Early glucose abnormalities are associated with pulmonary inflammation in young children with cystic fibrosis

BackgroundChildren with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation.MethodsWe assessed 18 children (5 females) with median age of 3.2 years (range 0·9–5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level.ResultsPeak sensor glucose (SG) was >11.1 mmol/L in 39% of participants. The percentage neutrophil count on BAL was positively correlated with elevated SG (peak SG r_s = 0.48, p = .044) and with glucose variability (SG standard deviation r = 0.62, β = 38.5, p = .006). BAL IL-8 level was significantly correlated with all measures of CGM hyperglycemia including % time > 7.8 mmol/L (p = .008) and standard deviation (p < .001). Participants with a history of Pseudomonas aeruginosa had a higher % time > 7.8 mmol/L glucose (16% versus 3%, p = .015).ConclusionChildren with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.     

Club cell secretory protein and lung function in children with cystic fibrosis

BackgroundClub cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF).MethodsWe used longitudinal data from CF children (EPIC Study) with no positive cultures for Pseudomonas aeruginosa prior to enrollment. Circulating levels of CC16 and an inflammatory score (generated from CRP, SAA, calprotectin, G-CSF) were compared between participants with the lowest and highest FEV₁ levels in adolescence (LLF and HLF groups, respectively; N = 130-per-group). Single nucleotide variants (SNVs) in the SCGB1A1, EHF-APIP loci were tested for association with circulating CC16 and with decline of FEV₁ and FEV₁/FVC% predicted levels between ages 7–16 using mixed models.ResultsCompared with the HLF group, the LLF group had lower levels of CC16 (geometric means: 8.2 vs 6.5 ng/ml, respectively; p = 0.0002) and higher levels of the normalized inflammatory score (-0.21 vs 0.21, p = 0.0007). Participants in the lowest CC16 and highest inflammation tertile had the highest odds for having LLF (p<0.0001 for comparison with participants in the highest CC16 and lowest inflammation tertile). Among seven SNVs associated with circulating CC16, the top SNV rs3741240 was associated with decline of FEV₁/FVC and, marginally, FEV₁ (p = 0.003 and 0.025, respectively; N = 611 participants, 20,801 lung function observations).ConclusionsSerum CC16 deficits are strongly associated with severity of CF lung disease and their effects are additive with systemic inflammation. The rs3741240 A allele is associated with low circulating CC16 and, possibly, accelerated lung function decline in CF.     

Very high-dose ergocalciferol is effective for correcting vitamin D deficiency in children and young adults with cystic fibrosis

Approximately 10–80% of patients with Cystic Fibrosis (CF) have vitamin D deficiency. Obtaining therapeutic vitamin D levels has been a challenge for CF care providers using current recommended high-dose oral ergocalciferol (400,000 IU over 2 months). The objective of this study was to evaluate the safety and efficacy of a 2-week, very high dose ergocalciferol (700,000 IU over 14 days) repletion strategy in children and young adults with CF.As part of a quality improvement initiative, a prospective cohort study was performed from January through May 2007. Phase I included identifying individuals with CF who were subtherapeutic in 25-OH D. In phase II, 50,000 IU of ergocalciferol was prescribed for a 14 day term and administered daily. During phase III, a post treatment 25-OH D level was obtained to determine improvement. Baseline demographics and clinical characteristics were obtained at study entry. Stratification of the post 25-OHD levels was defined.Eighteen individuals with CF participated in the study. The mean age was 17 ± 5 years (range 6–25 years). One hundred percent were pancreatic insufficient and required pancreatic enzyme replacement. All 18 had 25-OHD levels less than 30 ng/mL pre-treatment.Seventeen of the 18 (94%) participants became therapeutic in the 2-week interval. No patients had values considered high abnormal (100–150 ng/mL) or toxic (> 150 ng/mL). Mean change was noted at an increase of 37.3 ± 22 ng/mL in the 2-week period (p < 0.001). Pre and peripubertal individuals had a significantly greater increase in 25-OH D levels.The results of this study demonstrate that very high dosing of vitamin D using oral ergocalciferol over a 14 day period is an effective strategy in achieving therapeutic levels of 25-OH vitamin D in children and young adults with CF. We believe this regimen deserves further study.     

