Year in review 2013: Lung cancer, respiratory infections, tuberculosis, cystic fibrosis, pleural diseases, bronchoscopic intervention and imaging

Abstract

This Year in Review examines the most relevant articles published on lung cancer, respiratory infections, tuberculosis (TB), cystic fibrosis (CF), pleural diseases, and interventional pulmonology and imaging in Respirology and other respiratory medicine journals during 2013. Important findings are highlighted with comments in the following sections, each of which was contributed by an author as named in the beginning of each section. Kazuhisa Takahashi Lung cancer is the leading cause of cancer-related death worldwide.1 The economic and social burden of chronic obstructive pulmonary disease (COPD) and lung cancer is dramatically increasing worldwide.2, 3 The World Health Organization estimated that COPD and lung cancer will become the third and fifth causes of death in the year 2020, respectively.4 COPD is well known to be a risk factor and important coexisting disease for lung cancer. However, the current status of the epidemiological relationship between COPD and lung cancer and the management of COPD in lung cancer patients are not fully understood. Therefore, Zhang et al. investigated several clinical questions described as follows: (i) the rate of diagnosis of COPD in patients with lung cancer; (ii) conformity to the Global Initiative for Chronic Obstructive Lung Disease treatment guidelines for COPD; and (iii) factors that may promote the timely diagnosis of COPD in the lung cancer population.5 The authors retrospectively reviewed the medical records of hospitalized lung cancer patients, calculated the rate of diagnosis of COPD based on Global Initiative for Chronic Obstructive Lung Disease's spirometric criteria and investigated conformity to the Global Initiative for Chronic Obstructive Lung Disease treatment guidelines. The prevalence of COPD in hospitalized lung cancer patients was 21.6%. The overall rate for the diagnosis of COPD was 7.1%. Very interestingly, the treatment conformity for stable and acute exacerbation of COPD was 27.1% and 46.8%, respectively. Moreover, the rate of diagnosis of COPD was higher among patients with a history of smoking, respiratory diseases and symptoms. These results suggest that COPD is substantially underdiagnosed and undertreated in hospitalized patients with lung cancer. Documenting tobacco exposure and respiratory symptoms would help to improve COPD management. An excellent review with regard to lung cancer stem cells (CSC) was provided by Alamgeer et al.6 CSC are believed to be a phenotypically distinct population that possesses a tumourigenic potential. CSC are potential therapeutic targets, as they are considered to be involved in relapse after intensive treatment and innate resistance to chemotherapy and molecular target agents. Alamgeer et al. reviewed the evidence with regard to the existence and function of lung CSC in the context of experimental and clinical studies, and discussed the controversies regarding these models.6 The remarkable ability of lung cancer to recur despite definitive local and/or systemic therapy suggests that minimal residual disease contains a population of cells with an enormous capacity for self-renewal and regeneration, a biological function generally limited to somatic CSC. In order to detect CSC, identifying specific cell surface markers is essential. However, no universal lung CSC markers have been discovered to date. Although several CSC markers, such as the CD133, CD44 and aldehyde dehydrogenase activity, have been reported to be good candidates for CSC markers,7-9 none appears to be satisfactory with regard to specificity and sensitivity. Over the past few decades, the management of advanced-stage lung cancer has been revolutionized from systemic chemotherapy to the present stage of testing for molecular biomarkers (epidermal growth factor receptor (EGFR) gene mutations, the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene and so on) to select appropriate therapies and improve the efficacy of treatment. Molecular biomarkers for lung cancer may be used in the following situations, in addition to guiding treatment decisions: (i) risk identification using risk-associated markers; (ii) early detection or diagnosis; and (iii) prediction of the treatment response and prognosis. Lam published an excellent review article with regard to the current understanding of molecular targets that are important for personalized therapy for lung cancer, specifically how testing for these molecular targets, namely EGFR, Kirsten rat sarcoma viral oncogene homolog and anaplastic lymphoma kinase, guides therapeutic decision making in the setting of advanced stage lung cancer.10 He emphasized that multigene analyses could be of use in future individualized therapy for non-small cell lung cancer (NSCLC) and that several mass mutation assays, such as Raindance (RainDance Technologies, Lexington, KY, USA), SNaOshot (Applied Biosytems, Foster City, CA, USA), are already in place. Large prospective studies are ongoing among multiple institutions, including the Lung Cancer Mutation Consortium, performing mass mutation analyses in patients with advanced NSCLC, with specific clinical trials linked to different mutations. Whole genome deep sequencing is coming into application and will provide a more thorough and comprehensive view of lung cancer.11 The molecular profile of lung cancer, particularly adenocarcinoma, however, differs between patients in Asian and Western countries. For example, the rate of positive EGFR activation mutations is approximately 50% in Japanese patients and less than 30% in patients in the United States.12 Therefore, it is quite important to establish a comprehensive screening strategy to detect EGFR mutations in Asian patients with lung adenocarcinoma. Ho et al. reported a molecular diagnostic algorithm for EGFR gene mutation detection in Taiwanese patients with adenocarcinoma.13 A total of 445 adenocarcinoma patients were recruited for an analysis of tumour EGFR mutations using immunohistochemistry with mutation-specific antibodies, polymerase chain reaction-direct sequencing and Scorpion/amplified refractory mutation system methods. In this algorithm, immunohistochemistry with mutation-specific antibodies is used to screen EGFR mutations. Immunohistochemistry-negative samples are subjected to polymerase chain reaction-direct sequencing methods to identify EGFR mutations. polymerase chain reaction-wild samples are further analysed using Scorpion/amplified refractory mutation system technology. Samples negative for EGFR mutations using all methods are further examined for the status of other driver mutations, such as human epidermal growth factor receptor 2 and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase translocation. A recent publication indicated a relationship between the preoperative maximum standardized uptake value (SUVmax) in positron emission tomography and the EGFR mutation status in lung cancer.14 In this previous study, EGFR-mutated adenocarcinomas of the lungs presented with low SUVmax values, and the authors suggested that EGFR mutation testing may be omitted in patients with a high SUVmax. However, the relationship between the SUVmax on positron emission tomography and the EGFR mutation status remains controversial. Putora PM et al. investigated the SUVmax values in 14 patients with EGFR mutations and 14 patients with wild-type EGFR adenocarcinomas.15 The mean SUVmax value was 10.7 in the EGFR-mutated tumours and 9.9 in the wild-type adenocarcinomas. There were no correlations between the SUV values and EGFR mutation status. Therefore, excluding EGFR testing for lung cancer in patients with a low SUVmax is not feasible. Pemetrexed plus cisplatin has been shown to be efficacious as a first-line treatment for advanced NSCLC. In a recent randomized, non-inferiority, phase III trial, pemetrexed plus cisplatin and gemcitabine plus cisplatin were compared in patients with advanced NSCLC.16 Based on this study, the pemetrexed plus cisplatin regimen is effective and well tolerated and has therefore been approved by the US Federal Drug Administration for use in patients with non-squamous NSCLC. However, little is known about its efficacy and safety in the East Asian population. Zhang X et al. reported the final analysis of overall survival from a multicenter, randomized phase II study in chemotherapy-naïve Chinese patients with advanced NSCLC.17 In that study, a total of 254 patients with NSCLC were randomized to receive either pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) (day 1) or gemcitabine (1000 mg/m2) (day 1 and 8) plus cisplatin (75 mg/m2) (day 1). The median overall survival in the pemetrexed/cisplatin arm was 15.3 months, while that in the gemcitabine/cisplatin arm was 16.9 months (hazard ratio: 1.09; 95% confidence interval: 0.80–1.48, P = 0.488). The patients in the pemetrexed/cisplatin arm exhibited better tolerance than those in the gemcitabine/cisplatin arm. Secondary analysis suggested that the pemetrexed/cisplatin treatment was associated with longer survival among females and patients with non-squamous cell carcinoma. Marcos I. Restrepo Much interesting data have been reported during the past year in Respirology focusing on different pneumonia related issues, such as diagnosis, pneumonia characterization and treatment studies. Two interesting studies evaluated the use of a biomarker and Streptococcus pneumoniae urinary antigen test to improve the diagnosis and assess the prognosis of patients with pneumonia. Horita N et al.18 used a meta-analysis to assess the sensitivity and specificity of the Binax Now S. pneumoniae urinary antigen test (Binax, Portland, ME, USA) for unconcentrated urine from adult patients with pneumonia. The reference standard was the presence of at least one positive culture and/or smear for S. pneumoniae. The authors suggest that the