Hypersensitivity reactions to biologics in children.

INTRODUCTION: Hypersensitivity reactions (HSRs) have been observed with the use of biologics in children. The management of HSRs in children is mainly based on experiences from the adult population. Recently, data from different centers experienced in managing these reactions, including desensitization in children, have been published, allowing clinicians to have an appropriate global overview and compare results. AREAS COVERED: This review highlights the published data on hypersensitivity reactions to biologics in children and drug desensitization protocols adapted to the pediatric population. EXPERT OPINION: With regard to HSRs to biologics in children, few data are available. Compared with the adult population, there is a lack of knowledge in the endophenotypes, management and the standardization of protocols including premedication regimens in children. An international consensus is needed to provide clinicians with new insight on how to apply personalized management and to perform tailored desensitization protocols in pediatric populations. Various specialists including allergists, pediatricians, oncologists, hematologists, rheumatologists, and pharmacists, should build a multidisciplinary management team to keep pediatric patients on their best treatment options in the safest manner.

Amikacin Liposomal Inhalation Suspension in the Treatment of Mycobacterium abscessus Lung Infection: A French Observational Experience.

Background: Mycobacterium abscessus infections remain difficult to manage in both cystic fibrosis (CF) and non-CF patients and reported clinical outcomes are largely unsatisfactory. Clinical trial data are limited and no approved therapies are currently available for the management of M abscessus lung diseases. As an alternative, cohort studies may provide insightful information into the management of M abscessus pulmonary disease. Methods: Based on a retrospective observational cohort study, we investigated the safety and efficacy of amikacin liposome inhaled suspension (ALIS) as an adjunct to a standard antibiotic regimen for M abscessus lung infection in both CF and non-CF patients. We also assessed the association of patient drug compliance with culture conversion and clinical outcomes. Results: Twenty-six patients had long-term follow-up data available. Culture conversion was achieved in 54% (14/26) of the patients with no difference between CF and non-CF patients after an average treatment duration of 10 months. Patient treatment compliance was significantly better in the converter group compared to nonconverters with an odds ratio of 44.78 associated with good compared to poor patient compliance. Overall, 9 patients (35%) experienced an adverse event that led to treatment discontinuation. Conclusions: ALIS appears beneficial in both CF and non-CF populations with M abscessus lung disease.

DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study.

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis.

Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small.

Protocols for drug allergy desensitization in children.

Introduction: When a drug hypersensitivity reaction is proven, desensitization protocols allow the reintroduction of the molecule in patients for whom such therapy is essential. Through drug desensitization (DDS), a temporary immune tolerance is maintained for the single course of a specific therapy. In pediatrics, indications for such a procedure include children with chronic diseases, severe infectious diseases and/or malignancies, who have a proven drug hypersensitivity.Areas covered: We ran a search on PubMed and Web of Science for papers on DDS and on DDS in children. Most protocols and recommendations on DDS focus on adults and have been adapted for children. The best candidates for desensitization are children with a history of immediate, IgE-mediated drug allergy, but this therapy may be applied also in nonallergic hypersensitivities and in non-immediate reactions. Most protocols in literature focus on antibiotics, especially beta-lactams, on chemotherapeutic agents, and on monoclonal antibodies.Expert opinion: Pediatric allergists should cooperate with specialists in infectious diseases and onco-hematology to provide DDS to children in need. Standardized protocols and international guidelines are still needed to optimize such treatment and to implement it in clinical daily practice.

Dynamic changes of DNA methylation and lung disease in cystic fibrosis: lessons from a monogenic disease.

AIM: To assess whether DNA methylation levels account for the noninherited phenotypic variations observed among cystic fibrosis (CF) patients. PATIENTS & METHODS: Using the 450 K BeadChip, we profiled DNA methylation in nasal epithelial cells collected from 32 CF patients and 16 controls. RESULTS: We detected substantial DNA methylation differences up to 55% (median ß change 0.13; IQR: 0.15-0.11) between CF patients and controls. DNA methylation levels differed between mild and severe CF patients and correlated with lung function at 50 CpG sites. CONCLUSION: In CF samples, dynamic changes of DNA methylation occurred in genes responsible for the integrity of the epithelium and the inflammatory and immune responses, were prominent in transcriptionally active genomic regions and were over-represented in enhancers active in lung tissues. ( Clinicaltrials.gov NCT02884622).

Positive Effect of Liposomal Amikacin for Inhalation on Mycobacterium abcessus in Cystic Fibrosis Patients.

Mycobacterium abscessus is difficult to eradicate. At the Montpellier CF Center, we prescribed liposomal amikacin for inhalation to 5 patients with M abscessus infection. The 3 patients who completed the treatment did not have any respiratory exacerbation, showed negative cultures for M abscessus in their sputum, and stabilized their spirometric functions.

DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis.

