Antibody responses induced by long-term vaccination with an octovalent conjugate Pseudomonas aeruginosa vaccine in children with cystic fibrosis

We assessed the serological responses over 10 years to repeated immunization of cystic fibrosis (CF) patients with an O-polysaccharide (OPS)-toxin A conjugate vaccine against Pseudomonas aeruginosa. A retrospective analysis was performed with sera from 25 vaccinated and 25 unvaccinated children treated at the same CF centre and matched for clinical management, age and gender. Yearly immunization led to sustained elevations of serum immunoglobulin G (IgG) antibody levels to all vaccine components. Eighteen unvaccinated patients but only eight vaccinated ones developed chronic pseudomonal lung infections. Infection rapidly caused further marked elevations of polysaccharide- but not toxin A-specific serum IgG in both immunized and nonimmunized patients, indicating that protection did not depend on the quantity of IgG present. However, qualitative analyses revealed that the protective capacity of specific serum IgG antibodies was linked to high affinity and to specificity for OPS serotypes rather than for lipopolysaccharide core epitopes.

Autoantibodies directed against bactericidal/permeability-increasing protein in patients with cystic fibrosis: association with microbial respiratory tract colonization

BACKGROUND: Cystic fibrosis (CF) is associated with the appearance of serum autoantibodies directed against bactericidal/permeability-increasing protein (BPI). OBJECTIVES: To determine the age-specific seroprevalence rates of anti-BPI-IgG and IgA in a population of patients with CF and to correlate anti-BPI antibody concentrations with microbial respiratory tract colonization and pulmonary function variables at the time of serum sampling and 6 years thereafter. METHODS: Determination of BPI antibodies of the IgG and IgA isotypes using a commercial enzyme-linked immunosorbent assay in sera of a CF serum bank of 1992; correlation of anti-BPI antibody concentrations with age, clinical score, pulmonary function variables in 1992 and 1998, total serum immunoglobulin isotype concentrations and respiratory tract colonization with Pseudomonas aeruginosa and Aspergillus spp. RESULTS: Seventy-one patients (age in 1992, 14.1 +/- 7.5 years) were studied. Reactivities for anti-BPI-IgG and IgA were found in 28 (39%) and 26 (37%) patients, respectively. The seroprevalence of anti-BPI-IgA, but not IgG, increased significantly with age. P. aeruginosa colonization was associated with elevated concentrations of anti-BPI-IgG (P = 0.003) and IgA (P = 0.037). There were significant negative correlations between pulmonary function variables (vital capacity, forced expiratory volume in 1 s) in 1992 and 1998, respectively, and concentrations of anti-BPI-IgG or IgA in a multiple regression analysis. Anti-BPI-IgG, but not IgA, remained significantly associated with P. aeruginosa colonization (P = 0.006) and with reduced vital capacity (P = 0.01) in 1998 after correction for total serum isotype concentration. CONCLUSIONS: Anti-BPI-IgG are strongly associated with concurrent P. aeruginosa colonization and with long term restrictive pulmonary function abnormalities.

Which factors account for renal stone formation in cystic fibrosis?

Studies dealing with the increased tendency to stone formation noted in cystic fibrosis, focus on enteric hyperoxaluria. It is well recognized, however, that low urine volume, hypocitraturia and perhaps even hypercalciuria are further risk factors for stone formation.

Isolation and molecular characterization of recombinant Echinococcus granulosus P29 protein (recP29) and its assessment for the post-surgical serological follow-up of human cystic echinococcosis in young patients

We synthesized recombinant Echinococcus granulosus protoscolex recP29 antigen to be preliminarily assessed by ELISA and immunoblotting. RecP29-serology was carried out on 54 young patients with cystic echinococcosis (CE). Patients were classified into either cured (CCE) (n=40) or non-cured (NCCE) (n=14) CE patients. RecP29 ELISA showed a gradual decrease of antibody concentrations in all CCE cases that were initially (before treatment) seropositive to this antigen (25 out of 40) or that seroconverted following treatment. A complete seronegativity was reached within 3 years post-surgery in all of these cases. Conventional HCF ELISA yielded seronegativity in only 10% of initially recP29-seropositive CCE patients (P=0.086). Likewise, recP29 immunoblotting yielded seronegativity in 93% of 29 out of 40 initially recP29-immunoblot-positive CCE patients after 3 years follow-up, compared with 72% in the HCF immunoblotting (P=0.060). Eleven out of 14 NCCE patients were initially positive by recP29 ELISA, and 10 out of these maintained a marked anti-recP29 antibody reactivity until the endpoint of the follow-up period. All 14 NCCE cases were initially seropositive by recP29 immunoblotting, and 13 cases remained seropositive until the end of the study. Thus, recombinant P29 protein appears prognostically useful for monitoring those post-surgical CE cases with an initial seropositivity to this marker.