S. pneumoniae urinary antigen is an important test to rule in (95% specificity), but not perfect to rule out (75% sensitivity) pneumococcal infection, respectively. Lin SC et al.19 evaluated whether N-terminal pro-brain natriuretic peptide (NT-proBNP) could be used to assess prognosis among pneumonia patients who required intensive care unit (ICU) admission. NT-proBNP levels were statistically significantly higher in patients who died compared with survivors. Further studies are needed to evaluate the clinical application of this novel biomarker in patients with severe community-acquired pneumonia (CAP). Several manuscripts published during last year focused on health care-associated pneumonia (HCAP), aspiration pneumonia and necrotizing pneumonia. An elegant and thorough review performed by Dobler and Waterer20 exposed the similarities and differences of the term ‘HCAP’ and their clinical relevance between the United States and the Asia Pacific region. The authors explored the controversies that emerged over the past few years, questioning the risks related to overcall this condition and the need to cover empirically for multidrug-resistant (MDR) pathogens, which may potentially induce overtreatment. The authors suggested that for the Asia Pacific region, an individual MDR risk-factor assessment should be performed rather than applying the broad HCAP classification in order to inform the appropriate selection of empirical antimicrobial therapy. In the same area of research, Taylor and Taylor21 performed an important evaluation of HCAP patients who received haemodialysis according to the treatment with narrow versus broad-spectrum antibiotic therapy. HCAP patients were more likely to have longer time (by 6 days) to switch to oral therapy and longer length (by 6 days) of hospital stay. In addition, there was a trend towards longer time to achieve clinical stability and longer continuation of intravenous antibiotics after reaching clinical stability in HCAP patients compared with patients treated with CAP-concordant antibiotic regimens. The authors suggested that narrow-spectrum antibiotics might be safe in haemodialysis patients with no other HCAP risk factors. Komiya K et al.22 evaluated the impact of aspiration pneumonia in patients with CAP and HCAP. Aspiration pneumonia was defined as having both risk factors for aspiration (dysphagia due to a neurological disorder, or disturbance of consciousness) and evidence of gravity-dependent opacity on chest computed tomography (CT). Aspiration pneumonia occurred in 18% of the patients and it was independently associated with increased 30-day mortality. Prompt identification of aspiration risk among patients with pneumonia may predict a poorer outcome. Finally, Seo H et al.23 described the clinical characteristics and clinical course of patients with focal necrotizing pneumonia as a distinct entity from lung abscess. ‘Focal necrotizing pneumonia’ was defined as a localized type of necrotizing pneumonia characterized by a single or few cavities of low density without rim enhancement on CT scan. The authors concluded that compared with lung abscess, focal necrotizing pneumonia occurred more frequently in non-gravity-dependent segments, had higher rates of aerobic bacteria and had lower incidence of risk factors for aspiration. However, similar to lung abscess, patients with focal necrotizing pneumonia had a high rate of clinical success with appropriate treatment of 97%. Recent studies have raised concerns about the association between the use of inhaled corticosteroids (ICS) and the risk of developing pneumonia in patients with COPD. Zhang L et al.24 evaluated in a cross-sectional study the association between ICS and S. pneumoniae oropharyngeal colonization among asthmatic children. The authors identified that after adjusting for potential confounders, asthmatic children had a fourfold higher risk of oropharyngeal S. pneumoniae carriage when they received ICS therapy as compared with non-ICS exposed asthmatic children. Lee CH et al.25 evaluated the risk of hospital admission or emergency room visit for pneumonia in patients using respiratory inhalers such as long-acting β2 agonist and ICS. A large case-crossover Korean national claims database study was used to assess 186 018 inhaler users who visited the emergency department or were admitted to the hospital during a 3-year period. The results showed that the use of an ICS without a long-acting β2 agonist was associated with a 73% increased risk of hospital admission or emergency room visit for pneumonia. In contrast, the use of an ICS and a long-acting β2 agonist was associated with a 37% decreased risk for pneumonia-related hospital admission or emergency room visit. Polverino E et al.26 described the frequency of the use of systemic corticosteroids in patients with CAP, the reasons for use and the clinical impact on outcomes. The main reasons for administering systemic steroids were the presence of chronic respiratory comorbidity and