Aspergillus serology and clinical outcomes in patients with bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

INTRODUCTION: Aspergillus sp. cause diverse clinical manifestations in bronchiectasis including Allergic bronchopulmonary aspergillosis (ABPA), Aspergillus sensitization (AS) and raised IgG indicating exposure or infection with Aspergillus. RESEARCH QUESTION: What is the prevalence and clinical significance of Aspergillus-associated conditions in individuals with bronchiectasis? METHODS: Bronchiectasis patients enrolled into the EMBARC registry from 2015 to 2022 with laboratory testing for Aspergillus lung disease (total IgE, specific IgE to Aspergillus or Aspergillus skin test, IgG to Aspergillus and blood eosinophil counts) were included for analysis. Modified-ISHAM-ABPA working group criteria (2021) were used to define ABPA. RESULTS: 9953 patients were included. 608 (6.1%) were classified as having ABPA, 570 (5.7%) showed Aspergillus sensitization, 806 (8.1%) had raised Aspergillus-specific IgG without sensitisation, 184 (1.8%) were both sensitised to Aspergillus and had raised Aspergillus-specific IgG and 619 (6.2%) had eosinophilic bronchiectasis (elevated eosinophil counts without evidence of Aspergillus lung disease). The remaining 72.0% had negative Aspergillus serology. Patients with ABPA, Aspergillus sensitization, and raised Aspergillus-specific IgG had more severe disease, with worse lung function and more frequent exacerbations at baseline. During long-term follow-up, patients with raised Aspergillus-specific IgG had higher exacerbation frequency and more severe exacerbations. Aspergillus sensitization associated with increased exacerbations and hospitalisations only in patients not receiving inhaled corticosteroids. INTERPRETATION: Aspergillus lung disease is common in bronchiectasis. Raised IgG to Aspergillus is associated with significantly worse outcomes while ABPA and Aspergillus sensitization are associated with severe disease and exacerbations with a risk that is attenuated by inhaled corticosteroid use.

Predicting high risk of exacerbations in bronchiectasis: the E-FACED score.

BACKGROUND: Although the FACED score has demonstrated a great prognostic capacity in bronchiectasis, it does not include the number or severity of exacerbations as a separate variable, which is important in the natural history of these patients. OBJECTIVE: Construction and external validation of a new index, the E-FACED, to evaluate the predictive capacity of exacerbations and mortality. METHODS: The new score was constructed on the basis of the complete cohort for the construction of the original FACED score, while the external validation was undertaken with six cohorts from three countries (Brazil, Argentina, and Chile). The main outcome was the number of annual exacerbations/hospitalizations, with all-cause and respiratory-related deaths as the secondary outcomes. A statistical evaluation comprised the relative weight and ideal cut-off point for the number or severity of the exacerbations and was incorporated into the FACED score (E-FACED). The results obtained after the application of FACED and E-FACED were compared in both the cohorts. RESULTS: A total of 1,470 patients with bronchiectasis (819 from the construction cohorts and 651 from the external validation cohorts) were followed up for 5 years after diagnosis. The best cut-off point was at least two exacerbations in the previous year (two additional points), meaning that the E-FACED has nine points of growing severity. E-FACED presented an excellent prognostic capacity for exacerbations (areas under the receiver operating characteristic curve: 0.82 for at least two exacerbations in 1 year and 0.87 for at least one hospitalization in 1 year) that was statistically better than that of the FACED score (0.72 and 0.78, P<0.05, respectively). The predictive capacities for all-cause and respiratory mortality were 0.87 and 0.86, respectively, with both being similar to those of the FACED. CONCLUSION: E-FACED score significantly increases the FACED capacity to predict future yearly exacerbations while maintaining the score's simplicity and prognostic capacity for death.

Bronchiectasis: a retrospective study of clinical and aetiological investigation in a general respiratory department.

BACKGROUND: Bronchiectasis can result from many diseases, which makes the aetiological investigation a complex process demanding special resources and experience. The aetiological diagnosis has been proven to be useful for the therapeutic approach. OBJECTIVE: Evaluate how accurately and extensive the clinical and aetiological research was for adult bronchiectasis patients in pulmonology outpatient service which were not following a pre-existing protocol. METHODS: We retrospectively reviewed the records of 202 adult patients with bronchiectasis, including the examinations performed to explain the aetiology. RESULTS: The mean age of the patients was 54 ± 15 years, there was a predominance of female (63.9%) and non-smoker (70%) patients. Functional evaluation showed a mild airway obstruction. The sputum microbiological examination was available for 168 patients (43.1% had 3 or more sputum examinations during one year). Immunoglobulins and α1-antitrypsin were measured in around 50% of the patients. The sweat test and the CF genotyping test were performed in 18% and 17% of the patients, respectively. The most commonly identified cause was post-infectious (30.3%), mostly tuberculosis (27.2%). No definitive aetiological diagnosis was established in 57.4% of the patients. We achieved a lower aetiological diagnosis if we compare our series with studies in which a diagnostic algorithm was applied prospectively. CONCLUSIONS: The general characteristics of our patients were similar with other series. Detailed investigation of bronchiectasis is not a standard practice in our outpatient service. These results suggest that the use of a predefined protocol, based on current guidelines, could improve the assessment of these patients and facilitate the achievement of a definitive aetiology.

