Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p<0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p<0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross-reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work-up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate-reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspecte...

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

Capsule summary 55This article demonstrates that JAK inhibition represents a highly promising and well-tolerated 56 therapy for STING-associated vasculopathy, and which may also be relevant to the treatment 57 of other type I interferonopathies. 58 59Key words: Stimulator of Interferon genes, TMEM173, Janus kinase 1/2 inhibitor, type I 60 interferonopathy, interstitial lung disease, vasculopathy. 61 To the Editor: 62Gain-of-function mutations in TMEM173 encoding STING (Stimulator of Interferon Genes) 63 underlie a novel type I interferonopathy, 1 termed SAVI (STING-associated vasculopathy with 64 onset in infancy). 2,3 This disease is associated with high childhood morbidity and mortality. 65 STING is a central component of DNA sensing that leads to the induction of type I 66 interferons (IFN), which in turn drives the expression of IFN-stimulated genes (ISGs) through 67 the engagement of a common receptor and subsequent activation of Janus kinase 1 (JAK1) 68 and tyrosine kinase 2 (TYK2). 69We describe, for the first time, the use and efficacy of ruxolitinib, a selective oral JAK1/2 70 inhibitor, in three children with TMEM173-activating mutations over 6 to 18 months of 71 follow-up. The patients, aged between 5 and 12 years, exhibited the phenotypic variability 72 associated with TMEM173-activating mutations, 2,3,4 with lung disease and systemic 73 inflammation being the major features in P1 and P3, whilst in P2 skin involvement was most 74 prominent (Fig 1 and see Supplemental Text, Fig E3, and Table E1 in the Online Repository). 75There was minimal response to a broad spectrum of immunosuppressive therapies including 76 steroids, methotrexate and anti-CD20 monoclonal antibodies. 77 78An increased expression of ISGs, a so-called type I IFN signature, 5 was observed in all three 79 patients (see Fig E1, A in the Online Repository). Increased levels of STAT1 phosphorylation 80 were recorded in patient T lymphocytes (P1, P2, P3), T cultured lymphoblasts (P1) and 81 primary fibroblasts (P3) compared to controls (see Fig E2, A in the Online Repository). Liu et 82 al. demonstrated that, in vitro, three JAK1 inhibitors (ruxolitinib, tofacitinib and baricitinib) 83 were able to block the constitutive phosphorylation of STAT1 in lymphocytes from 84 TMEM173-mutated patients, 2 and we saw that exposure to ruxolitinib inhibited the 85 constitutive phosphorylation of STAT1 and decreased the expression of IL-6 and 3 ISGs 86 tested in T lymphoblasts from P1 (see Fig E2, B, C in the Online Repository). Considering the 87 severity of the phenotype and the poor response to conventional immunosuppressive 88 therapies, we hypothesized that JAK1 inhibition would block IFN signaling in the context of 89 activating mutations in TMEM173. 90 91We observed a marked positive effect on all aspects of the phenotype in all three treated 92 children. There was a general improvement in patient-reported well-being, a reduction of 93 febrile episodes, an almost complete resolution of the associated cutaneous lesions and a 94 major impr...

We prospectively studied 298 patients with cystic fibrosis (mean age 11.3 years; range 2 months to 32 years; sex ratio, 0.47) for nontuberculous mycobacteria in respiratory samples from January 1, 1996, to December 31, 1999. Mycobacterium abscessus was by far the most prevalent nontuberculous mycobacterium: 15 patients (6 male, 9 female; mean age 11.9 years; range 2.5–22 years) had at least one positive sample for this microorganism (versus 6 patients positive for M. avium complex), including 10 with >3 positive samples (versus 3 patients for M. avium complex). The M. abscessus isolates from 14 patients were typed by pulsed-field gel electrophoresis: each of the 14 patients harbored a unique strain, ruling out a common environmental reservoir or person-to-person transmission. Water samples collected in the cystic fibrosis center were negative for M. abscessus. This major mycobacterial pathogen in children and teenagers with cystic fibrosis does not appear to be acquired nosocomially.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