severe clinical presentation, but therapy did not influence mortality or clinical stability. In contrast, systemic corticosteroid administration was associated with prolonged hospital stay. These results suggest that well-designed randomized clinical trials are needed to evaluate the influence of systemic corticosteroids on clinical outcomes of patients with CAP. Marras TK et al.27 assessed the associations among CT features, symptoms and microbiological disease criteria in patients with pulmonary Mycobacterium xenopi infection. Seventy consecutive immunocompetent patients with pulmonary M. xenopi isolation and classified according to the American Thoracic Society diagnostic criteria for disease were included in the study. Among them, cavitation and large pulmonary nodules predicted fulfilling microbiological disease criteria, while bronchiectasis and small pulmonary nodules predicted active symptoms. Jeon K et al.28 evaluated in an age- and gender-matched case–control study the prevalence and degree of severity of vitamin D deficiency in patients with NTM lung disease. After adjusting for potential confounding factors, the authors identified that severe vitamin D deficiency with levels below 10 ng/mL was independently associated with NTM lung disease. However, they suggest that further studies are needed to assess for causality. Burguete SR et al.29 performed an elegant review on lung transplant-related infections. The authors emphasized that despite improved survival rates over the decades, lung transplant recipients have lower survival rates compared with other solid organ transplant recipients. The morbidity and mortality following lung transplantation is largely due to infection and rejection-related complications. This comprehensive review focused on the most common infections that develop in lung transplant recipients, including the epidemiology and risk factors, microbiology, diagnosis, prophylaxis, treatment and outcomes. Chi Chiu Leung A recent analysis of the genomic sequences of Mycobacterium tuberculosis complex isolates from different parts of world suggested that the tubercle bacillus emerged about 70 000 years ago, accompanying migrations of anatomically modern humans out of Africa.30 The pathogen has developed various mechanisms to allow its successful co-existence with the human host during the long period of co-evolution, and the gap in our current knowledge on the complex microbe–host interactions has been hindering research and development in various aspects of TB control.31 Bacillus Calmette–Guérin vaccine offers only partial and unreliable protection against pulmonary TB in adults, the crucial transmission link for this airborne infection.31 Wang CC et al. reviewed new discoveries in latency antigens and new next-generation candidate vaccines that could promise the possibility of sterile eradication.32 In the development of TB vaccine, the conventional ‘Identify, Inactivate/Attenuate, Administer’ approach is limited the lack of long-lasting immunity following recovery from natural infection/disease.31, 32 Systems biology and vaccinomics may help to shorten development of an efficacious TB vaccine targeting both growing bacteria and non-growing persisters through utilization of high-throughput technology, computer modelling and integrative approaches.32 Targeted screening and treatment of latent TB infection with the currently available immunodiagnostic tools and treatment regimens aims more for personal protection than major epidemiological impact or elimination.30, 33 Positive predictive values of the immunodiagnostic tests for the development of TB are substantially influenced by the type of test, the age of the person being tested, the prevalence of TB in the society and the risk group to which the person belongs.33 Although interferon-γ release assay, not being affected by cross-reaction to the bacillus Calmette–Guérin vaccine, has improved the diagnosis of latent TB infection in immunocompetent individuals, its respective sensitivity/specificity values in patients with immune-mediated inflammatory diseases to be started on biologics are unknown owing to variable pretest probability and lack of confirmatory test.34 The use of interferon-γ release assay for such screening is therefore variable among different countries. Serial interferon-γ release assay, being done in vitro, has a theoretical advantage of not affecting subsequent test response in situations with ongoing TB exposure. However, there is question on its intrinsic reproducibility as well as the actual criteria and implication for test conversion.31, 35 Randomized controlled trials have established the protective efficacy of isoniazid therapy for 6–12 months among human immunodeficiency virus (HIV)-infected and non-HIV-infected subjects with latent TB infection, even though controversies remain on the optimal treatment duration.31, 34 Directly observed weekly therapy with rifapentine plus isoniazid for 12 weeks offers an attractive alternative