Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung.

Short-chain fatty acids (SCFAs) are metabolites that are produced after microbial fermentation of dietary fiber and impact cell metabolism and anti-inflammatory pathways both locally in the gut and systemically. In preclinical models, administration of SCFAs, such as butyrate, ameliorates a range of inflammatory disease models including allergic airway inflammation, atopic dermatitis, and influenza infection. Here we report the effect of butyrate on a bacteria-induced acute neutrophil-driven immune response in the airways. Butyrate impacted discrete aspects of hematopoiesis in the bone marrow resulting in the accumulation of immature neutrophils. During Pseudomonas aeruginosa infection, butyrate treatment led to the enhanced mobilization of neutrophils to the lungs as a result of increased CXCL2 expression by lung macrophages. Despite this increase in granulocyte numbers and their enhanced phagocytic capacity, neutrophils failed to control early bacterial growth. Butyrate reduced the expression of nicotinamide adenine dinucleotide phosphate, oxidase complex components required for reactive oxygen species production, and reduced secondary granule enzymes, culminating in impaired bactericidal activity. These data reveal that SCFAs tune neutrophil maturation and effector function in the bone marrow under homeostatic conditions, potentially to mitigate against excessive granulocyte-driven immunopathology, but their consequently restricted bactericidal capacity impairs early control of Pseudomonas infection.

Urinary bicarbonate and metabolic alkalosis during exacerbations in cystic fibrosis.

The aetiology of increased serum bicarbonate and metabolic alkalosis in CF is complex and appears to be driven, at least in part, by renal tubular CFTR dysfunction https://bit.ly/3NFPkUu.

Nutritional status and intake in patients with non-cystic fibrosis bronchiectasis (NCFB) - a cross sectional study.

BACKGROUND & AIMS: Bronchiectasis is a heterogeneous, chronic respiratory condition, in which the role of nutrition remains unclear and nutritional guidance is lacking. Few studies have explored the role of nutrition in disease management, and little is known about nutritional requirements during periods of stability or metabolic stress. The aim of this study was to characterise nutritional status and intakes in a cohort of patients and identify potential associations with body composition and functional capacity. METHODS: A prospective observational cohort study was undertaken in an adult population (>17 years). Bronchiectasis was confirmed by high-resolution computerised tomography (HRCT). Anthropometric (weight, height, Body Mass Index (BMI), triceps skinfold thickness (TSF), mid upper-arm circumference (MUAC) and mid arm muscle circumference (MAMC)] lung function and nutritional intakes were measured. Results were analysed as a whole and by disease aetiology [primary ciliary dyskinesia (PCD), Idiopathic cause (IC), bronchiectasis in association with asthma and other] and associations tested. RESULTS: In total, 128 participants (65.5% female) completed the study. Median handgrip strength (HGS) in the total sample was only 66.5% (IQR 60.5-89.8) of reference population norms and was low for those with PCD [58.0% (IQR 43.5-70.0))]. Univariate regression indicated that BMI was a statistically significant predictor of lung function in the whole population with HGS and weight identified as statistically significant predictors of lung function in PCD. The total population and each sub-group failed to meet estimated average requirements for energy but exceeded the Reference nutrient intake (RNI) for protein. Vitamin D was consistently <35% of the RNI. CONCLUSION: BMI lay within normal to overweight ranges within the whole population and sub-groups, but masked important functional, body composition and nutritional deficits. This was particularly so within a younger sub-group with PCD, who had impaired muscle function, when compared to other causal and associative diseases.

Nasal high-flow therapy as an adjunct to exercise in patients with cystic fibrosis: A pilot feasibility trial.

