The microbiome and the pathophysiology of asthma

Asthma is a chronic respiratory disease whose prevalence is increasing in the western world. Recently research has begun to focus on the role the microbiome plays in asthma pathogenesis in the hope of further understanding this respiratory disorder. Considered sterile until recently, the lungs have revealed themselves to contain a unique microbiota. A shift towards molecular methods for the quantification and sequencing of microbial DNA has revealed that the airways harbour a unique microbiota with apparent, reproducible differences present between healthy and diseased lungs. There is a hope that in classifying the microbial load of the asthmatic airway an insight may be afforded as to the possible role pulmonary microbes may have in propagating an asthmatic airway response. This could potentially pave the way for new therapeutic strategies for the treatment of chronic lung conditions such as asthma

Gastric aspiration and its role in airway inflammation

Gastro-Oesophageal Reflux (GOR) has been associated with chronic airway diseases while the passage of foreign matter into airways and lungs through aspiration has the potential to initiate a wide spectrum of pulmonary disorders. The clinical syndrome resulting from such aspiration will depend both on the quantity and nature of the aspirate as well as the individual host response. Aspiration of gastric fluids may cause damage to airway epithelium, not only because acidity is toxic to bronchial epithelial cells but also due to the effect of digestive enzymes such as pepsin and bile salts. Experimental models have shown that direct instillation of these factors to airways epithelia cause damage with a consequential inflammatory response. The pathophysiology of these responses is gradually being dissected, with better understanding of acute gastric aspiration injury, a major cause of acute lung injury, providing opportunities for therapeutic intervention and potentially, ultimately, improved understanding of the chronic airway response to aspiration. Ultimately, clarification of the inflammatory pathways which are related to micro-aspiration via pepsin and bile acid salts may eventually progress to pharmacological intervention and surgical studies to assess the clinical benefits of such therapies in driving symptom improvement or reducing disease progression

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

Post-tuberculosis mycetoma: bronchoscopic removal

A 76‐year‐old male non‐smoker presented to our institution with cough and haemoptysis. He had been treated for cavitatory pulmonary Mycobacterium tuberculosis of the right upper lobe 10 years previously. Chest radiograph and subsequent computed tomography (CT) of the chest demonstrated a right upper cavity containing a mass suspicious for mycetoma. Flexible bronchoscopy under conscious sedation demonstrated a mass obstructing the anterior segment of the right upper lobe. The abnormality was subsequently removed using a flexible endobronchial cryoprobe. Histopathological analysis demonstrated abundant fungal organisms morphologically consistent with Aspergillus species. Microbiological culture of the bronchoalveolar lavage (BAL) from the cavity isolated both Aspergillus fumigatus and Staphylococcus aureus. The patient was commenced on the anti‐fungal drug posaconazole and received a course of flucloxacillin. Three months later, there was no endobronchial obstruction and lavage of the affected cavity again isolated Staphylococcus aureus without Aspergillus species. Repeat thoracic CT and flexible bronchoscopy demonstrated no further re‐occurrence of the mycetoma at 3 months

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

Global MYCN Transcription Factor Binding Analysis in Neuroblastoma Reveals Association with Distinct E-Box Motifs and Regions of DNA Hypermethylation

BACKGROUND: Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is a major cause of childhood cancer related deaths. The single most important prognostic indicator of poor clinical outcome in this disease is genomic amplification of MYCN, a member of a family of oncogenic transcription factors. METHODOLOGY: We applied MYCN chromatin immunoprecipitation to microarrays (ChIP-chip) using MYCN amplified/non-amplified cell lines as well as a conditional knockdown cell line to determine the distribution of MYCN binding sites within all annotated promoter regions. CONCLUSION: Assessment of E-box usage within consistently positive MYCN binding sites revealed a predominance for the CATGTG motif (p\u3c0.0016), with significant enrichment of additional motifs CATTTG, CATCTG, CAACTG in the MYCN amplified state. For cell lines over-expressing MYCN, gene ontology analysis revealed enrichment for the binding of MYCN at promoter regions of numerous molecular functional groups including DNA helicases and mRNA transcriptional regulation. In order to evaluate MYCN binding with respect to other genomic features, we determined the methylation status of all annotated CpG islands and promoter sequences using methylated DNA immunoprecipitation (MeDIP). The integration of MYCN ChIP-chip and MeDIP data revealed a highly significant positive correlation between MYCN binding and DNA hypermethylation. This association was also detected in regions of hemizygous loss, indicating that the observed association occurs on the same homologue. In summary, these findings suggest that MYCN binding occurs more commonly at CATGTG as opposed to the classic CACGTG E-box motif, and that disease associated over expression of MYCN leads to aberrant binding to additional weaker affinity E-box motifs in neuroblastoma. The co-localization of MYCN binding and DNA hypermethylation further supports the dual role of MYCN, namely that of a classical transcription factor affecting the activity of individual genes, and that of a mediator of global chromatin structure

Coexistent sarcoidosis and lymphangioleiomyomatosis in a patient with cystic lung disease

