Pneumothorax in cystic fibrosis: beyond the guidelines.

Pneumothorax is a serious but common complication in patients with cystic fibrosis (CF). It has adverse prognostic implications as well as associations with subsequent reduction in lung function and significant risk of recurrence. Management dilemmas frequently occur that are beyond current guidelines. We review the evidence and highlight management difficulties in pneumothoraces in CF.

Rapid Detection of Emerging Pathogens and Loss of Microbial Diversity Associated with Severe Lung Disease in Cystic Fibrosis.

Respiratory infection in cystic fibrosis (CF) is polymicrobial, but standard sputum microbiology does not account for the lung microbiome or detect changes in microbial diversity associated with disease. As a clinically applicable CF microbiome surveillance scheme, total sputum nucleic acids isolated by a standard high-throughput robotic method for accredited viral diagnosis were profiled for bacterial diversity using ribosomal intergenic spacer analysis (RISA) PCR. Conventional culture and RISA were performed on 200 paired sputum samples from 93 CF adults; pyrosequencing of the 16S rRNA gene was applied to 59 patients to systematically determine bacterial diversity. Compared to the microbiology data, RISA profiles clustered into two groups: the emerging nonfermenting Gram-negative organisms (eNFGN) and Pseudomonas groups. Patients who were culture positive for Burkholderia, Achromobacter, Stenotrophomonas, and Ralstonia clustered within the eNFGN group. Pseudomonas group RISA profiles were associated with Pseudomonas aeruginosa culture-positive patients. Sequence analysis confirmed the abundance of eNFGN genera and Pseudomonas within these respective groups. Low bacterial diversity was associated with severe lung disease (P < 0.001) and the presence of Burkholderia (P < 0.001). An absence of Streptococcus (P < 0.05) occurred in individuals with lung function in the lowest quartile. In summary, nucleic acids isolated from CF sputum can serve as a single template for both molecular virology and bacteriology, with a RISA PCR rapidly detecting the presence of dominant eNFGN pathogens or P. aeruginosa missed by culture (11% of cases). We provide guidance for how this straightforward CF microbiota profiling scheme may be adopted by clinical laboratories.

Exhaled breath hydrogen cyanide as a marker of early Pseudomonas aeruginosa infection in children with cystic fibrosis.

Hydrogen cyanide is readily detected in the headspace above Pseudomonas aeruginosa cultures and in the breath of cystic fibrosis (CF) patients with chronic (P. aeruginosa) infection. We investigated if exhaled breath HCN is an early marker of P. aeruginosa infection. 233 children with CF who were free from P. aeruginosa infection were followed for 2 years. Their median (interquartile range) age was 8.0 (5.0-12.2) years. At each study visit, an exhaled breath sample was collected for hydrogen cyanide analysis. In total, 2055 breath samples were analysed. At the end of the study, the hydrogen cyanide concentrations were compared to the results of routine microbiology surveillance. P. aeruginosa was isolated from 71 children during the study with an incidence (95% CI) of 0.19 (0.15-0.23) cases per patient-year. Using a random-effects logistic model, the estimated odds ratio (95% CI) was 3.1 (2.6-3.6), which showed that for a 1- ppbv increase in exhaled breath hydrogen cyanide, we expected a 212% increase in the odds of P. aeruginosa infection. The sensitivity and specificity were estimated at 33% and 99%, respectively. Exhaled breath hydrogen cyanide is a specific biomarker of new P. aeruginosa infection in children with CF. Its low sensitivity means that at present, hydrogen cyanide cannot be used as a screening test for this infection.

Incidence and clinical impact of respiratory viruses in adults with cystic fibrosis.

BACKGROUND: Viral respiratory infection (VRI) is a common cause of pulmonary exacerbations in children with cystic fibrosis (CF). The importance of VRI in adult CF populations is unclear. OBJECTIVE: To determine the incidence and clinical impact of VRI among adults with CF. METHODS: One hundred adults with CF were followed up prospectively for 12 months. Sputum, nose swabs and throat swabs were collected every 2 months and at onset of pulmonary exacerbation. PCR assays for adenovirus, influenza A&B, human metapneumovirus, parainfluenza 1-3, respiratory syncytial virus and human rhinovirus were performed on each sample. Symptom scores, spirometry and inflammatory markers were measured at each visit. RESULTS: One or more respiratory viruses were detected in 191/626 (30.5%) visits. Human rhinovirus accounted for 72.5% of viruses. Overall incidence of VRI was 1.66 (95% CI 1.39 to 1.92) cases/patient-year. VRI was associated with increased risk of pulmonary exacerbation (OR=2.19; 95% CI 1.56 to 3.08; p<0.001) and prescription of antibiotics (OR=2.26; 95% CI 1.63 to 3.13; p<0.001). Virus-positive visits were associated with higher respiratory symptom scores and greater C-reactive protein levels. Virus-positive exacerbations had a lower acute fall in FEV1 than virus-negative exacerbations (12.7% vs 15.6%; p=0.040). The incidence of exacerbations, but not VRI, was associated with greater lung function decline over 12 months (-1.79% per pulmonary exacerbation/year; 95% CI -3.4 to -0.23; p=0.025). CONCLUSION: VRI is common in adults with CF and is associated with substantial morbidity. Respiratory viruses are a potential therapeutic target in CF lung disease.

