Lung cancer in never smokers (LCINS) is often considered a different disease entity with a distinct molecular sub-classification. Notably, actionable mutations in epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten Rat sarcoma viral oncogene homolog (KRAS) and anaplastic lymphoma kinase (ALK)-rearrangement are three major recurrent oncogenic alterations in LCINS. HER2 and BRAF mutations, ROS1 and RET rearrangements are also included, although these are known to occur with low frequencies. Although the overall response rate (ORR) to EGFR tyrosine kinase inhibitors (TKIs) in unselected patients was only 10 %, subgroup analyses revealed comparatively higher response rates and survival in women, never smokers and Asians harbouring EGFR mutations, suggesting a predictive and/or prognostic significance among patients with mutated EGFR by smoking status. Differences in the prevalence of KRAS mutations between subgroups have also been described: 8 % of never smokers versus 57 % of former/current smokers with lung adenocarcinoma harbour KRAS mutations, and although 3 % to 5 % of unselected patients with lung adenocarcinoma have ALK rearrangements, the frequency appears to be more pronounced in never smokers. There is a suggestion that prognostic and predictive relevance of KRAS mutations varies by smoking status, but it is still less characterized as well as the smoking-related prognostic and predictive value of ALK rearrangement and the other alterations, which are still largely unknown. Clinical trials of lung cancer patients should always be stratified by smoking history and the identification of differences according to smoking status may help optimize future targeted therapies.
The recognition that chronic graft dysfunction after lung transplantation is a heterogeneous phenomenon has led to the introduction of a new term: chronic lung allograft dysfunction (CLAD). An International Society for Heart and Lung Transplantation working group will determine a definition of CLAD in 2014. It is thought that CLAD should not totally replace bronchiolitis obliterans syndrome (BOS), the conventional phenotype of chronic graft dysfunction, but that it should be a more comprehensive category that includes BOS as a purely obstructive disorder. Another phenotype to be included is restrictive allograft syndrome, a restrictive form of graft dysfunction that is distinct from BOS. Neutrophilic reversible allograft dysfunction may be included in CLAD as well. Further discussion is required before including other conditions associated with impaired pulmonary function after transplantation. Recent progress in the management of patients with CLAD includes the development of a series of diagnostic tests and recognition of the benefits of a trial of low-dose azithromycin. Further refinement of our understanding of the pathophysiology of CLAD and clinical care pathways is necessary.
In the majority of pleural effusions, chest radiograph and transthoracic ultrasonography (TUS) are sufficient for clinical management. TUS is able to identify very small volumes of fluid, suggest a malignant etiology, and guide pleural procedures. Computed tomography is of particular value in pleural effusions of uncertain etiology, whereas positron emission tomography and, specifically, magnetic resonance imaging are solely indicated for very select cases. This pictorial review addresses the main radiological signs of frequently encountered causes of pleural effusions.
Fibrotic hypersensitivity pneumonitis (FHP) is a specific form of HP defined by chest imaging evidence or pathologic evidence of fibrosis or scarring. Fibrotic HP appears to be irreversible, is often progressive and frequently indistinguishable from other forms of chronic fibrosing interstitial lung diseases (ILD), in particular idiopathic pulmonary fibrosis (IPF). Accurate diagnosis is a challenge given the diverse and often nonspecific clinicoradiologic patterns, heterogenous clinical course, and a frequent lack of a readily recognizable temporal relationship between exposure to an inciting antigen (IA) and symptoms in more than half of the patients. This chapter focuses on the clinical features, diagnostic evaluation and management of FHP.
Lung cancer has long been regarded as a poor candidate for immunotherapy, because it has a relatively low content of tumor-infiltrating lymphocytes compared with, for example, melanoma. However, new developments in immunotherapy are about to change this situation. Therapeutic vaccines are different from the well-known prophylactic vaccines, in that they are designed to treat patients already suffering from a disease instead of preventing the disease in healthy individuals. Several therapeutic vaccines are in late-stage clinical development for non-small-cell lung cancer (NSCLC). These vaccines use different approaches, including peptides, cell lines or viral vectors, and are used in different settings within the pathology. Some are given as monotherapy, whereas others are combined with traditional therapy for this indication. More recently developed, and very promising, are the checkpoint-blocking antibodies. It is likely that in the future several approaches, including immunotherapy products, will be combined in the evolving standard of care for lung cancer. This review gives a summary of the candidate immunotherapy products currently in late-stage clinical development for NSCLC.