BACKGROUND: Lung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the CFTR gene, polymorphic variations in disease modifier genes, and environmental exposure. The contribution of genetic factors has been extensively investigated, whereas the mechanism whereby environmental factors modulate the lung disease is unknown. In this project, we hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation variations at disease modifier genes modulate the lung function in CF patients. RESULTS: We profiled DNA methylation at CFTR, the disease-causing gene, and at 13 lung modifier genes in nasal epithelial cells and whole blood samples from 48 CF patients and 24 healthy controls. CF patients homozygous for the p.Phe508del mutation and ≥18-year-old were stratified according to the lung disease severity. DNA methylation was measured by bisulfite and next-generation sequencing. The DNA methylation profile allowed us to correctly classify 75% of the subjects, thus providing a CF-specific molecular signature. Moreover, in CF patients, DNA methylation at specific genes was highly correlated in the same tissue sample. We suggest that gene methylation in CF cells may be co-regulated by disease-specific trans-factors. Three genes were differentially methylated in CF patients compared with controls and/or in groups of pulmonary severity: HMOX1 and GSTM3 in nasal epithelial samples; HMOX1 and EDNRA in blood samples. The association between pulmonary severity and DNA methylation at EDNRA was confirmed in blood samples from an independent set of CF patients. Also, lower DNA methylation levels at GSTM3 were associated with the GSTM3*B allele, a polymorphic 3-bp deletion that has a protective effect in cystic fibrosis. CONCLUSIONS: DNA methylation levels are altered in nasal epithelial and blood cell samples from CF patients. Analysis of CFTR and 13 lung disease modifier genes shows DNA methylation changes of small magnitude: some of them are a consequence of the disease; other changes may result in small expression variations that collectively modulate the lung disease severity.

Rhinovirus-associated pulmonary exacerbations show a lack of FEV1 improvement in children with cystic fibrosis.

BACKGROUND: Respiratory viral infections lead to bronchial inflammation in patients with cystic fibrosis, especially during pulmonary exacerbations. The aim of this study was to determine the impact of viral-associated pulmonary exacerbations in children with cystic fibrosis and failure to improve forced expiratory volume in 1 s (FEV1 ) after an appropriate treatment. METHODS: We lead a pilot study from January 2009 until March 2013. Children with a diagnosis of cystic fibrosis were longitudinally evaluated three times: at baseline (Visit 1), at the diagnosis of pulmonary exacerbation (Visit 2), and after exacerbation treatment (Visit 3). Nasal and bronchial samples were analyzed at each visit with multiplex viral respiratory PCR panel (qualitative detection of 16 viruses). Pulmonary function tests were recorded at each visit, in order to highlight a possible failure to improve them after treatment. Lack of improvement was defined by an increase in FEV1 less than 5% between Visit 2 and Visit 3. RESULTS: Eighteen children were analyzed in the study. 10 patients failed to improve by more than 5% their FEV1 between Visit 2 and Visit 3. Rhinovirus infection at Visit 2 or Visit 3 was the only risk factor significantly associated with such a failure (OR, 12; 95% CI, 1·3-111·3), P = 0·03. CONCLUSIONS: Rhinovirus infection seems to play a role in the FEV1 recovery after pulmonary exacerbation treatment in children with cystic fibrosis. Such an association needs to be confirmed by a large-scale study because this finding may have important implications for pulmonary exacerbation management.

Adenoids in children: Advances in immunology, diagnosis, and surgery.

Adenoids are strategically located for mediating local and regional immune functions as they are exposed to antigens from both the outside air and the alimentary tract. Recurrent or chronic respiratory infections can induce histomorphological and functional changes in the adenoidal immunological barrier, sometimes making surgical treatment necessary. Our aim in this review is to summarize the crucial points about not only the immunological histopathology of adenoidal tissue, especially in patients with adenoid hypertrophy, but also the most common and useful diagnostic techniques and surgical options.

Comprehensive allergy work-up is mandatory in cystic fibrosis patients who report a history suggestive of drug allergy to beta-lactam antibiotics.

BACKGROUND: In the general population, reports on suspected ß-lactam hypersensitivity are common. After a drug allergy work-up at best 20% of the selected patients are positive. However, these considerations have not been explored in cystic fibrosis patients for whom antibiotics are even more crucial. METHODS: The study, part of the Drug Allergy and Hypersensitivity (DAHD) cohort, was performed in the regional cystic fibrosis center of Montpellier, France. After identifying patients with a clinical history suggestive of drug allergy to ß-lactams, a complete drug allergy work-up, was carried out according to the EAACI recommendations. RESULTS: Among the 171 patients involved, 23 reported clinical manifestations potentially compatible with a drug allergy to ß-lactams. After performing the complete drug-allergy work-up, 7 were considered as drug hypersensitive (3 had positive skin tests, 1 a positive provocation test, 3 declined the tests). Excluding the latter 3 patients with incomplete drug allergy work-up, the rate of proven drug allergy was 2.3%. CONCLUSIONS: Drug allergy to ß-lactams in cystic fibrosis patients is of importance. A full drug allergy work-up is mandatory in case of suspicion, because ß-lactam responsibility is often ruled out.

Kikuchi-Fujimoto disease complicated by peripheral neuropathy.

