Non-invasive ventilation is associated with long-term improvements in lung function and gas exchange in cystic fibrosis adults with hypercapnic respiratory failure.

BACKGROUND: Non-invasive ventilation (NIV) is an established treatment option for cystic fibrosis (CF) patients with type 2 respiratory failure but the benefits of this therapy remain unclear. This study examined the long-term outcomes and response to NIV in a large adult CF cohort. METHODS: All patients attending a UK adult CF Centre receiving NIV as treatment for hypercapnic respiratory failure over a nine-year period were studied prospectively. Detailed clinical data was recorded and longitudinal data measurements were examined for the three years pre and post NIV initiation to assess effect of this intervention. RESULTS: 94 patients, mean age 29.9 (SD 9.7) years, percent predicted FEV1 21.5 (7.3), received NIV. All patients commenced NIV in a hospital setting. 21 remain alive, 24 received double lung transplant, 49 died without lung transplantation. NIV use was associated with a stabilisation and improvement in both FEV1 and FVC from NIV set up to three years post follow-up, in addition to an increase in body mass index and attenuation of PCO2 (all p<0.001). No single parameter was found to predict long-term NIV response but baseline PCO2 (p=0.005), CRP (p=0.004) and age (p=0.009) were identified as independent predictors of mortality. CONCLUSIONS: NIV use in CF adults is associated with improvements in lung function and attenuation of hypercapnia which is maintained for up to three years post NIV initiation. Outcomes for CF patients with severe pulmonary disease commenced on NIV have significantly improved with fifty percent of patients expected to survive for approximately five years.

Ralstonia infection in cystic fibrosis.

This study aimed to determine prevalence of Ralstonia spp. in cystic fibrosis patients, look for any evidence of cross infection and to describe clinical outcomes for patients infected by Ralstonia spp. Prevalence of Ralstonia spp. was calculated annually from 2008 to 2016. Pulsed-field gel electrophoresis was performed on ⩾1 sample from patients with an isolation of Ralstonia spp. between 2008 and 2016. A prospective, longitudinal observational study of adult patients was performed with 12 months follow-up from recruitment. Prevalence of Ralstonia spp. rose from 0·6% in 2008 to 2·4% in 2016. In total 12 out of 14 (86%) patients with ⩾1 isolation of Ralstonia spp. developed chronic infection. A pair and a group of three unrelated patients with epidemiological connections shared strains of Ralstonia mannitolilytica. Lung function of Ralstonia spp. infected patients was moderately to severely impaired. Prevalence of Ralstonia spp. is low but increasing. The risk of a patient developing chronic Ralstonia spp. infection following first acquisition is high and cross-infection may be possible. Whether Ralstonia spp. infection causes increased pulmonary exacerbation frequency and lung function decline needs to be evaluated in larger prospective studies.

Outcomes Following Bronchial Artery Embolisation for Haemoptysis in Cystic Fibrosis.

BACKGROUND: Bronchial artery embolisation (BAE) is recommended for the treatment of massive haemoptysis in cystic fibrosis (CF), but there are no randomised controlled trials of this therapy and its role in sub-massive haemoptysis is unclear. This study aimed to determine the outcomes and safety of BAE in adults with CF. MATERIALS AND METHODS: All patients with CF undergoing BAE at our centre between March 2011 and January 2015 were identified at the time of the procedure. Patient records were reviewed at hospital discharge, death or one month post-procedure (whichever was soonest). Follow-up continued to January 2016. Severity of haemoptysis was classified as: massive (>240 ml/24 h or >100 ml/day for ≥2 days), moderate-severe (>20 ml/24 h) or mild (<20 ml/24 h). RESULTS: Twenty-seven patients underwent 51 BAE procedures over a median follow-up period of 26 months (range 1-54). Ten patients (37%) required more than one BAE during the study. BAE was performed for massive haemoptysis in 18 cases (35%). Haemoptysis recurred after 31 (61%) of BAE procedures with no difference in recurrence rates between massive and sub-massive haemoptysis. Side effects were reported after 61% of procedures with chest pain the most common adverse event . Mortality after first BAE in the study was 3.9% at 30 days and 14.8% at 12 months. No significant predictors of mortality were identified. CONCLUSIONS: BAE is often effective in controlling haemoptysis but is associated with considerable morbidity and high recurrence rates.

Drug-related hepatitis in patients treated with standard anti-tuberculosis chemotherapy over a 30-year period.