Chronic rhinovirus infection in an adult with cystic fibrosis.

Rhinovirus is a common cause of exacerbations of cystic fibrosis (CF) and is usually considered a self-limiting infection. We report a case of chronic infection with rhinovirus A type 33 in a 43-year-old male with CF which has persisted for over 2 years.

Is hydrogen cyanide a marker of Burkholderia cepacia complex?

Biofilm cultures of Burkholderia cepacia complex (BCC) infection have been found to generate the nonvolatile cyanide ion. We investigated if gaseous hydrogen cyanide (HCN) was a marker of BCC infection. Selected ion flow tube mass spectrometry analysis showed HCN was not elevated in the headspace of planktonic or biofilm cultures or in the exhaled breath of adult cystic fibrosis patients with chronic BCC infection. HCN is therefore not an in vitro or in vivo marker of BCC.

Hydrogen cyanide concentrations in the breath of adult cystic fibrosis patients with and without Pseudomonas aeruginosa infection.

Elevated concentrations of hydrogen cyanide (HCN) have been detected in the headspace of Pseudomonas aeruginosa (PA) cultures and in the breath of children with cystic fibrosis (CF) and PA infection. The use of mouth-exhaled breath HCN as a marker of PA infection in adults is more difficult to assess as some without PA infection generate HCN in their mouths. The analysis of breath exhaled via the nose, thereby avoiding volatile compounds produced in the mouth, will demonstrate elevated concentrations of HCN in adult CF patients chronically infected with PA. Using selected ion flow mass spectrometry (SIFT-MS), the mouth and the nose-exhaled breaths of 20 adult CF patients; 10 with chronic PA infection and 10 free from PA infection, were analysed for HCN. Acetone and ethanol were also measured as controls. SIFT-MS allows direct sampling and analysis of single breath exhalations, obviating the need to collect samples into bags or onto traps, which can compromise samples. HCN was detected in the mouth-exhaled breath of patients in both groups and in the nose-exhaled breath of patients with chronic PA infection. The difference in median (IQR) nose-exhaled HCN between the groups is statistically significant (11 (0.8-18) ppbv versus 0 (0-3.2) ppbv, p = 0.03). The concentrations of acetone and ethanol in nose-exhaled and mouth-exhaled breath are in keeping with previous studies. HCN in nose-exhaled breath is a biomarker of chronic airway infection with PA in adults with CF. Its application as a non-invasive diagnostic test for early PA infection warrants further investigation.

Intravenous antibiotics reduce the presence of Aspergillus in adult cystic fibrosis sputum.

BACKGROUND: Pseudomonas aeruginosa and Aspergillus fumigatus frequently co-colonise the airways of patients with cystic fibrosis (CF). This study aimed to assess the impact of short-term administration of intravenous antipseudomonal antibiotics during CF exacerbations on the presence of Aspergillus. METHODS: Pre- and post-antibiotic sputum samples from 26 adult patients with CF and chronic Pseudomonas colonisation were analysed for the presence of Aspergillus by fungal culture, real-time PCR and galactomannan antigen (GM). Lung function (forced expiratory volume in 1 s and forced vital capacity % predicted) and blood levels of total IgE, specific A fumigatus IgE and specific A fumigatus IgG were measured at the start and end of antibiotics. Respiratory viral real-time PCR and bacterial community profiling using ribosomal intergenic spacer analysis (RISA) were performed to estimate concurrent changes in the lung microbiome. RESULTS: Aspergillus PCR and GM were more sensitive than culture in detecting Aspergillus species (culture 8%, GM 31%, PCR 77%). There was a significant decline in the presence of Aspergillus, measured both by PCR and GM index, following antibacterial therapy (PCR: median increase in crossing threshold 1.7 (IQR 0.5-3.8), p<0.001; GM: median fall in GM index 0.7 (IQR 0.4-1.6), p=0.016). All patients improved clinically with a significant increase in lung function (p<0.0001). RISA community analysis showed large changes in bacterial community similarity in 67% of patients following antibiotics. Viral RT-PCR demonstrated the presence of a concurrent respiratory virus in 27% of patients. CONCLUSIONS: Intravenous antibiotics targeting Pseudomonas during CF pulmonary exacerbations have a negative impact on the presence of Aspergillus in sputum samples.

Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis.