Gas exchange in stable patients with moderate-to-severe lung disease from cystic fibrosis

BACKGROUND: Studies using the multiple inert gas elimination technique (MIGET) to characterise the mechanisms of impaired gas exchange in CF, provide conflicting results on the importance of ventilation-perfusion (VA/Q) inequality over shunt. We hypothesise that the mechanisms of gas exchange abnormality have changed with changing CF management over the last two decades. METHODS: Detailed gas exchange was evaluated by MIGET with venous sampling in stable patients, age > 20 years, FEV1% predicted < or = 50. RESULTS: Fifteen (14 male) subjects were studied with a mean +/- SD age 28.1 +/- 8.4 years, FEV1% 32.6 +/- 10.3, TLC% 111.5 +/- 12.9, PaO2 9.3 +/- 1.3 kPa, (69.5 +/- 9.6 mm Hg), and PaCO2 6.2 +/- 0.7 kPa, (45.9 +/- 5.3 mm Hg). The predominant gas exchange abnormality was VA/Q inequality with a log SD of the distributions of perfusion 0.91 +/- 0.30 and of ventilation 0.60 +/- 0.14. Unimodal distributions were seen in nine subjects, a low VA/Q mode in five and one subject had a bimodal distribution, mean intrapulmonary shunt was negligible. CONCLUSIONS: Subjects had a lower FEV1% by comparison with previously published studies and demonstrated severe VA/Q inequality and negligible shunt. This suggests a low degree of complete obstruction of airways in adults with CF and severe stable pulmonary disease. The primary mechanism of hypoxaemia in CF subjects reaching adulthood today appears to have changed with modern management over the last two decades.     

Mucoid Pseudomonas aeruginosa and regional inflammation in the cystic fibrosis lung

BackgroundPseudomonas aeruginosa is the prominent bacterial pathogen in the cystic fibrosis (CF) lung and contributes to significant morbidity and mortality. Though P. aeruginosa strains initially colonizing the CF lung have a nonmucoid colony morphology, they often mutate into mucoid variants that are associated with clinical deterioration. Both nonmucoid and mucoid P. aeruginosa variants are often co-isolated on microbiological cultures of sputum collected from CF patients. With regional variation in bronchiectasis, tissue damage, inflammation, and microbial colonization, lobar distribution of nonmucoid and mucoid P. aeruginosa variants may impact local microenvironments in the CF lung, but this has not been well-studied.MethodsWe prospectively collected lobe-specific bronchoalveolar lavage (BAL) fluid from a CF patient cohort (n = 14) using a standardized bronchoscopic protocol where collection was performed in 6 lobar regions. The lobar BAL specimens were plated on P. aeruginosa-selective media and proinflammatory cytokines (IL-1, TNF, IL-6 and IL-8) were measured via cytokine array. Correlations between infecting P. aeruginosa variants (nonmucoid, mucoid, or mixed-variant populations), the lobar regions in which these variants were found, and regional proinflammatory cytokine concentrations were measured.ResultsP. aeruginosa mucoid and nonmucoid variants were homogenously distributed throughout the CF lung. However, infection with mucoid variants (found within single- or mixed-variant populations) was associated with significantly greater regional inflammation. The upper and lower lobes of the CF lung did not exhibit differences in inflammatory cytokine concentrations.ConclusionsMucoid P. aeruginosa infection is a microbial determinant of regional inflammation within the CF lung.     

Variability of lung clearance index in clinically stable cystic fibrosis lung disease in school age children

Background

Data on long term variability of Lung Clearance Index (LCI) in Cystic Fibrosis (CF) is urgently needed to guide test result interpretation. Our aim was to evaluate LCI variability in clinically stable CF lung disease in school age children.

Cellular proteolysis and systemic inflammation during exacerbation in cystic fibrosis

BACKGROUND: Weight loss indicates a poor prognosis in cystic fibrosis (CF). We hypothesised that fat-free mass (FFM) depletion and increased systemic inflammation would be associated with increased cellular proteolysis during an exacerbation of the respiratory symptoms. Patients were studied prospectively from the beginning of treatment with antibiotics when admitted to the Adults CF Centre. METHODS: Twenty six patients with CF were studied at the start and end of antibiotic treatment and 2 weeks later. Mean (95% CI) FEV1 when clinically stable was 54.1 (44.5, 62.6)% predicted. Urinary excretion of Pseudouridine (5-ribosyluracil, PSU) was determined as an indicator of cellular protein breakdown. Body composition was assessed by dual energy X-ray absorptiometry (DXA). RESULTS: Patients had increased concentrations of PSU at all assessments (p<0.01). Those with a low FFM had greater PSU (ratio to FFMI) than those with a normal FFM at all assessments. At the start of treatment, PSU was related to FFM, C-reactive protein (CRP) (p<0.05) and tumour necrosis factor (TNF)alpha soluble receptors (sr) I and II (p<0.01). Circulating inflammatory mediators were greater in patients than in healthy subjects at all assessments. CONCLUSION: Increased protein breakdown is associated with a low FFM and increased systemic inflammation and it may be a contributory mechanism of poor weight preservation in CF.     

