The Journal Club

This is the Irish Thoracic Society (ITS) monthly journal club.  This journal club will alternate between SpRs and Consultants reviewing interesting and pivotal articles in press. The SpR Pick will be every other month where a pre assigned SpR will review a specific Respiratory Journal and identify and summarize four to five key articles within the last year.  The Expert Journal Review, will also be every other month where a Consultant will be invited to review pivotal articles that influenced their clinical practice.

November 2015 Dr Breda Cushen

In Case You Missed It: 

Important Articles from the American Journal of Respiratory and Critical Care Medicine 2015 by Dr. Breda Cushen


Impact of Prolonged Exacerbation Recovery in Chronic Obstructive Pulmonary Disease.

Donaldson, G. C., Law, M., Kowlessar, B., Singh, R., Brill, S. E., Allinson, J. P., & Wedzicha, J. A. American journal of respiratory and critical care medicine, 192(8), 943-950.

This group analysed symptom, peak expiratory flow (PEF), spirometric, exacerbation and quality of life (QOL) data from the London COPD cohort (N=384), from 1995 and 2013, to examine the impact of delayed exacerbation recovery on lung function decline and QOL and to identify any association between symptoms at exacerbation onset and non-recovery. Delayed exacerbation recovery was defined as failure of PEF to return to pre-exacerbation level within 99 days.

Prolonged exacerbation recovery was associated with shorter time to next exacerbation (HR 1.0004 per day, p<0.013). Annual lung function decline was found to be 10.8ml/year greater in patients with one or more prolonged exacerbation (p<0.001) and to result in poorer health-related QOL  as determined by the St George Respiratory Questionnaire (increase of 0.20units per 1 day longer recovery, p=0.04). Those reporting upper airway symptoms (upper airway colds and sore throat) on the day of exacerbation onset were significantly more likely to have non-recovered exacerbations (37.7% vs. 29.8% and 17.5% vs 12%, respectively p<0.01) suggesting a possible viral exacerbation trigger.

Final Statement: This study emphasises the need for close clinical follow-up of patients with AE COPD, particularly those presenting with viral symptoms, and the need for better therapies to both prevent and treat these events.


Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Toward Better Risk Stratification

Escalante, P., Peikert, T., Van Keulen, V. P., Erskine, C. L., Bornhorst, C. L., Andrist, B. R.,& Limper, A. H.  American journal of respiratory and critical care medicine, 192(5), 605-617.

The hypothesis of this study was that TB immunoreactivity profiles differ between unexposed patients, untreated and treated Latent TB (LTBI) patients and may be used to differentiate patients at high and low risk of TB reactivation.  Biomarker profiles were determined on 65 subjects, most of whom were healthcare workers using combined Quantiferon (QFT) and flow cytometry (FC) assay of CD25 and CD134 T cell expression to TB antigens.  An online calculator was used to estimate the cumulative risk of TB reactivation.  Significant differences in immune profile were identified between groups. Unexposed subjects and those with previously treated LTBI had negative FC assays with 8 of the 17 treated LTBI patients retaining QFT positivity. Untreated subjects varied between those with low/undetectable to high CD25 and CD134 T cell expression and all subjects with both FC assays positive were QFT positive. Cumulative TB reactivation risk also differed between groups. Those with combined QFT and FC assay positivity had the highest cumulative risk of TB reactivation (4.11±2.11% and 3.94±2.08%). The risk of reactivation in those who were QFT positive but FC assay negative was significantly reduced (1.62±1.68% and 1.71±1.82%) and the lowest risk was amongst those who were both QFT and FC assay negative (0.34±0.77% and 0.42±0.97%).

Final Statement: The predictive value of these biomarkers need to be evaluated in a larger and wider patient population.


Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive Pulmonary Disease Implications for Dyspnea and Exercise Intolerance

Amany F. Elbehairy, Casey E. Ciavaglia, Katherine A. Webb, Jordan A. Guenette, Dennis Jensen, Sahar M. Mourad, J. Alberto Neder, and Denis E. O’Donnell; on behalf of the Canadian Respiratory Research Network, American Journal of Respiratory and Critical Care Medicine, Vol.191, No. 12 (2015), pp.1384-1394.

