Current Respiratory Medicine Reviews - Volume 1, Issue 2, 2005

Tuberculosis is exacting a great toll on the lives of many people worldwide. Despite seemingly previous successes in controlling the disease, tuberculosis is now re-emerging as the leading cause of mortality due to infectious diseases in many parts of the world. The high incidence of the disease has been attributed mainly to its combination with HIV infection and the emergence of multi-drug resistant strains. In addition, the low diagnostic reliability and therapeutic coverage, as well as the absence of a fully protective vaccine, configure the current situation of the disease at a worrying level. Taking into account these antecedents, it is considered that the development of an effective vaccine is the most important and urgent element for the control of the disease. Supported by the better understanding of the immune response to the infection, the biology of Mycobacterium tuberculosis and the availability of new technologies in genomics and proteomics, a wide range of experimental vaccines have been attempted. These approaches include the use of inactivated strains; live genetically attenuated strains; live vectors expressing M. tuberculosis antigens; recombinant subunits, conjugated, and DNA vaccines as well as the combination of selected strategies in prime boost immunisations. Furthermore, the use of novel adjuvants, delivery systems and routes of immunisation have also been evaluated. Some of the candidate vaccines demonstrated significant levels of efficacy in animal models and are now in initial clinical evaluation. This review analyzes the main aspects related to the development of new generation vaccines against tuberculosis, as well as the challenges and complexities inherent to this endeavour.

Mycobacterium tuberculosis, the causative agent of pulmonary tuberculosis (TB), remains a major public health risk worldwide. It is still not clear why a small percentage of the infected progress to active disease during their lifetime. It seems likely that TB develops by complex environmental factors and genetic susceptibility. Genetic factors, such as Human Leukocyte Antigens (HLA) in particular, are important determinants of susceptibility to TB. The HLA system is a T cell restriction element closely related to immuneresponsive and immune-suppressive genes. The expression of particular HLA class I and II antigens in an individual determines the ability of that individual to respond to particular mycobacterial antigens and epitopes. The most frequently reported immunogenetic associations have been found with HLA-B5,-B8,-B15,- B27,-B35,-Cw5 antigens and DRB1*1501, DRB1*1506, DRB1*1601, DRB1*1602, DQB1*0501, DQB1*0502, DQB1*0503, DQB1*0601 alleles, but these associations varied in reported studies of TB patients from different races and ethnic populations from Asia, North and Latin America and Europe. Although variations were apparent in the antigens/alleles associated with susceptibility, the increase in the frequency of DR2 antigen and DQB*05 allele was remarkably consistent in the analysed populations. A negative correlation of M. tuberculosis with HLA-DR4,-DR6,-DR8 antigens, DRB1*07, DRB1*13 and DQB1*0201, DQB1*0301, DQB1*0402 alleles was noted, but reductions in the frequency of alleles associated with protection were inconsistent in TB patients from different ethnic groups.

Tuberculosis of the thymus is extremely rare and is commonly mistaken for thymoma. We present a case of what we believe is tuberculosis of the thymus in a 62 year old woman, which was mistaken for a thymoma. The clinical, radiological and pathological findings are described, as well as review of the English literature. A diagnosis of tuberculosis is still possible, despite a negative confirmatory test. Preservation of tissue sample for culture may improve detection of tuberculous infection in resected anterior mediastinal masses.

Influenza A virus poses particular problems in host defense due to its ability to vary antigenic properties. Innate immunity is most critical during the early phase of IAV infection prior to elaboration of adaptive immune responses. Recent research highlights the importance of pulmonary surfactant collectins (especially surfactant protein D or SP-D) in both restricting the extent of viral replication and limiting potentially damaging inflammation in the first few days of IAV infection. Other innate inhibitors of importance for host defense against IAV include type I IFNs and alveolar macrophages. Recent studies also highlight the role of Toll-like receptors (TLRs) 3 and 7, plasmacytoid dendritic cells, and natural killer (NK) cells. Soluble scavenger receptor rich glycoprotein 340 (gp-340) and defensins also have anti-IAV activity. Neutrophils also contribute in complex ways to host response to IAV, and increased neutrophil influx characterizes severe IAV infection in which the usual innate responses are ineffective. Some innate mechanisms strongly affect elaboration and intensity of the adaptive immune response to IAV. A key conclusion of this review is that the innate immune system not only plays a role in non-specific restriction of viral replication, but also in down regulating non-specific and antigen specific immune injury. Excessive inflammatory responses are now implicated in many severe outcomes of IAV infection. Better understanding of innate immunity to IAV should clarify why some subjects are at greater risk for severe IAV infection, and why certain IAV strains are more virulent, and also suggest novel anti-viral and anti-inflammatory therapeutic approaches.

