elevated in patients treated with biological therapy compared to healthy controls (p2 = 0.017). In contrast, the number of CD56+ natural killer cells was significantly lower in children receiving biological therapy in comparison with healthy donors (p2 = 0.039). A significant alteration was also demonstrated between patients treated with MTX and MTX/ADA group concerning CD 19+ B-cells (p3 = 0.042). This is the first study that demonstrates significant alterations in the number of B-cells and T-cells with a relative decrease of NK-cell ratios in JIA patients receiving different DMARD therapy. Clinical Trial Registration: NCT03833271. 21.01.2019.

Pregnancy outcomes of women whom spouse fathered children after tyrosine kinase inhibitor therapy for chronic myeloid leukemia: A systematic review.

INTRODUCTION: The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML). Although the efficacy of TKIs is beyond dispute, conception-related safety issues are still waiting to be explored, particularly in males. This systematic review aimed to summarize all available evidence on pregnancy outcomes of female spouses of male CML patients who fathered children after TKI treatment for CML. METHODS: We performed a systematic search in seven electronic databases for studies that reported on male CML patients who did or did not discontinue TKI treatment before conceiving, and the pregnancy outcomes of their female spouse are available. The search centered on the TKI era (from 2001 onward) without any other language or study design restrictions. RESULTS: Out of a total of 38 potentially eligible papers, 27 non-overlapping study cohorts were analyzed. All were descriptive studies (case or case series studies). Altogether, 428 pregnancies from 374 fathers conceived without treatment discontinuation, 400 of which (93.5%) ended up in a live birth. A total of ten offspring with a malformation (2.5%) were reported: six with imatinib (of 313 live births, 1.9%), two with nilotinib (of 26 live births, 7.7%), one with dasatinib (of 43 live births, 2.3%), and none with bosutinib (of 12 live births). Data on CML status were scarcely reported. Only nine pregnancies (from nine males) and no malformation were reported in males who discontinued TKI treatment before conception. CONCLUSION: Malformations affected, on average 2.5% of live births from fathers who did not discontinue TKI treatment before conception, which is comparable with the rate of malformations in the general population. Large-scale studies with representative samples are awaited to confirm our results.

Computed Tomography Severity Index vs. Other Indices in the Prediction of Severity and Mortality in Acute Pancreatitis: A Predictive Accuracy Meta-analysis.

Background: The management of the moderate and severe forms of acute pancreatitis (AP) with necrosis and multiorgan failure remains a challenge. To predict the severity and mortality of AP multiple clinical, laboratory-, and imaging-based scoring systems are available. Aim: To investigate, if the computed tomography severity index (CTSI) can predict the outcomes of AP better than other scoring systems. Methods: A systematic search was performed in three databases: Pubmed, Embase, and the Cochrane Library. Eligible records provided data from consecutive AP cases and used CTSI or modified CTSI (mCTSI) alone or in combination with other prognostic scores [Ranson, bedside index of severity in acute pancreatitis (BISAP), Acute Physiology, and Chronic Health Examination II (APACHE II), C-reactive protein (CRP)] for the evaluation of severity or mortality of AP. Area under the curves (AUCs) with 95% confidence intervals (CIs) were calculated and aggregated with STATA 14 software using the metandi module. Results: Altogether, 30 studies were included in our meta-analysis, which contained the data of 5,988 AP cases. The pooled AUC for the prediction of mortality was 0.79 (CI 0.73-0.86) for CTSI; 0.87 (CI 0.83-0.90) for BISAP; 0.80 (CI 0.72-0.89) for mCTSI; 0.73 (CI 0.66-0.81) for CRP level; 0.87 (CI 0.81-0.92) for the Ranson score; and 0.91 (CI 0.88-0.93) for the APACHE II score. The APACHE II scoring system had significantly higher predictive value for mortality than CTSI and CRP (p = 0.001 and p < 0.001, respectively), while the predictive value of CTSI was not statistically different from that of BISAP, mCTSI, CRP, or Ranson criteria. The AUC for the prediction of severity of AP were 0.80 (CI 0.76-0.85) for CTSI; 0.79, (CI 0.72-0.86) for BISAP; 0.83 (CI 0.75-0.91) for mCTSI; 0.73 (CI 0.64-0.83) for CRP level; 0.81 (CI 0.75-0.87) for Ranson score and 0.80 (CI 0.77-0.83) for APACHE II score. Regarding severity, all tools performed equally. Conclusion: Though APACHE II is the most accurate predictor of mortality, CTSI is a good predictor of both mortality and AP severity. When the CT scan has been performed, CTSI is an easily calculable and informative tool, which should be used more often in routine clinical practice.

