Current Respiratory Medicine Reviews - Volume 3, Issue 2, 2007

In their original description Ashbaugh and coworkers, in 1967, described a syndrome characterized by refractory hypoxemia, diffuse lung infiltrates on chest radiograph, and decreased lung compliance in a group of 12 patients suffering from severe respiratory failure [1]. This syndrome would be later known as the adult or acute respiratory distress syndrome (ARDS). The mainstay therapy of ARDS for the past 5 decades has remained the management of the underlying disorder causing it, when feasible. To date, there are no specific pharmacological interventions of proven value for the treatment of ARDS. Although corticosteroids and other agents have been widely used clinically, large multi-center trials in the past have failed to show any benefit in outcome, lung compliance, pulmonary shunts, chest radiograph, severity score or survival [2- 4]. For years, the role of corticosteroids in ARDS has been controversial at best. These agents may have, however, a role in situations when ARDS has been precipitated by a corticosteroid-responsive process, such as acute eosinophilic pneumonia. Sepsis is by far the most common cause ARDS [5,6]. The mortality rate for patients with sepsis complicated by ARDS has been reported to be as high as 60% [5,6]. In this clinical entity, the role of corticosteroids has been redefined in recent years. In this issue of Current Respiratory Medicine Reviews, Han and Hizy extensively review the role of corticosteroids in the critically ill patient with sepsis and ARDS [7]. These authors review the importance of the hypothalamic-pituitaryadrenal (HPA) axis in critical illness. Over the past two decades, evidence-based medicine has found that the activation of the HPA axis with the production of adrenocorticotrophin (ACTH) and cortisol is a fundamental part of the host response to stress such as ARDS or sepsis. Glucocorticoids in this context, appear to have two vital and disparate effects that allow the host to deal with acute stress. One is the permissive effect of steroids to prepare the host for a “fight and flight” response by providing a ready source of fuel (glucose) and adequate hemodynamic reserve. The second function is to suppress activated defense mechanisms, preventing them from overshooting and damaging the host. The HPA axis and the immune response are linked in a negative feedback loop, in which activated immune cells produce cytokines that signal increased immune activity to the brain, thereby stimulating the HPA axis, which through glucocorticoids suppress the immune reaction [8]. Cytokines, which are produced both in patients with sepsis and ARDS, however, also suppress the HPA-axis and glucocorticoid receptor function. For example, tumor necrosis factor (TNF) - alpha impairs ACTH release, and a number of clinical studies have reported inappropriately low ACTH levels in patients with severe sepsis and the systemic inflammatory response syndrome (SIRS) [9-10]. As noted by Han and Hizy, acute adrenal insufficiency should always be suspected in critically ill patients who fail to respond to catecholamines. An ACTH infusion test and a trial of stress doses of glucocorticoids pending the results is suggested when this disorder is suspected. Whether or not corticosteroids will be used routinely in patients with sepsis complicated with ARDS in the absence of adrenal dysfunction is a matter of constant debate and likely to continue for years to come. REFERENCES [1] Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2: 319-323. [2] Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988; 138: 62-68. [3] Bernard GR, Luce J, Sprung C, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 1987; 317: 1565-1570. [4] Melot C, Leujeune P, Leemam M, Moraine JJ, Neaije R. Prostaglandin E1 in the adult respiratory distress syndrome. Am Rev Respir Dis 1989; 139: 106-110. [5] Marik P, Varon J. Sepsis: State-of-the-art. Dis Month 2001; 42: 462-532. [6] Lechin AE, Varon J. Adult respiratory distress syndrome (ARDS): The basics. J Emerg Med, 1994; 12(1): 63-8. [7] Han MK, Hyzy RC: The role of corticosteroids in sepsis and acute respiratory distress syndrome. Curr Respir Med Rev 2007; 3: 141- 146......

Cell therapy is a new research approach being vigorously pursued for the treatment of patients who suffer from many respiratory diseases, ranging from acute respiratory distress syndrome (ARDS), emphysema to idiopathic pulmonary hypertension etc. In such studies, stem cells or progenitor cells are administered with the goal to regenerate damaged pulmonary tissues and to improve their functions. Various adult and embryo derived stem cells are being employed for such investigations. However, as the first crucial step for this approach to be successful, cell delivery methods need to be optimized such that the cells can not only reach the target organs but also can be retained in sufficient quantities. The optimal strategy for cell delivery will depend on the anatomical and functional characteristics of the target organs. For example, for solid organs such as the brain (e.g. for Parkinson's disease) or the heart (for myocardial infarction), direct injection of the cells is being employed, although for the latter, powerful myocardial contractions could cause massive mechanical cell loss from the cell implant sites. For the islet cell transplants (for diabetes), intrahepatic implantation via portal vein appears convenient and effective. As the lung is neither a solid nor an endocrine organ, cell delivery via vascular route appears mandatory. It is now well established that many marrow derived stem / progenitor cells, such as the endothelial progenitor cells (EPCs), are capable of homing in to the tissues suffering from acute injuries (e.g. the lung with ARDS). The roles of inflammatory cytokines and endothelial adhesion molecules for such homing mechanism are being elucidated. Thus for patients suffering from acute lung injuries, intravenous administration of donor cells could be an effective method of cell delivery. However, in patients with chronic conditions such as emphysema, pulmonary fibrosis or hypertension, intravascular delivery of cells results in minimal cell retention, as the donor cells will pass through the pulmonary circulation readily. In this review, we will examine a number of respiratory diseases for which stem cell therapy is being studied, then focusing on the strategies to enable the “trapping” of donor cells administered into the pulmonary circulation in lungs without acute injuries. They may include the pre-treatment of the pulmonary capillary endothelium to induce the expression of adhesion molecules, and more recently the use of innovatively engineered biodegradable microcapsules which can enhance intravascular cell retention and survival. Successful strategies to deliver donor cells to the lung will enable us to rigorously examine the efficacy of cell therapy, thus potentially benefit vast population of patients who suffer wide varieties of respiratory diseases.

