Current Respiratory Medicine Reviews - Volume 2, Issue 1, 2006

Centuries of scientific enquiry have produced improved preventive and therapeutic interventions through basic and clinical research. The history of modern medicine appears to be the story of the never-ending struggle of physicians to apply the newest scientific medical wonders to the care of their patients. Discussions of p values, clinical trials, and statistical methodology are currently common in the halls of medicine. Journals such as Current Respiratory Medicine Reviews have an enormous responsibility when publishing either new data or literature reviews to ensure proper dissemination of scientific information. Systematic literature reviews help to improve patient care since pooling of appropriate data sometimes enables us to see the results without the noise of the random play of chance. However, we must be careful in our choice of reviews. Some editors say that their role and responsibility is no different in covering health information than it is in covering politics, business, or any other topic. I assert that it isn't sufficient to be accurate and clear when writing a scientific manuscript. Authors have a responsibility to mirror a society's needs and issues, comprehensively and proportionally. As I assume the role of Editorin- Chief of Current Respiratory Medicine Reviews, I will carry out the responsibilities expected of an Editor-in-Chief, as noted by the World Association of Medical Editors [1]. One of my goals is to provide readers of Current Respiratory Medicine Reviews with scholarly publications that are useful to clinicians and basic scientists. In addition, I want to meet the needs and interests of our readers. For that reason, I have added members to the editorial board with specific expertise in areas that are considered of extreme importance for anyone engaged in the care of patients with pulmonary and chest disorders. I thank the current ad hoc reviewers for their prompt reviews. However, as many editors of brand new journals can attest, you start with no papers and suddenly you have too many. The information contained within Current Respiratory Medicine Reviews needs to be up-to-date and useful. Clearly, with a continuous healthy flow of good quality papers we should be able to meet that challenge. I welcome suggestions for interesting topics both at the clinical and basic level ([email protected]). In order for the success and stature of Current Respiratory Medicine Review to be elevated to the highest level, we must continuously strive to earn the trust of readers, authors and researchers. In our current era of entanglement, authors and members of the editorial board must investigate and report the possible conflicts of interest among sources of health information and those who promote a new idea or therapy. Such conflicts may not be readily apparent to some of us. Therefore, authors and members of the editorial board must investigate and report the possible links between researchers and private companies, public institutions, patient advocacy groups, celebrity spokespersons, and professional organizations. To fail to do so may mean that both authors and editors become unwitting mouthpieces for incomplete, biased, and imbalanced information. I will strive to make Current Respiratory Medicine Reviews as a leader in its field during my tenure as Editor-in-Chief. REFERENCE [1] The World Association of Medical Editors. A syllabus for prospective and newly appointed editors. Available at: http://www.wame.org/syllabus.htm. Accessed October 1, 2005.

Invasive pulmonary aspergillosis (IPA) is a frequently life-threatening fungal infection that complicates acute leukemia patients following conventional chemotherapy and bone marrow transplantation. The mortality rate reaches 50% in leukemic patients during chemotherapy-induced neutropenia and can exceed 90% in bone marrow transplantation patients. Despite advances in antimicrobial therapy and supportive care, IPA remains a major clinical problem in patients with acute leukemia. Current issues for IPA in adults are reviewed.

The signaling mechanisms defining the role of protein kinases in pulmonary vascular physiology regulation is an area of great interest. Normally, signaling mechanisms which elevate cyclic AMP (cAMP) and cyclic GMP (cGMP) maintain the pulmonary vasculature in a relaxed state. Modulation of large-conductance, calcium- and voltage-activated potassium (BKCa) channels is important in the regulation of pulmonary arterial pressure and inhibition of BKCa channels is implicated in the development of pulmonary hypertension. Accordingly, studies done in pulmonary arterial smooth muscle cells of the Fawn-Hooded rat, a recognized animal model of pulmonary hypertension, shows that cAMP opens BKCa channels. Treatment with KT5823, a selective inhibitor of cGMP-dependent protein kinase (PKG) inhibits the effect of cAMP. In contrast, blocking cAMP-dependent protein kinase (PKA) with KT5720 has no effect indicating that cAMP activates BKCa channels via PKG-dependent and PKA-independent signaling pathways which suggests 'cross-activation' between cyclic nucleotide-dependent protein kinases in hypertensive pulmonary arterial smooth muscle. In addition, protein kinase C (PKC) activation inhibits the BKCa channel response to cAMP, which is blocked by the specific PKC isozyme inhibitors Gö 6983, and Gö 6976. These studies indicate that specific PKC isozymes inhibit cAMP-induced activation of BKCa channels via PKG in hypertensive pulmonary arterial smooth muscle.