This study examined pulmonary gas exchange during incremental exercise and its relationship with clinical symptoms, exercise tolerance and dynamic respiratory mechanics in a cohort of 11 patients with symptomatic mild COPD (GOLD Grade 1B) as compared with 11 healthy, age-matched, non-smoking controls. In exercise, COPD patients had reduced peak work rate (102±43 vs 158±40) and peak VO2 versus control. Minute ventilation (VE) increased achieved by increasing respiratory rate.  For a given work rate, tidal volume responses were similar in both groups up to a plateau point seen in late exercise. In COPD patients this point occurred at a lower VE (44.5±13 vs. 61.4±16). Greater dynamic hyperinflation (reduction in IC from rest) was noted during exercise in COPD patients who also showed greater expiratory flow limitation (EFL) than control subjects. VE/VCO2, dead space to tidal volume ratio and arterial to end-tidal CO2 difference were higher in COPD subjects throughout exercise. Within all subjects, VD/VT correlated with the VE/VCO2 ratio during submaximal exercise.

Final Statement: Patients with mild COPD demonstrate greater physiological deadspace and wasted ventilation at rest and during exercise when compared with age-matched healthy controls and the increase in ventilatory demand results in greater dynamic hyperinflation during exercise.


TOLLIP, MUC5B and the Response to N-acetylcysteine Among Individuals with Idiopathic Pulmonary Fibrosis

Oldham, J. M., Ma, S. F., Martinez, F. J., Anstrom, K. J., Raghu, G., Schwartz, D. A., & Noth, I. American journal of respiratory and critical care medicine. In Press

A post-hoc exploratory analysis of non-Hispanic white patients enrolled in the PANTHER-Idiopathic Pulmonary Fibrosis (IPF) trial was carried out to determine whether single nucleotide polymorphisms (SNPs) within toll interacting protein (TOLLIP) and mucin 5B (MUC5B) modified the effect of N-AcetylCysteine (NAC)  therapy on composite endpoints- time from enrolment to death, transplant or ≥10% FVC decline. Results were verified in a further cohort of patients from the University of Chicago (UChicago) and the INSPIRE trial.

Analysis of a total of 559 participants from the three cohorts found that NAC was associated with significantly worse survival compared with placebo in those patients with a CC genotype for the rs3750920 (TOLLIP) SNP. In the UChicago and INSPIRE cohort this risk was also increased in those with CT genotype. A significantly reduced endpoint risk was seen in those with TT genotype (HR 0.14; 95% CI 0.02-0.83; p=0.03 and HR 0.23; 95% CI 0.06-0.93; p=0.04 for PANTHER and UChicago plus INSPIRE respectively).

Final Statement: In those IPF patients who carry the TT genotype (~25%), NAC therapy may result in significant reductions in the risk of death, hospitalisations, or ≥10% FVC decline, however in those with the CC and potentially the CT genotype it can cause significant harm.


Thinking Forward: Future-oriented Thinking Among Patients with Tobacco-associated Thoracic Diseases and Their Surrogates

Hart, J. L., Pflug, E., Madden, V., & Halpern, S. D. American journal of respiratory and critical care medicine In Press

Through semi-structured interview, this study explored whether 46 patients with smoking-related disease and their surrogates could engage in future-oriented thinking when faced with one of three specific scenarios: intubation or palliative care for respiratory failure in COPD patients; biopsy or surveillance of a pulmonary nodule; and ICU or palliative care for patients with NSCLC who become critically ill.  Participants did attempt to engage in future-oriented thinking during deliberation but often made systematic errors. Despite being informed of all potential outcomes, they were often unwilling to entertain notions of the future particularly those which involved potentially negative outcomes. They relied heavily on prior personal experiences to inform future predictions and many were willing to accept or reject the most familiar option based on prior experience even when there was little similarity between the previous and current situation. Participants also relied heavily on hope in deliberating treatment options whilst acknowledging that this may lead to inaccurate evaluation of treatment options.

Final Statement: Clinicians should explore the references patients are using to make treatment choices and guide them in addressing the similarities and differences between past experiences and the present situation so that patients can make a more informed decision.