A 45-year-old lady presented acutely with pleuritic chest pain, haemoptysis, and dyspnoea. Her background was significant for a 1.4 cm renal angiomyolipoma, and she was an ex-smoker without any relevant family history. A computed tomography (CT) pulmonary angiogram was negative for a pulmonary embolism but demonstrated diffuse cystic change throughout both lungs. A bronchoscopy confirmed a normal endobronchial tree, and pulmonary function tests demonstrated moderate airways obstruction, with reversibility and a normal diffusion capacity for carbon monoxide (DLCO). A video-assisted thoracoscopic surgery (VATS) lung biopsy showed non-caseating granulomas, and serum angiotensin converting enzyme (ACE) was elevated consistent with a diagnosis of pulmonary sarcoidosis. Further sectioning indicated focal areas that stained positive for Human Melanoma Black 45 (HMB-45), confirming lymphangioleiomyomatosis (LAM). A diagnosis of cystic lung disease secondary to coexistent sarcoidosis and LAM was made

Bronchoscopy in the investigation of outpatients with hemoptysis at a lung cancer clinic

Background: In the investigation of lung cancer, current practice in many healthcare systems would support bronchoscopy regardless of CT findings in patients with hemoptysis. We sought to identify the cause, the diagnostic yield of CT and bronchoscopy and the requirement for bronchoscopy in at risk patients with hemoptysis with a normal CT scan through our rapid access lung cancer clinic (RALC). Methods: Initially, a chart review was performed on all patients with hemoptysis (2011–2012) and thereafter a prospective analysis was performed (2013–2016). Results: Our analysis represents the largest study to date in outpatients with hemoptysis. In our retrospective study, 155 patients reported hemoptysis. Causes were lower respiratory tract infections (RTIs) (47%) and lung cancer (16%). Our prospective study included 182 patients. The causes of hemoptysis were RTIs (50%) and lung cancer (18%). There were no false negative CT-scans for lung cancer. 47/57 present with lung cancer underwent bronchoscopy and 43/47 were positive for lung cancer (92%). Patients with hemoptysis and lung cancer have a higher stage of malignancy with a predominance of squamous cell lung carcinoma. Smoking status, the duration of hemoptysis or description of hemoptysis were not predictive of lung cancer however lung cancer was not identified in patients age <50. Conclusions: One sixth of patients presenting with hemoptysis to our lung cancer clinic had lung cancer. No patient identified with cancer related haemoptysis had a CT negative for lung cancer and a combination of bronchoscopy plus endobronchial ultrasound trans-bronchial needle aspiration (EBUS-TBNA) in those patients with a CT suspicious of lung cancer is 92% sensitive for lung cancer causing hemoptysis

Tuberculosis in cattle: the results of the four-area project

<p/> <p>The four-area project was undertaken to further assess the impact of badger removal on the control of tuberculosis in cattle herds in Ireland. It was conducted between 1997 and 2002 in matched removal and reference areas in four counties, namely Cork, Donegal, Kilkenny and Monaghan, representing a wide range of Irish farming environments. In the removal areas, a proactive programme of badger removal was conducted, on two or three occasions each year, whereas in the reference areas, badger removal was entirely reactive following severe outbreaks of tuberculosis amongst cattle. A detailed statistical analysis of this study has already been presented by Griffin <it>et al. </it><abbrgrp><abbr bid="B13">13</abbr></abbrgrp>; this paper presents further, mainly descriptive, findings from the study. In total, 2,360 badgers were captured in the removal areas of which 450 (19.5%) were considered positive for tuberculosis and 258 badgers were captured in the reference areas, with 57 (26.1%) positive for tuberculosis. The annual incidence of confirmed herd restrictions was lower in the removal area compared to the reference area in every year of the study period in each of the four counties. These empirical findings were consistent with the hazard ratios found by Griffin <it>et al. </it><abbrgrp><abbr bid="B13">13</abbr></abbrgrp>. Further, the effect of proactive badger removal on cattle tuberculosis in the four-area project and in the earlier east-Offaly project, as measured using the number of reactors per 1,000 cattle tested, were very similar, providing compelling evidence of the role of badgers in the epidemiology of tuberculosis in Irish cattle herds. The validity of the four-area project was discussed in detail. Efforts to minimise badger-to-cattle transmission in Ireland must be undertaken in association with the current comprehensive control programme, which has effectively minimised opportunities for cattle-to-cattle transmission.</p

Pulmonary embolism and COVID-19

Aims: There is increasing concern amongst clinicians of a possible increase in venous thromboembolism (VTE) events in patients with COVID-19. There remains limited data defining the incidence of VTE in this population and thus also a paucity of research examining the impact of targeted treatment in patients with thrombotic complications. Methods: We examined the number of symptomatic VTE events amongst proven COVID-19 patients admitted to a tertiary level academic hospital, over a one-month period. Patient characteristics, admission and discharge inflammatory and coagulation markers were included in the analysis. Results: Sixty-one patients were identified. Twelve patients (19.6%) admitted with COVID-19 were treated for a suspected PE. Of these patients, 3 patients were discharged on anticoagulation, 3 died and 6 remain inpatients at the end of the study period. Discussion: COVID-19 patients are at increased risk of VTE. This risk may extend beyond the period of admission. Further research examining the role of extending the duration of thromboprophylaxis in COVID-19 patients beyond hospital discharge is warranted