The identification of nonfermenting gram-negative bacilli isolated from cystic fibrosis (CF) patients is usually achieved by using phenotype-based techniques and eventually molecular tools. These techniques remain time-consuming, expensive, and technically demanding. We used a method based on matrixassisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) for the identification of these bacteria. A set of reference strains belonging to 58 species of clinically relevant nonfermenting gram-negative bacilli was used. To identify peaks discriminating between these various species, the profile of 10 isolated colonies obtained from 10 different passages was analyzed for each referenced strain. Conserved peaks with a relative intensity greater than 0.1 were retained. The spectra of 559 clinical isolates were then compared to that of each of the 58 reference strains as follows: 400 Pseudomonas aeruginosa, 54 Achromobacter xylosoxidans, 32 Stenotrophomonas maltophilia, 52 Burkholderia cepacia complex (BCC), 1 Burkholderia gladioli, 14 Ralstonia mannitolilytica, 2 Ralstonia pickettii, 1 Bordetella hinzii, 1 Inquilinus limosus, 1 Cupriavidus respiraculi, and 1 Burkholderia thailandensis. Using this database, 549 strains were correctly identified. Nine BCC strains and one R. mannnitolilytica strain were identified as belonging to the appropriate genus but not the correct species. We subsequently engineered BCC-and Ralstonia-specific databases using additional reference strains. Using these databases, correct identification for these species increased from 83 to 98% and from 94 to 100% of cases, respectively. Altogether, these data demonstrate that, in CF patients, MALDI-TOF-MS is a powerful tool for rapid identification of nonfermenting gram-negative bacilli.

Pneumococcal antigen detection in pleural fluid specimens from children provides a rapid and sensitive method of diagnosis of pneumococcal empyema, which can be confirmed by specific pneumolysin PCR when culture results are negative. Broad-range 16S rDNA PCR has value in detecting bacterial agents responsible for culture-negative pleural empyema.

We studied the prevalence and species distribution of nontuberculous mycobacteria (NTM) in relation to age in 385 patients with cystic fibrosis (CF) (mean age ؎ standard deviation [range], 12.0 ؎ 6.1 [1 to 24] years; sex ratio, 0.53) attending three Parisian centers. The overall prevalence of NTM in sputum was 8.1% (31 out of 385). The following NTM were isolated (n ‫؍‬ 33): Mycobacterium abscessus (n ‫؍‬ 13, 39.4%), Mycobacterium avium complex (MAC) (n ‫؍‬ 7, 21.2%), Mycobacterium gordonae (n ‫؍‬ 6, 18.2%), and other (n ‫؍‬ 7, 21.2%). Sixteen patients met the American Thoracic Society microbiological criteria for NTM infection, including 11 patients positive for M. abscessus, 4 for MAC, and 1 for MAC and Mycobacterium kansasii. The overall prevalence of NTM was significantly lower in patients under 15 years old than for patients equal to or more than 15 years old (4.8 versus 14.9%, respectively; P ‫؍‬ 0.001). M. abscessus was isolated at all ages, while MAC was not recovered before 15 years (prevalence of 0.0 and 5.2% in patients aged 1 to 14 and 15 to 24, respectively; P ‫؍‬ 0.001).Since 1990, an increasing number of studies have reported the recovery of nontuberculous mycobacteria (NTM) from the respiratory tract of patients with cystic fibrosis (CF) (1,12,13,16). In a recent multicenter study carried out in the United States using standardized bacteriological methods, the overall prevalence of NTM in sputum (percent of patients with at least one positive NTM culture) was 13%, ranging from 7 to 24% depending on the center (16). Mycobacterium avium complex (MAC) (72%) and Mycobacterium abscessus (16%) were the most common species. Other NTM (Mycobacterium gordonae, Mycobacterium kansasii, Mycobacterium lentiflavum, Mycobacterium peregrinum) were much rarer. About 20% of the culture-positive subjects met the American Thoracic Society (ATS) microbiological criteria for NTM pulmonary disease (2); most of these patients were positive for MAC or M. abscessus.Paradoxically, although we know that CF children are vulnerable to bacterial infections from birth, most previous studies on NTM in CF have been conducted in populations mostly or exclusively composed of adults (1, 13, 16). For example, only patients who were 10 years or older were recruited in the multicenter United States study cited above, and the mean age Ϯ standard deviation (SD) was 21 Ϯ 9 years (16). Very few case series involving children with CF have been carried out, and those that have been done mainly used inadequate culture and species identification techniques. However, although imperfect, these studies suggest some differences in the epidemiology of NTM between pediatric and adult CF populations. One of the most intriguing differences is the apparent propensity of CF children to be infected with rapidly growing mycobacteria (RGM). In 1980, Boxerbaum reported that 8 out of 430 CF children were infected with RGM: 6 with organisms referred to as Mycobacterium chelonei (now the M. chelonaeabscessus group) and two with M. fortuitum (4). M. chelonei in...