The effect of azithromycin on sputum inflammatory markers in bronchiectasis.

BACKGROUND: Long term macrolide treatment has been found beneficial in bronchiectasis (BE) -pathogical bronchial dilatation- possibly due to a combined anti-bacterial and immunomodulatory effect. The exact mechanism of inflammatory response is unknown. Here, we investigated the effect of maintenance macrolide treatment on the inflammatory response in BE. In addition, we assessed the inflammatory profile in BE in relation to disease severity. METHODS: During the BAT randomized controlled trial (investigating the effect of 1 year of azithromycin (AZM) in 83 BE patients), data on BE severity, lung function and sputum microbiology was collected. For the current study, a wide range of inflammatory markers were analysed in 3- monthly sputum samples in all participants. RESULTS: At baseline, marked neutrophilic but also eosinophilic inflammation was present in both groups, which remained stable throughout the study and was not affected by AZM treatment. Significant upregulation of pro-inflammatory markers correlated with FEV1 < 50% (TNFα, ECP, IL-21, IL-1, p = 0.01- 0.05), H. influenzae (HI) colonization (MPO, ECP, MIP-1, TNFα, IL-21, Il-8, IL-1, IL-1α, p < 0.001 - 0.04) and number of exacerbations (MPO, ECP, VEGF, MMP-9, p = 0.003 - 0.01). Surprisingly, colonization with P. aeruginosa (PA) was found to correlate with an attenuated inflammatory response compared to non-PA colonized. In placebo-treated patients, presence of an infectious exacerbation was reflected by a significant excessive increase in inflammation as compared to a non-significant upregulation in the AZM-treated patients. CONCLUSION: One year of AZM treatment did not result in attenuation of the inflammatory response in BE. Increasing disease severity and the presence of an exacerbation were reflected by upregulation of pro-inflammatory markers.

The BATTLE study: Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis. Study protocol of a double blind, randomized, placebo-controlled trial: study protocol.

Background: Patients with bronchiectasis typically suffer from chronic symptoms such as a productive cough with or without exacerbations leading to hospitalization, causing reduced quality of life (QoL) and mortality. Long-term inhaled antibiotics to treat chronic bronchial infection is registered for use in cystic fibrosis (CF) bronchiectasis. However, in patients with non-CF bronchiectasis data on long-term antibiotics are limited. Objective: To investigate the effectiveness of maintenance tobramycin inhalation solution (TIS) in bronchiectasis patients without cystic fibrosis. Study design: The BATTLE study is a randomized, double blind placebo controlled, multicenter study in the Netherlands performed in patients aged ≥18-year-old with confirmed bronchiectasis, at least two exacerbations in the preceding year, and minimal one positive sputum culture with gram negative pathogens or Staphylococcus aureus, sensitive to tobramycin in the preceding year and at baseline. Patients will be treated with TIS once daily (OD) or placebo (saline 0.9%) OD for 52 weeks followed by a run-out period of 4 weeks after the last dose. The primary outcome is the yearly rate of pulmonary exacerbations. Among secondary outcome parameters are time to exacerbation, lung function, QoL, microbiological evaluation and safety. Discussion: The BATTLE study is designed to determine the efficacy and safety of maintenance TIS OD in bronchiectasis patients colonized by different pathogens and could lead to important new evidence for TIS therapy in this population.The BATTLE study is registered in Clinical trials.gov with registration number: NCT02657473.

Forskolin induced swelling (FIS) assay in intestinal organoids to guide eligibility for compassionate use treatment in a CF patient with a rare genotype.

BACKGROUND: Forskolin-induced swelling of patient-derived organoids has been used to measure patient-specific CFTR function and CFTR modulator response. We present a case where CFTR function assessment in intestinal organoids was decisive for a patients' acceptance to a compassionate use program. CASE DESCRIPTION: A 56 years old female with cystic fibrosis compound heterozygous for F508del and a rare CFTR allele (c.3717+5G>T) experienced rapid clinical deterioration. The forskolin-induced swelling assay on her rectal organoids was used to confirm that the rare mutation is a minimal residual function mutation, and that other CFTR modulators would not likely be effective. Based on these two criteria and her clinical status, she was accepted for compassionate use of elexacaftor/tezacaftor/ivacaftor and showed improvement in all clinical parameters. CONCLUSIONS: This reports describes a first example that intestinal organoids were used to identify a previously unknown CFTR mutation as a minimal function mutation. The individual FIS-based definition of minimal residual function, response to ele/tez/iva and/or lack of response to other CFTR modulating drugs, may thus provide a tool for access to ele/tez/iva treatment for people with rare genotypes.