Introducing the need for lung transplantation in children with cystic fibrosis: Parental experiences

Lung transplantation (LTx) is the only treatment available for adult and pediatric end-stage lung disease secondary to cystic fibrosis (CF). The timing of introducing LTx has significant medical and psychological implications for the child and the family. This study explored the views and recommendations of parents of children with CF, who had been asked to consider LTx and referred to a national transplant centre. Parents participated in a telephone-based, semi-structured interview. Responses were analysed using Content Analysis. Parental recommendations and the emergent protocol are discussed, together with implications for clinical practice.     

Real-life acute lung function changes after lumacaftor/ivacaftor first administration in pediatric patients with cystic fibrosis

The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of ? 4.1% predicted forced expiratory volume in 1 s (FEV₁) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV₁ changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV₁ consistently decreased (? 10.4 ± 4.6%, range: ? 1.5; ? 21.8%). FEV₁ only partially resumed after salbutamol inhalation. Patients with previously known significant reversible airway obstruction and low FEV₁ were more at risk of FEV₁ decrease.     

Regional differences in infection and structural lung disease in infants and young children with cystic fibrosis

BackgroundBoth infection and inflammation are critical to the progression of cystic fibrosis (CF) lung disease. Potential anatomical differences in lower airway infection, inflammation and bronchiectasis in young children with CF raise questions regarding the pathogenesis of early structural lung disease.MethodsA longitudinal multi-centre birth cohort study of infants newly diagnosed with CF was conducted. Paired bronchoalveolar lavage (BAL) samples were obtained from the right middle lobe (RML) and lingula bronchi. Chest computed tomography (CT) was performed biennially and analysed using the modified CF-CT scoring system.ResultsOne hundred and twenty-four children (0.11 - 7.0 years) contributed 527 BAL samples and underwent 388 CT chest scans. Pro-inflammatory microbes were detected in 279 BAL samples (53%), either in both lingula and RML samples (69%), in the lingula alone (24%), or in the RML alone in only 7% of samples. Overall, the prevalence of structural lung disease was greater in the setting of pro-inflammatory microbes. Although infection was less commonly isolated in the right lung, bronchiectasis was more commonly detected in the right lung compared with the left. No anatomical differences in the presence of air trapping were detected.ConclusionOverall, the detection of pro-inflammatory microbes in the lower airways was associated with increased risk of both air trapping and bronchiectasis. However, the apparent discordance between commonest sites of isolation of pro-inflammatory microbes and the anatomical site of early bronchiectasis warrants further exploration.     

Pulmonary exacerbations and acute declines in lung function in patients with cystic fibrosis

Background

Patients with cystic fibrosis (CF) who experience acute declines in percent predicted FEV₁ (ppFEV₁ decreased ≥10% relative to baseline) are often not treated with antibiotics for pulmonary exacerbations (PEx), whereas other patients are treated even when they have not experienced a decline in lung function.

Year to year change in FEV1 in patients with cystic fibrosis and different mutation classes

In patients with cystic fibrosis, most treatments addressing the underlying basic defect are mutation or mutation class specific. These treatments are disease modifying if they lower the year to year change in lung function. We therefore calculated the current loss of lung function, measured by year to year change in forced expired volume in 1 s in 11,417 patients included in the European Cystic Fibrosis Society Patient Registry. Whereas patients with at least one mutation of class IV or V have on average a lower year to year change, we did not find a difference between patients with a stop codon mutation, homozygous for F508del or at least one class III mutation. These data are useful background information to discuss the impact of different disease modifying treatments.     

Peak OGTT glucose is associated with lower lung function in young children with cystic fibrosis

BackgroundScreening for Cystic Fibrosis-related diabetes is recommended in patients with CF <10 years old when there are concerns about growth and lung function. The Oral Glucose Tolerance Test (OGTT) is recommended but has not been validated in this cohort. We sought to determine whether the 2-h OGTT, the gold standard diagnostic test for CFRD, detects clinical decline in children with CF <10 years old.MethodsWe analysed blood glucose(BG) levels collected every 30 min during OGTT in 27 children with CF < 10 years old, comparing the 2-hour BG (BG_120min), peak BG (BG_max) and Area Under the Curve(AUC) for glucose and the association with lung function and nutritional status. We also compared the OGTT results with results from Continuous Glucose Monitoring (CGM) performed in 11 participants.ResultsThe BG_max was higher than the BG_120min in 25/27 (93%) participants. There was a significant inverse correlation between BG_max and weight z-score (r_s = −0.56, p = .002) and between BG_max and FEV₁ (r_s = −0.54, p = .014) that was not present for BG_120min. A significant inverse correlation was also identified between fasting insulin level and elevated glucose on CGM, defined as AUC >7.8 mmol/L (r_{s =} − 0.69, p = .027) or as % time > 7.8 (r_s = − 0.76, p = .011).ConclusionsChildren with CF < 10 years of age with higher BG_max on OGTT have lower lung function and weight z- scores that may not be identified using the 2 h OGTT BG_120min. CGM also identifies glucose excursions in young children with CF.     

Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial

Introduction

Inhaled mannitol has beneficial effects on lung function, mucociliary clearance, quality of life and sputum properties. This trial examined the efficacy of inhaled mannitol in children with cystic fibrosis (CF).

Immediate effects of lumacaftor/ivacaftor administration on lung function in patients with severe cystic fibrosis lung disease

Safety-data for lumacaftor/ivacaftor (LUM/IVA) combination therapy in patients with severe lung disease (percent predicted forced expiratory volume in 1 s [ppFEV₁] < 40) remain limited. We report immediate post-dose respiratory-related adverse events in 12 patients with severe cystic fibrosis (CF) lung disease (median [IQR] ppFEV₁: 34 [31–36]) prescribed LUM/IVA. All patients experienced a decline in ppFEV₁ from baseline at 2-hours (median [IQR] relative change: ? 19 [? 21 to ? 11]%, p < 0.001) that persisted at 24-hours but recovered in most patients at 1-month. No pre- and post-differences in bronchodilator response were observed. Ten (83.3%) patients reported non-severe respiratory-related adverse events within 24-hours of LUM/IVA initiation. At 1-month, eight (67%) patients had persistent symptoms and six (50%) were treated for a pulmonary exacerbation. Our results highlight that LUM/IVA respiratory-related adverse events are common in patients with a ppFEV₁ < 40. We recommend close assessment of adverse events. Further studies are required to evaluate the efficacy of LUM/IVA in patients with severe lung disease.     

Multicentre standardisation of chest MRI as radiation-free outcome measure of lung disease in young children with cystic fibrosis

Background

A recent single-centre study demonstrated that MRI is sensitive to detect early abnormalities in the lung and response to therapy in infants and preschool children with cystic fibrosis (CF) supporting MRI as an outcome measure of early CF lung disease. However, the feasibility of multicentre standardisation remains unknown.

Elevated gamma-glutamyltransferase is associated with mortality in lung transplantation for cystic fibrosis

Cystic fibrosis (CF) is a life-threatening autosomal recessive hereditary disease, affecting multiple organs. In end stage disease, lung transplantation improves the quality of life and prolongs survival. CF liver disease (CFLD) as co-morbidity develops in 8-17% of CF patients. We aimed to investigate the impact of liver injury on prognosis following lung transplantation. Thirty-one patients with CF who underwent double lung transplantation (DLTx) from 1999 to 2009 were included. Post-transplant survival, liver serum parameters as well as INR, creatinine and the MELD-Score were determined preoperatively, 1 day and 4 weeks postoperatively. Prognostic impact of liver function on outcome was analysed. Mean patient age was 25 (15-38) and post-transplant 1 year-survival was 74%, 3 years 71% and 5 years 68%. Patients were grouped according to post-transplant survival, those deceased within the first year as group I (n = 8) and patients who survived longer as group II (n = 23). Group I exhibited significantly elevated gamma-glutamyltransferase (GGT), bilirubin and reduced platelets postoperatively. Low platelet count, increased bilirubin and GGT were associated with mortality after DLTx. Prospective studies are needed to determine a potential use and clinical implications for liver function tests in patients with CF before lung transplantation.     

Impact of the A (H1N1) pandemic influenza (season 2009–2010) on patients with cystic fibrosis

Background

Influenza, like other respiratory viral infections, can cause acute deterioration of lung function in patients with cystic fibrosis (CF). Previous studies on a small number of patients reported that most people with CF infected with A (H1N1) influenza experienced a mild course of disease.

Aim

To characterise the impact of A (H1N1) infection on CF in a large number of patients from different centres and countries.

Methods

CF centres accessing the web-site of the European Cystic Fibrosis Society (ECFS) were asked to report clinical data on patients with an ascertained diagnosis of influenza caused by the A (H1N1) virus. The study was web-based and data were collected through an electronic data sheet on the ECFS website.

Results

Twenty-five centres from 10 countries caring for 4698 patients with CF reported data on 110 patients (2.3%), median age 13 years (range 1–39 years). The prevalence of infection in each centre ranged from 0% to 9.4%. Only 8.8% of the patients had been vaccinated. The main symptoms were fever and respiratory exacerbation requiring IV antibiotics in 53% of the patients; 48% of the patients were hospitalised for an average of 12.9 days (range 2–56) and 31% required oxygen treatment during the time of the infection. Most of the patients recovered and FEV₁ 1 month after the infection was similar to that before the infection. However, 6 patients were admitted to ICU, 5 with mechanical ventilation. Three patients with severe respiratory disease died.

Conclusions

A (H1N1) influenza infection caused transient but significant morbidity in most of the patients with CF. However, in a small number of patients with severe lung disease, A (H1N1) influenza was associated with respiratory deterioration, mechanical ventilation and even death.