Alveolar and cystic echinococcosis: towards novel chemotherapeutical treatment options

Echinococcus granulosus and Echinococcus multilocularis are cestode parasites, of which the metacestode (larval) stages cause the neglected diseases cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. The benzimidazoles albendazole and mebendazole are presently used for the chemotherapeutical treatment, alone or prior to and after surgery. However, in AE these benzimidazoles do not appear to be parasiticidal in vivo. In addition, failures in drug treatments as well as the occurrence of side-effects have been reported, leading to discontinuation of treatment or to progressive disease. Therefore, new drugs are needed to cure AE and CE. Strategies that are currently employed in order to identify novel chemotherapeutical treatment options include in vitro and in vivo testing of broad-spectrum anti-infective drugs or drugs that interfere with unlimited proliferation of cancer cells. The fact that the genome of E. multilocularis has recently been sequenced has opened other avenues, such as the selection of novel drugs that interfere with the parasite signalling machinery, and the application of in silico approaches by employing the Echinococcus genome information to search for suitable targets for compounds of known mode of action.

One-year evaluation of a neonatal screening program for cystic fibrosis in Switzerland

BACKGROUND From January 2011 onward, the Swiss newborn screening (NBS) program has included a test for cystic fibrosis (CF). In this study, we evaluate the first year of implementation of the CF-NBS program. METHODS The CF-NBS program consists of testing in two steps: a heel prick sample is drawn (= Guthrie test) for measurement of immunoreactive trypsinogen (IRT) and for DNA screening. All children with a positive screening test are referred to a CF center for further diagnostic testing (sweat test and genetic analysis). After assessment in the CF center, the parents are given a questionnaire. All the results of the screening process and the parent questionnaires were centrally collected and evaluated. RESULTS In 2011, 83 198 neonates were screened, 84 of whom (0.1%) had a positive screening result and were referred to a CF center. 30 of these 84 infants were finally diagnosed with CF (positive predictive value: 35.7%). There was an additional infant with CF and meconium ileus whose IRT value was normal. The 31 diagnosed children with CF correspond to an incidence of 1 : 2683. The average time from birth to genetically confirmed diagnosis was 34 days (range: 13-135). 91% of the parents were satisfied that their child had undergone screening. All infants receiving a diagnosis of CF went on to receive further professional care in a CF center. CONCLUSION The suggested procedure for CF-NBS has been found effective in practice; there were no major problems with its implementation. It reached high acceptance among physicians and parents.

Biokinetics of nanoparticles and susceptibility to particulate exposure in a murine model of cystic fibrosis.

BACKGROUND Persons with cystic fibrosis (CF) are at-risk for health effects from ambient air pollution but little is known about the interaction of nanoparticles (NP) with CF lungs. Here we study the distribution of inhaled NP in a murine CF model and aim to reveal mechanisms contributing to adverse effects of inhaled particles in susceptible populations. METHODS Chloride channel defective CftrTgH (neoim) Hgu mice were used to analyze lung function, lung distribution and whole body biokinetics of inhaled NP, and inflammatory responses after intratracheal administration of NP. Distribution of 20-nm titanium dioxide NP in lungs was assessed on ultrathin sections immediately and 24 h after a one-hour NP inhalation. NP biokinetics was deduced from total and regional lung deposition and from whole body translocation of inhaled 30-nm iridium NP within 24 h after aerosol inhalation. Inflammatory responses were assessed within 7 days after carbon NP instillation. RESULTS Cftr mutant females had moderately reduced lung compliance and slightly increased airway resistance compared to wild type mice. We found no genotype dependent differences in total, regional and head deposition or in secondary-organ translocation of inhaled iridium NP. Titanium dioxide inhalation resulted in higher NP uptake by alveolar epithelial cells in Cftr mutants. Instillation of carbon NP induced a comparable acute and transient inflammatory response in both genotypes. The twofold increase of bronchoalveolar lavage (BAL) neutrophils in Cftr mutant compared to wild type mice at day 3 but not at days 1 and 7, indicated an impaired capacity in inflammation resolution in Cftr mutants. Concomitant to the delayed decline of neutrophils, BAL granulocyte-colony stimulating factor was augmented in Cftr mutant mice. Anti-inflammatory 15-hydroxyeicosatetraenoic acid was generally significantly lower in BAL of Cftr mutant than in wild type mice. CONCLUSIONS Despite lacking alterations in lung deposition and biokinetics of inhaled NP, and absence of significant differences in lung function, higher uptake of NP by alveolar epithelial cells and prolonged, acute inflammatory responses to NP exposure indicate a moderately increased susceptibility of lungs to adverse effects of inhaled NP in Cftr mutant mice and provides potential mechanisms for the increased susceptibility of CF patients to air pollution.

Effect of different breathing AIDS on ventilation distribution in adults with cystic fibrosis.

