The diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work-up in cystic fibrosis patients.

Cystic fibrosis (CF) patients receive many antibiotic treatments for recurrent respiratory infections and frequently report antibiotic hypersensitivity reactions (HSRs). In this retrospective study, medical records of CF patients were reviewed to clarify the clinical features, the culprit antibiotics, and the prevalence of antibiotic HSRs in the CF population. From 601 CF patients, 95 suspected antibiotic HSRs occurred in 60 patients (prevalence of 10.0%). ß-Lactams were the most common inducers, but cotrimoxazole was also frequently involved. Seventy-six of 95 suspected HSRs were assessed by allergy workup including skin tests (43/76 reactions) and/or drug reintroduction as a full course of the culprit antibiotic (73 of 76 reactions). From the 43 suspected HSRs that were skin-tested, only three had positive skin tests and were not subjected to drug readministration. All the other 73 suspected HSRs received a full course of the culprit antibiotic: HSR symptoms recurred in 10 of 73 cases and therefore were considered as confirmed antibiotic HSRs; for the remaining 63 suspected HSRs that did not relapse after drug readministration, the diagnosis of antibiotic HSRs was excluded. In summary, 13 of 76 suspected HSRs were confirmed as antibiotic HSRs. The prevalence of suspected and confirmed antibiotic HSRs in CF patients appears similar to that reported in the general population. Of note, most of the antibiotic suspected HSRs are not confirmed after allergology workup. A complete allergy workup appears therefore crucial to make a correct diagnosis and to avoid unnecessary contraindication of major antibiotics.

Real-life acute lung function changes after lumacaftor/ivacaftor first administration in pediatric patients with cystic fibrosis.

The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of -4.1% predicted forced expiratory volume in 1s (FEV1) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV1 changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV1 consistently decreased (-10.4±4.6%, range: -1.5; -21.8%). FEV1 only partially resumed after salbutamol inhalation. Patients with previously known significant reversible airway obstruction and low FEV1 were more at risk of FEV1 decrease.

An impulse oscillometry system is less efficient than spirometry in tracking lung function improvements after intravenous antibiotic therapy in pediatric patients with cystic fibrosis.

A literature search identified one retrospective study on the responsiveness of impulse oscillometry (IOS) in pediatric patients with cystic fibrosis. The aim of this prospective observational study was to assess this property in an adequately powered study after intravenous antibiotic therapy (IVAT) administered for an acute episode of pulmonary exacerbation. Spirometry and IOS were done on the same day as the start and the end of IVAT. Data from 34 patients' of mean age 11.9 years (range, 5-17 years) were studied. The mean FEV1 at the start and at the end of the IVAT was 73.1 ± 23.8% (range, 23.4-122%) and 88.3 ± 21.3% (range, 29.4-131%), respectively. The mean relative change (mean ± SD) was 20.2 ± 14.2% for FEV1 (ΔFEV1 ), -21.9 ± 23.8% for reactance at 5 Hz (ΔX5) and -13.4 ± 18.9% for resistance at 5 Hz (Δ R5) (all P-values <0.05). There was a weak but significant correlation between ΔFEV1 and ΔX5 (r =-0.473; p = 0.01). The magnitude of improvement of ΔX5 was not statistically different between patients with normal versus abnormal lung function at the start of IVAT. Furthermore, using ΔX5 alone as an outcome measure of IVAT efficiency resulted in a significant improvement in 44% of the patients, while it was 79% with ΔFEV1 . These results indicate that IOS may track changes after IVAT, but that this improvement may be insufficiently evaluated using IOS alone.

Negative regulation of NKG2D expression by IL-4 in memory CD8 T cells.

IL-4 is one of the main cytokines produced during Th2-inducing pathologies. This cytokine has been shown to affect a number of immune processes such as Th differentiation and innate immune responses. However, the impact of IL-4 on CD8 T cell responses remains unclear. In this study, we analyzed the effects of IL-4 on global gene expression profiles of Ag-induced memory CD8 T cells in the mouse. Gene ontology analysis of this signature revealed that IL-4 regulated most importantly genes associated with immune responses. Moreover, this IL-4 signature overlapped with the set of genes preferentially expressed by memory CD8 T cells over naive CD8 T cells. In particular, IL-4 downregulated in vitro and in vivo in a STAT6-dependent manner the memory-specific expression of NKG2D, thereby increasing the activation threshold of memory CD8 T cells. Furthermore, IL-4 impaired activation of memory cells as well as their differentiation into effector cells. This phenomenon could have an important clinical relevance as patients affected by Th2 pathologies such as parasitic infections or atopic dermatitis often suffer from viral-induced complications possibly linked to inefficient CD8 T cell responses.

T inflammatory memory CD8 T cells participate to antiviral response and generate secondary memory cells with an advantage in XCL1 production.

Besides the classically described subsets of memory CD8 T cells generated under infectious conditions, are T inflammatory memory cells generated under sterile priming conditions, such as sensitization to allergens. Although not fully differentiated as pathogen-induced memory cells, they display memory properties that distinguish them from naive CD8 T cells. Given these memory cells are generated in an antigen-specific context that is devoid of pathogen-derived danger signals and CD4 T cell help, we herein questioned whether they maintained their activation and differentiation potential, could be recruited in an immune response directed against a pathogen expressing their cognate antigen and further differentiate in fully competent secondary memory cells. We show that T inflammatory memory cells can indeed take part to the immune response triggered by a viral infection, differentiate into secondary effectors and further generate typical central memory CD8 T cells and effector memory CD8 T cells. Furthermore, the secondary memory cells they generate display a functional advantage over primary memory cells in their capacity to produce TNF-α and the XCL1 chemokine. These results suggest that cross-reactive stimulations and differentiation of cells directed against allergens or self into fully competent pathogen-induced memory cells might have incidences in inflammatory immuno-pathologies.

Risk factors for Aspergillus colonization and allergic bronchopulmonary aspergillosis in children with cystic fibrosis.

BACKGROUND: The annual prevalence of Aspergillus colonization (AC) and allergic bronchopulmonary aspergillosis (ABPA) has recently increased in pediatric patients with cystic fibrosis (CF). The reasons remain unclear although a number of factors have been suggested to be involved. This study was set up to investigate the association between potential predisposing factors, including new therapies recommended in CF, and the occurrence of AC or ABPA in children with CF. METHODS: The medical records of 85 children monitored regularly in the Pediatric Reference Centre for Cystic Fibrosis Care (RCCFC) of the University Hospital of Marseille (France) were analyzed from the first time they attended the RCCFC until either the occurrence of an end event, or their last visit to the RCCFC. Risk factors for AC or ABPA were analyzed by univariate and multivariate logistic regression. RESULTS: Eight children developed ABPA and 18 had AC. In univariate analysis, ABPA was significantly associated with RhDNase therapy, sensitization to Alternaria and Candida, and a low body mass index (BMI). Multivariate analysis identified an independent association between low BMI and ABPA (OR = 10.6, 95% CI [2.2-51.8], P = 0.004), and for the first time, between long-term azithromycin therapy and AC (OR = 6.4, 95% CI [2.1-19.5], P = 0.001). This latter association might be explained by the inhibitory effect of azithromycin on both the recruitment and the activation of neutrophils, which represent the first-line defenses against Aspergillus. CONCLUSIONS: The risk factors associated with AC and ABPA in children with CF identified in this comprehensive exploratory study now need to be confirmed in further prospective studies.