Paediatric non-infectious granulomatous uveitis: a retrospective cohort study.

INTRODUCTION: Paediatric granulomatous uveitis (PGU) is rare. In addition, lack of awareness often leads to delayed diagnosis and poor visual outcome. Identifying the underlying cause and deciding how best to treat each patient is challenging. OBJECTIVES: To evaluate the demographics, aetiologies, complications, treatments, and visual prognosis of paediatric non-infectious granulomatous uveitis. METHODS: Retrospective chart review of non-infectious PGU occurring in children before the age of 16 years recruited from the Paediatric Rheumatology Unit, Bicêtre Hospital, France, from 2001 to 2023. RESULTS: We included 50 patients with 90 affected eyes: 29 with idiopathic uveitis, 15 with sarcoidosis, 5 with juvenile idiopathic arthritis, and one with Vogt-Koyanagi-Harada disease. Median age at diagnosis was 9.8 years (range 7.2-12.5). The sex-ratio M/F was 0.52. The most common features of PGU were: panuveitis (56%), bilateral (84%), and chronic (84%). Sarcoidosis was the most frequent diagnosis after idiopathic disease, particularly in the presence of lymphopenia and hypergammaglobulinemia. Uveomeningitis was present in 12% of cases. Upon diagnosis, ocular complications were present in 68 of 90 eyes (76%) particularly in cases of panuveitis. The most commonly used treatments were systemic corticosteroids (72%) and methotrexate (80%). Twenty-three percent of eyes were in remission at last follow-up, 68% were inactive and 4% remained active. The median duration of follow-up was 5.8 years. CONCLUSION: We report the largest cohort of PGU. PGU were mostly idiopathic and had a high rate of complications. Sarcoid and idiopathic panuveitis are serious illnesses in which disease-modifying therapy should be initiated at diagnosis to improve management.

Extra-osseous manifestations in chronic recurrent multifocal osteomyelitis: a retrospective study.

OBJECTIVES: Extra-osseous (EO) manifestations are poorly characterized in chronic recurrent multifocal osteomyelitis (CRMO). This study aimed to further define the frequency, characteristics and treatment of EO events in CRMO and whether different phenotypes can be distinguished and benefit from special management. METHODS: This multicentre retrospective study included CRMO patients followed in several paediatric rheumatology departments in France, between 2015 and 2022. EO manifestations were defined as skin lesions, gastrointestinal manifestations, arthritis, enthesitis, sacroiliitis, uveitis, vasculitis, and fever. At the last visit, the physician defined CRMO as active in the presence of clinical manifestations including both osseous and EO symptoms. RESULTS: We included 133 patients; 87 (65.4%) were girls; the median age at first symptoms was 9.0 years (interquartile range 7.0-10.0). EO manifestations were described in 90 (67.7%) patients, with a predominance of skin lesions (n = 51/90; 56.7%), followed by sacroiliitis (n = 38/90; 42.2%), enthesitis (n = 21/90; 23.3%), arthritis (n = 14/90, 15.6%) and gastrointestinal manifestations (n = 6/90, 6.7%). The use of non-steroidal anti-inflammatory drugs and bisphosphonates did not differ by presence or not of EO manifestations. Biologics were taken more frequently by patients with than without EO manifestations (p< 0.001); tumour necrosis factor inhibitors were used in 33 (36.7%) EO+ patients. Under this treatment, 18 (54.5%) patients achieved complete remission of osseous and EO manifestations. At the last visit, more EO-positive than EO-negative patients were on treatment (p= 0.009), with active disease in 58 (64.4%) patients. CONCLUSION: The analysis of EO manifestations in CRMO delineates 2 groups of patients in terms of severity and treatments used. Our study opens up new pathophysiological leads that may underlie the wide range of CRMO phenotypes.

Ocular involvement in pediatric Behçet's disease: is it different than in adults? (a short case series and mini review).

BACKGROUND: Pediatric Behçet's disease (PBD) is rarer than BD and can be a challenging diagnosis as clinical picture may be incomplete. As in adult patients, sight-threatening ocular manifestations may lead to diagnosis. In this study, we aimed to report a series of cases of PBD with ocular manifestations and provide a review of the literature. METHODS: Retrospective case series of PBD patients with ocular manifestations. Demographic, ophthalmological and systemic data at presentation and during follow-up were collected and analyzed. RESULTS: Four patients, aged 13.0 ± 2.9 years (9-16) were included. Posterior uveitis with retinal vasculitis, papillitis and macular edema was present in all patients, with associated anterior uveitis in 2 cases. Other features included occlusive vasculitis (2/4) and necrotizing retinitis (2/4). All patients were improved by systemic treatments except one patient with severe bilateral optic neuropathy. Ocular manifestations were the presenting symptoms in 3/4 cases. CONCLUSION: Ocular manifestations and systemic associations of PBD are comparable to those encountered in adult patients. The lack of complains in pediatric patients may lead to a longer diagnosis delay, especially in unilateral uveitis. Aggressive and long-term treatment is mandatory to prevent vision loss and recurrences.