Bronchiolitis obliterans and organizing pneumonia (BOOP) represent complex clinical syndromes expressing a similar morphologic pattern, which are observed in a variety of lung diseases. In this view, the Authors report on the clinical and diagnostic profile, radiological features, laboratory and histopathological findings, and management issues of these broad-spectrum pulmonary disorders. Idiopathic forms, infectious disease-associated features, complications of solid organ transplant recipients and bone marrow recipients, collagen vascular- and bowel inflammatory-related forms, the role of drugs and that of irritating and toxic inhalants, and more infrequent ethiologies (which are able to support a bronchiolitis obliterans-organizing pneumonia and related conditions), all these items are thoroughly discussed on the ground of our own experience in this field, and an updated literature review.

Community-acquired pneumonia (CAP) is a major health concern and the subject of extensive research. In the past, efforts have been focused on addressing antibiotic resistance patterns, instituting preventive measures, and the development of prediction tools. Despite these efforts, improvement in outcome from CAP, particularly in the elderly, has remained inadequate. Inappropriate antibiotic therapy, potential lack of efficacy of pneumoccocal vaccine and limited use of prediction tools have led to a marked increase in attempts to explore genetic influences on CAP. There is evidence that genetics plays a role not only in acquiring CAP, but also in the ultimate outcome of this disease. Since morbidity and mortality are related to septic complications, examining the genetics of sepsis along with CAP is essential. Single nucleotide polymorphisms (SNPs) and mutations have been shown to be associated with outcomes (ex. SP-B +1580, LTA +250, and HSP70-2+1267 polymorphisms ) in CAP and infectious causes of sepsis. Unfortunately, some results have had inconsistent associations with outcome (TNF -308 and IL-10 polymorphisms); lending support to the postulation that studying larger population samples and levels of RNA expression may provide clarifying data. It is anticipated that genetic research involving CAP and its outcomes will lead to the use of genetic data in prediction and therapeutic tools.

Pulmonary structural changes that lead to decreased airway function are the cardinal features of chronic diseases such as asthma and chronic obstructive pulmonary disease (COPD). Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes that can alter lung architecture by inducing tissue damage and modifying repair mechanisms. The activity of these enzymes is regulated by a group of proteins called tissue inhibitors of matrix metalloproteinases (TIMPs, classes 1-4). Because MMP activities are induced following exposure to allergens and environmental toxins, it is crucial to evaluate potential cellular sources for these proteins. This review specifically focuses on the relevance of the pulmonary epithelium to produce this family of proteins and propagate pulmonary inflammation, destroy parenchymal tissue, and affect repair mechanisms. Data from human and animal studies are reviewed, and the relevance of MMPs and TIMPs in chronic respiratory diseases is discussed.

Nocturnal worsening of asthma is very common and employed in clinical practice as a marker of asthma severity. The fall in overnight lung function can reach 50%. Several mechanisms contribute to this circadian (24 h) variation. Cortisol, steroid responsiveness, vagal tone, leukotriene, airway inflammation and airway hyperresponsiveness vary in a circadian fashion and have been described as potential mechanisms. Studies on the ability of corticosteroids to block circadian recruitment of inflammatory cells show that a single corticosteroid systemic dose in the afternoon results in a significant pancellular reduction in bronchoalveolar lavage cytology at 4: 00 h and a reduction in the overnight fall in FEV1. The same single dose in the morning or night does not lead to significant improvement. Further studies on chronotherapy of asthma have revealed a rapid and time-dependent effect of inhaled steroids. A single dose of inhaled steroid in the afternoon has a protective effect against asthma worsening in the same night. Chronotherapeutic principles are also applied with other than corticosteroid drugs in the regular asthma treatment.