BACKGROUND AND OBJECTIVES We investigated the effect of different breathing aids on ventilation distribution in healthy adults and subjects with cystic fibrosis (CF). METHODS In 11 healthy adults and 9 adults with CF electrical impedance tomography measurements were performed during spontaneous breathing, continuous positive airway pressure (CPAP) and positive expiratory pressure (PEP) therapy randomly applied in upright and lateral position. Spatial and temporal ventilation distribution was assessed. RESULTS The proportion of ventilation directed to the dependent lung significantly increased in lateral position compared to upright in healthy and CF. This effect was enhanced with CPAP but neutralised with PEP, whereas the effect of PEP was larger in the healthy group. Temporal ventilation distribution showed exactly the opposite with homogenisation during CPAP and increased inhomogeneity with PEP. CONCLUSIONS PEP shows distinct differences to CPAP with respect to its impact on ventilation distribution in healthy adults and CF subjects EIT might be used to individualise respiratory physiotherapy.

Novel antiviral properties of azithromycin in cystic fibrosis airway epithelial cells.

Virus-associated pulmonary exacerbations, often associated with rhinoviruses (RVs), contribute to cystic fibrosis (CF) morbidity. Currently, there are only a few therapeutic options to treat virus-induced CF pulmonary exacerbations. The macrolide antibiotic azithromycin has antiviral properties in human bronchial epithelial cells. We investigated the potential of azithromycin to induce antiviral mechanisms in CF bronchial epithelial cells. Primary bronchial epithelial cells from CF and control children were infected with RV after azithromycin pre-treatment. Viral RNA, interferon (IFN), IFN-stimulated gene and pattern recognition receptor expression were measured by real-time quantitative PCR. Live virus shedding was assessed by assaying the 50% tissue culture infective dose. Pro-inflammatory cytokine and IFN-β production were evaluated by ELISA. Cell death was investigated by flow cytometry. RV replication was increased in CF compared with control cells. Azithromycin reduced RV replication seven-fold in CF cells without inducing cell death. Furthermore, azithromycin increased RV-induced pattern recognition receptor, IFN and IFN-stimulated gene mRNA levels. While stimulating antiviral responses, azithromycin did not prevent virus-induced pro-inflammatory responses. Azithromycin pre-treatment reduces RV replication in CF bronchial epithelial cells, possibly through the amplification of the antiviral response mediated by the IFN pathway. Clinical studies are needed to elucidate the potential of azithromycin in the management and prevention of RV-induced CF pulmonary exacerbations.

Disease-modifying genes and monogenic disorders: experience in cystic fibrosis

The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene.

Multiple breath washout is feasible in the clinical setting and detects abnormal lung function in infants and young children with cystic fibrosis.

BACKGROUND Cystic fibrosis (CF) lung disease starts in the first months of life often before the onset of clinical symptoms. Multiple breath washout (MBW) detects abnormal lung function in infants and young children in the laboratory setting. OBJECTIVE The aim of this study was to determine the feasibility of MBW in 0- to 4-year-old children with CF and non-CF controls in the clinical setting. METHODS Fourteen children with CF (mean age 1.3 ± 1.0 years) and 26 age-matched non-CF controls were sedated with chloral hydrate and MBW was performed with sulfur hexafluoride. RESULTS MBW measurements were successful in 27 of 40 children (67.5%). The mean lung clearance index (LCI) was significantly higher in CF patients compared to non-CF controls (p = 0.006). Further, the frequency of elevated LCI (z-score >1.96) was significantly increased in CF patients compared to controls (p = 0.0003). CONCLUSIONS We conclude that MBW is feasible and sensitive to detect abnormal lung function in infants and young children with CF in the clinical setting.

[Transition - how adolescents with cystic fibrosis their parents experience the change from paediatric to adult care].

BACKGROUND Cystic Fibrosis is the most common autosomal-recessive hereditary disease among white Europeans. The average survival of CF patients has increased to above 40 years and transition from paediatric to adult care has therefore become a significant issue. AIM With this study, experiences of adolescents with CF and their parents with the transition from the paediatric to the adult care were explored. METHODS At a Swiss university CF centre, six adolescents and their mothers were recruited. Twelve narrative interviews were conducted on how the phase of transition was experienced. The transcribed interviews were analysed according to the method of hermeneutic phenomenology. RESULTS Positive and negative experiences with long term routine care in the paediatric service, general themes of adolescence and the quality of the relationship with paediatric doctors influenced the families' experience during transition significantly. For mothers, insensitive information on the CF diagnosis might have influenced the transition experience. The adolescents welcomed an individualized and age appropriate care. Continuity in care, the announcement of, and involvement in the planning of the transfer were of great importance. The families particularly appreciated the timed adaptations of the transfer to individual needs. CONCLUSIONS Flexibility and a strong collaboration between paediatric and adult CF teams are most relevant in the care of families.

Current concepts: host-pathogen interactions in cystic fibrosis airways disease.

Chronic infection and inflammation are defining characteristics of cystic fibrosis (CF) airway disease. Conditions within the airways of patients living with CF are conducive to colonisation by a variety of opportunistic bacterial, viral and fungal pathogens. Improved molecular identification of microorganisms has begun to emphasise the polymicrobial nature of infections in the CF airway microenvironment. Changes to CF airway physiology through loss of cystic fibrosis transmembrane conductance regulator functionality result in a wide range of immune dysfunctions, which permit pathogen colonisation and persistence. This review will summarise the current understanding of how CF pathogens infect, interact with and evade the CF host.