ROCK STUDY in CF: sustained anti-inflammatory effects of lumacaftor-ivacaftor in sputum and peripheral blood samples of adult patients with cystic fibrosis-an observational study.

BACKGROUND: Previous studies showed that the combination of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) corrector and potentiator, lumacaftor-ivacaftor (LUMA-IVA) provides meaningful clinical benefits in patients with cystic fibrosis who are homozygous for the Phe508del CFTR mutation. However, little is known about the effect of LUMA-IVA on Proinflammatory Cytokines (PICs). OBJECTIVES: To investigate the impact of LUMA-IVA CFTR modulation on circulatory and airway cytokines before and after 12 months of LUMA-IVA treatment in a real-world setting. METHODS: We assessed both plasma and sputum PICs, as well as standard clinical outcomes including Forced Expiratory Volume in one second (FEV1) %predicted, Body Mass Index (BMI), sweat chloride and pulmonary exacerbations at baseline and prospectively for one year post commencement of LUMA-IVA in 44 patients with cystic fibrosis aged 16 years and older homozygous for the Phe508del CFTR mutation. RESULTS: Significant reduction in plasma cytokines including interleukin (IL)-8 (p<0.05), tumour necrosis factor (TNF)-α (p<0.001), IL-1ß (p<0.001) levels were observed while plasma IL-6 showed no significant change (p=0.599) post-LUMA-IVA therapy. Significant reduction in sputum IL-6 (p<0.05), IL-8 (p<0.01), IL-1ß (p<0.001) and TNF-α (p<0.001) levels were observed after LUMA-IVA therapy. No significant change was noted in anti-inflammatory cytokine IL-10 levels in both plasma and sputum (p=0.305) and (p=0.585) respectively. Clinically significant improvements in FEV1 %predicted (mean+3.38%, p=0.002), BMI (mean+0.8 kg/m2, p<0.001), sweat chloride (mean -19 mmol/L, p<0.001), as well as reduction in intravenous antibiotics usage (mean -0.73, p<0.001) and hospitalisation (mean -0.38, p=0.002) were observed after initiation of LUMA-IVA therapy. CONCLUSION: This real-world study demonstrates that LUMA-IVA has significant and sustained beneficial effects on both circulatory and airway inflammation. Our findings suggest that LUMA-IVA may improve inflammatory responses, which could potentially contribute to improved standard clinical outcomes.

Portable HEPA filtration successfully augments natural-ventilation-mediated airborne particle clearance in a legacy design hospital ward.

As the severe acute respiratory syndrome coronavirus-2 pandemic has proceeded, ventilation has been recognized increasingly as an important tool in infection control. Many hospitals in Ireland and the UK do not have mechanical ventilation and depend on natural ventilation. The effectiveness of natural ventilation varies with atmospheric conditions and building design. In a challenge test of a legacy design ward, this study showed that portable air filtration significantly increased the clearance of pollutant aerosols of respirable size compared with natural ventilation, and reduced spatial variation in particle persistence. A combination of natural ventilation and portable air filtration is significantly more effective for particle clearance than either intervention alone.

Modulation, microbiota and inflammation in the adult CF gut: A prospective study.

BACKGROUND: Cystic Fibrosis (CF) has prominent gastrointestinal and pancreatic manifestations. The aim of this study was to determine the effect of Cystic fibrosis transmembrane conductance regulator (CFTR) modulation on, gastrointestinal inflammation, pancreatic function and gut microbiota composition in people with cystic fibrosis (CF) and the G551D-CFTR mutation. METHODS: Fourteen adult patients with the G551D-CFTR mutation were assessed clinically at baseline and for up to 1 year after treatment with ivacaftor. The change in gut inflammatory markers (calprotectin and lactoferrin), exocrine pancreatic status and gut microbiota composition and structure were assessed in stool samples. RESULTS: There was no significant change in faecal calprotectin nor lactoferrin in patients with treatment while all patients remained severely pancreatic insufficient. There was no significant change in gut microbiota diversity and richness following treatment. CONCLUSION: There was no significant change in gut inflammation after partial restoration of CFTR function with ivacaftor, suggesting that excess gut inflammation in CF is multi-factorial in aetiology. In this adult cohort, exocrine pancreatic function was irreversibly lost. Longer term follow-up may reveal more dynamic changes in the gut microbiota and possible restoration of CFTR function.