[Clinical features and therapy of uveitis in childhood]. / A gyermekkori uveitis klinikai jellemzoi és terápiája.

Introduction: Uveitis is characterized by inflammation of the middle layer of the eye. Its overall incidence is low. Autoimmune diseases and infections are the most common underlying diseases. Out of the autoimmune diseases, juvenile idiopathic arthritis is associated most frequently with uveitis. The topical ophthalmological treatment may fail in a significant proportion of the patients and immunomodulatory therapy may be required. Aim and method: In a retrospective study, data of 33 children diagnosed and treated with uveitis at the Department of Pediatrics and Ophthalmology, University of Pécs during the last 5 years were collected and analyzed. Results: The mean age of the patients was 9.3 (0.3-17.8) years. Boys and girls were equally affected with an exception of patients with juvenile idiopathic arthritis where female predominance was found. An underlying disease could be identified in 60% of the cases (20/33). Uveitis was associated in 12 patients with juvenile idiopathic arthritis, in 2 patients with Behcet's disease and in a single case with inflammatory bowel disease. Infections have been proven in 5 patients. The autoimmune diseases caused an eye inflammation typically in anterior localization, in contrast to the infections that resulted in posterior uveitis. The majority of the patients required systemic treatment. 3 of them received systemic corticosteroid and 18 patients methotrexate as disease-modifying antirheumatic drug. 13 children with severe disease activity required biological therapy (adalimumab injection). Remission could be achieved in 1.45 (0.75-2.5) months. Conclusion: Pediatric uveitis is of great importance. Early diagnosis, adequate therapy and follow-up require multidisciplinary cooperation. Orv Hetil. 2019; 160(34): 1335-1339.

The effects of TNF-alpha inhibitor therapy on the incidence of infection in JIA children: a meta-analysis.

BACKGROUND: Juvenile Idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. The diagnosis is based on the underlying symptoms of arthritis with an exclusion of other diseases Biologic agents are increasingly used on the side of disease-modifying anti-rheumatic drugs (DMARD) in JIA treatment. MAIN BODY: The aim of this meta-analysis was to investigate the observed infections in JIA children during tumor necrosis factor (TNF)-alpha inhibitor therapy. A systematic search of three databases (Medline via PubMed, Embase, Cochrane Library) was carried out up to May 2018. Published trials that evaluated the infectious adverse events in patients receiving TNF-alpha inhibitor vs. a control group were included in the analysis. Full-text data extraction was carried out independently by the investigators from ten relevant publications. 1434 patients received TNF-alpha inhibitor therapy; the control group consisted of 696 subjects. The analysis presented the risk of infection in the active treatment group (OR = 1.13; 95% CI: 0.76-1.69; p = 0.543). The majority of infections were upper respiratory tract infections (URTIs). Furthermore, the subgroup analysis demonstrated a higher infection rate in the observed localization. CONCLUSION: Anti-TNF therapy slightly but not significantly increases the incidence of infection in JIA children compared to other therapies (GRADE: moderate evidence). The most common infections reported were mild URTIs. Further studies with larger patients number with a strong evidence level are crucially needed to finalize the answer whether anti-TNF therapy elevates and if yes on what extent the incidence of infection in JIA children. TRIAL REGISTRATION: Prospero: CRD42017067873 .

Pancreatitis-Associated Genes and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to evaluate the connection between pancreatic cancer (PC) and genetic variants associated with chronic pancreatitis via systematic review and meta-analysis. METHODS: The data search was performed in 3 major databases (PubMed, Embase, and Cochrane Library). The selected studies have looked into the presence of the pancreatitis-associated genes in patients with PC and in control subjects, the outcome being the frequency of the mutations in the 2 groups. For the binary outcomes, pooled odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: Ten articles proved to be eligible for the qualitative synthesis, and 8 articles were suitable for statistical analysis. Six case-control studies, comprising 929 PC cases and 1890 control subjects for serine protease inhibitor Kazal type 1 (SPINK1) mutations, and 5 case-control studies, comprising 1674 PC cases and 19,036 control subjects for CFTR mutations, were enrolled in our analysis. SPINK1 mutations showed no association with PC (OR, 1.52; 95% CI, 0.67-3.45; P = 0.315), whereas mutations in CFTR modestly increased the risk of PC (OR, 1.41; 95% CI, 1.07-1.84; P = 0.013). CONCLUSION: Our meta-analysis showed that mutations in CFTR modestly increase the risk of PC, whereas no association was found between SPINK1 and PC.