BACKGROUND: Exercise tolerance in people with CF and advanced lung disease is often reduced. While supplemental oxygen can improve oxygenation, it does not affect dyspnoea, fatigue or comfort. Nasal high-flow therapy (NHFT), thanks to its pathophysiological mechanisms, could improve exercise tolerance, saturation and dyspnoea. This study explores the feasibility of conducting a clinical trial of using NHFT in patients with CF during exercise. METHODS: A pilot, open-label, randomized crossover trial was performed, enroling 23 participants with CF and severe lung disease. Participants completed two treadmill walking test (TWT) with and without NHFT at 24-48 h interval. Primary outcome was trial feasibility, and exploratory outcomes were TWT distance (TWTD), SpO2, transcutaneous CO2, dyspnoea and comfort. RESULTS: Recruitment rate was 2.4 subjects/month with 1.3:1 screening-to-randomization ratio. No adverse events caused by NHFT were observed. Tolerability was good and data completion rate was 100%. Twenty subjects (91%) were included in the exploratory study. Mean difference in TWTD on NHFT was 19 m (95% CI [4.8 - 33.1]). SpO2 was similar, but respiratory rate and mean tcCO2 were lower on NHFT (mean difference = -3.9 breaths/min 95% CI [-5.9 - -1.9] and -0.22 kPa 95% CI [-0.4 - 0.04]). NHFT reduced exercise-induced dyspnoea and discomfort. CONCLUSION: Trials using NHFT in patients with CF during exercise are feasible. NHFT appears to improve walking distance, control respiratory rate, CO2, dyspnoea and improve comfort. A larger trial with a longer intervention is feasible and warranted to confirm the impact of NHFT in training programmes for patients with CF.

Noninvasive Ventilation in Cystic Fibrosis: Clinical Indications and Outcomes in a Large UK Adult Cystic Fibrosis Center.

BACKGROUND: Noninvasive ventilation (NIV) is routinely used to treat patients with cystic fibrosis and respiratory failure. However, evidence on its use is limited, with no data on its role in disease progression and outcomes. The aim of this study was to assess the indications of NIV use and to describe the outcomes associated with NIV in adults with cystic fibrosis in a large adult tertiary center. METHODS: A retrospective analysis of data captured prospectively on the unit electronic patient records was performed. All patients with cystic fibrosis who received NIV over a 10-y period were included in the study. A priori, 2 groups were identified based on length of follow-up, with 2 subgroups identified based on duration of NIV treatment. RESULTS: NIV was initiated on 64 occasions. The duration of follow-up was categorized as > 6 months or < 6 months in 31 (48.4%) and 33 (51.6%) occasions, respectively. The most common indications for starting NIV were chronic (48.5%) and acute (32.8%) hypercapnic respiratory failure. Among those with a follow-up > 6 months, subjects who stopped using NIV early showed a steady median (interquartile range) decline in FEV1 (pre-NIV: -0.04 [-0.35 to 0.03] L/y vs post-NIV: -0.07 [-0.35 to 0.01] L/y, P = .51), while among those who continued using it had an improvement in the rate of decline (pre-NIV: -0.25 [-0.52 to -0.02] L/y vs post-NIV: -0.07 [-0.13 to 0.16] L/y, P = .006). No differences in intravenous antibiotic requirement or pulmonary exacerbations were noted with the use of NIV. Pneumothorax and massive hemoptysis occurred independently in 4 cases. CONCLUSIONS: NIV is being used in cystic fibrosis as adjunct therapy for the management of advanced lung disease in a similar fashion to other chronic respiratory conditions. Adherence to NIV treatment can stabilize lung function but does not reduce pulmonary exacerbations or intravenous antibiotic requirement.

Assessing arthritis in the context of cystic fibrosis.

Inflammatory arthritis in the context of cystic fibrosis (CF) can represent a diagnostic and therapeutic challenge. Poor recognition and under-treatment of musculoskeletal conditions increases symptom burden, affects quality of life, and may lead to changes to an individual's ability to carry out activities of daily living and to exercise. A careful assessment and multidisciplinary approach is essential when considering a diagnosis of CF-associated arthritis (CFA), both in terms of identifying other treatable conditions, such as rheumatoid arthritis, and effectively addressing symptoms. In this collaboration between CF specialists and Rheumatologists, we consider joint symptoms in patients with CF, with a focus on CFA. We offer a differential diagnosis list and consider steps to assess and manage CF patients presenting with arthralgia including appropriate up-to-date rheumatological assessment.