Recurrent asthma exacerbations: co-existing asthma and common variable immunodeficiency.

Common variable immunodeficiency is characterized by impaired B-cell differentiation and defective immunoglobulin production manifesting as recurrent respiratory tract infections. While the condition can masquerade as asthma, late diagnosis of CVID in known asthmatic is rarely reported.We present the case of a 43-year-old lady with recurrent episodes of wheeze, cough, sinusitis and multiple lower respiratory tract infections. Transiently responsive to antibiotics and steroids. These episodes had been occurring for many years and she had a longstanding clinical diagnosis of asthma.As part of her work up for recurrent respiratory tract infections a CT thorax was performed and demonstrated bronchiectasis. Further tests including Immunoglobulin levels revealed critically low IgG, IgM, and IgA levels. Immunoglobulin replacement therapy was commenced with a reduction in exacerbation frequency and severity, and objective improvement of asthma control. Subsequent lung function tests demonstrated reversible airflow limitation (obstructive lung function with 13% reversibility in FEV1 post-bronchodilator) consistent with asthma.Our case illustrates the importance of searching for alternate and co-existent diagnoses in patients diagnosed with asthma who are unresponsive to conventional therapy. We believe that serum immunoglobulin measurement should form a component of such a workup.

Containment of procedure-associated aerosols by an extractor tent: effect on nebulized drug particle dispersal.

BACKGROUND: Several medical procedures involving the respiratory tract are considered as 'aerosol-generating procedures'. Aerosols from these procedures may be inhaled by bystanders, and there are consequent concerns regarding the transmission of infection or, specific to nebulized therapy, secondary drug exposure. AIM: To assess the efficacy of a proprietary high-efficiency-particulate-air-filtering extractor tent on reducing the aerosol dispersal of nebulized bronchodilator drugs. METHODS: The study was conducted in an unoccupied outpatient room at St. James's Hospital, Dublin, Ireland. A novel real-time, fluorescent particle counter, the Wideband Integrated Bioaerosol Sensor (WIBS), monitored room air continuously for 3 h. Baseline airborne particle count and count during nebulization of bronchodilator drug solutions were recorded. FINDINGS: Nebulization within the tent prevented any increase over background level. Nebulization directly into room air resulted in mean fluorescent particle counts of 4.75 x 105/m3 and 4.21 x 105/m3 for Ventolin and Ipramol, respectively, representing more than 400-fold increases over mean background level. More than 99.3% of drug particles were <2 µm in diameter and therefore small enough to enter the lower respiratory tract. CONCLUSION: The extractor tent was completely effective for the prevention of airborne spread of drug particles of respirable size from nebulized therapy. This suggests that extractor tents of this type would be efficacious for the prevention of airborne infection from aerosol-generating procedures during the COVID-19 pandemic.

Ultra-low-dose thoracic CT with model-based iterative reconstruction (MBIR) in cystic fibrosis patients undergoing treatment with cystic fibrosis transmembrane conductance regulators (CFTR).