[Autoinflammatory diseases]. / Autoinflammatiós kórképek.

Autoinflammatory diseases are disorders of the innate immune system characterized by recurrent systematic inflammation and serious complications. Dysregulation of inflammasome and overproduction of interleukin-1 play a major role in the pathogenesis of autoinflammatory diseases. The diagnosis of these rare conditions rely on recognising the pattern of presentation and differential diagnosis. Manifestations may include fever, rash, serositis (pleuritis and peritonitis), arthritis, meningitis and uveitis. Secondary amyloidosis may complicate longstanding disease. Advances in our understanding of the molecular and pathophysiological basis of the autoinflammatory diseases have resulted in new treatment strategies. Early diagnosis and effective therapy are critical to prevent irreversible organ damage. The purpose of this review is to describe the major clinical, genetic, and therapeutic features of the most common autoinflammatory syndromes. Orv Hetil. 2018; 159(23): 898-907.

Impairment of microcirculation and vascular responsiveness in adolescents with primary Raynaud phenomenon.

BACKGROUND: Raynaud's phenomenon (RP) is a functional vascular disease, presenting with recurrent episodes of ischemia of extremities in response to cold and emotional stress. Investigating cutaneous microcirculation is an important tool in understanding the complex neuro-immuno-vascular interactions in its pathophysiological mechanisms. Since there is no available data on vascular responsiveness in RP in the paediatric population, we investigated skin perfusion and heat-induced hyperaemia in comparison with clinical severity and laboratory parameters of the disease. METHODS: Fifty two adolescents (27 patients with primary RP and 25 age-matched healthy controls) were investigated in the study. Patients were divided into two groups according to the symptoms existing within the previous 2 months. Following baseline microcirculation measurement with Laser Doppler flowmetry (Periflux 5000 system), all subjects underwent local heating test at 42 °C and 44 °C. Besides routine laboratory parameters, immune-serological tests and the vasoactive sensory neuropeptides somatostatin and pituitary adenylate-cyclase activating polypeptide (PACAP) were measured. RESULTS: Baseline perfusion measured in perfusion units (PU) at 32 °C was significantly lower in symptomatic RP patients (97.6 ± 22.4 PU) compared with both healthy volunteers (248.3 ± 23.5 PU, p < 0.001) and RP patients without symptoms (187.4 ± 24.9 PU, p < 0.05). After local heating to 42 °C maximum blood flow was significantly reduced in primary RP participants with current symptoms (358.6 ± 43.9 PU, p < 0.001), but not in asymptomatic ones (482.3 ± 28.7 PU, p > 0.05) when compared with healthy subjects (555.9 ± 28.2 PU). Both the area under the response curve and the latency to reach the maximum flow were significantly increased in both RP groups (symptomatic 164.6 ± 7.4 s, p < 0.001, asymptomatic 236.4 ± 17.4 s, p < 0.001) when compared with the control group (101.9 ± 4.7 s). The heat-induced percentage increase from baseline to maximal blood flow was significantly greater in symptomatic RP adolescents in comparison with healthy ones. Laboratory parameters and neuropeptide plasma levels were not altered in any groups. CONCLUSION: To our knowledge this is the first study in paediatric population to show altered heat-induced cutaneous hyperaemia responses in relation with the clinical severity and symptomatology.

Younger age at diagnosis predisposes to mucosal recovery in celiac disease on a gluten-free diet: A meta-analysis.