Females with cystic fibrosis have a larger decrease in sweat chloride in response to lumacaftor/ivacaftor compared to males.

AIM: To explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data. METHODS: 160 CF patients were identified who had used lumacaftor/ivacaftor for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations. RESULTS: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy. CONCLUSION: Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor. Sweat chloride response does not correlate with the responses in ppFEV1 and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments, and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.

Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.

BACKGROUND: Beneficial effects of pulmonary rehabilitation at high-altitude (HAPR) in patients with severe refractory asthma have been reported earlier, but evidence for the effectiveness is limited. AIM: To investigate the effectiveness of high-altitude pulmonary rehabilitation to comparable treatment at sea-level (LAPR) on patient outcome parameters. METHODS: Adults with severe refractory asthma living in The Netherlands were included. Treatment consisted of a 12-week personalized multidisciplinary rehabilitation program either at high-altitude (Davos Switzerland) (n = 93) or in a tertiary lung center at sea-level in The Netherlands (n = 45). At baseline, after treatment, and during 12 months follow-up asthma related quality of life (AQLQ), asthma control (ACQ), pulmonary function and OCS-dose were assessed. Patients could not be randomized resulting in different asthma populations. Groups were compared using linear regression analysis (ANCOVA) adjusted for baseline values, in addition to age, atopy, smoking history, BMI and gender. RESULTS: After treatment, and at 12 months follow-up, improved AQLQ(0.92,p < 0.001 and 0.82,p = 0.001, respectively), ACQ(-0.87,p < 0.001 and -0.69,p = 0.008, respectively) and lower maintenance OCS dose (Unadjusted linear regression analysis-5.29 mg, p = 0.003 and Crude Odds Ratio-1.67, p = 0.003, respectively) were observed in the HAPR-group compared to the LAPR group. Patients receiving HAPR also had less asthma exacerbations (≥1 exacerbation: 20% vs 60%,p < 0.001) and showed improvement in lung function (%predFEV1 3.4%,p = 0.014) compared to the LAPR group, but at 12 months no differences between groups were observed. CONCLUSION: HAPR resulted in a larger improvement in patient outcome parameters compared to LAPR, on the long run the improvement in patient reported symptoms and lower maintenance OCS-dose persists. Underlying factors that explain this observed effect need to be investigated.

Clinical effect of lumacaftor/ivacaftor in F508del homozygous CF patients with FEV1 ≥ 90% predicted at baseline.

OBJECTIVE: The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor, has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group. METHODS: In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously. RESULTS: We identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later. CONCLUSION: Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.

Non-fasting bioelectrical impedance analysis in cystic fibrosis: Implications for clinical practice and research.

BACKGROUND: Nutritional status affects pulmonary function in cystic fibrosis (CF) patients and can be monitored by using bioelectrical impedance analysis (BIA). BIA measurements are commonly performed in the fasting state, which is burdensome for patients. We investigated whether fasting is necessary for clinical practice and research. METHODS: Fat free mass (FFM) and fat mass (FM) were determined in adult CF patients (n = 84) by whole body single frequency BIA (Bodystat 500) in a fasting and non-fasting state. Fasting and non-fasting BIA outcomes were compared with Bland-Altman plots. Pulmonary function was expressed as Forced Expiratory Volume at 1 s percentage predicted (FEV1%pred). Comparability of the associations between fasting and non-fasting body composition measurements with FEV1%pred was assessed by multiple linear regression. RESULTS: Fasting FFM, its index (FFMI), and phase angle were significantly lower than non-fasting estimates (-0.23 kg, p = 0.006, -0.07 kg/m2, p = 0.002, -0.10°, p = 0.000, respectively). Fasting FM and its index (FMI) were significantly higher than non-fasting estimates (0.22 kg, p = 0.008) 0.32%, p = 0.005, and 0.07 kg/m2, (p = 0.005). Differences between fasting and non-fasting FFM and FM were <1 kg in 86% of the patients. FFMI percentile estimates remained similar in 83% of the patients when measured after nutritional intake. Fasting and non-fasting FFMI showed similar associations with FEV1%pred (ß: 4.3%, 95% CL: 0.98, 7.70 and ß: 4.6%, 95% CI: 1.22, 8.00, respectively). CONCLUSION: Differences between fasting and non-fasting FFM and FM were not clinically relevant, and associations with pulmonary function remained similar. Therefore, BIA measurements can be performed in a non-fasting state.