Oxidized phospholipids (OxPL) appear in the lung circulation as a result of increased oxidative stress that accompanies pathological conditions such as acute lung injury, lung inflammation, adult respiratory distress syndrome (ARDS), ventilator-induced lung injury (VILI), systemic inflammatory response syndrome (SIRS) and sepsis. Under these conditions, lung vascular barrier function is largely compromised. The severity of vascular endothelial dysfunction is determined by a balance between barrier-disruptive and barrier-protective agents present in the pulmonary circulation. Oxidation of phospholipids such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group of bioactive oxidized phospholipid species that demonstrate a wide spectrum of physiological effects including activation of monocyte adhesion to endothelial cells and attenuation of inflammatory cascades triggered by bacterial lipopolysaccharide (LPS). Moreover, our studies and other previous reports strongly suggest barrier-protective effects of OxPAPC on human pulmonary EC, and EC from systemic circulation. In this review, we will discuss a potential role for biologically active oxidized phospholipids in the regulation of vascular barrier integrity and LPS-induced inflammation in the injured lung.

Neutrophils play a crucial role in acute lung injury as well as of chronic pulmonary diseases, e.g. pulmonary fibrosis or COPD. The sticking of neutrophils in the pulmonary microvasculature is regarded as an initial event of acute lung injury. Activated neutrophils may affect the surrounding tissue via several pathogenic mechanisms, including the release of proteolytic lysosomal enzymes, the generation of prostanoids and the production of oxidants. The activation of neutrophils includes stimulation of the membrane associated enzyme NADPH oxidase, which generates superoxide anion radical. Superoxide anion radical dismutates to form H2O2. The neutrophil-released heme enzyme myeloperoxidase catalyzes the formation of hypochlorous acid, which is a powerful neutrophil-derived oxidant. This review summarizes the action of hypochlorous acid on the pulmonary microvasculature. It compares the effects of this oxidant with the effects of stimulated neutrophils. The hypochlorous acid-induced effects on pulmonary artery pressure and on pulmonary vascular permeability are discussed together with the effects of this oxidant on biochemical parameters of oxidative stress (tissue GSH content and accumulation of lipid peroxidation products) and effects of this oxidant on pulmonary concentration of energy rich phosphates (ATP). Additionally, data on the relation between oxidative stress and pulmonary eicosanoid metabolism are discussed.

Multidrug resistant tuberculosis (MDR TB) is defined as resistance to isoniazid and rifampicin. The recent Global Project on drug-resistant TB confirmed that multidrug-resistant TB was found in all regions of the world. Misdiagnosis of MDR tuberculosis due to laboratory related errors has been reported recently and hence susceptibility results alone should not dictate treatment and careful clinical correlation is necessary. Drug-susceptible TB can be cured in six to eight months with first-line anti-TB drugs. However, incorrect or partial treatment results in drug-resistant TB. WHO has recommended that multidrug resistant tuberculosis should be considered after failure of fully supervised category II or I treatment regimen. In a retrospective study of 55 cases of MDR pulmonary TB referred to our centre treated with kanamycin, ethionamide, cycloserine and PAS (KCEP) +/- quinolones, 38 (69.09%) patients completed treatment, 11 defaulted and 6 died. 31/38 (81.57%) cases were cured and 7/38 (18.4%) failed on therapy. All cases that failed had received one or more second line drugs previously. The cost of treatment ranged from $1000 to $3000. Adverse drug effects were seen in 8/55 patients (14.54%). Second line drugs for tuberculosis have been now listed under the WHO essential drugs list and are available through the Green Light Committee. Adherence to the strict guidelines will result in proper management of existing cases of MDRTB.