A treatment evaluator tool to monitor the real-world effectiveness of inhaled aztreonam lysine in cystic fibrosis.

BACKGROUND: Studies are required that evaluate real-world outcomes of inhaled aztreonam lysine in patients with cystic fibrosis (CF). METHODS: Our treatment-evaluator tool assessed the effectiveness of inhaled aztreonam in routine practice in 117 CF patients across four time periods (6-12 (P2) and 0-6months (P1) pre-initiation, and 0-6 (T1) and 6-12months (T2) post-initiation). Outcomes were: changes in %-predicted forced expiratory volume in 1s (FEV1), body-mass index (BMI), hospitalisation days and intravenous antibiotic usage. RESULTS: Median FEV1% predicted for each 6-month period was 38.9%, 34.6%, 37.1% and 36.5%; median change was -2.0% between P2 and P1, increasing to +0.6% (p<0.001) between P1 and T1. Annualised hospital bed-days was reduced (p=0.05) post-initiation, as was intravenous antibiotics days (p=0.001). BMI increased over 6months post-initiation (p≤0.001). CONCLUSIONS: In patients with CF in routine practice, inhaled aztreonam lysine is associated with improved lung function and weight, and reduced hospitalisation and intravenous antibiotic use.

Defining routes of airborne transmission of Pseudomonas aeruginosa in people with cystic fibrosis.

Pseudomonas aeruginosa is a common and important pathogen in people with cystic fibrosis (CF). With the advent of modern genotyping, a number of clonal strains of P. aeruginosa have been identified, some of which are associated with increased morbidity. The route of cross-infection between people with CF is not clear, but there is evidence that an airborne route may be important. Laboratory studies have shown that P. aeruginosa can survive within droplet nuclei and can potentially remain suspended within aerosols for prolonged periods. Depending upon the air flows, this may result in the bacteria travelling significant distances. A number of clinical studies have demonstrated that people with CF can produce aerosols containing P. aeruginosa and Burkholderia cepacia complex. Infection control guidelines need to consider the possibility of droplet, including small-droplet nuclei, transmission of P. aeruginosa and other pathogens between people with CF. Further studies are needed to more accurately quantify the risk of cross-infection between people with CF and to evaluate interventions to minimize the risk.

A laminar flow model of aerosol survival of epidemic and non-epidemic strains of Pseudomonas aeruginosa isolated from people with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is an inherited multi-system disorder characterised by chronic airway infection with pathogens such as Pseudomonas aeruginosa. Acquisition of P. aeruginosa by patients with CF is usually from the environment, but recent studies have demonstrated patient to patient transmission of certain epidemic strains, possibly via an airborne route. This study was designed to examine the survival of P. aeruginosa within artificially generated aerosols. RESULTS: Survival was effected by the solution used for aerosol generation. Within the aerosols it was adversely affected by an increase in air temperature. Both epidemic and non-epidemic strains of P. aeruginosa were able to survive within the aerosols, but strains expressing a mucoid phenotype had a survival advantage. CONCLUSION: This would suggest that segregating individuals free of P. aeruginosa from those with chronic P. aeruginosa infection who are more likely to be infected with mucoid strains may help reduce the risk of cross-infection. Environmental factors also appear to influence bacterial survival. Warming and drying the air within clinical areas and avoidance of humidification devices may also be beneficial in reducing the risk of cross-infection.

Concurrent pulmonary zygomycosis and Mycobacterium tuberculosis infection: a case report.