Efficacy and safety of Hizentra(®) in patients with primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous replacement therapy.

A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra(®), a 20% human IgG for subcutaneous administration, in 51 primary immunodeficiency patients over 40 weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra(®) at doses equivalent to their previous treatment. IgG levels achieved with Hizentra(®) were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient, the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra(®)-related adverse events were reported. Individual median infusion durations ranged between 1.14 and 1.27 h. Hizentra(®) maintained or improved serum IgG levels without dose increases and effectively protected patients against infections.

Bronchoscopic balloon dilatation in the management of bronchial stenosis following lung transplantation.

BACKGROUND: Bronchial stenosis (BS) is currently found in 7-15% of lung transplantation (LT) recipients. Current treatment strategies have included Nd:Yag laser, cryotherapy, bougie dilatation and stent placement. Bronchoscopic balloon dilatation has been used as alternative treatment in a few cases with controversial results. This is a study to prospectively assess the efficacy of bronchoscopic balloon dilatation as a first step in the management of post-LT BS. METHODS: From January 1995 to December 2002, bronchoscopic balloon dilatation was evaluated as first therapeutic option in all consecutive LT patients with BS. Symptoms, pulmonary function tests, airway diameter and use of other therapeutic techniques were evaluated. RESULTS: A total of 10 out of 284 anastomed airways (3.5%) in 9 out of 152 LT patients were included in the study and follow-up lasted from 6 to 81 months. Dilatation of all but one BS met with initial success: increase of both luminal dimensions and forced vital capacity (P=0.01), and relief of symptoms. Bronchoscopic balloon dilatation long-term follow-up showed effective results in 5 out of 10 (50%) bronchial stenoses, after an average of 4 bronchoscopic balloon dilatation procedures (range 1-8). No severe complications were observed. Stent placement was required in the other 5 bronchial stenoses. CONCLUSIONS: Bronchoscopic balloon dilatation is a safe method that should be considered as first therapeutic treatment of post-LT BS. Its use avoids the need for stent placement in up to 50% of cases.

Elevated serum interleukin (IL)-12p40 levels in common variable immunodeficiency disease and decreased peripheral blood dendritic cells: analysis of IL-12p40 and interferon-gamma gene.

Common variable immunodeficiency disease (CVID) is a heterogeneous syndrome characterized by low immunoglobulin serum levels and recurrent bacterial infections. Several studies suggest that CVID patients have a polarized immune response towards a T helper type 1 phenotype (TH1). However, the factors causing the TH1 polarization remain to be determined in this disease. In the present study, serum interleukin (IL)-12, interferon (IFN)-gamma levels and the IL-12p40 and IFN-gamma gene were studied in CVID patients. Furthermore, we evaluate dendritic cells (DCs) compartment, myeloid dendritic cells (mDCs) and plasmocytoid dendritic cells (pDCs), which help to differentiate naive T cells preferentially into TH1 and TH2, respectively. The serum IL-12p40 subunit levels were increased significantly in CVID patients compared to healthy controls. We examined whether these elevated serum IL-12p40 levels are associated with IFN-gamma or IL-12p40 gene polymorphisms, or with new mutations in the IL-12p40 promoter gene. In our hands, no new mutations were found and gene polymorphisms frequencies in CVID patients were similar to the control population. In conclusion, the elevated serum levels of IL-12p40 found in our CVID patients were not related to these genetic variations. The DC compartment analysis did not show an imbalance between pDCs and mDCs, but revealed the presence of low numbers and percentage of both DC populations in CVID.

Antimicrobial therapy for pulmonary pathogenic colonisation and infection by Pseudomonas aeruginosa in cystic fibrosis patients.