BACKGROUND: Although there have been case reports of hypothalamic-pituitary-adrenal (HPA) axis suppression in patients with cystic fibrosis (CF) caused by the combination of oral itraconazole and inhaled fluticasone, to date no study has assessed the incidence of this potentially serious side effect. METHODS: Synacthen tests were conducted on all patients with CF receiving itraconazole and inhaled fluticasone and an equal number of patients with CF receiving inhaled fluticasone but not itraconazole. Itraconazole levels were measured in patients receiving the therapy. RESULTS: Twelve patients receiving itraconazole and fluticasone underwent synacthen tests. All 12 had abnormal synacthen test results and 10/12 (83%) had HPA axis suppression. Two patients had severe HPA axis suppression with a peak cortisol <75 nmol/L and further 3 patients had moderately severe suppression with a peak cortisol <250 nmol/L. In contrast, only 2/12 on fluticasone alone had HPA axis suppression (both mild). The median (range) basal cortisol levels were significantly lower in those patients receiving itraconazole and inhaled fluticasone compared to those on fluticasone alone (219(22-508)nmol/L v 348(41-738)nnmol/L, p=0.02), similar results were seen for peak cortisol levels (404(59-706)nmol/L v 672(432-1178)nmol/L, p<0.001) and cortisol rise (179(37-240)nmol/L v 368(210-539)nmol/L, p<0.001). The median (range) itraconazole level was 5.5(1.7-14.7)mg/L. Neither itraconazole levels nor fluticasone dose correlated with the degree of adrenal suppression. CONCLUSIONS: In this study, all patients receiving itraconazole and inhaled fluticasone had abnormal synacthen test results. The incidence of HPA axis suppression with this treatment combination appears to be higher than that previously reported with itraconazole and inhaled budesonide.

IgE-mediated immune responses and airway detection of Aspergillus and Candida in adult cystic fibrosis.

BACKGROUND: The recovery of Aspergillus and Candida from the respiratory secretions of patients with cystic fibrosis (CF) is common. Their relationship to the development of allergic sensitization and effect on lung function has not been established. Improved techniques to detect these organisms are needed to increase knowledge of these effects. METHODS: A 2-year prospective observational cohort study was performed. Fifty-five adult patients with CF had sputum monitored for Aspergillus by culture and real-time polymerase chain reaction and Candida by CHROMagar and carbon assimilation profile (API/ID 32C). Skin prick tests and ImmunoCAP IgEs to a panel of common and fungal allergens were performed. Lung function and pulmonary exacerbation rates were monitored over 2 years. RESULTS: Sixty-nine percent of patient sputum samples showed chronic colonization with Candida and 60% showed colonization with Aspergillus. There was no association between the recovery of either organism and the presence of specific IgE responses. There was no difference in lung function decline for patients with Aspergillus or Candida colonization compared with those without (FEV1 percent predicted, P = .41 and P = .90, respectively; FVC % predicted, P = .87 and P = .37, respectively). However, there was a significantly greater decline in FEV1 and increase in IV antibiotic days for those sensitized to Aspergillus (FEV1 decline, P = .03; IV antibiotics days, P = .03). CONCLUSIONS: Allergic sensitization is not associated with recovery of Candida or Aspergillus from the sputum of patients with CF. Aspergillus but not Candida sensitization is associated with greater lung function decline and pulmonary exacerbations.

An investigation of suitable bag materials for the collection and storage of breath samples containing hydrogen cyanide.

The SPACE study will assess exhaled breath hydrogen cyanide (HCN) concentrations as a marker of Pseudomonas aeruginosa (PA) infection in 240 children with cystic fibrosis (CF). It will use off-line selected ion flow tube mass spectrometry (SIFT-MS) analysis and so we needed to investigate which breath sampling bag material to use, the maximum storage time before analysis and the benefit of warming the bag samples. We studied 15 children with CF, 8 had chronic PA infection and 7 did not. Each exhaled directly into the instrument (on-line) and also into two 25 µm thick Nalophan (25N), two 70 µm Nalophan (70N) and two Tedlar® bags. Bags were stored at 20 or 37 °C. HCN concentrations were analysed at 1, 6, 24 and 48 h (off-line). Acetone and water vapour concentrations were also measured in parallel. Correlation between on-line and off-line concentrations measured by SIFT-MS was better for all compounds and bag types at 37 °C. The median (IQR) on-line HCN concentration was 8.9(4.4-13.7) parts per billion by volume, ppbv. Both on-line and off-line HCN concentrations were significantly higher in patients with PA infection than those without. At 37 °C the correlation between on-line and off-line HCN concentrations was good up to 6 h in the 25N bag (R(2) = 0.79) and up to 24 h for the 70N and Tedlar bags (R(2) = 0.82 and 0.86). The correlation between on- and off-line acetone concentrations at 37 °C was good up to 24 h in 25N, 70N and Tedlar bags (R(2) = 0.89, 0.93 and 0.97). In all three types of bag the water vapour concentration fell quickly and by 24 h was equivalent to that of lab air. Samples stored in Tedlar or 70N bags, warmed to 37 °C and analysed within 24 h, give HCN and acetone concentrations which correlate well with on-line measurements.