AIM: To assess the utility of a volumetric low-dose computed tomography (CT) thorax (LDCTT) protocol at a dose equivalent to a posteroanterior (PA) and lateral chest radiograph for surveillance of cystic fibrosis (CF) patients. MATERIALS AND METHODS: A prospective study was undertaken of 19 adult patients with CF that proceeded to LDCTT at 12 and 24 months following initiation of ivacaftor. A previously validated seven-section, low-dose axial CT protocol was used for the 12-month study. A volumetric LDCTT protocol was developed for the 24-month study and reconstructed with hybrid iterative reconstruction (LD-ASIR) and pure iterative reconstruction (model-based IR [LD-MBIR]). Radiation dose was recorded for each scan. Image quality was assessed quantitatively and qualitatively, and disease severity was assessed using a modified Bhalla score. Statistical analysis was performed and p-values of <0.05 were considered statistically significant. RESULTS: Volumetric LD-MBIR studies were acquired at a lower radiation dose than the seven-section studies (0.08 ± 0.01 versus 0.10 ± 0.02 mSv; p=0.02). LD-MBIR and seven-section ASIR images had significantly lower levels of image noise compared with LD-ASIR images (p<0.0001). Diagnostic acceptability scores and depiction of bronchovascular structures were found to be acceptable for axial and coronal LD-MBIR images. LD-MBIR images were superior to LD-ASIR images for all qualitative parameters assessed (p<0.0001). No significant change was observed in mean Bhalla score between 1-year and 2-year studies (p=0.84). CONCLUSIONS: The use of a volumetric LDCTT protocol (reconstructed with pure IR) enabled acquisition of diagnostic quality CT images, which were considered extremely useful for surveillance of CF patients, at a dose equivalent to a PA and lateral chest radiograph.

A study to assess smoking habits and smoking exposure in sportspeople.

BACKGROUND: Tobacco smoking is a leading public health concern and is the most preventable cause of morbidity and mortality worldwide. Sportspeople are no exception and those who smoke are predisposed to the same hazardous health effects as the general public, in addition to the potential effects it may have on their sporting performance. AIM: We aimed to ascertain the prevalence of tobacco consumption in a sporting population. We also endeavoured to quantify the use of electronic cigarettes (e-cigarettes) and assess exposure to passive smoking. DESIGN: Observational study. METHODS: A web-based e-questionnaire was distributed to participants from various sports across Ireland between November 2017 and January 2018, and data were analysed using SPSS. RESULTS: A total of 546 sportspeople completed the survey with more than twice as many male respondents. Of whom, 16% of participants were current smokers, with males significantly more likely to smoke (P < 0.001), 26% of rugby players were current smokers which was significantly higher when compared with other sports (P < 0.01), 10% of all participants were exposed to second-hand smoke for more than 1 h per day and 2% of all participants were current users of e-cigarettes. CONCLUSION: The prevalence of smoking in our study population was higher than other literature reports. Further studies are essential to evaluate the potential negative effects this may be having on sporting performance, career progression and indeed injury occurrence/rehabilitation. It is imperative to address the matter of smoking in athletes, not only for public health concerns but also considering they are important role models in our society.

Effectiveness of a plasma treatment device on microbial air quality in a hospital ward, monitored by culture.

This study analysed the effectiveness of plasma treatment on airborne bacteria and surface counts during a 14-day intervention within a four-bedded bay in an adult respiratory ward at Cork University Hospital, Ireland. One-hundred-litre air samples were collected twice daily every weekday for 4 weeks, with settle plates and surface swabs. The plasma treatment did not have an effect on airborne bacteria and fungi that was detectable by culture. However, the possibility that culture-based sampling may be insufficiently sensitive to detect an effect, or that the duration of the study was insufficient for plasma treatment to affect a complex environment, cannot be excluded.

Outcomes Post Thrombolysis for Acute Pulmonary Embolism.

Background Pulmonary embolism (PE) remains a significant cause of mortality in Europe1. Thrombolytic therapy is often utilised as a therapeutic strategy in massive and sub-massive PE. There is a dearth of research on short term complications and subsequent outcomes in patients who have received thrombolysis for PE in Ireland. Methods This retrospective study examined patients who underwent thrombolysis for acute sub massive PE whilst under the care of the respiratory service in Cork University Hospital (CUH) from 2010-2018. All patients had CTPA done for diagnosis of PE. Alteplase was used as a thrombolytic agent. Patient records were perused. Follow-up pulmonary functions tests (PFTs) and trans-thoracic echocardiogram (TTE) results were assessed for evidence of impairment of diffusing capacity (DLCO) and pulmonary hypertension (PH) respectively. Results Twenty five patients were included in the study. Nine patients (36%) were women and 64% men. Average age was 55.1 years. Four patients suffered complications related to thrombolysis (average age 63.3 years). Twenty-Two patients (88%) underwent a follow-up echocardiography (mean 30 weeks post PE). Three patients (13%) had echocardiographic evidence of possible mild PH (i.e. RVSP >40mmhg) at initial follow-up. Fourteen patients (56%) who underwent thrombolysis had follow-up PFTs (mean 11.8 months post PE). The diffusing capacity (DLCO) was normal in all patients. Conclusion Thrombolysis was a relatively safe intervention in this small study.