A non-smoking 77-year old gentleman of Indian origin was admitted with a 4-month history of intermittent night sweats, haemoptysis and 6 kg of weight loss. CT scan of thorax demonstrated a 2.5 cm mass in the right middle lobe with multiple small nodules within the right lung and confirmed the presence of mediastinal and hilar lymph nodes.Fibreoptic bronchoscopy demonstrated a distorted right main bronchus, anterior shift of the right upper lobe and occlusion of the right middle lobe bronchus with a black necrotic ulcer. Mycobacterium tuberculosis was found in the bronchoalveolar lavage and histology demonstrated numerous fungal hyphae with a morphological appearance of zygomycetes within necrotic areas of tissue. Medical management with anti-fungal and anti-mycobacterial treatment was instigated as the patient's pre-existing IHD did not permit surgical intervention. Subsequently CT imaging following completion of therapy demonstrated improvement of the mass and a resolution of the associated nodules. The patient has been followed for 6 months to date and there has been no recurrence of symptoms. Recent bronchoalveolar lavage cultures have been negative for M. tuberculosis and zygomycetes.

Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis--caution with trough concentrations.

BACKGROUND: : Once daily intravenous aminoglycoside dosing (ODD) is widely used to treat acute Pseudomonas aeruginosa exacerbations in patients with cystic fibrosis. Controversy exists as to what is the most appropriate method of therapeutic drug monitoring (TDM) of such therapy with recommendations including trough plasma concentrations of <1 mg/L or <2 mg/L, area under curve (AUC) and various nomograms. This study aimed to compare the exposures to ODD of tobramycin in adults and children with cystic fibrosis using the AUC and trough TDM approaches. METHODS: : Using a mono-exponential software program to calculate AUC from 2 plasma concentrations, AUCs were determined in 22 adults with pre-dose tobramycin concentrations <1 mg/L. The exposure of 5 children with reduced tobramycin clearances was simulated at the usual recommended dose of 10 mg/kg/daily but retaining a trough <1 mg/L. RESULTS: : A tobramycin dose of 10 mg/kg of tobramycin in these patients with normal serum creatinine and a trough concentration <1 mg/L resulted in exposures in excess of those associated with conventional 8-hourly dosing. CONCLUSIONS: : The TDM approach of a trough <1 mg/L, as used with conventional 8-hourly tobramycin dosing, is not relevant to ODD.

Optimizing treatment policies and improving care: impact on outcome in patients with cystic fibrosis.

There is no cure for cystic fibrosis but recent advances in care have increased the average life expectancy to over 30 years. However, patients may find themselves prescribed over seven to eight different medications a day, some of which are laborious and time consuming to administer. The physician should balance potential benefits from treatments against quality-of-life requirements. In this review, the authors examine the place in the overall treatment regimen of recently available, and often expensive, drugs. The review concentrates on eradication regimens for early or recurrent Pseudomonas aeruginosa infection; inhaled tobramycin therapy; regular versus on-demand intravenous antibiotics; treatment of respiratory methicillin-resistant Staphylococcus aureus infection; the role of macrolide antibiotics and the role of inhaled dornase alfa in early treatment.

Pharmacokinetics and safety of itraconazole in patients with cystic fibrosis.

OBJECTIVE: To assess the pharmacokinetics of itraconazole and hydroxy-itraconazole in patients with cystic fibrosis. METHODS: Patients were divided into those <16 and >/=16 years of age. All received itraconazole oral solution 2.5 mg/kg twice daily for 14 days. Serial blood samples were taken for itraconazole and hydroxy-itraconazole plasma level measurements. Safety was assessed from biochemistry and haematology data and reported adverse events. RESULTS: Seventeen patients entered the study. Steady-state concentrations were achieved after maximally 8 days of dosing. On day 14 average peak plasma concentrations were 404 +/- 268 ng/mL (<16 years, n = 5) and 779 +/- 470 ng/mL (>/=16 years, n = 11 excluding one patient concurrently receiving oral clarithromycin). A high inter-subject variability in itraconazole pharmacokinetics was seen. Intra-subject variability was low. All the younger patients and 50% of the older patients failed to achieve a plasma steady-state trough concentration of >250 ng/mL. Adverse events were reported by 53% of subjects. Most were mild or moderate in intensity and not considered related to treatment. One patient withdrew from the study because of two severe adverse events. Ten significant laboratory abnormalities were reported in seven of 16 patients with paired data. Six of these were clinically relevant. CONCLUSION: 2.5 mg/kg itraconazole oral solution twice daily in patients with cystic fibrosis achieves steady-state concentrations in maximally 8 days. The pharmacokinetics showed marked inter-subject variability. Plasma concentrations of >250 ng/mL were not reached in the paediatric cohort or in 50% of the adult cohort. The dosage regimen was safe and well tolerated.

