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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

International audience; STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

A 15-year-old girl presented with gradual-onset dysphonia and dysphagia. Laryngoscopy revealed significant supraglottic airway obstruction with swelling of both the epiglottis and arytenoids. After emergency tracheostomy, biopsy of the epiglottis revealed lymphoid hyperplasia with focal non-necrotising granulomata, leading to a presumed diagnosis of laryngeal sarcoidosis. Treatment with prednisolone and methotrexate produced minimal clinical improvement. A switch to sirolimus was followed by significant reduction in the laryngeal swelling, allowing decannulation of the tracheostomy. Treatment with sirolimus should be considered as a steroid sparing agent in laryngeal sarcoidosis, particularly in the presence of lymphoid hyperplasia on biopsy.

Infection and persistent inflammation have a prominent role in the pathogenesis of brain injury and cerebral palsy, as well as other conditions associated with prematurity such as bronchopulmonary dysplasia. The NLRP3 inflammasome-interleukin (IL)-1β pathway has been extensively studied in adults and pre-clinical models, improving our understanding of innate immunity and offering an attractive therapeutic target that is already contributing to clinical management in many auto-inflammatory disorders. IL-1 blockade has transformed the course and outcome of conditions such as chronic infantile neurological, cutaneous, articular (CINCA/NOMID) syndrome. Inflammasome activation and upregulation has recently been implicated in neonatal brain and lung inflammatory disease and may be a novel therapeutic target.

Introduction Auto-inflammatory syndromes (AIS) are inherited disorders of the innate immune system that lead to pathogenic inflammation. Multiple organ systems can be involved and disease can lead to significant end organ damage. Early diagnosis and treatment may improve outcome;1 Diagnosis is often delayed due to the low incidence of these disorders. An autoinflammatory clinic was established in OLCH Crumlin, Dublin, a tertiary level Paediatric Hospital, in November 2015 to assess patients with known or suspected auto-inflammatory disease within a multi-disciplinary setting. This clinic is attended by immunology, rheumatology and dermatology specialists with multi-disciplinary team input as required. Aim The aim of this study was to survey the diagnosis and management of patients attending this clinic over a 2 and a half year period. Methods A retrospective observational chart review of all patients attending the Autoinflammatory clinic from November 2015 to June 2018. Age of onset, demographic details, diagnosis (if known) and management were documented. Details of any genetic analysis if undertaken were also included. Results A total of 47 patients attended the auto-inflammatory clinic over the identified period. Age of onset at first symptoms ranged from birth to 15 years. A diagnosis of an AIS was made in 57% with PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) accounting for the majority. An undetermined autoinflammatory syndromes was suspected in 40%. 3% who attended had no symptoms or features supportive of an AIS. Overall, 36% were found to have a confirmed genetic mutation, either benign or pathogenic and 28% had a positive family history of auto-immune or auto-inflammatory syndrome in a 1st degree relative. Colchicine monotherapy (32%) was the first choice of therapy followed by anakinra monotherapy (19%) or a combination of both. All treated patients reported symptom improvement on therapy with the exception of 2. Conclusion This study gives an overview on the spectrum of autoinflammatory disease presenting in Ireland and their current management. The majority of patients attending were appropriately referred to this clinic and had improvement in symptoms following initiation of treatment. Reference Ter Haar NM, Oswald M, Jeyaratnam J, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis 2015;74:1636–1644.

Introduction Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most common autoinflammatory disorder in childhood, with multifactorial, polygenic causes postulated. Objective To appraise the clinical features, inflammatory characteristics and management of children with PFAPA attending a tertiary Autoinflammatory Clinic. Methods A retrospective observational chart review of all children with confirmed clinical or suspected PFAPA attending the autoinflammatory clinic at Our Lady’s Children’s Hospital, Dublin from January 2016. Data were collected on basic demographics, route of referral, symptoms and signs and inflammatory markers during disease episodes (febrile) and non-episodes. Molecular gene analysis if performed, were included. Documentation of all therapeutic agents to date was collated. Results Thirteen children were identified as having PFAPA. The median age of disease onset was 16 months, (4 months to 4 years). The route of referral was via Immunology (4 patients), Rheumatology (6 patients) and Infectious disease (3 patients). All children presented with episodic, recurrent febrile episodes with associated features. (table 1). Median range of duration of episodes was 3–4 days. 69% of patients had documented raised inflammatory markers during a flare, with 84% having high serum amyloid A (SAA) levels, the highest documented being 122 0 mg/l ( 11 patients had a significant response to an initial trial of corticosteroids, 2 reported rebound flares. Colchicine was the treatment of choice (11), 9 who had a good response. Tonsillectomy was performed in 5 patients, 3 of whom reported benefit. Biologic agents, Anakinra (2) and Adalimumab (1) were instituted in those refractory to colchicine with variable response. Conclusion This study gives an over view of the burden of disease imposed by PFAPA on an Irish population. All the children presented with fevers, not all had the triad of aphthous stomatitis, pharyngitis and cervical adenitis. The majority of patients had relief of symptoms with an initiation trial of corticosteroid. Colchicine was the most frequently used therapeutic agent to prevent disease flares. Tonsillectomy and biological agents are potential alternative options in some resistant/severe cases.

