Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: Analysis by the Pharmachild Safety Adjudication Committee

Background: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. Trial registration: Clinicaltrials.gov NCT 01399281; ENCePP seal: awarded on 25 November 2011

Kawasaki disease and acute haemolytic anaemia after two IVIG infusions

Kawasaki disease (KD) is one of the most common vasculitis disorders of childhood, affecting predominantly medium-sized arteries, particularly the coronary arteries. For treatment, high-dose intravenous immunoglobulin (IVIG) is indicated. IVIG infusions are usually safe and well tolerated even though serious complications can be observed. We present a brief overview of KD and report a two-year-old girl with KD and two IVIG infusions (Gammagard®) because of persistent fever after the completion of the first IVIG. Haemolytic anaemia developed after IVIG retreatment. The direct antiglobulin test after haemolysis was positive. The etiology of the haemolysis was related to the presence of transient, passively acquired antibodies that cause a direct antibody-mediated attack. There are few reports of haemolytic anaemia after IVIG infusions. The haemolysis in KD is dose-dependent and occurs more frequently after the second IVIG dose. Non-0 blood group patients are at greater risk. Another factor increasing the risk of haemolysis is also the presence of anaemia due to inflammation in KD

The role of gut microbiota in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood, with prevalence of 16–150 cases per 100,000 children. The etiopathogenesis of JIA is a challenge incorporating a complex network with only 18% attributed to genetic factors. The remaining part should therefore be explained by non-hereditary factors. Given that around 70% of the immune cells are located in the gut, the potential role of the gut microbiota in the etiopathogenesis of JIA has been recently investigated. The aim of this review is to discuss the complexity of the link between gut microbiota and JIA, the different methods for identifying bacteria, the shape-up of the microbiota from birth to adulthood. The objectives are to discuss various pathways involved in this process: changes in the microbiota contents in healthy individuals and JIA patients, increased gut permeability, influence on T-cell differentiation and proliferation. Factors that have been associated with dysbiosis: diet, pathogens and drug use, are discussed. JIA is not a benign disease, it is a chronic disease and an important cause of short- and long-term disability-significant joint contractures, leg-length inequalities and uveitis, which can lead to impaired vision. It is known that at least one-third of children will have ongoing active disease into their adult years, and many will have some limitation in their daily life activities. A deeper understanding of the pathways by which disturbances in the microbiome may evolve to disease may open doors to the development of new treatment or prevention strategies in the future

Kawasaki disease – experience of Pediatric University Hospital, Sofia, Bulgaria, 1993–2014. Part I: clinical manifestations

Kawasaki disease (KD) is a vasculitis syndrome causing coronaritis in young children. As a result of the vascular damage, coronary lesions (CL), ectasia and aneurysms form in 20%–25% of the untreated children. The assessment of KD is difficult and challenging because of the lack of specific diagnostic or laboratory criteria. This is a retrospective study of 107 patients for a period of 21 years (1993–2014). In the cohort, 30.8% of patients had CL (19.6% had coronary aneurysms and 11.2% had significant coronary dilatations). The number of CL was high compared to that reported in international studies, although 45% of children were treated by modern protocols. In an attempt to analyse the reasons for the high coronary risk, the aim of this study was to investigate the clinical aspects of the disease and to establish the diagnostic problems causing diagnosis delay, which is subsequently related to increased coronary risk. The high incidence of the observed CL was associated with the failure of recognizing the disease, delayed diagnosis and, subsequently, lack of correct treatment. The analysis of the clinical presentation indicated significant correlation of gastrointestinal syndrome with typical and atypical KD. The incidence of the gastrointestinal syndrome correlated with the typical KD symptoms (p = 0.030), suggesting that it could be considered as a further diagnostic criterion

Kawasaki disease – experience of Pediatric University Hospital, Sofia, Bulgaria, 1993–2014. Part II: cardiovascular manifestations and treatment

Kawasaki disease (KD) is a childhood vasculitis syndrome and the coronary arteries are the main target of the vascular damage. The outcome is formation of coronary lesions (CL) that develop in 20%–25% of untreated children. KD is the leading cause of myocardial infarction in infancy. Its consequences among young people are acute coronary syndrome and susceptibility to early atherosclerosis, if the disease were to remain unrecognized. We investigated the cardiac manifestations during the acute phase of the disease, the values of the fever, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) and the therapeutic factors that created increased coronary risk in our cohort of patients. The study is retrospective (1993–2014). In the cohort (n = 107), 30.8% had coronary lesions, including 19.6% coronary aneurysms and 11.2% significant dilatations. We found association between myocarditis, papillary and left ventricular dysfunction in the acute phase of KD and the risk of coronary aneurysms (p < 0.001). The expressively elevated CRP levels and the persistent fever during the early subacute phase correlated significantly with coronary risk (p < 0.002). The treatment with intravenous immunoglobulin (IVIG) reduced the risk of coronary aneurysms 4.8 times (p < 0.002). A follow-up was performed in 53 children with coronary lesions during the first year of the disease. A longitudinal follow-up was performed in 38 patients. Their results indicate that cardiac monitoring is obligatory for all patients who have experienced KD

A clinical prediction model for estimating the risk of developing uveitis in patients with juvenile idiopathic arthritis

To build a prediction model for uveitis in children with JIA for use in current clinical practice

Treatment of multisystem inflammatory syndrome in children

BACKGROUND: Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.METHODS: We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.RESULTS: Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.CONCLUSIONS: We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).</p