Specific airway resistance is a better outcome parameter in bronchial provocation testing compared to FEV1 in patients with bronchial asthma.

OBJECTIVES: Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR). A bronchial provocation test (BPT) is used to test for AHR. However forced expiratory volume in one second (FEV1), used as outcome parameter is effort-related, in contrast to specific airway resistance (sRaw). This research was conducted to provide insight in the usefulness of sRaw as an outcome parameter in BPT. METHODS: A total of 85 patients performing a BPT were included in the study. Bronchial reactivity was defined as the provocative dosage or provocative concentration causing a 20% decrease in FEV1 (PC-20) or a 100% increase in sRaw (PC+100). RESULTS: No significant response in either FEV1 or sRaw was found in 20 patients (24%). Twenty-nine patients (34%) only had a positive response for sRaw; 24 out of these 29 patients recognized their symptoms. 36 patients (42%) showed a positive response for both PC-20 and PC + 100. CONCLUSIONS: Twenty-nine patients (34%) showed a significant increase in sRaw without a fall in FEV1. As performing sRaw is not a routine investigation, these patients are at risk of being excluded from a diagnosis of asthma. We suggest performing sRaw for patients without a fall in FEV1 during BPT when they report recognizable symptoms.

CT-abnormalities, bacteriology and symptoms of sinonasal disease in children with Cystic Fibrosis.

BACKGROUND: Sinonasal pathology in adults with Cystic Fibrosis (CF) is common but the extent of CT-abnormalities and symptoms of sinonasal disease in children with CF and the age of onset are less frequently studied. METHODS: In this observational, cross-sectional study 58 children with CF from two CF centres were included. All subjects completed a questionnaire regarding sinonasal symptoms, underwent a CT scan of the paranasal sinuses, and in each subject a culture of the upper airways was performed. Subjects were divided in 6 age cohorts (0-2, 3-5, 6-8, 9-11, 12-14 and 15-17years) and were divided into severe and mild CF based on their CFTR mutation. Opacification of the sinonasal system of the subjects was compared with opacification on MRI-scans of an age-matched control group without CF. RESULTS: Most frequently reported symptoms were nasal obstruction and posterior/anterior nasal discharge. Opacification was abundant in every age cohort of the study group and was significantly more compared to the control group. In patients with severe CF the opacification was higher than subjects with mild CF. Upper airway cultures showed predominantly Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. CONCLUSION: CT-abnormalities indicating sinonasal disease and symptoms are present from shortly after birth which may argue for a thorough examination of the upper airways in children with CF.

Pharmacokinetics and Tolerability of Once Daily Double Dose Tobramycin Inhalation in Cystic Fibrosis Using Controlled and Conventional Nebulization.

BACKGROUND: Better treatment outcomes in cystic fibrosis (CF) may be expected by changing standard twice daily (BID) tobramycin inhalation with the conventional nebulizer to once daily (OD) inhalation at double the standard BID dose with a controlled-inhalation nebulizer. We aimed to determine the pharmacokinetics and tolerability of inhaled double-dose tobramycin with the controlled-inhalation AKITA(®) and conventional PARI-LC(®) Plus nebulizer in patients with CF. METHODS: Randomized, open label, crossover study. Pharmacokinetics were assessed in 10 adult CF patients following inhalation of tobramycin (Bramitob(®)) at double the recommended BID dose with the AKITA (300 mg fill dose) and PARI-LC Plus (600 mg fill dose). RESULTS: No significant differences were found in pharmacokinetic parameters between the two nebulizers. Median maximum serum levels were 3.44 (2.25-5.49) and 2.84 (0.82-6.63) mg/L for AKITA and PARI-LC Plus, respectively. Trough serum levels were very low for both nebulizers: 0.03 (0.00-0.09) and 0.02 (0.00-0.06) mg/L for AKITA and PARI-LC Plus, respectively. Time to maximum level was comparable: 0.44 (0.08-0.96) and 0.40 (0.08-0.96) hours for AKITA and PARI-LC Plus, respectively. Serum levels were well below the toxic limit. Inhalations were well tolerated and no serious adverse events occurred. Nebulization time was 33% shorter with the AKITA. CONCLUSIONS: OD tobramycin inhalation of the double standard BID dose with a controlled-inhalation and conventional nebulizer resulted in similar pharmacokinetics in the doses given, with serum levels below the toxic limit. Further research demonstrating clinical efficacy and safety of this treatment approach is required. Dutch trial register number NTR4525.