At birth, the successful transition to extra-uterine life is dependent upon the ability of the lung to take over the role of respiratory gas-exchange. Before birth, the future airways of the lungs are filled with a liquid that is produced by the lung and leaves the lungs by flowing out of the trachea. At rest, adduction of the larynx restricts lung liquid efflux and promotes its retention within the airways, thereby generating a 1- 2mmHg internal distending pressure on the lung. At birth the airways must be cleared of liquid to allow the entry of air, but a thin film must remain to protect the epithelium from desiccation. This creates an air/liquid interface across the large internal surface of the lung which increases lung recoil, despite the presence of surfactant. Thus, after birth, the loss of the distending influence of lung liquid, and the increase in lung recoil associated with lung aeration greatly alters the distribution of forces exerted within lung tissue. As a result, lung luminal volumes decrease and the tendency for the lung to collapse away from the chest wall increases, leading to the creation of a sub-atmospheric intra-pleural pressure. Until recently, the role of lung aeration and the resultant changes in physical forces, have been over-looked as factors regulating the normal changes in lung physiology that are required for the lung to adopt the role of respiratory gas exchange at birth. As these changes in the respiratory system are essential for the independent survival of the newborn infant after birth, it is important to understand the mechanisms involved so that these changes are not impeded in the sick, ventilated very preterm infant. At birth numerous changes in lung physiology occur which transform the respiratory system into an efficient gas-exchange system. For instance, the number of surfactant secreting type-II epithelial cells increases, chest wall compliance decreases and pulmonary blood flow (PBF) markedly increases. One of the most remarkable changes in lung physiology that occurs at birth is the large increase in PBF, resulting from a marked decrease in pulmonary vascular resistance (PVR). Before birth, most (∼88%) of right ventricular output by-passes the lungs and passes through the ductus arteriosus (DA) into the systemic circulation. This is primarily attributed to the high PVR in the fetus which is also responsible for the unique PBF waveform contour, which is mainly characterized by a large retrograde, flow of blood away from the lungs during diastole; this blood exits the pulmonary circulation via the DA. At birth, the rapid decrease in PVR causes marked changes in the contour of the PBF waveform with the disappearance of the negative or retrograde component. As a result, forward flow occurs throughout the cardiac cycle. Although many factors are thought to contribute to this decrease in PVR at birth, the accumulating evidence indicates that a change in the distribution of forces within lung tissue is a major contributing factor. Other changes in the lung that occur at birth include a change in the relative proportions of type-I and type-II epithelial cells and a gradual stiffening of the chest wall to enhance breathing efficiency. Although these changes, including the changes in PVR, are usually assumed to be independent events, recent evidence suggests that they are inter-related and that they are precipitated by the replacement of lung liquid with air. In this review, our primary aims are to discuss how the presence of liquid-filled airways influences lung physiology in the fetus and the role that changing the internal environment of the lung from liquid to air plays in the adaptation of the respiratory system to air-breathing at birth. It is important to understand these interrelationships as positive pressure ventilation can oppose these changes in lung physiology. Thus, in very preterm infants (born <30 weeks GA), who require resuscitation and assisted ventilation during their first weeks of life, it is important to adopt ventilation strategies that do not impede these normal physiological changes.

Enhanced mitochondrial oxidative damage has been implicated in pathogenesis of various human diseases. This mini review will discuss the role of mitochondria in oxidative lung injury and the pathways induced by oxidant signaling. Recent studies suggest that mitochondrial targeting of antioxidants can reduce oxidant signaling and oxidant-stress while preserving mitochondrial structure and function. The impact on the treatment and prevention of acute lung injury will also be discussed.

The morbidity and mortality from asthma remains high in patients over the age of 75 years in developed countries, in contrast to the improving mortality from that condition in children and younger adults. One of the reasons for this might be the relatively poor performance with inhaler devices confirmed by surveys of technique in elderly patients. This review explores the pattern of observed and measured errors in the use of various inhalers in old age. The physical barriers to a successful grasp of inhaler technique are explained. The review then proceeds to describe a systematic research sequence by the author and others to identify factors that determine the likelihood of an aged person being able reliably to self-administer medication by the inhaled route. Relatively simple tests of cognition, praxis and executive function are described which have been shown to have predictive value in assessing frail elderly subjects for potential inhaler therapy. The evidence presented can enable clinicians to approach inhaled therapy for asthma and chronic obstructive pulmonary disease in a logical and effective way for their frail elderly patients.

Psychological factors have long been suspected to influence lung function in asthma. While earlier experimental research has demonstrated the susceptibility of the airways to suggestion, only recent studies have investigated the impact of various emotional states and stressful challenge on the airways in health and asthma. We reviewed studies from the last 15 years that have used experimental emotion and stress induction techniques or longitudinal diary observations to explore these influences. Findings suggest that unpleasant emotional states are associated with a decline in lung function in health and asthma. Changes are usually small on average, but usually reach clinical significance in a subset of patients. Pleasant emotional states are also sometimes associated with a lung function decline, suggesting a susceptibility of the airways to arousal in general. From longitudinal studies, more evidence for effects of both pleasant and unpleasant states is available, but also highly idiosyncratic associations between mood, stress, and lung functions were observed. While initial findings indicate the importance of specific autonomic, ventilatory, and immunological pathways for emotion-induced lung function changes, more research is needed on these underlying mechanisms.