SETTING: Drug-induced hepatitis is known to occur in a proportion of patients on treatment for active tuberculosis (TB). DESIGN: We prospectively examined the incidence of drug-induced hepatitis in 2070 patients treated for TB with the standard regimen based on 6 months of rifampicin (R, RMP) and isoniazid (H, INH), with 2 months of initial pyrazinamide (Z, PZA) and ethambutol (E, EMB), over a 30-year period from 1981 to 2010, in Blackburn, UK. RESULTS: Of the 1031 (49.8%) males and 1039 (50.2%) females studied, 451 (21.8%) were White and 1585 (76.6%) were of South Asian origin. Only 34 (1.6%) were of African or other origins. Of the total number of patients treated, 63 (3.0%) had drug-related hepatitis, 26 (5.8%) of whom were White, 37 (2.33%) Asians and 0 other. Incidence was significantly higher in Whites than Asians (OR 2.13, P = 0.008). Incidence increased with increasing age (OR 1.16, P = 0.02). The presumed causative drug was PZA 57%, RMP 32%, INH 11%, EMB 0%. There was no trend of increased hepatitis rates over time. CONCLUSION: Rates of drug-induced hepatitis where change of treatment is required are low in patients treated with standard RHZE-based therapy (3%). Caucasians and older patients were more likely to develop hepatitis than their counterparts.

Adequacy of diagnostic tests and surgical management of symptomatic invasive lobular carcinoma of the breast.

INTRODUCTION: Invasive lobular carcinoma (ILC) presents diagnostic and therapeutic challenges as it produces subtle radiological changes. It has been suggested that it is not suitable for breast conserving surgery (BCS). The aim of this study was to ascertain the diagnostic adequacy of modern mammography and ultrasonography in the context of a fast track symptomatic diagnostic clinic in the UK. It also sought to compare the mastectomy, re-excision and BCS rates for ILC with those for invasive ductal carcinoma (IDC). METHODS: A retrospective analysis of prospectively collected data was carried out on all new symptomatic cancers presenting to the one-stop diagnostic clinic of a single breast unit between 1998 and 2007. RESULTS: Compared with IDC, ILC was significantly larger at presentation (46mm vs 25mm), needed re-excision after BCS more often (38.8% vs 22.3%) and required mastectomy more frequently (58.8% vs 40.8%). Although mammography performs poorly in diagnosing ILC compared with IDC, when combined with ultrasonography, sensitivity of the combined imaging was not significantly different between these two histological types. CONCLUSIONS: Provided ultrasonography is performed, standard radiological imaging is adequate for initial diagnosis of symptomatically presenting ILC but some additional preoperative workup should clearly be employed to reduce the higher number of reoperations for this histological type.

The effect of the weather on pulmonary exacerbations and viral infections among adults with cystic fibrosis.

The effect of changes in the weather on the respiratory health of patients with cystic fibrosis (CF) is unclear. We conducted a prospective study to determine the impact of climate and season on the incidence of viral respiratory infections (VRI) and pulmonary exacerbations (PEx) among adults with CF. Between December 2010 and April 2012, 98 adults with CF were followed for 12 months. Polymerase chain reaction assays for nine viruses were performed on sputum, nose and throat swabs every 2 months and additionally at onset of PEx. Hourly temperature and relative humidity measurements were recorded throughout the study. Statistical analysis utilized generalized estimating equation (GEE) models. Pre-specified criteria for VRI and PEx were met at 29% and 37% of visits, respectively. Rhinovirus accounted for 72% of identified viruses. Incidence of rhinovirus peaked in autumn while non-rhinovirus VRI peaked in winter. Rhinovirus was associated with increased mean temperatures (OR 1.07; p = 0.001), while non-rhinovirus VRI was associated with lower mean temperatures (OR 0.87; p < 0.001). PEx occurred frequently throughout the study with no clear seasonal pattern observed. There was no significant association between climate variables and the incidence of either PEx or antibiotic prescription. There is a seasonal pattern to VRI in adults with CF. The incidence of VRI but not PEx is associated with changes in ambient temperature.

Association of airway cathepsin B and S with inflammation in cystic fibrosis.