Pseudomonas aeruginosa colonisation has a negative effect on pulmonary function in cystic fibrosis patients. The organism can only be eradicated in the early stage of colonisation, while reduction of bacterial density is desirable during chronic colonisation or exacerbations. Monthly, or at least 3-monthly, microbiological culture is advisable for patients without previous evidence of P. aeruginosa colonisation. Cultures should be performed at least every 2-3 months in patients with well-established colonisation, and always during exacerbations or hospitalisations. Treatment of patients following the first isolation of P. aeruginosa, but with no clinical signs of colonisation, should be with oral ciprofloxacin (15-20 mg/kg twice-daily for 3-4 weeks) plus inhaled tobramycin or colistin (intravenous treatment with or without inhaled treatment can be used as an alternative), while patients with acute infection should be treated for 14-21 days with high doses of two intravenous antimicrobial agents, with or without an inhaled treatment during or at the end of the intravenous treatment. Maintenance treatment after development of chronic P. aeruginosa infection/colonisation (pathogenic colonisation) in stable patients (aged>6 years) should be with inhaled tobramycin (300 mg twice-daily) in 28-day cycles (on-off) or, as an alternative, colistin (1-3 million units twice-daily). Colistin is also a possible choice for patients aged<6 years. Treatment can be completed with oral ciprofloxacin (3-4 weeks every 3-4 months) for patients with mild pulmonary symptoms, or intravenously (every 3-4 months) for those with severe symptoms or isolates with ciprofloxacin resistance. Moderate and serious exacerbations can be treated with intravenous ceftazidime (50-70 mg/kg three-times-daily) or cefepime (50 mg/kg three-times-daily) plus tobramycin (5-10 mg/kg every 24 h) or amikacin (20-30 mg/kg every 24 h) for 2-3 weeks. Oral ciprofloxacin is recommended for patients with mild pulmonary disease. If multiresistant P. aeruginosa is isolated, antimicrobial agents that retain activity are recommended and epidemiological control measures should be established.

Genotype-phenotype correlation for pulmonary function in cystic fibrosis.

BACKGROUND: Since the CFTR gene was cloned, more than 1000 mutations have been identified. To date, a clear relationship has not been established between genotype and the progression of lung damage. A study was undertaken of the relationship between genotype, progression of lung disease, and survival in adult patients with cystic fibrosis (CF). METHODS: A prospective cohort of adult patients with CF and two CFTR mutations followed up in an adult cystic fibrosis unit was analysed. Patients were classified according to functional effects of classes of CFTR mutations and were grouped based on the CFTR molecular position on the epithelial cell surface (I-II/I-II, I-II/III-V). Spirometric values, progression of lung disease, probability of survival, and clinical characteristics were analysed between groups. RESULTS: Seventy four patients were included in the study. Patients with genotype I-II/I-II had significantly lower current spirometric values (p < 0.001), greater loss of pulmonary function (p < 0.04), a higher proportion of end-stage lung disease (p < 0.001), a higher risk of suffering from moderate to severe lung disease (odds ratio 7.12 (95% CI 1.3 to 40.5)) and a lower probability of survival than patients with genotype I-II/III, I-II/IV and I-II/V (p < 0.001). CONCLUSIONS: The presence of class I or II mutations on both chromosomes is associated with worse respiratory disease and a lower probability of survival.

Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations?

While all patients with cystic fibrosis (CF) have mutations in both CFTR alleles, often only one CFTR change is detected in patients with other lung disorders. The aim of this study was to investigate whether heterozygosity for CFTR mutations could be a determinant risk factor in the development of bronchiectasis in adult patients. We have performed the CFTR gene analysis in a cohort of 55 bronchiectasis adult patients with unknown etiology. The 5T variant (TG)m and the M470V polymorphisms were also analyzed. A general population in which the same molecular analysis was previously performed was used as the control group. The mutational spectrum of patients was also compared with that found in our CF population. CFTR mutations/variants were found in 20 patients (36%), 14 with only one mutant gene (25%). All six patients colonized by Staphylococcus aureus presented with at least one CFTR change (p = 0.001). No statistical significance was observed between patients with and without mutations for other clinical features. The 5T variant was found in four patients. Additionally, 90% of patients with mutations had the more functional M470 allele (p < 0.001). These results suggest the involvement of the CFTR gene in bronchiectasis of unknown etiology in adult patients.

Gastrointestinal, liver, and pancreatic involvement in adult patients with cystic fibrosis.