Primary mediastinal B-cell lymphoma is an established subtype of non-Hodgkin Lymphoma with distinguishable histopathological and clinical features. It characteristically presents with a bulky mediastinal mass and in a younger, predominantly female population. Advanced age, high LDH levels, and poor performance status are associated with poorer prognosis. Endobronchial ultrasound-guided transbronchial needle aspiration may be a valuable tool for establishing the diagnosis. At a molecular level, it has overlapping traits with nodular sclerosis classical Hodgkin Lymphoma. There is a variety of treatment options, with no standardized regimen. The use of rituximab combined with chemotherapy has correlated with good outcomes. The use of consolidative radiotherapy is controversial, with questionable benefit and established long-term toxicity, including secondary malignancy and cardiovascular disease. An FDG-PET scan is indicated when monitoring for response, because a residual mediastinal mass is commonly seen upon treatment completion but does not always indicate active disease. Relapse usually occurs within the first year, but overall survival is similar to that for diffuse large B-cell lymphoma.
The diagnosis and management of nontuberculous mycobacterial (NTM) lung infection remains difficult even among experienced clinicians. Both the incidence and prevalence are likely expected to rise with an aging population. Careful assessment of clinical, radiologic, and microbiologic studies is warranted before initiating therapy, which is often complicated by significant drug side effects and limited sputum conversion rates. Indications to treat are best based on a number of factors, including specific NTM species, NTM lung-infection–associated symptoms, advanced bronchiectatic or cavitary disease, expected tolerance of therapy, and related comorbidities. Surgical resection of localized disease or refractory infection may warrant consideration, but should be done by an experienced surgeon and mycobacterial program. Increased awareness and treatment of NTM lung infection in recent years is likely due to earlier recognition and improved treatment strategies, though the approach to the NTM lung infection patient most often involves chronic lung disease management. NTM lung infection is perhaps is best characterized as a treatable lung infection, even without universally curable outcomes.
The field of pulmonary fungal infections is constantly evolving. The at-risk population continues to increase, and the endemic areas for the dimorphic fungi are expanding with new outbreaks reported across the world. Novel diagnostic methods are being developed and existing methods improved and refined. If started in a timely fashion, currently available antifungal agents are fairly effective. In this review we highlight the recent updates in fungal pneumonias focusing on epidemiology, diagnosis, and treatment.
Optical coherence tomography (OCT) is a high-resolution imaging modality that uses near infrared light reflected from the tissue optical interfaces to generate real-time images with near-histology resolution. Bronchoscopic use of OCT has potential applications in the study, diagnosis, monitoring, and treatment of asthma, COPD, and histologically benign and malignant central airway disorders. This paper provides an overview of the rationale and principles of OCT imaging, describes the limitations of current technology, and summarizes potential future developments that may overcome the existing challenges.
Lung transplantation (LT) for treatment for end stage lung disease is becoming increasingly available, and can improve survival and quality of life for some patients. Because of limited availability of donor organs and because of limited post-transplant survival of recipients, appropriate selection of candidates is invariably important. Since the revision of the 2006 international guidelines for selection of lung-transplant recipients, new literature has continued to improve our understanding of the effect of non-pulmonary comorbidities on disease-specific prognosis. By applying this new understanding to evaluation of potential lung-transplant recipients, we can best ensure optimum allocation of the limited resource of donor organs to recipients that are most likely to benefit from LT. This article will review the most recent literature on lung transplant candidate selection to provide an updated framework for optimum allocation of this limited resource.
Roentgenographically occult lung cancers can rarely be detected in high-risk patients with either sputum cytology or bronchoscopic inspection. Photodynamic therapy is the most extensively studied endobronchial treatment for early lung cancer in inoperable patients.
Electronic cigarettes (e-cigarettes) have surged in popularity since their introduction in 2007. Sales of e-cigarettes and related products in the US were expected to exceed $ 1B in 2013. With the popularity of the electronic cigarette on the rise, physicians are sure to get questions from patients about the safety of e-cigarettes and their effectiveness as tools for smoking cessation or reduction. Most users of the electronic cigarette are so-called dual users-current cigarette smokers who also use e-cigarettes. The appeal of these devices is largely based on a perception that they are not as harmful as traditional cigarettes. Other factors that contribute to the popularity of e-cigarettes are that they have the look and feel of a traditional cigarette, that they can be used in locations where cigarette smoking is forbidden, and that they are perceived by smokers as tools to help to reduce or eliminate the smoking of traditional cigarettes. At present, e-cigarettes are not formally regulated for safety or quality control. As a result, nicotine delivery with these devices is not consistent. There is significant concern in the medical community that these e-cigarettes may not be as safe as is publicly perceived, particularly in the context of dual use. The use of e-cigarettes in harm-reduction strategies is a very divisive one in the public health arena. During the last few years, there have been longitudinal, crosssectional, and randomized clinical trials evaluating the efficacy of electronic cigarettes as smoking cessation aids. This review presents a focused analysis of these studies.
Patients admitted to intensive care units (ICU) have significantly disrupted sleep with circadian displacement. In this article we briefly discuss factors related to sleep disruption in ICU and the tasks of individual members of ICU multidisciplinary teams in promoting consolidated nocturnal sleep of critically ill patients.