in both HIV-infected and non-HIV-infected subjects.34, 36 Uncertainty remains on the role of prolonged isoniazid therapy among HIV-infected individuals.36 Controversies also persist over the use and the choice of preventive treatment for MDR-TB contacts, largely as a result of the variable risks of developing either drug-susceptible TB or MDR-TB and the currently limited treatment options.31, 34 An accurate and affordable point-of-care test is needed to address the currently unmet needs in the diagnosis of TB.37 Controversies remain over TB screening among immigrants from high-prevalence countries, regarding when, where and in whom radiographs are best done for transborder TB control.38 Enhanced symptom screening and wider application of affordable molecular diagnostics are urgently needed to facilitate early diagnosis of TB in an HIV-infected person.36 While some genotypic diagnostic tools, such as the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA), may show promise as a potential point-of-care test for diagnosis of both TB and drug resistance,37 genomic sequencing of M. tuberculosis isolates discovered a large number of new genes, intergenic regions and non-synonymous single nucleotide polymorphisms, showing consistent associations with drug resistance, which indicates that the genetic basis of drug resistance is more complex than previously anticipated.39 In contrast with conventional phenotypic drug susceptibility testing using automated liquid culture system (Bactec MGIT960, Becton, Dickinson and Company, Franklin Lakes, NJ, USA), neither line probe assays nor sequencing were able to detect the clinically important 1% resistant bacteria in simulated patient samplings containing mixtures of rifampicin-resistant and susceptible M. tuberculosis strains.40 However, highly discordant drug susceptibility test results were observed between Löwenstein–Jensen medium and MGIT960 for M. tuberculosis isolates with certain rpoB mutations (511Pro, 516Tyr, 533Pro, 572Phe and several 526 mutations), with MGIT-drug susceptibility test failing to give a result or declaring the strains susceptible.41 In another study comparing the MGIT 960 System against Löwenstein–Jensen proportion method, the critical concentrations of moxifloxacin (0.5 μg/mL), levofloxacin (1.0 μg/mL), kanamycin (2.5 μg/mL) and capreomycin (2.5 μg/mL) were concordant and reliable for testing second line drug resistance, while further studies are required for ethionamide and ρ-aminosalicylic acid.42 In an observational study by Horita N et al. in Japan, decreased activity of daily living was found to be a strong risk factor for liver injury among adult inpatients treated with a standard regimen for newly diagnosed smear-positive pulmonary TB.43 To balance the competing risks related to delayed antiretroviral therapy and antiretroviral therapy-related immune reconstitution inflammatory syndrome, early initiation of antiretroviral therapy is indicated, preferably within 2 weeks after starting TB treatment, for patients with a cluster of differentiation 4 cell count of <50 cells/μL, except in case of central nervous system involvement.36 Globally, 3.7% of new cases and 20% of previously treated cases have MDR-TB, but the scale-up of programmatic management of drug-resistant TB remains slow.42 The overall treatment success rate of MDR-TB cases notified to World Health Organization in 2009 was only 48%, far below the global target of 75%.44 Management strategies for established cases of difficult MDR-TB/extensively drug-resistant TB rely on harnessing existing drugs (notably newer generation fluoroquinolones, high-dose isoniazid, linezolid and pyrazinamide with in vitro activity) in the best combinations and dosing schedules, together with adjunctive surgery in carefully selected cases.45 Linezolid 300 mg daily46 or intermittent administration of higher doses47 may help to reduce its often treatment-limiting toxicity. Bedaquiline has recently been approved by the US Federal Drug Administration to treat adults with MDR-TB when other alternatives are not available, but concerns remain over possible fatal arrhythmia risk associated with prolonged Q-T interval.48 The use of delamanid for 6 months or more significantly improved outcomes and reduced mortality in MDR-TB as compared with its use for 2 months or less in an observational study, but the European Medicines Agency considers the currently available evidence inadequate for substantiating use of delamanid for treating MDR-TB.49 Claire E. Wainwright In January 2012, the US Federal Drug Administration approved the registration of ivacaftor for patients with CF aged ≥6 years carrying at least one copy of the G551D mutation. Ivacaftor is a potentiator and increases the open probability of the G551D protein. The G551D mutation is a gating mutation that results in a normal quantity of protein available in the plasma membrane but with reduced open probability of the channel. The impressive and sustained improvements in