Tuberculosis (TB) remains a serious global health problem. The infrastructure necessary for delivering the TB treatment regimens recommended for use today accounts for more than two-thirds of the total cost of treating TB patients. Reducing the duration of the treatment regimen from the currently recommended six months to two months could result in significant cost savings and make treatment available to more patients worldwide. The objective of this review is to highlight potential new agents for treatment of drug-susceptible TB disease that are currently under study or were recently evaluated through clinical trials. We conducted a literature search in the English language for clinical studies as well as an electronic computer-assisted and manual search. The literature search was conducted on August 30, 2006, using MEDLINE (2000-2006), EMBASE (2000-2006) and the National Institute of Health (NIH) Clinical Trials Register database (2000-2006). Most of the new agents identified as anti-TB drug candidates are still in the preclinical phases. Only the diarylquinolines and the fluoroquinolones are being evaluated for potential inclusion in new ultra-short TB treatment regimens through clinical studies phases II/III. In this article, we present a summary of the studies reviewed and discuss their potential for modifying future treatment recommendations for TB treatment.

In chronic obstructive pulmonary disease (COPD), cognitive dysfunction - mainly of secondary memory, executive, and constructional abilities - is a marker of disease severity with important clinical and prognostic implications. It correlates with poor compliance with pharmacological therapy, and poor compliance, in turn, increases the cost/effectiveness ratio of home care programs. Executive dysfunction is associated with difficulty with inhaler devices and should be systematically evaluated before prescribing. Drawing impairment has been associated with mortality, although the underlying neurologic abnormalities (right insular damage with autonomic dysfunction or subcortical damage) remain to be defined. Depression is also negatively correlated with survival, besides being a risk factor for quitting respiratory rehabilitation. Cognitive dysfunction should always be considered among the systemic effects of COPD and be the object of systematic screening in COPD patients. Identifying cognitive impairment would prompt either interventions promoting the adherence to the therapy or further investigations to exclude respiratory (nocturnal or effort hypoxemia, coexistent obstructive sleep apnoea) or non respiratory (decompensated diabetes, hypoglycaemic crises, poorly controlled hypertension etc.) causes of cognitive dysfunction. Cognitive enhancing strategies deserve consideration in the framework of a comprehensive approach aimed at improving the health status of people with COPD.

The influence of tobacco smoke on human health is still an important problem worldwide. Complex inflammatory processes and changes in the immune system are crucial in the pathogenesis of smoking related disorders like chronic obstructive lung disease (COPD), lung cancer, asthma, interstitial lung diseases (ILD) and atherosclerosis. The objective of this review is to present the alterations in the immune system in smokers. Discrete changes in peripheral blood of smokers may be found, such as leukocytosis and elevated proportion of T cells. However, the mainly affected system is the respiratory tract. In bronchial epithelium, metaplastic and dysplastic changes are accompanied by elevated expression of adhesion molecules and secretion of many proinflammatory cytokines. In the population of pulmonary macrophages, an elevated proportion of cells, changes in expression surface markers: CD14, CD54, CD11 and CD71 with impaired phagocytic and antigen presenting function were observed. The influence of tobacco smoke on the population of granulocytes results in elevated proportion of neutrophils and eosinophils and elevated concentration of the products of neutrophils: neutrophil elastase (NE), interleukin- 8 (IL-8) and tumor necrosis factor (TNFα). Tobacco smoke seems to alter the way of death of neutrophils from apoptosis to necrosis. On the other hand, an elevated expression of the receptors of apoptosis on lymphocytes was found. Cigarette smoke enhances the recirculation of lymphocytes, which results in the augmentation of activated and cytotoxic/ suppressor cells in the bronchial lumen. Smoking cessation is the most effective method of prophylaxis and treatment of diseases related to tobacco smoking. However, many immunological changes in smokers are not completely reversible after quitting smoking.

Pulmonary arterial hypertension is a feature of a spectrum of diseases that includes elevated pulmonary vascular resistance, induces right ventricular insufficiency and heart failure, and threatens the life. The aetiology and pathogenesis is diverse and associated with elevated morbidity and mortality. Treatment is frequently deficient and empirical. Fortunately, in recent years, randomized clinical trials have shown useful effects of various drugs on pulmonary arterial hypertension. This article reviews the pharmacological and not pharmacological therapeutic options to treat pulmonary arterial hypertension and attempts to provide a proposal of algorithm for its management based upon the evidence and available guidelines for clinical management.