Serum and sputum concentrations following the oral administration of linezolid in adult patients with cystic fibrosis.

OBJECTIVES: Linezolid is a new oxazolidinone antibiotic with efficacy against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the serum and sputum linezolid concentrations in adults with cystic fibrosis (CF) following oral drug administration. METHODS: Eleven adult patients with CF were recruited. Subjects received 600 mg of linezolid orally every 12 h for a total of six doses. Serum and sputum levels were measured just before and at 2 h after the final dose of linezolid. A further serum level was measured at 4 h. RESULTS: Ten adult patients completed the study. Mean (s.d.) serum linezolid concentrations were 2.3 mg/L (1.5) at 12 h following the fifth dose. At 2 and 4 h following the sixth dose, concentrations were 13.5 (4.3) and 8.1 (3.3). Mean (s.d.) linezolid sputum concentrations were 3.6 (2.1) and 17.4 (7.2) mg/L at 0 and 2 h following drug administration. CONCLUSIONS: The oral administration of linezolid results in good sputum penetration in patients with CF. Mean levels exceed the required MIC for the treatment of MRSA for >80% of the dosing period for serum and the majority of the dosing period for sputum.

Cystic fibrosis presenting as acute pancreatitis and obstructive azoospermia in a young adult male with a novel mutation in the CFTR gene.

Cystic fibrosis is rare in the Asian population, and is often associated with consanguinity and rare genotypes. We report on a 23-year-old Asian man from a consanguineous pedigree referred to the regional cystic fibrosis unit after a diagnosis of congenital bilateral absence of the vas deferens during investigations for infertility. A detailed history revealed several previous episodes of acute pancreatitis. Full diagnostic appraisal showed homozygosity for a novel cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, but normal sweat test and nasal potential difference studies. An endoscopic retrograde cholangiopancreatogram (ERCP) showed chronic pancreatitis with bulky side branches. The vas deferens and the pancreas appeared exquisitely sensitive to mild CFTR dysfunction. Patients with cystic fibrosis and unexplained upper abdominal pain should be screened for pancreatitis, and consideration should be given to screening patients with idiopathic pancreatitis for mutations in the CFTR gene.

Alcaligenes infection in cystic fibrosis.

The aim of this study was to investigate the effect of chronic Alcaligenes species infection of the respiratory tract on the clinical status of patients with cystic fibrosis. We conducted a retrospective case-controlled study. The microbiological records of all patients attending the Leeds Regional Pediatric and Adult Cystic Fibrosis Units from 1992-1999 were examined. Chronic Alcaligenes infection was defined as a positive sputum culture on at least three occasions over a 6-month period. These patients were compared with controls matched for age, gender, respiratory function, and Pseudomonas aeruginosa infection status. Respiratory function tests, anthropometric data, Shwachman-Kulczycki score, Northern chest x-ray score, intravenous and nebulized antibiotic treatment, and corticosteroid treatment were compared from 2 years before to 2 years after Alcaligenes infection. From a clinic population of 557, 13 (2.3%) fulfilled the criteria for chronic infection. The median age at acquisition of infection was 17.2 years (range, 6.5-33.6). There was no significant difference in the changes of percentage predicted values for FEV(1), FVC, FEF(25-75), or Shwachman-Kulczycki and Northern chest x-ray scores, or in weight, height, and body mass index z-scores between Alcaligenes-infected cases and controls. There was also no significant difference in the use of antibiotics (intravenous and nebulized) or corticosteroids (inhaled and oral). We conclude that in our clinic, chronic infection with Alcaligenes species was uncommon. Chronically infected patients showed no excess deterioration in clinical or pulmonary function status from 2 years before to 2 years after primary acquisition.