Saliva for molecular detection of SARS-CoV-2 in pre-school and school-age children.

SARS-CoV-2 diagnosis is a cornerstone for the management of coronavirus disease 2019 (COVID-19). Numerous studies have assessed saliva performance over nasopharyngeal sampling (NPS), but data in young children are still rare. We explored saliva performance for SARS-CoV-2 detection by RT-PCR according to the time interval from initial symptoms or patient serological status. We collected 509 NPS and saliva paired samples at initial diagnosis from 166 children under 12 years of age (including 57 children under 6), 106 between 12 and 17, and 237 adults. In children under 12, overall detection rate for SARS-CoV-2 was comparable in saliva and NPS, with an overall agreement of 89.8%. Saliva sensitivity was significantly lower than that of NPS (77.1% compared to 95.8%) in pre-school and school-age children but regained 96% when considering seronegative children only. This pattern was also observed to a lesser degree in adolescents but not in adults. Sensitivity of saliva was independent of symptoms, in contrary to NPS, whose sensitivity decreased significantly in asymptomatic subjects. Performance of saliva is excellent in children under 12 at early stages of infection. This reinforces saliva as a collection method for early and unbiased SARS-CoV-2 detection and a less invasive alternative for young children.

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. Design, Setting, and Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. Exposures: IVIG and methylprednisolone vs IVIG alone. Main Outcomes and Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). Conclusions and Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort.

BACKGROUND: Current data suggest that COVID-19 is less frequent in children, with a milder course. However, over the past weeks, an increase in the number of children presenting to hospitals in the greater Paris region with a phenotype resembling Kawasaki disease (KD) has led to an alert by the French national health authorities. METHODS: Multicentre compilation of patients with KD in Paris region since April 2020, associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ('Kawa-COVID-19'). A historical cohort of 'classical' KD served as a comparator. RESULTS: Sixteen patients were included (sex ratio=1, median age 10 years IQR (4·7 to 12.5)). SARS-CoV-2 was detected in 12 cases (69%), while a further three cases had documented recent contact with a quantitative PCR-positive individual (19%). Cardiac involvement included myocarditis in 44% (n=7). Factors prognostic for the development of severe disease (ie, requiring intensive care, n=7) were age over 5 years and ferritinaemia >1400 µg/L. Only five patients (31%) were successfully treated with a single intravenous immunoglobulin (IVIg) infusion, while 10 patients (62%) required a second line of treatment. The Kawa-COVID-19 cohort differed from a comparator group of 'classical' KD by older age at onset 10 vs 2 years (p<0.0001), lower platelet count (188 vs 383 G/L (p<0.0001)), a higher rate of myocarditis 7/16 vs 3/220 (p=0.0001) and resistance to first IVIg treatment 10/16 vs 45/220 (p=0.004). CONCLUSION: Kawa-COVID-19 likely represents a new systemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children. Further prospective international studies are necessary to confirm these findings and better understand the pathophysiology of Kawa-COVID-19. Trial registration number NCT02377245.

Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE.

BACKGROUND: Therapeutic normal IgG or intravenous immunoglobulin (IVIG) exerts anti-inflammatory effects through several mutually nonexclusive mechanisms. Recent data in mouse models of autoimmune disease suggest that IVIG induces IL-4 in basophils by enhancing IL-33 in SIGN-related 1-positive innate cells. However, translational insight on these data is lacking. OBJECTIVE: We sought to investigate the effect of IVIG on human basophil functions. METHODS: Isolated circulating basophils from healthy donors were cultured in the presence of IL-3, IL-33, GM-CSF, thymic stromal lymphopoietin, or IL-25. The effect of IVIG and F(ab')2 and Fc IVIG fragments was examined based on expression of various surface molecules, phosphorylation of spleen tyrosine kinase, induction of cytokines, and histamine release. Basophil phenotypes were also analyzed from IVIG-treated patients with myopathy. Approaches, such as depletion of anti-IgE reactivity from IVIG, blocking antibodies, or inhibitors, were used to investigate the mechanisms. RESULTS: We report that IVIG directly induces activation of IL-3-primed human basophils, but IL-33 and other cytokines were dispensable for this effect. Activation of basophils by IVIG led to enhanced expression of CD69 and secretion of IL-4, IL-6, and IL-8. IVIG-treated patients with myopathy displayed enhanced expression of CD69 on basophils. The spleen tyrosine kinase pathway is implicated in these functions of IVIG and were mediated by F(ab')2 fragments. Mechanistically, IVIG induced IL-4 in human basophils by interacting with basophil surface-bound IgE but independent of FcγRII, type II Fc receptors, C-type lectin receptors, and sialic acid-binding immunoglobulin-like lectins. CONCLUSION: These results uncovered a pathway of promoting the TH2 response by IVIG through direct interaction of IgG with human basophils.