Indwelling pleural catheters (IPCs) have an established role in the management of recurrent pleural effusions due to malignancy. They are typically used in patients with trapped lung, those who have previously failed an attempted talc pleurodesis, or as first-line therapy. Experience of, and evidence for, IPC use in this setting is well established. In contrast, IPC use in patients with recurrent pleural effusions due to benign disease is limited, and there are no randomized studies evaluating their efficacy and safety in this patient group. Retrospective data suggest that IPCs may be effective at reducing breathlessness with acceptable complication rates, comparable to those seen in malignant effusions. This paper summarizes the epidemiology, pathophysiology and treatment options for benign pleural effusions, and reviews the published data assessing IPC use in this population.
Transbronchial biopsy is required for evaluation of some patients with interstitial lung disease (ILD). The diagnostic success of histopathologic assessment is variable, and affected by such factors as specimen size and the presence of crush artifact attributable to the use of conventional biopsy forceps. Use of cryoprobes to perform transbronchial biopsy enables larger and better quality samples to be obtained compared with conventional methods. The safety profile of transbronchial cryobiopsy is similar to that of transbronchial biopsy with forceps. Diagnostic success of histopathology seems higher when the cryoprobe is used although multidisciplinary agreement with close interaction between clinicians, radiologist, and pathologist is essential to assess the utility of this transbronchial procedure. Larger multisite randomized trials are required to confirm the potential benefits of transbronchial cryobiopsy.
This literature review updates the reader on the new studies regarding steroid therapy over the last year in stable COPD and in exacerbations. In stable COPD, we critique the 2011 update and 2013 revision of the GOLD guidelines, discuss why combining inhaled corticosteroids (ICS) with long-acting beta-agonists (LABA) (ICS/LABA) is preferable over LABA alone and review the literature for intraclass differences, finding that the evidence does not clearly support superiority of any particular ICS/LABA. We also address other comparisons against ICS/LABA, including triple therapy. We briefly review which type of inhaler should be chosen. For exacerbations, we report the REDUCE trial findings favouring a 5-day course of systemic steroids, and other trials addressing which steroid and route to use, including in an intensive care setting. Lastly, the future lies in new anti-inflammatories and re-phenotyping the heterogeneous amalgamation of COPD. A Spanish guideline recommends distinguishing steroid-responsive eosinophilic exacerbators from other phenotypes.
The development of a pleural effusion represents a common complication of pneumonia. Clinically there is a recognised spectrum of effusions from simple parapneumonic, which typically resolve without requiring intervention other than antibiotic treatment, to complicated parapneumonic effusions associated with bacterial infection and inflammatory cell infiltration, through to empyema, with the presence of frank pus in the pleural space. It was previously believed that no clinical features could identify patients at risk of pleural infection, but recent research suggests this is not the case. Patients with pleural infection after pneumonia are younger, more frequently have a history of alcohol or substance abuse, and have evidence of marked systemic inflammation, with higher levels of C-reactive protein, leucocyte counts and platelet counts compared to patients with pneumonia who do not develop pleural complications. Intriguingly, patients with chronic obstructive pulmonary disease have a low risk of pleural infection, despite a high frequency of pneumonia, and it has been speculated that bacterial colonisation or inhaled corticosteroids may play a protective role in these patients.This review summarises the data on the incidence and clinical predictors of pleural infection in patients with pneumonia, and considers the implications of these risk factors for management and what we know of the pathophysiology of parapneumonic effusions.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and not all patients respond to all currently available drugs. The importance of personalized treatment of COPD is increasingly recognized. The new GOLD guidelines have moved the principles of treatment of stable COPD forward by including concepts of symptoms and risks into the decision for therapy. COPD phenotypes are the basis of personalized treatment in clinical practice. Consensus has been reached concerning several phenotypes: phenotypes according to the evaluation of image; the frequent exacerbator and infrequent exacerbator; asthma and COPD overlap syndrome; and the persistent systemic inflammation phenotype. These phenotypes can help clinicians identify patients that respond to specific pharmacological interventions. Comorbidities and other factors, such as social and economic status, must also be considered. Future research needs to validate potential phenotypes in longitudinal studies, and examine the responses of different phenotypes to existing and future therapies.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and inflicts substantial public health challenge for all human beings. It is characterized by destructive emphysematous changes and thickened bronchiolar walls with inflammation infiltration and luminal mucus occlusion. Current therapies can partly alleviate respiratory symptoms, but not prevent disease progression or reduce mortality. Therefore, novel approaches with less adverse reactions and more therapeutic effects are desperately needed for COPD. Stem cells with rigorous differentiation and regeneration properties have been investigated in many regressive and injurious diseases. Because of immunosupression, mesenchymal stem cells (MSCs) can modulate local and systemic inflammatory and immune responses, which have been extensively studied in inflammatory lung disease, such as COPD, asthma, and acute lung injury. In this review, we will describe the effect of MSCs on COPD, both in preclinical and clinical studies, and further discuss the underlying mechanisms of MSCs on COPD in recent years.