Pulmonary hypoplasia, the result of abnormal antenatal lung growth, occurs as a primary anomaly or more usually the consequence of disorders resulting in reduction of amniotic fluid volume, intra-thoracic space or fetal breathing movements. Two dimensional (2D) ultrasound examination yields useful information on amniotic fluid volume and the presence of congenital abnormalities associated with pulmonary hypoplasia. Assessment of the thoracic or lung size by 2D ultrasound examination, is insufficiently specific, but a very low lung to head ratio predicts a fatal outcome in fetuses with congenital diaphragmatic hernia (CDH). Three-D ultrasound examination provides information on fetal lung volume prior to 34 weeks of gestation but can be inaccurate if there is oligohydramnios. Magnetic resonance imaging is expensive and has limited patient acceptability. Antenatal interventions attempted to prevent pulmonary hypoplasia include amnioinfusion, which can facilitate ultrasound examination, but only temporarily relieves oligohydramnios. Thoraco-amniotic shunting results in effective drainage of pleural effusions, facilitating resuscitation, but is usually performed too late in pregnancy to influence lung growth. In utero surgical repair of CDH has been attempted, but a more promising technique is obstruction of the normal egress of fetal lung fluid by placing a balloon in the trachea.

The use of corticosteroids in the treatment of critically ill patients has been the subject of controversy for decades. Information from recent clinical trials has helped to more clearly define their use in the acute setting. Cortisol is produced in response to pituitary corticortopin secretion which is in turn released in response to hypothalamic corticorpinreleasing hormone. Acute illness should result in increased cortisol production, although relative corticosteroid insufficiency can occur in sepsis and appears to be associated with increased mortality. Despite this, diagnosing corticosteroid insufficiency in patients with septic shock remains difficult. Investigators have failed to find a reliable relationship between random cortisol levels and mortality. However, recent evidence demonstrated an increase of serum cortisol <9 mcg/dL following corticotropin stimulation is associated with increased mortality from septic shock. Corticosteroid replacement therapy in these patients reduces mortality. The mortality benefit seen in this setting may be limited to septic patients with acute respiratory distress syndrome. Corticosteroids have been used in a variety of conditions causing hypoxemic respiratory failure. While empiric steroids were widely used to treat ARDS in the 1970's and 1980's, more recent evidence from the ARDS clinical trial network failed to demonstrate a mortality benefit, despite the fact that patients were able to be weaned to unassisted breathing more quickly. Tight glycemic control in ARDS patients receiving corticosteroids can help avoid neuromyopathy and may afford an opportunity to prevent a return to assisted breathing in these patients. While steroids have also been reported for use in the treatment of SARS, no trials have been performed which support their efficacy.

α1-antitrypsin, an acute phase protein, is the prototypic member of the serpin super family and a major inhibitor of serine proteases. As an acute phase protein, α1-antitrypsin is thought to play an important role in limiting host tissue injury at sites of inflammation. The clinical importance of α1-antitrypsin is highlighted in individuals with inherited α1- antitrypsin deficiency who exhibit an increased susceptibility to develop chronic inflammatory conditions including chronic obstructive pulmonary disease, systemic vasculitis and necrotizing panniculitis. There is now an increasing evidence that α1-antitrypsin may also exhibit biological activity independent of its protease inhibitor function. Thus, conformationally modified and degraded forms of α1-antitrypsin, which lack antiprotease activity, demonstrate specific biological effects in vitro and in vivo and highlight the potentially broader modulatory role of α1-antitrypsin in inflammatory diseases. In this review we discuss the biological properties of α1-antitrypsin and its role in chronic obstructive pulmonary diseases. A more comprehensive understanding of the biology of native α1-antitrypsin and its modified forms may have a significant impact on our understanding and ultimately treatment of disease pathologies arising from both natural point mutations and from post-synthetically modified byproducts of α1-antitrypsin.

The human epidermal growth factor receptor (EGFR) biology is not completely explained; however EGFRtargeting has formed the basis of extensive and growing drug development. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade is a fundamental mechanism for the use of EGFR specific tyrosine kinase (TK) inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Despite initially promising results in chemotherapy-resistant patients with non small cell lung cancer (NSCLC), disappointing results from phase III trials of gefitinib in NSCLC have been of concern of some. When EGFR-targeting drugs were introduced into the clinic, the specific targets affected in human tumors were unknown. Recently, different studies reported that mutations in the TK domain of EGFR are strongly associated with gefitinib- or erlotinib-sensitivity in patients with NSCLC. This article reviews the rationale for targeting EGFR by TK inhibitors, the discovery of EGFR mutations and subsequent studies to define the incidence, spectrum and functions of EGFR mutations. This paper represents the effort of a lung cancer focused translational research team made up of molecular biologists, medical oncologists and thoracic surgeons. The final objective is to achieve a comprehensive, but simple, review of the current status of the shift from cytotoxic to molecularly targeted therapy in lung cancer treatment potentially useful in the planning of translational research trials.