BACKGROUND AND AIMS: Persistent intestinal damage is associated with higher complication rates in celiac disease. We aimed to assess the potential modifiers of mucosal recovery. MATERIALS AND METHODS: We screened databases (PubMed, Embase, Cochrane Trials, and Web of Science) for papers on celiac disease. Papers discussing (1) celiac patients (2) follow-up biopsy and (3) mucosal recovery after commencement of a gluten-free diet were included. The primary outcome was to produce a comprehensive analysis of complete mucosal recovery (i.e., Marsh 0 on follow-up). We compared children's recovery ratios to those of adults. Patients following a strict gluten-free dietary regimen were included in a subgroup. Summary point estimates, 95% confidence intervals (CIs), and 95% predictive intervals (PIs) were calculated. Heterogeneity was tested with I2-statistic. The PROSPERO registration number is CRD42016053482. RESULTS: The overall complete mucosal recovery ratio, calculated from 37 observational studies, was 0.36 (CI: 0.28-0.44, PI: -0.12-0.84; I2: 98.4%, p<0.01). Children showed higher complete mucosal recovery ratio than adults (p<0.01): 0.65 (CI: 0.44-0.85, PI: -0.10-1.39; I2: 96.5%, p<0.01) as opposed to 0.24 (CI: 0.15-0.33, PI: -0.19-1.08; I2: 96.3%, p<0.01). In the strict dietary adherence subgroup, complete mucosal recovery ratio was 0.47 (CI: 0.24-0.70, PI: -0.47-1.41; I2: 98.8%, p<0.001). On meta-regression, diagnostic villous atrophy (Marsh 3) ratio (-8.97, p<0.01) and male ratio (+6.04, p<0.01) proved to be a significant determinant of complete mucosal recovery, unlike duration of gluten-free diet (+0.01, p = 0.62). The correlation between complete mucosal recovery ratio and age on diagnosis is of borderline significance (-0.03, p = 0.05). CONCLUSIONS: There is considerable heterogeneity across studies concerning complete mucosal recovery ratios achieved by a gluten-free diet in celiac disease. Several celiac patients fail to achieve complete mucosal recovery even if a strict dietary regimen is followed. Younger age on diagnosis, less severe initial histologic damage and male gender predispose for achieving mucosal recovery.

Severe acrocyanosis precipitated by cold agglutinin secondary to infection with Mycoplasma pneumoniae in a pediatric patient.

This is the first report describing a severe form of cold agglutinin-induced acrocyanosis with cutaneous necrosis after Mycoplasma infection in a 9-year-old patient without any other severe symptoms and laboratory alterations. We also present the results of two non-invasive methods used to determine the viability of tissues, degree of tissue perfusion impairment, and the responsiveness of the microvasculature. Laser Doppler flowmetry and laser speckle contrast imaging, both suitable to measure tissue blood perfusion non-invasively, have been used in the diagnosis and follow-up of various peripheral vascular diseases. In our patient, we demonstrated remarkably reduced microcirculation before the treatment and a significant perfusion increase in the acral regions after pentoxifylline therapy. The investigational techniques were useful tools to assess and quantify the severity of peripheral perfusion disturbances and to monitor the efficacy of the treatment in our patient.

Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe: a cohort study.

Primary immunodeficiency disorders are a recognized public health problem worldwide. The prototype of these conditions is X-linked agammaglobulinemia (XLA) or Bruton's disease. XLA is caused by mutations in Bruton's tyrosine kinase gene (BTK), preventing B cell development and resulting in the almost total absence of serum immunoglobulins. The genetic profile and prevalence of XLA have not previously been studied in Eastern and Central European (ECE) countries. We studied the genetic and demographic features of XLA in Belarus, Croatia Hungary, Poland, Republic of Macedonia, Romania, Russia, Serbia, Slovenia, and Ukraine. We collected clinical, immunological, and genetic information for 122 patients from 109 families. The BTK gene was sequenced from the genomic DNA of patients with a high susceptibility to infection, almost no CD19(+) peripheral blood B cells, and low or undetectable levels of serum immunoglobulins M, G, and A, compatible with a clinical and immunological diagnosis of XLA. BTK sequence analysis revealed 98 different mutations, 46 of which are reported for the first time here. The mutations included single nucleotide changes in the coding exons (35 missense and 17 nonsense), 23 splicing defects, 13 small deletions, 7 large deletions, and 3 insertions. The mutations were scattered throughout the BTK gene and most frequently concerned the SH1 domain; no missense mutation was detected in the SH3 domain. The prevalence of XLA in ECE countries (total population 145,530,870) was found to be 1 per 1,399,000 individuals. This report provides the first comprehensive overview of the molecular genetic and demographic features of XLA in Eastern and Central Europe.

[Early recognition and successful treatment of an infant with severe combined immune deficiency]. / Súlyos kombinált immundeficiencia korai felismerése és eredményes kezelése.

A male infant of three month presented with recurrent mucosal and fungal infections, diarrhoea and failure to thrive from the age of three weeks. Laboratory test revealed T-B-NK + severe combined immunodeficiency (SCID). Family history and immunolaboratory findings suggested autosomal recessive form of the disease. Haploidentical maternal bone marrow transplantation (BMT) was carried out at five and half months of age. Over the two years after BMT, the patient's somatomotoric and mental development is normal. Cellular immune responses and the substantial immunoglobulin production suggest immunoreconstruction in the child born with complete lack of adaptive immunity. According to the author's knowledge, this is the first T-B-NK + patient in Hungary, whose disease was diagnosed and adequately treated in infancy.