The influence of breathing mode on tobramycin serum levels using the I-neb AAD system in adults with cystic fibrosis.

BACKGROUND: The clinical effectiveness of inhaled tobramycin depends on the dose reaching the desired regions of the lungs. This study evaluates the influence of breathing mode on tobramycin lung deposition using its pharmacokinetics as surrogate for deposition. METHODS: In a randomized, open-label, crossover study lung deposition in 18 adult CF patients is evaluated following inhalation of tobramycin aerosol using the I-neb nebulizer with TBM (Tidal Breathing Mode) and TIM (Target Inhalation Mode) breathing patterns. Breathing in TIM forced the patient to inhale in a slow and deep manner. Patients were categorized in three subgroups according to their lung function: ≤59%, 60-79% or ≥80% of FEV1 predicted. Blood samples were collected in order to model tobramycin pharmacokinetics. Nebulization time was recorded. RESULTS: Inhalation with TIM resulted in significantly higher maximum serum levels and area under the concentration-time curves (0-24h). Mean bioavailability of TIM relative to TBM was 1.53±0.41. Mean nebulization time was reduced by half with TIM. Subgroup category did not affect the results. CONCLUSIONS: Slow and deep inhalation of aerosolized tobramycin resulted in higher lung deposition and shorter nebulization time compared to tidal breathing, regardless of the disease severity of the CF patient. Dutch trial register number NTR3109.

Ivacaftor and sinonasal pathology in a cystic fibrosis patient with genotype deltaF508/S1215N.

In patients with Cystic Fibrosis and a type III mutation, ivacaftor (Kalydeco(®), Vertex) can increase the opening time of the CFTR channel and improve chloride transport. Research showed significant improvement of lung function and increase in weight following ivacaftor use. However, ivacaftor showed to have adverse events on the sinonasal system as well, such as upper respiratory tract infections, nasal congestion and headaches. This case report showed a positive effect of ivacaftor on the sinonasal pathology in a 17 year old patient with CF. After 5 months of ivacaftor use, the CT-sinus showed complete resolution of the opacification of the paranasal sinuses and a decrease in symptoms of sinonasal disease. This positive effect of ivacaftor on sinonasal pathology seems promising, therefore more research is needed to evaluate the effect of ivacaftor on the upper airways in CF.

Systemic absorption of nasally administered tobramycin and colistin in patients with cystic fibrosis.

OBJECTIVES: In cystic fibrosis (CF) patients the paranasal sinuses can constitute a niche for bacteria, which can migrate to the lungs. Nasal administration of antibiotics may be effective, but safety of this treatment has to be established first. The objective of this study was to investigate the systemic absorption of nasally administered tobramycin, colistin (administered as colistin sulfomethate sodium; CMS) and a combination of both drugs using systemic absorption as surrogate for safety. In addition, tolerability of the nasal irrigations was examined. METHODS: Ten adult CF patients performed three different nasal irrigations: 300 mg of tobramycin; 160 mg of CMS; and 300 mg of tobramycin combined with 160 mg of CMS. Serum concentrations of tobramycin and colistin A and B (the main components of colistin) were analysed. Tolerability was measured using a visual analogue scale. Dutch Trial Register: NTR 4008. RESULTS: Following the tobramycin and the combined irrigation, only two patients had detectable tobramycin serum levels, with the highest being 0.054 mg/L. Serum levels of colistin A and B were not detectable. All three nasal irrigation solutions were well tolerated with a higher tolerability for CMS compared with tobramycin. CONCLUSIONS: Nasal irrigations with tobramycin, CMS and a combination of tobramycin and CMS resulted in safe serum levels and were well tolerated.

Sinonasal manifestations of cystic fibrosis: a correlation between genotype and phenotype?

BACKGROUND: Patients with Cystic Fibrosis are prone to develop sinonasal disease. Studies in genotype-phenotype correlations for sinonasal disease are scarce and inconclusive. METHODS: In this observational study several aspects of sinonasal disease were investigated in 104 adult patients with CF. In each patient a disease specific quality of life questionnaire (RSOM-31), nasal endoscopy and a CT scan of the paranasal sinuses were performed. Patients were divided into two groups, class I-III mutations and class IV-V mutations, based on their CFTR mutations. RESULTS: The prevalence of rhinosinusitis in adult patients with CF was 63% and the prevalence of nasal polyps 25%. Patients with class I-III mutations had significantly smaller frontal sinuses, sphenoid sinuses, more opacification in the sinonasal area and more often osteitis/neoosteogenesis of the maxillary sinus wall compared to patients with class IV and V mutations. CONCLUSION: These data suggest more severe sinonasal disease in patients with class I-III mutations compared to patients with class IV-V mutations.