Acid Stripping of Surface IgE Antibodies Bound to FcεRI is Unsuitable for the Functional Assays that Require Long-Term Culture of Basophils and Entire Removal of Surface IgE.

Basophils are rare granulocytes and dysregulated functions of these cells are associated with several atopic and non-atopic allergic diseases of skin, respiratory system and gastrointestinal tract. Both cytokines and immunoglobulin E (IgE) are implicated in mediating the basophil activation and pathogenesis of these disorders. Several reports have shown that healthy individuals, and patients with allergic disorders display IgG autoantibodies to IgE and hence functional characterization of these anti-IgE IgG autoantibodies is critical. In general, anti-IgE IgG autoantibodies modulate basophil activation irrespective of allergen specificity by interacting with constant domains of IgE. Therefore, an ideal solution to prove the functions of such anti-IgE IgG autoantibodies would be to completely eliminate type I high affinity immunoglobulin E receptor (FcɛRI)-bound IgE from the surface of basophils and to demonstrate in an unequivocal manner the role of anti-IgE IgG autoantibodies. In line with previous reports, our data show that FcɛRI on peripheral blood basophils are almost saturated with IgE. Further, acetic acid buffer (pH 4) efficiently removes these FcɛRI-bound IgE. Although immediately following acetic acid-elution of IgE had no repercussion on the viability of basophils, following 24 hours culture with interleukin-3 (IL-3), the viability and yield of basophils were drastically reduced in acid-treated cells and had repercussion on the induction of activation markers. Lactic acid treatment on the other hand though had no adverse effects on the viability of basophils and IL-3-induced activation, it removed only a small fraction of the cell surface bound IgE. Thus, our results show that acid buffers could be used for the elution of FcɛRI-bound IgE on the basophil surface for the biochemical characterization of IgE antibodies or for the immediate use of basophils to determine their sensitivity to undergo degranulation by specific allergens. However, these methods are not utile for the functional assays of basophils that require longer duration of culture and entire removal of surface IgE to validate the role of anti-IgE IgG autoantibodies that interact with FcɛRI-bound IgE irrespective of allergen specificity.

[Experience of parents administering a subcutaneous injection on their child]. / Vécu des parents réalisant une injection sous-cutanée sur leur enfant.

Studies and the experience of caregivers in paediatric hospital departments reveal the difficulties encountered by families and children when the treatment of a chronic disease requires injections to be administered by the family at home. Many treatments in paediatrics are administered by subcutaneous injection which means parents need to perform this procedure on their child, often for organisational reasons. However, injecting medication into one's child is not easy for the parent, even when the technique is mastered.

IVIG-mediated effector functions in autoimmune and inflammatory diseases.

Intravenous immunoglobulin (IVIG) is a pooled preparation of normal IgG obtained from several thousand healthy donors. It is widely used in the immunotherapy of a large number of autoimmune and inflammatory diseases. The mechanisms of action of IVIG are complex and, as discussed in this review, experimental and clinical data provide an indicator that the therapeutic benefit of IVIG therapy is due to several mutually non-exclusive mechanisms affecting soluble mediators as well as cellular components of the immune system. These mechanisms depend on Fc and/or F(ab')2 fragments. A better understanding of the effector functions of IVIG should help in identification of biomarkers of responses to IVIG in autoimmune patients.

Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection.

BACKGROUND: Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa. METHODS: We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy. RESULTS: We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele. CONCLUSIONS: These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.

Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a disease of early onset which can lead to significant morbidity. In 2012, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched with the aim of optimising and disseminating diagnostic and management regimens for children and young adults with rheumatic diseases. The objective was to establish recommendations for FMF focusing on provision of diagnostic tools for inexperienced clinicians particularly regarding interpretation of MEFV mutations. Evidence-based recommendations were developed using the European League against Rheumatism standard operating procedure. An expert committee of paediatric rheumatologists defined search terms for the systematic literature review. Two independent experts scored articles for validity and level of evidence. Recommendations derived from the literature were evaluated by an online survey and statements with less than 80% agreement were reformulated. Subsequently, all recommendations were discussed at a consensus meeting using the nominal group technique and were accepted if more than 80% agreement was reached. The literature search yielded 3386 articles, of which 25 were considered relevant and scored for validity and level of evidence. In total, 17 articles were scored valid and used to formulate the recommendations. Eight recommendations were accepted with 100% agreement after the consensus meeting. Topics covered were clinical versus genetic diagnosis of FMF, genotype-phenotype correlation, genotype-age at onset correlation, silent carriers and risk of amyloid A (AA) amyloidosis, and role of the specialist in FMF diagnosis. The SHARE initiative provides recommendations for diagnosing FMF aimed at facilitating improved and uniform care throughout Europe.

Recommendations for the management of autoinflammatory diseases.

: Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.

How French paediatric emergency departments manage painful vaso-occlusive episodes in sickle cell disease patients.

AIM: The most common manifestation of sickle cell disease (SCD) is painful vaso-occlusive episodes (PVOE), and inappropriate treatment leads to unnecessary suffering and potentially fatal complications. This study describes how French paediatric emergency departments (EDs) manage PVOE and their knowledge, and implementation of the French National Authority for Health recommendations on the management of sickle cell patients. METHODS: A questionnaire on managing PVOE was sent to all the 111 French paediatric EDs. RESULTS: We received responses from 81 (72.9%) of the EDs. Of those who responded to each individual question, 85% said that they had read the national recommendations, 71.6% said they used nalbuphine for moderate PVOE, and 85% used intravenous morphine for severe PVOE. The majority (91.7%) of EDs thought that intravenous morphine provided relief for severe PVOE, but only 30.9% thought that intravenous nalbuphine did. A 50:50 nitrous oxide/oxygen mix was used by 71.3% of departments to relieve procedural pain and by 48% to enhance analgesia when morphine was insufficient for severe pain. CONCLUSIONS: Most French EDs follow the national recommendations for PVOE. Nalbuphine was the most commonly used opioid for moderate PVOE and morphine for severe PVOE. A nitrous oxide/oxygen mixture was widely used for PVOE.

[Mevalonate kinase deficiency]. / Déficit en mévalonate kinase.

MEVALONATE KINASE DEFICIENCY. Mevalonate kinase deficiency is a rare, autosomal recessive, auto- inflammatory disease, linked to mutations in the gene MVK, resulting in the activation of pyrin inflammasome and hypersecretion of interleukin-1ß (IL-1ß). The clinical spectrum realizes a continuum which extends from the mild phenotype of the partial MVK deficiency (hyperimmunoglobulinemia D) resulting in periodic fever syndrome to a letal form of mevalonate aciduria (MA, complete MVK deficiency). Symptoms occur before the age of one, often with a trigger. The partial MVK deficiency (HIDS) is characterized by recurrent episodes of fever with an intense inflammatory syndrome, accompanied with lymphadenopathy, aphthous stomatitis, digestive, articular and cutaneous symptoms. There is in more in mevalonate aciduria a psychomotor retardation, a failure to thrive, a cerebellar ataxia and a dysmorphic syndrome. The diagnosis is based on the mevalonic aciduria during febrile attack and the search for mutations in MVK. The most severe patients can be treated by anti-IL-1.

DÉFICIT EN MÉVALONATE KINASE. Le déficit en mévalonate kinase (MVK) est une maladie autoinflammatoire rare, de transmission autosomique récessive, liée à des mutations dans le gène MVK, aboutissant à une activation de l'inflammasome pyrine et à une hypersécrétion d'interleukine 1ß (IL-1ß). Le spectre clinique est large : de la forme modérée de syndrome avec déficit partiel en MVK (anciennement appelé syndrome hyper-IgD) à des formes létales d'acidurie mévalonique (AM ; déficit complet). Les symptômes surviennent avant l'âge de 1 an, souvent déclenchés par un trigger. Le déficit partiel en MVK comporte des accès de fièvre périodique avec un syndrome inflammatoire important, accompagnés d'adénopathies cervicales, d'une stomatite aphteuse, de signes digestifs, articulaires et cutanés. Il existe également dans l'AM un retard psychomoteur, un retard de croissance, une ataxie et un syndrome dysmorphique. Le diagnostic repose sur la mise en évidence de la mévalonaturie en période fébrile et sur la recherche de mutations dans le MVK. Les patients les plus sévères reçoivent des anti-IL-1.