A bolt from the blue; A case report of an unusual asthma exacerbation.

BACKGROUND: We describe this case of a young gentleman presenting with acute dyspnoea on a background history of known, long-standing asthma. His dramatic presentation, notable for profound hypoxia and cyanosis, led to an unexpected additional diagnosis of type one congenital methaemoglobinaemia. CASE PRESENTATION: A 26-year-old Irish gentleman was transferred urgently to the emergency department resuscitation room with marked cyanosis and tachypnoea. His oxygen saturation was 70% on 100% high flow oxygen. His arterial blood gas (On Fi02 90%) demonstrated a PaO2 = 76.8 kPa, SpO2 = 99%, pCO2 = 3 kPa and pH = 7.51. A saturation gap was evident and on further analysing the arterial blood gas, the methaemoglobin level was noted to be 28%. No contributing drugs were identified. Our patient was diagnosed with type one congenital methaemoglobinaemia. He recovered well from this admission, however, has had recurrent presentations to hospital since with high methaemoglobin levels noted on each occasion. DISCUSSION: Congenital methemoglobinemia is a rare, often overlooked differential diagnosis in patients presenting with cyanosis and dyspnoea. This is the only case, to our knowledge, of a patient with both asthma and congenital methaemoglobinaemia. Congenital methaemoglobinaemia was first described in 1943 by Dr Deeny who described two siblings as suffering from 'Familial Idiopathic Methaemoglobinaemia'. The case we present is the first reported Irish case of congenital methaemoglobinaemia, we are aware of, since 1943.Current treatment strategies include high-flow oxygen, methylene blue infusion (contraindicated in glucose-6-phosphate-dehydrogenase deficiency) and red cell exchange transfusions in the emergency setting whilst oral ascorbic acid and riboflavin are preventative.

The effectiveness of Reslizumab in severe asthma treatment: a real-world experience.

BACKGROUND: Increased numbers of blood and sputum eosinophils are associated with higher exacerbation frequency and increased asthma severity. In clinical trials, targeting Interleukin-5 has been shown to be a useful therapeutic strategy for patients with severe eosinophilic asthma. METHODS: Twenty-six patients have been commenced on Reslizumab in our institution since early 2017. Safety and clinical efficacy parameters were recorded at regular intervals. RESULTS: Mean ACQ-6 score at the start of treatment was 3.5. The average number of exacerbations in the year preceding treatment was 8.3 per person. 30% of patients had been admitted to hospital at least once over the 12 months preceding therapy. 54% of our patients were on long term oral steroid. Our data showed sustained improvement of Asthma control (Mean improvement in ACQ-6 was 1.7 at 1 year, and 2.0 at 2 years, P = 0.0001). Of the patients who were on long term systemic steroids, 35.7% discontinued steroids completely, with a mean reduction of prednisolone dose of 5.2 mg at 1 year. There was a 79% reduction in the annual exacerbation frequency at 1 year, and 88% at 2 years (P = < 0.0001). Modest, albeit statistically significant increases in creatine kinase which seemed to plateau by 1 year were noted. CONCLUSIONS: Overall, Reslizumab was well tolerated with discontinuation of treatment due to side effects recorded in only one patient. Our data confirm the utility of anti-IL5 therapy in a carefully selected phenotype of severe asthma with evidence of eosinophilic airway inflammation.

A pilot study demonstrating the altered gut microbiota functionality in stable adults with Cystic Fibrosis.