BACKGROUND: The clinical prevalence of cystic fibrosis (CF) in adults continues to rise, with a consequent impact on adult gastroenterology practice. AIM: To characterize the gastrointestinal manifestations of CF in adult patients. PATIENTS AND METHODS: The clinical records of 89 adult CF patients treated at our institution from 1992 to 1999 were reviewed. Patients were distributed into two groups: group A (39 patients), which consisted of patients who were diagnosed with CF at when they were younger than 14 years old and who survived into adulthood; and group B (50 patients), who were diagnosed with CF at the age of 14 years or older. Data on CF genetic mutations, nutritional state, evidence of pulmonary, gastrointestinal, liver, or pancreatic involvement were collected for each patient. RESULTS: The most prevalent genetic mutation in our series was deltaF508, present in 50 patients (56.2%), 29 of whom belonged to group A and 21 who belonged to group B. In group A, the deltaF508 mutation was associated with exocrine pancreatic insufficiency (PI) in 26 of 29 patients (89.6%), whereas in group B it was associated with PI in only four patients (19%). Overall, PI was present in 33 of 39 patients (84.6%) in group A and in eight of 50 patients (16%) in group B. Four patients in group B had experienced previous episodes of acute pancreatitis; two of them had associated PI. Of the 89 patients, 12 (10 in group A) were malnourished. Malnutrition was invariably associated with PI. Hepatic and biliary tree abnormalities were particularly prevalent in patients in group A and was usually associated with PI. Intestinal manifestations were uncommon. CONCLUSIONS: Diagnosis of CF before the age of 14 years is associated with greater gastrointestinal compromise than diagnosis at an older age, particularly with regard to PI. CF carriers of the deltaF508 mutation have an increased risk of developing gastrointestinal manifestations.

Utility of the antibody response to a conjugated Haemophilus influenzae type B vaccine for diagnosis of primary humoral immunodeficiency.

Antibody response to an Haemophilus influenzae type b (Hib)-conjugated vaccine was studied in 59 healthy adults (mean age: 32 yr) and 22 patients with humoral immunodeficiencies (mean age: 32 yr) to determine its usefulness in the diagnosis of defective antibody formation. Twenty of the healthy adults and nine of the patients were also immunized with a pneumococcal vaccine. Serum specific antibodies were measured by ELISA. Adequate response to both vaccines was defined using the lower limit of the two-tailed 90% probability interval of postimmunization specific IgG of the healthy adults. By using this cutoff, responders were considered to be those with an absolute increase in anti-Hib IgG titers higher than 2.28 microgram/ml, and in anti-Streptococcus pneumoniae IgG higher than 395 arbitrary units/ml. With these criteria, 85% (50 of 59) of the healthy adults responded with anti-Hib IgG and 75% (15 of 20) with anti-pneumococcal IgG. All healthy adults receiving both vaccines responded to at least one. None of the patients with humoral immunodeficiencies responded to either vaccine. Evaluation of the antibody response to both the Hib and pneumococcal vaccines may facilitate the diagnosis of humoral immunodeficiency and selection of patients to receive immunoglobulin therapy.

Specific antibody response against the 23-valent pneumococcal vaccine in patients with alpha(1)-antitrypsin deficiency with and without bronchiectasis.

OBJECTIVE: To assess the specific antibody response against polyvalent pneumococcal vaccine in patients with alpha(1)-antitrypsin deficiency (AATD) and respiratory infections. DESIGN AND PARTICIPANTS: We investigated specific IgG, IgG1, and IgG2 antibody responses against the 23-valent antipneumococcal vaccine in 18 patients with AATD phenotype PiZZ, 9 of whom had bronchiectasis and 4 a history of recurrent pneumonia, and compared them with a control group of 40 healthy volunteers. INTERVENTIONS: Blood samples were drawn just prior to and 3 weeks after immunization. MEASUREMENTS AND RESULTS: Quantification of specific IgG and its subclasses was performed by an enzyme-linked immunosorbent assay. For patients with AATD, mean increases in specific antipneumococcal titers were 4.7-fold (25 to 75% quartiles, 2.5- to 6.8-fold) for total IgG, 3.2-fold (1.2- to 4.9-fold) for IgG1, and 2.1-fold (1.8- to 3.7-fold) for IgG2. For the control group, the values were 3.3-fold (1.8- to 5.8-fold) for total IgG, 2. 5-fold (1.9- to 3.4-fold) for IgG1, and 3.1-fold (1.9- to 4.5-fold) for IgG2; differences were not significant. Patients with bronchiectasis showed a tendency toward higher levels of IgG subclasses than both control subjects and patients without bronchiectasis; however, there was a tendency toward lower postvaccination serum levels of specific antipneumococcal IgG, IgG1, and IgG2 in patients with bronchiectasis compared with patients without bronchiectasis, but this trend did not reach statistical significance. Three of the four patients with recurrent pneumonia did not show an appropriate IgG2 response. CONCLUSIONS: These results suggest that, as a group, patients with AATD have a preserved antibody response against pneumococcal polysaccharides. Patients with bronchiectasis show a tendency toward a decreased antibody response, even with increased serum levels of most Ig types. Individuals with an impaired IgG2 response seem to be at increased risk of recurrent pneumonia. Considering the pernicious effect of pulmonary infections on these patients and the preserved antibody response in a majority of them, pneumococcal vaccination should be recommended to patients with AATD.