SUMMARY: Irreversible tissue damage within the cystic fibrosis (CF) lung is mediated by proteolytic enzymes during an inflammatory response. Serine proteinases, in particular neutrophil elastase (NE), have been implicated however, members of the cysteine proteinase family may also be involved. The aim of this study was to determine cathepsin B and S levels in cystic fibrosis (CF) sputum and to assess any relationship to recognized markers of inflammation such as sputum NE, interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha), urine TNF receptor 1 (TNFr1), plasma IL-6, and serum C-reactive protein (CRP). Proteinase activities were measured in the sputum of 36 clinically stable CF patients using spectrophotometric and fluorogenic assays. Immunoblots were also used to confirm enzyme activity data. All other parameters were measured by ELISA. Patients had a mean age of 27.2 (8.2) years, FEV. of 1.6 (0.79) L and BMI of 20.7 (2.8). Both cathepsin B and S activities were detected in all samples, with mean concentrations of 18.0 (13.5) microg/ml and 1.6 (0.88) microg/ml, respectively and were found to correlate not only with each other but with NE, TNF-alpha and IL-8 (in all cases . < 0.05). Airway cathepsin B further correlated with circulatory IL-6 and CRP however, no relationship for either cathepsin was observed with urine TNFr1. This data indicates that cathepsin B and S may have important roles in the pathophysiology of CF lung disease and could have potential as markers of inflammation in future studies.

Effectiveness of 3 months of rifampicin and isoniazid chemoprophylaxis for the treatment of latent tuberculosis infection in children.

UNLABELLED: BACKGROUND/SETTING: Treatment for 3 months with rifampicin (R) and isoniazid (H) (3RH) for latent tuberculosis infection (LTBI), defined as an inappropriately positive tuberculin skin test with no clinical or x-ray evidence of disease, has been used locally since 1989. The efficacy of this regimen in children in the UK has only been studied indirectly. The long-term outcome of those children treated with 3RH, in the Chest Clinic of this high tuberculosis (TB) incidence district, has been studied to derive a more direct assessment of effectiveness. METHODS: All children treated with 3RH for LTBI from 1989 to 2004 inclusive were matched with the local patient administration system (PAS), GP registration and local TB notification databases. Only those persons still registered locally on PAS, or locally GP registered were then checked for subsequent TB notification. RESULTS: A total of 334 patients were identified, of whom 252 remained locally, with 82 lost to follow-up; 3 cases of clinical TB developed in the 252 (1.19%), with 3113 years observation (mean 12.35 years) giving 0.964/1000 person years (95% CI 0.199 to 2.816). Sensitivity analyses showed a 'best case' scenario of 0.727/1000 person years (95% CI 0.15 to 2.12), and if 10% of those lost to follow-up developed clinical TB of 2.66/1000 person years (95% CI 1.33 to 4.77). CONCLUSIONS: Follow-up of those cases treated with 3RH, for a mean of 12.35 years, and over 3100 patient years observation, shows a rate of active TB of under 1/1000 patient years. This suggests that 3RH has very high efficacy when used to treat LTBI in children in the UK and compares favourably with the expected untreated TB rate.

Pseudomonal breast infection.

Breast infection and breast sepsis secondary to Pseudomonas aeruginosa is uncommon. We report two cases of pseudomonal breast infection leading to septic shock and abscess formation in women with non-responding breast infection. The management of breast infection is broad-spectrum antibiotics and ultrasound with aspiration of any collection. To treat breast infection effectively, the causative organism must be isolated to enable appropriate antibiotic therapy.

Patient segregation and aggressive antibiotic eradication therapy can control methicillin-resistant Staphylococcus aureus at large cystic fibrosis centres.

BACKGROUND: The prevalence of MRSA in patients with CF has risen in recent years. We adhere to a policy of segregation and barrier nursing to manage patients with MRSA, and we actively pursue eradication of MRSA. We have evaluated our experiences of MRSA infection in our large adult CF centre. METHOD: A retrospective review of all MRSA-positive patients from 1998 to 2008 was undertaken. Isolates were subjected to molecular identification to elucidate possible patient-to-patient transmission events. Eradication attempts were scrutinised. RESULTS: We have maintained a low incidence and prevalence (below 3%) of MRSA within this large cohort. A total of 15 pulsotypes of MRSA were identified among the 24 isolates examined, epidemiological data suggested no patient-patient transmission. Based on 6 month follow-up data, successful eradication was achieved in 81% patients. This includes those who had harboured infection for some time. Twenty-one (80.8%) required only one course of treatment, 3 (11.6%) patients required two different regimes and 2 (7.5%) required three courses to fully eradicate the organism. CONCLUSION: Strict infection control procedures can control MRSA infection and keep the prevalence low in CF clinics. Eradication is achievable in the majority of patients even when significant time has lapsed from initial isolation. In some instances, up to 3 courses of antibiotics were required to achieve eradication.