We report the case of a 15 year old girl with a four month history of gradual onset dysphonia and dysphagia. Endoscopy revealed a significantly enlarged epiglottis and arytenoids causing supraglottic airway obstruction (pinpoint airway). She progressed to emergency tracheostomy and a biopsy of the epiglottis was taken. Histology revealed lymphoid hyperplasia with focal non-necrotizing granulomata. A screen for infection was negative, as was a serum ACE. The patient was commenced on corticosteroids and methotrexate, but after three months, there was no improvement. Therafter, she was switched to sirolimus, which led to resolution of her epiglottic swelling, allowing the tracheostomy to be reversed and corticosteroid therapy to be discontinued. Conclusion This is the first case, to our knowledge, of sirolimus being successfully used in treatment of laryngeal sarcoidosis. Sirolimus could be considered a treatment option in these instances, particularly in the presence of lymphoid aggregates on histology.

Background Down syndrome (DS) is the most common syndromic immunodeficiency with an increased risk of infection, mortality from sepsis, and autoinflammation. Innate immune function is altered in DS and therefore we examined responses in CD11b and Toll like receptor 4 (TLR-4), which are important immune cell surface markers upregulated in response to Lipopolysaccharide (LPS) endotoxin, and the immunomodulator melatonin. Neutrophil and monocyte responses to LPS and melatonin in children with Down syndrome (DS) who were clinically stable were compared to age-matched controls. Whole blood was incubated with LPS and melatonin and the relative expression of CD11b and TLR-4 evaluated by flow cytometry. Results Children with DS had an increased response to LPS in neutrophils and intermediate monocytes, while also having elevated TLR-4 expression on non-classical monocytes compared to controls at baseline. Melatonin reduced CD11b expression on neutrophils, total monocytes, both classical and intermediate sub-types, in children with DS and controls. Conclusion Melatonin could represent a useful clinical adjunct in the treatment of sepsis as an immunomodulator. Children with DS had increased LPS responses which may contribute to the more adverse outcomes seen in sepsis.

This study aimed to determine whether antimicrobial susceptibility testing of Pseudomonas aeruginosa grown as a biofilm, rather than planktonically, improves efficacy of antibiotic treatment for pulmonary exacerbations. This was a multicenter randomized, double-blind controlled trial of 14 days of intravenous antibiotic treatment for pulmonary exacerbations chosen based on conventional vs. biofilm antimicrobial susceptibility results in CF patients with chronic P. aeruginosa infection. There were 74 exacerbations in 39 patients. A total of 46% (12/26) exacerbations in the conventional group compared to 40% (19/48) exacerbations in the biofilm group achieved a ≥3 log drop in P. aeruginosa sputum density (difference -0.03, 95% CI -0.5 to 0.4, p=0.9). Lung function improvements were similar in both groups. Biofilm antimicrobial susceptibility testing did not lead to improved microbiological or clinical outcomes compared to conventional methods in the treatment of pulmonary exacerbations in CF patients with chronic P. aeruginosa.

We have previously reported on a unique patient in whom homozygosity for a mutation at IRF8 (IRF8(K108E)) causes a severe immunodeficiency. Laboratory evaluation revealed a highly unusual myeloid compartment, remarkable for the complete absence of CD141 and CD161 monocytes, absence of CD11c1 conventional dendritic cells (DCs) and CD11c1/CD1231 plasmacytoid DCs, and striking granulocytic hyperplasia. The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant. Sequencing RNA from the IRF8(K108E) patient's primary blood cells prior to transplant shows not only depletion of IRF8-bound and IRF8-regulated transcriptional targets, in keeping with the distorted composition of the myeloid compartment, but also a paucity of transcripts associated with activated CD41 and CD81 T lymphocytes. This suggests that T cells reared in the absence of a functional antigen-presenting compartment in IRF8(K108E) are anergic. Biochemical characterization of the IRF8(K108E) mutant in vitro shows that loss of the positively charged side chain at K108 causes loss of nuclear localization and loss of transcriptional activity, which is concomitant with decreased protein stability, increased ubiquitination, increased small ubiquitin-like modification, and enhanced proteasomal degradation. These findings provide functional insight into the molecular basis of immunodeficiency associated with loss of IRF8.