lung function and weight and reduction in sweat chloride levels reported in the first phase 3 trial were mirrored in the second of the phase 3 trials which recently report the paediatric results that supported the Federal Drug Administration registration of ivacaftor.50 While the prevalence of patients carrying a G551D mutation varies, on average, approximately 4% of patients carry the mutation. This therapy has heralded a new dawn of personalized medicine specific for genetic mutations for patients with CF. The most common, the CF transmembrane regulator mutation, a deletion of phenylalanine at position 508 in the nucleotide binding domain 1 of CF transmembrane regulator (ΔF508) is carried on at least one allele by around 66% of patients with CF worldwide. This mutation leads to impairment and disruption of protein folding leading to degradation in the ubiquitin proteasome system, and as a result, there is almost no functional protein expression at the plasma membrane. Complex approaches appear to be required to chaperone and rescue the ΔF508 protein. Okiyoneda T et al. describe the molecular targets of available correctors and how a combination of mechanism-based approaches will be needed to more fully correct the ΔF508 protein.51 While the ΔF508 is the most common mutation, there are now almost 2000 variants of CF transmembrane regulator reported and understanding which of these variants are actually disease causing and the functional consequences of the mutations will be key in both establishing appropriate diagnoses through newborn screening and enabling mutation specific treatment approaches in the future. Sosnay PR et al. used a combination of genotype and phenotype data from 39 696 individuals with CF in registries from Europe and North America.52 They evaluated 159 variants with allele frequency ≥ 0.01% and assessed for clinical and functional criteria to identify 127 disease-causing mutations. For 32 mutations that were unable to be characterized, they performed a novel disease penetrance study in 2188 fathers of patients with CF and were able to assign 12 as non-disease variants. End-stage lung disease in CF is characterized by both bronchiectasis which increases in prevalence and severity with age, and air trapping which occurs frequently in early infancy.53, 54 2013 has seen two landmark studies that shed new understanding of early lung disease in CF. Sly PD et al. reported that free neutrophil elastase activity in bronchoalveolar lavage at 3 months of age was associated with persistent bronchiectasis at 12 and 36 months of follow up.55 These important results provide new opportunities for the development of interventions aimed at preventing early lung disease. In a paradigm shifting paper, Adam RJ et al. have demonstrated that air trapping and airflow obstruction occur in newborn CF piglets prior to any airway infection and inflammation suggesting that CF is associated with congenital airway abnormalities which are likely to impact on the development of lung disease.56 Clinical trials in young children are complicated by the difficulty in finding objective, non-invasive outcome measures. Lung clearance index (LCI) measured using a multiple breath washout detects ventilation inhomogeneity which is a recognized consequence of CF lung disease. LCI has been shown to predict subsequent pulmonary exacerbations in children aged 5–19 years with CF.57 A statistically significant treatment effect in favour of inhaled hypertonic saline on LCI performed at a single centre as a substudy of the randomized controlled Infant Study of Inhaled Saline trial suggested that LCI may be a feasible outcome measure in young children.58 The United Kingdom CF Gene Therapy Consortium conducted a multicentre observational study of patients aged ≥10 years at the start and after completion of treatment of a physician-defined pulmonary exacerbation using intravenous antibiotic therapy. The study was designed to identify and investigate changes in 46 different assays spread across domains of lung structure, lung function, clinical symptoms, and pulmonary and systemic inflammatory markers.59 Improvements were detected predominantly in large airway parameters and systemic inflammation in response to the acute intervention, and the use of LCI was extended to a multicentre setting with suggestion that it may be better suited as an outcome measure in milder lung disease. A recent randomized controlled trial of inhaled glutathione given twice daily over 6 months in patients ≥8 years aimed at reducing oxidant stress and inflammation in the airways showed no clinically relevant benefits in lung function or markers of oxidative stress or inflammation.60 Survival has improved dramatically over the last 30 years in patients with CF, and in many countries, there are now more adults than children with CF. As a result, there are increasing numbers of adult patients with severe lung disease and limited respiratory reserve who are living much longer making the