Inflammatory markers in cystic fibrosis patients with transmissible Pseudomonas aeruginosa.

Chronic Pseudomonas aeruginosa infection in cystic fibrosis (CF) leads to a damaging host inflammatory response. There are an increasing number of reports of P. aeruginosa cross-infection at CF centres. The clinical significance of acquisition of a transmissible strain for patients who already harbour P. aeruginosa is unclear. In this study, levels of inflammatory markers in clinically stable adult CF patients who harbour transmissible and sporadic strains of P. aeruginosa have been compared. Patients with CF and chronic P. aeruginosa infection were grouped into those who harbour a transmissible P. aeruginosa and those who harbour their own sporadic strains. Total white cell and differential counts, sputum neutrophil elastase (NE), interleukin (IL)-8, tumour necrosis factor (TNF)-alpha, plasma IL-6 and NE/alpha1-antitrypsin complexes, serum C-reactive protein, and urine TNF receptor 1 were all measured in clinically stable patients 4-6 weeks following completion of intravenous antibiotic therapy. The two groups (both n=20) were well matched for per cent predicted forced expiratory volume in one second, per cent predicted forced vital capacity and body mass index. There were no significant differences in levels of white cell counts or inflammatory markers between the two groups. At times of clinical stability, cystic fibrosis patients infected with transmissible Pseudomonas aeruginosa do not have a heightened inflammatory response above that of those harbouring sporadic strains.

APC, beta-Catenin and hTCF-4; an unholy trinity in the genesis of colorectal cancer.

Mutations in APC have been identified in up to 80% of 'classic' sporadic colorectal cancers. Although the APC gene was first sequenced over a decade ago, new functions are still being described and its importance in the genesis of colorectal cancer continues to increase. The current focus of attention is on the APC/beta-Catenin/TCF signal transduction pathway as the main effector mechanism, and recent work has also implicated this pathway in the aetiology of the minority of CRCs that develop through mismatch repair. At the same time, new evidence on the interactions of APC with the cytoskeleton and the demonstration of a nuclear export function in the protein have shown that it has multiple additional roles in colorectal carcinogenesis. Thus this is an area that benefits from further review of the ever expanding literature.

Preclinical studies of gene transfer for the treatment of desmoid disease in familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) arises following mutation or loss of the adenomatous polyposis coli (APC) gene. Desmoid tumours are proliferations of fibroblasts and occur as an extracolonic manifestation of FAP. They are a leading cause of death after colectomy. The aim of this study was to assess the potential for APC gene transfer into fibroblasts in vitro and in vivo as a basis for consideration of gene therapy in the prevention or treatment of desmoid tumours. METHODS: The APC gene was transferred by lipofection into fibroblasts in tissue culture and into peritoneum and small bowel mesentery in vivo. Reverse transcriptase-polymerase chain reaction was used to determine whether or not transfection was successful. RESULTS: Transgene expression was recorded in vitro to 7 days after transfection. High levels of transgene expression were also seen in samples of peritoneum (all eight mice), small bowel mesentery (seven of eight), liver (seven of eight) and intestinal tissues (five to six of eight) following intraperitoneal treatment. Interestingly, transgene expression in gonadal tissues was occasionally noted. CONCLUSION: Liposomal transfection of APC gave prolonged high-level expression of the transgene, an important basis for gene therapy. No adverse effects were recorded. Further work is needed in animal models of desmoid disease to assess the clinical effects of gene therapy.

Regulation of interleukin-6 release by human thyrocytes.

Autoimmune thyroiditis is characterized by lymphocytic accumulation within the thyroid which may be the result, in part, of immunomodulatory cytokine secretion by thyrocytes. We have tested human thyroid cell cultures (n = 9) for interleukin-6 (IL-6) release using two bioassays. IL-6 was detected in all culture supernatants under basal conditions and was increased by gamma-interferon, tumour necrosis factor and TSH in a dose-dependent manner. The bioactivity was confirmed as IL-6 by immunoblotting experiments and could not be accounted for by contamination of the thyroid cell cultures with fibroblasts, lymphocytes or monocytes. Circulating IL-6 levels were not raised in patients with Graves' hyperthyroidism. Exogenous recombinant IL-6 reduced cyclic AMP production in response to TSH when added to thyroid cell cultures. Since IL-6 plays a major role in B cell differentiation and T cell activation, release of IL-6 by thyrocytes may increase the intrathyroidal autoimmune response in Graves' disease and Hashimoto's thyroditis. Our results also suggest that IL-6 may modulate thyroid cell function.