Design Children with HIV are especially susceptible to complications from influenza infection, and effective vaccines are central to reducing disease burden in this population. We undertook a prospective, observational study to investigate the safety and immunogenicity of the inactivated split-virion AS03-adjuvanted pandemic H1N1(2009) vaccine in children with HIV. Setting National referral centre for Paediatric HIV in Ireland. Sample Twenty four children with HIV were recruited consecutively and received two doses of the vaccine. The serological response was measured before each vaccine dose (Day 0 and Day 28) and 2 months after the booster dose. Antibody titres were measured using a haemagglutination inhibition (HAI) assay. Seroprotection was defined as a HAI titre ≥ 1:40; seroconversion was defined as a ≥ fourfold increase in antibody titre and a postvaccination titre ≥ 1:40. Main outcome measures The seroconversion rates after prime and booster doses were 75% and 71%, respectively. HIV virological suppression at the time of immunization was associated with a significantly increased seroconversion rate (P = 0·009), magnitude of serological response (P = 0·02) and presence of seroprotective HAI titres (P = 0·017) two months after the booster dose. No other factor was significantly associated with the seroconversion/seroprotection rate. No serious adverse effects were reported. Vaccination had no impact on HIV disease progression. The AS03-adjuvanted pandemic H1N1 vaccine appears to be safe and immunogenic among HIV-infected children. A robust serological response appears to be optimized by adherence to a HAART regimen delivering virological suppression.

Answers from Exomes Exome sequencing, which targets only the protein-coding regions of the genome, has the potential to identify the underlying genetic causes of rare inherited diseases. Angulo et al. (p. 866 , published online 17 October; see Perspective by Conley and Fruman ) performed exome sequencing of individuals from seven unrelated families with severe, recurrent respiratory infections. The patients carried the same mutation in the gene coding for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). The mutation caused aberrant activation of this kinase, which plays a key role in immune cell signaling. Drugs inhibiting PI3Kδ are already in clinical trials for other disorders.

A single-center retrospective study was undertaken in children with cystic fibrosis (CF) to evaluate (1) risk factors for acquisition; (2) molecular epidemiology; and (3) impact on disease progression of borderline oxacillin-resistant Staphylococcus aureus (BORSA) versus mecA-positive methicillin-resistant Staphylococcus aureus (MRSA). The study comprised of (1) identification of all children with at least one respiratory specimen positive for either BORSA or MRSA during the study period; (2) compilation of relevant clinical and epidemiological data from 12-month period leading up to first positive (index) culture; (3) microbiological and molecular characterization of index isolates and (4) measurement of subsequent clinical outcome. Thirty-eight children were identified with at least one positive isolate; 4 were excluded due to insufficient clinical or laboratory data. Eighteen children (53%) grew BORSA in their index culture. Children who acquired BORSA only (n = 16) were more likely to have had prior MSSA colonization (P < 0.0001). Usage of oral cephalexin (P < 0.01) and inhaled tobramycin (P < 0.03) prior to index culture was significantly and independently associated with acquisition of BORSA. The majority of BORSA isolates were hyper β-lactamase producers and susceptible to a greater range of antibiotics. Strain relatedness was not evident within the BORSA group. There was no difference in disease progression between the two groups. This is the first study to demonstrate that a significant proportion of S. aureus isolates with methicillin resistance in the CF population are BORSAs that lack mecA. Antibiotic pressure may lead to the development of BORSA in CF patients. Prospective studies are needed to assess its clinical impact.

Lung disease in patients with both primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) is associated with impaired mucociliary clearance; however, clinical outcomes are typically worse in CF patients. We assessed whether CF and PCD patients differ in inflammatory response in the airways during pulmonary exacerbation.We first studied clinically stable PCD patients with a spectrum of bacterial pathogens to assess inflammatory response to different pathogens. Subsequently, PCD and CF patients with similar bacterial pathogens were studied at the time of a pulmonary exacerbation and after 21 days of antibiotics treatment. Qualitative and quantitative microbiology, cell counts, interleukin-8 concentrations, and neutrophil elastase activity were assessed in sputum samples obtained before and after treatment.In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonised with different bacterial pathogens. Pulmonary exacerbation severity assessed by a pulmonary exacerbation score and lung function decline from their previous baseline did not differ between CF and PCD patients. Bacterial density for Staphylococcus aureus and Haemophilus influenzae was higher in CF versus PCD (pPCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment.

A three-year-old boy presented with community-acquired pneumonia complicated by empyema.Streptococcus pyogenes(group A streptococcus) was identified on culture of the pleural fluid. The patient improved with antibiotic therapy and drainage of the empyema.During his convalescence, the patient developed persistent fever, lethargy and anorexia. His inflammatory markers were elevated, and repeat cultures were negative. Although the patient had none of the classical mucocutaneous features of Kawasaki disease, an echocardiogram was performed, which revealed coronary artery dilation.The patient was diagnosed with incomplete Kawasaki disease and treated with intravenous immunoglobulin and high-dose acetylsalicylic acid. The fever subsided within 48 h.To the authors’ knowledge, the present report is the first report of Kawasaki disease associated with complicatedS pyogenespneumonia. It emphasizes the importance of considering incomplete Kawasaki disease among children with persistent fever, the role of echocardiography in diagnosis, and the potential link between Kawasaki disease and superantigen-producing organisms such asS pyogenes.