Kikuchi-Fujimoto disease is a necrotizing lymphadenitis, mainly characterized by lymphadenopathy, fever, hepatosplenomegaly, nocturnal sweats, myalgia, weight loss, and arthralgia. Its diagnosis is most often based on lymph node biopsy. Differential diagnoses with several other diseases, e.g., malignant lymphoma, necrotizing lymphadenitis, and infective lymphadenopathies, may be challenging. Neurologic involvement is rarely reported in patients diagnosed with Kikuchi-Fujimoto disease. In this subset of patients, the great majority manifest signs involving the central nervous system. We present a 14-year-old boy with a severe form of Kikuchi-Fujimoto disease, complicated by peripheral neuropathy. This patient is interesting for both his age and his peculiar complication.

Role of adenoids and adenoiditis in children with allergy and otitis media.

Adenoids and/or tonsil inflammation with concomitant obstructive hypertrophy is one of the oldest and most common pediatric problems. Adenoids are a component of Waldeyer's ring and because of their anatomic position can be relevant in the pathogenesis of otitis media when they are inflamed and/or enlarged. Adenoid pads can create mechanical eustachian tube obstruction. Therefore, in some cases, adenoidectomy may have a role in the clinical management of otitis media with effusion. However, eustachian tube dysfunction related to the adenoids may also have an allergy-related functional component. Allergic inflammation has been described for middle ear effusion, and some studies have reported that mast cells increase and allergic mediators release in adenoids as well. Nasal endoscopy has a key role in confirming a diagnosis of adenoid hypertrophy and/or adenoiditis and in detecting an association between adenoid inflammation/infection and otitis media with effusion, especially during infancy and early childhood.

Passive exposure to smoke results in defective interferon-gamma production by adenoids in children with recurrent respiratory infections.

There is evidence that exposure to passive smoke is associated with an increased susceptibility to respiratory infections. Indeed, cigarette smoke extracts may interfere with the immune system, even though the precise mechanism has not been fully understood yet. Recurrent respiratory infections may be sustained by a defective immune response. The aim of the present study was to evaluate whether, in a cohort of children presenting both with recurrent respiratory infections and with a history of exposure to tobacco smoke, these factors were related to a lower local production of interferon-gamma (IFN-gamma) when compared to a similar non-exposed population. The study group included 128 children undergoing adenoidectomy, presenting with more than three respiratory infections per year, independently of exposure to passive smoke at home. The intracellular cytokine profile of lymphocyte subsets in adenoids was evaluated by flow cytometry analysis. Children exposed to tobacco smoke suffered from a significantly greater number of respiratory infections and had a lower percentage of IFN-gamma-producing CD8+ cells in adenoids than non-exposed children, while other T-cell subsets were not affected. The effect of smoke exposure seems to be specific to the IFN-gamma-producing CD8+ cells in adenoids and may contribute to the increased susceptibility to the recurrence of respiratory infections.

Increased risk of otitis media with effusion in allergic children presenting with adenoiditis.

OBJECTIVE: Otitis media with effusion (OME) is a common disorder in childhood. The aim of the study was to assess the association of atopy and endoscopic features with the presence of OME. SUBJECTS AND METHODS: This cross-sectional study evaluated 287 children presenting with acute upper-airway infections persistent for at least ten days and tested through nasal endoscopy and skin-prick test. RESULTS: Fifty-three patients had a diagnosis of OME; out of them, 23 showed acute rhinosinusitis, ten adenoiditis, and 20 both features. OME was diagnosed in 26 atopic children and in 27 nonatopic ones. On a multivariable analysis, allergic rhinitis, endoscopic pattern of adenoiditis, and younger age were all shown to be independently associated with a diagnosis of OME. CONCLUSIONS: This study suggests that allergic rhinitis and adenoiditis are significant risk factors to OME development and that the risk becomes higher when these two conditions are concomitantly present.

Nasal obstruction is the key symptom in hay fever patients.

BACKGROUND: Allergic rhinitis is characterized by a Th2-dependent inflammation. Nasal obstruction largely depends on allergic inflammation. OBJECTIVE: The aim of this study was to evaluate the possible role of the symptom nasal obstruction in assessing patients with hay fever. METHODS: Fifty patients (mean age, 23.7 +/- 4.9 years) with hay fever were evaluated both during and outside pollen season. All of them had moderate-severe grade of nasal obstruction. Total symptom score (TSS), rhinomanometry, nasal lavage, nasal scraping, spirometry, and methacholine bronchial challenge were performed in all subjects. RESULTS: During the pollen season, patients with severe nasal obstruction showed significantly higher values of TSS, IL-4, IL-5, IL-8, nasal eosinophils and neutrophils, and significantly lower values of nasal airflow, IFNgamma, FEV1, FVC, and FEF 25-75 in comparison with patients with moderate nasal obstruction. Twenty (83%) patients with severe nasal obstruction showed bronchial hyperreactivity (BHR), whereas only 6 (25%) patients with moderate nasal obstruction had BHR. Outside the pollen season overlapping results were observed. CONCLUSIONS: This study provides evidence about the key role played by nasal obstruction in assessing patients with allergic rhinitis.