Importance of bacteriology in upper airways of patients with Cystic Fibrosis.

BACKGROUND: Recently the influence of the upper airways (UAW) on the general health of a patient with Cystic Fibrosis (CF) has been acknowledged. Surprisingly the microbiology of the upper compartment of the airways receives barely any attention in the treatment of CF. The aim of the present study was to investigate the microbiology of the upper airways in adult patients with CF, to correlate these findings with cultures from the lower airways (LAW) and with clinical characteristics. METHODS: In this cross-sectional study bacteriological and clinical data were gathered from 104 adult patients with CF. UAW samples for culture were collected by nasal lavage and middle meatal swabs; LAW cultures were performed on expectorated sputum or cough swabs. Each patient performed the Rhinosinusitis Outcome Measure (RSOM-31). RESULTS: In 72 patients (69.2%) UAW cultures yielded microorganisms other than normal nasal flora and in 50 patients (48.1%) Pseudomonas aeruginosa grew from the UAW cultures. Similarity between UAW and LAW cultures was determined in 50.0% of these 72 patients. In 3 patients P. aeruginosa was cultured from the UAW after successful eradication of P. aeruginosa from the LAW. P. aeruginosa in the UAW did not influence symptoms of sinonasal disease compared to other microorganisms. CONCLUSIONS: Comparison of UAW and LAW cultures in adult patients with CF showed one or more concordant microorganism in 50.0% of the patients. P. aeruginosa was most frequently cultured from the UAW. P. aeruginosa can be cultured from the UAW after eradication therapy which may suggest persistence of P. aeruginosa in the UAW. We feel this is may be a motive to include the UAW in eradication therapy in Cystic Fibrosis.

Clinical impact of a highly prevalent Pseudomonas aeruginosa clone in Dutch cystic fibrosis patients.

Studies suggest that infection with highly prevalent Pseudomonas aeruginosa clones in cystic fibrosis (CF) is associated with an unfavourable clinical outcome. We studied the clinical characteristics of patients infected with a recently described, highly prevalent P. aeruginosa clone (ST406) in two CF centres in The Netherlands. Multilocus sequence typing data were available for 219 patients, of whom 40 (18.3%) were infected with ST406 and 179 with other sequence types. ST406 infection was independently associated with age, having a sibling with ST406 infection and use of inhaled antibiotics, but not with unfavourable clinical outcome, suggesting that high transmissibility is not necessarily associated with high virulence.

Long-term effects of birth order and age at diagnosis in cystic fibrosis: a sibling cohort study.

BACKGROUND: Siblings with cystic fibrosis (CF) share many genetic and environmental factors but may present different phenotypes. Younger sibs are mostly earlier diagnosed with CF than their older sibs, but might be at risk for an earlier colonization with Pseudomonas aeruginosa (PA) than their older counterparts due to cross-infection within families. AIMS: To analyze the effects of birth order and age at diagnosis on lung function, PA colonization, nutritional status, and survival during the first two decades of life in siblings with CF. METHODS: A retrospective cohort study of 52 sibling pairs was performed in two Dutch CF centers. Data were analyzed both cross-sectionally and longitudinally using Kaplan-Meier curves and modified log-rank tests. RESULTS: Median age at diagnosis was significantly higher in the older sib compared with the younger sib (3.0 and 0.2 years, respectively, P < 0.0001). At the age of 5, 10, and 15 years no difference in lung function was found. However, at the age of 20 years, forced expiratory volume in 1 sec (FEV(1)) in older sibs was 19.4% (95% CI: 5.9-32.9%, P = 0.007) lower than in younger sibs. In the younger sibs group, FEV(1) at age 20 years was significantly better in those who had a diagnosis before the age of 6 months (difference 22.9%, 95% CI: 0.1-45.8%, P < 0.05). In the first 10 years of life the younger sibs tended to be earlier colonized with PA than their older counterparts. No differences in nutritional status and survival were observed. CONCLUSION: In this sibling cohort study, an early diagnosis of CF was associated with better lung function after two decades of life. Although younger siblings tended to be colonized with PA at an earlier age, they showed better lung function outcomes. This underscores the importance of early diagnosis with newborn screening and early referral to a specialized center in the prevention of long-term deleterious effects on lung function.