Cystic Fibrosis (CF) and its treatment result in an altered gut microbiota composition compared to non-CF controls. However, the impact of this on gut microbiota functionality has not been extensively characterised. Our aim was to conduct a proof-of-principle study to investigate if measurable changes in gut microbiota functionality occur in adult CF patients compared to controls. Metagenomic DNA was extracted from faecal samples from six CF patients and six non-CF controls and shotgun metagenomic sequencing was performed on the MiSeq platform. Metabolomic analysis using gas chromatography-mass spectrometry was conducted on faecal water. The gut microbiota of the CF group was significantly different compared to the non-CF controls, with significantly increased Firmicutes and decreased Bacteroidetes. Functionality was altered, with higher pathway abundances and gene families involved in lipid (e.g. PWY 6284 unsaturated fatty acid biosynthesis (p = 0.016)) and xenobiotic metabolism (e.g. PWY-5430 meta-cleavage pathway of aromatic compounds (p = 0.004)) in CF patients compared to the controls. Significant differences in metabolites occurred between the two groups. This proof-of-principle study demonstrates that measurable changes in gut microbiota functionality occur in CF patients compared to controls. Larger studies are thus needed to interrogate this further.

The altered gut microbiota in adults with cystic fibrosis.

BACKGROUND: Cystic Fibrosis (CF) is an autosomal recessive disease that affects the function of a number of organs, principally the lungs, but also the gastrointestinal tract. The manifestations of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the gastrointestinal tract, as well as frequent antibiotic exposure, undoubtedly disrupts the gut microbiota. To analyse the effects of CF and its management on the microbiome, we compared the gut microbiota of 43 individuals with CF during a period of stability, to that of 69 non-CF controls using 454-pyrosequencing of the 16S rRNA gene. The impact of clinical parameters, including antibiotic therapy, on the results was also assessed. RESULTS: The CF-associated microbiome had reduced microbial diversity, an increase in Firmicutes and a reduction in Bacteroidetes compared to the non-CF controls. While the greatest number of differences in taxonomic abundances of the intestinal microbiota was observed between individuals with CF and the healthy controls, gut microbiota differences were also reported between people with CF when grouped by clinical parameters including % predicted FEV1 (measure of lung dysfunction) and the number of intravenous (IV) antibiotic courses in the previous 12 months. Notably, CF individuals presenting with severe lung dysfunction (% predicted FEV1 ≤ 40%) had significantly (p < 0.05) reduced gut microbiota diversity relative to those presenting with mild or moderate dysfunction. A significant negative correlation (-0.383, Simpson's Diversity Index) was also observed between the number of IV antibiotic courses and gut microbiota diversity. CONCLUSIONS: This is one of the largest single-centre studies on gut microbiota in stable adults with CF and demonstrates the significantly altered gut microbiota, including reduced microbial diversity seen in CF patients compared to healthy controls. The data show the impact that CF and it's management have on gut microbiota, presenting the opportunity to develop CF specific probiotics to minimise microbiota alterations.

A Study To Assess The Prevalence Of Exercise-Induced Bronchoconstriction In Inter-County Hurling.

Exercise-Induced Bronchoconstriction (EIB) is an acute, transient airway narrowing occurring after exercise which may impact athletic performance. Studies report 10% of the general population and up to 90% of asthmatics experience EIB. Ninety-two players from three elite hurling squads underwent a spirometric field-based provocation test with real-time heart rate monitoring and lactate measurements to ensure adequate exertion. Players with a new diagnosis of EIB and those with a negative field-test but with a previous label of EIB or asthma underwent further reversibility testing and if negative, methacholine challenge. Eight (8.7%) of players had EIB, with one further athlete having asthma with a negative field test. Interestingly, only three out of 12 players who had previously been physician-labelled with EIB or asthma had their diagnosis objectively confirmed. Our study highlights the role of objective testing in EIB.

Clostridium difficile carriage in adult cystic fibrosis (CF); implications for patients with CF and the potential for transmission of nosocomial infection.