A therapeutic conundrum: recurrent cystic-fibrosis-related haemoptysis complicated by acute pulmonary embolism.

The authors present the case of an older patient with cystic fibrosis (CF) and recurrent haemoptysis complicated by acute pulmonary embolism. The patient was treated successfully with a combination of anticoagulation and bronchial artery embolisation. The management of CF-related haemoptysis, the impact of an ageing CF population and the incidence of thromboembolic disease in CF are discussed.

Pulmonary artery pressure in cystic fibrosis adults: characteristics, clinical correlates and long-term follow-up.

BACKGROUND: We examined pulmonary artery pressure (PAP) characteristics of CF adults, studied clinical correlates and long-term survival. METHODS: Comprehensive clinical data were collected and Doppler echocardiography was used to estimate PAP in 109 stable CF adults and 50 healthy controls. RESULTS: CF patients had lower day and night-time oxygen status, elevated CRP and BNP, and elevated PAP (27.7(13.2, 62.8) mmHg patients v 17.9(11.3, 30.9) mmHg controls, p<0.001). Even patients with mild pulmonary disease had raised PAP. PAP measurements strongly correlated with arterial partial pressure of oxygen (PaO(2), r=-0.673, p<0.001), and FEV(1) percentage predicted (FEV(1)%, r=-0.642, p<0.001) which were both independent predictors of PAP. At 10 year follow up PAP measurements were related to survival but FEV(1)% and PaO(2) were both stronger predictors of death. CONCLUSIONS: PAP is raised in CF adults and correlates with pulmonary disease severity. Unlike PaO(2) and FEV(1)%, it does not appear to be an independent prognostic marker.

Successful treatment of cepacia syndrome with a combination of intravenous cyclosporin, antibiotics and oral corticosteroids.

Burkholderia cepacia complex (BCC) is a group of 17 closely related bacterial species that can cause pulmonary infection in patients with cystic fibrosis (CF). The clinical manifestations of BCC infection are varied but can include cepacia syndrome, which is a rapidly progressing necrotising pneumonia with an almost universally fatal outcome. We report the case of a 38 year old man, known to have chronic infection with the ET12 strain of Burkholderia cenocepacia who developed cepacia syndrome 26 years after initial infection. Aggressive treatment with a combination of 4 intravenous antibiotics, oral corticosteroids and cyclosporin brought about clinical, radiological and biochemical resolution of his cepacia syndrome. This case highlights the possible role of cyclosporin in the treatment of cepacia syndrome.

Long-term non-invasive ventilation in cystic fibrosis -- experience over two decades.

BACKGROUND: Non-invasive ventilation (NIV) is accepted as a bridge to lung transplantation in cystic fibrosis (CF) but there is little evidence to support its use outside this setting. METHODS: We reviewed the records of all patients with CF who received domiciliary NIV at our centre between 1991 and 2010. RESULTS: Of 47 patients studied, 36% underwent lung transplantation, 28% died without transplantation and 30% remain alive on NIV. Median duration of NIV was 16 months (range 2-90). Mean FEV(1) fell by 212 ml over the year before NIV but increased by 18 ml in the following year (p<0.01). Individual response to NIV was associated with lower baseline and more rapid decline in FEV(1). From 1991 to 2000, 70% underwent lung transplantation; from 2001 to 2010 only 27% were transplanted. CONCLUSIONS: NIV may slow or reverse the decline in lung function in advanced CF. NIV is increasingly used beyond a bridge to transplantation at our centre.

Pseudomonas aeruginosa bacteraemia in an adult with cystic fibrosis and acute appendicitis.

Despite their high bacterial load, bacteraemia is rare in patients with cystic fibrosis (CF). We report an adult with CF who developed Pseudomonas aeruginosa bacteraemia during an episode of acute appendicitis. The Pseudomonas aeruginosa isolated from the blood culture was confirmed by molecular typing to be the same transmissible strain responsible for the patient's chronic pulmonary infection. We hypothesise that this patient's bacteraemia was caused by Pseudomonas aerunginosa in swallowed sputum, crossing the inflamed appendiceal wall and entering the blood stream.

Treatment of cystic fibrosis associated cutaneous vasculitis with chloroquine.

Vasculitis is a well recognised complication of Cystic Fibrosis. Corticosteroids are the mainstay of treatment but some cases can be resistant and may require additional disease modifying agents. We describe a case of steroid resistant cutaneous vasculitis which was successfully treated with chloroquine in addition to corticosteroids and a subsequent relapse with chloroquine alone.