Clostridium difficile is an anaerobic Gram-positive, spore-forming, toxin-producing bacillus transmitted among humans through the faecal-oral route. Despite increasing carriage rates and the presence of C. difficile toxin in stool, patients with CF rarely appear to develop typical manifestations of C. difficile infection (CDI). In this study, we examined the carriage, toxin production, ribotype distribution and antibiotic susceptibility of C. difficile in a cohort of 60 adult patients with CF who were pre-lung transplant. C. difficile was detected in 50% (30/60) of patients with CF by culturing for the bacteria. C. difficile toxin was detected in 63% (19/30) of C. difficile-positive stool samples. All toxin-positive stool samples contained toxigenic C. difficile strains harbouring toxin genes, tcdA and tcdB. Despite the presence of C. difficile and its toxin in patient stool, no acute gastrointestinal symptoms were reported. Ribotyping of C. difficile strains revealed 16 distinct ribotypes (RT), 11 of which are known to be disease-causing including the hyper-virulent RT078. Additionally, strains RT002, RT014, and RT015, which are common in non-CF nosocomial infection were described. All strains were susceptible to vancomycin, metronidazole, fusidic acid and rifampicin. No correlation was observed between carriage of C. difficile or any characteristics of isolated strains and any recorded clinical parameters or treatment received. We demonstrate a high prevalence of hypervirulent, toxigenic strains of C. difficile in asymptomatic patients with CF. This highlights the potential role of asymptomatic patients with CF in nosocomial transmission of C. difficile.

Molecular epidemiology of Mycobacterium abscessus complex isolates in Ireland.

BACKGROUND: The Mycobacterium abscessus complex are the rapidly growing mycobacteria (RGM) most commonly causing lung disease, especially in cystic fibrosis (CF) patients. Ireland has the world's highest CF incidence. The molecular epidemiology of M. abscessus complex in Ireland is unreported. METHODS: We performed rpoB gene sequencing and multi-locus sequence typing (MLST) on M. abscessus complex strains isolated from thirty-six patients in 2006-2012 (eighteen known CF patients). RESULTS: Twenty-eight strains (78%) were M. abscessus subsp. abscessus, eight M. abscessus subsp. massiliense, none were M. abscessus subsp. bolletii. Sequence type 1 (ST1) and ST26 (M. abscessus subsp. abscessus) were commonest. Seven M. abscessus subsp. abscessus STs (25%) were novel (two with novel alleles). Seven M. abscessus subsp. massiliense STs were previously reported (88%), including two ST23, the globally successful clone. In 2012, of 552 CF patients screened, eleven were infected with M. abscessus complex strains (2%). CONCLUSIONS: The most prevalent M. abscessus subsp. abscessus and M. abscessus subsp. massiliense strains in Ireland belong to widely-distributed STs, but there is evidence of high M. abscessus subsp. abscessus diversity.

Nasal endoscopy and paranasal sinus computerised tomography (CT) findings in an Irish cystic fibrosis adult patient group.

Cystic fibrosis (CF) is a common inherited disorder in Caucasians in Ireland having the highest reported incidence. CF has well-recognised clinical sequelae in several physiological systems. Its' impact on the sinonasal system is less well established. We evaluated symptoms, endoscopic and computerised tomographic (CT) findings in an Irish adult CF group with the aim of characterising the relationship between these clinical features in an Irish CF group. Adult CF patients attending a specialist clinic underwent prospective evaluation of sinonasal symptoms using a specifically designed questionnaire. They subsequently underwent nasoendoscopy and CT scanning of their paranasal sinuses. Abnormalities identified were quantified using established radiological (Lund-Mackay) and endoscopic (Lund-Kennedy) scoring systems. The relationship between symptoms of chronic rhinosinusitis (CRS), endoscopic findings and CT abnormalities were then compared. Sixty-three CF patients (n = 63) were studied. 29 patients had a CT scan. Thirty-three CF patients (52%) had no symptoms of CRS. Fifty CF patients (80% of CF group) had evidence of CRS on nasoendoscopy including thirteen patients (20%) with nasal polyposis. 98% of patients scanned have positive findings on CT scan. There was no significant difference between symptomatic and asymptomatic CF groups with respect to their Lund-Kennedy endoscopic score or their Lund-Mackay CT score. 86% demonstrated one or more hypoplastic sinus. There was no increased incidence of hypoplastic sinuses amongst Δf508 homozygotes than other mutation groups.