Lung cancer is one of the commonest malignancies worldwide and the incidence continues to increase. Small cell lung cancer accounts for approximately 15% of all lung cancer cases although incidence of this subtype appears to be falling. It is an aggressive malignancy but responds well to chemotherapy and radiotherapy. The prognosis for untreated small cell lung cancer is less than 3 months. Small cell lung carcinoma is considered to be either limited-stage (LS) or extensive-stage (ES) on the basis of anatomical staging. In spite of high initial response rates in both limited- and extensive-stage patients, the relapse rate is high and overall median survival in LS and ES is 18 months and 9 months respectively. Standard chemotherapy regimens for small cell lung cancer patients with good performance status are platinum based, the commonest being cisplatin/etoposide. However, many patients present with a poor performance status (ECOG performance status of 2 or more and Karnofsky performance status of 60 or less) and these patients are at higher risk of toxicity from chemotherapy. Furthermore, the lung cancer population is largely elderly, 40% of patients being over 75 years. Whilst age is not an independent poor prognostic factor in itself, 90% of older patients have co-morbidity and may be at increased risk of toxicity due to functional organ impairment. Most clinical trials do not include patients with poor performance status and also the elderly (more than 70 years of age) tend to be under-represented, therefore not really reporting on the elderly. This review summarizes the evidence for treating small cell lung carcinoma patients with a poor performance in order to guide clinical decision-making. Treatment decisions should reflect not only the prognostic groups but take into account performance status and co-morbidities as well. It is important to differentiate between poor performance due to comorbidities and that due to the aggressive nature of small cell carcinoma. In the latter case a patient may have been previously fit and well and compromise on treatment based solely on poor performance may not be desirable, as the performance may improve dramatically if patient responds well to treatment.

In the pathogenesis of asthma, chronic inflammation within the airways plays a major role. Corticosteroids (or glucocorticosteroids) have beneficial anti-inflammatory effects and are recommended in all international guidelines for treating asthmatic inflammation. However, control remains difficult for almost 5% of asthmatics despite high doses of inhaled corticosteroids. Several classes of difficult asthma have been described: "brittle asthma", "steroid-resistant asthma", "steroid-dependent asthma", and "refractory asthma", and used interchangeably. Some hypotheses have been posed regarding the pathogenesis of difficult/therapy resistant asthma. Recent studies indicate that steroid-resistant asthma is associated with a failure of corticosteroids to inhibit T-lymphocyte proliferation and secretion or their cytokines. In cases of severe asthma, sputum and tissue eosinophilia vary from "normal" to "elevated" levels, and increased numbers of neutrophils are common. It also appears that conditional to a poor response to the treatment with corticosteroids are the abnormalities in glucocorticoid receptor (GR) number, GR binding, or corticosteroid-GR complex binding to DNA. The causes and predictors of difficult asthma are still uncertain. One predicting possibility is tobacco smoke. Smoking induces the release of interleukin-8, which is the potent neutrophil chemoattractant. Further research is required to clarify the exact mechanisms in difficult/therapy-resistant asthma, and to develop an optimal treatment approaches.

Pneumonia is the fourth overall leading cause of death and is the leading infectious cause of death in the elderly. Half of all pneumonia cases are reported in those 65 years of age and older. The increased frequency and severity of pneumonia in this age group is attributed to the aging of organ systems and the increased frequency of debilitating comorbidities. Risk factors include aspiration, alcoholism, heart disease, malnutrition, and immunosuppression. Recognition may be delayed because pneumonia often presents without fever, cough, or chest pain. Accurate identification of the etiological agent is reported to be less than 50% of the cases as sputum specimens are considered either inadequate or contaminated by the oropharyngeal flora. The pathogens involved depend on the setting in which the pneumonia develops: either the non-hospitalized elderly patients with community-acquired pneumonia or the institutionalized patients who develop nursing home-acquired pneumonia. The timing of administration and the choice of antibiotic therapy are highly correlated with outcome. A systematic approach to assessment, management, and preventive measures is essential to decrease morbidity and mortality from pneumonia. The purpose of this review is to summarize the current evidence associated with the etiology, risk factors, clinical presentation, management, and prevention of nonmycobacterial community-acquired and nursing home-acquired pneumonia in persons aged 65 years and older.

The increasing occurrence of antibiotic-resistant pathogens influences the treatment approach to respiratory tract infections and complicates the selection of the anti-infectious drug and dosing regimen. Pharmacokinetic (PK) and pharmacodynamic (PD) characteristics both influence dosing regimens of antimicrobials. PK (the overall disposition of the drug in the body) is reflected by the serum concentration profile over time. PD can be characterized by the susceptibility of the pathogen to the drug, determined by measuring the minimum inhibitory concentration (MIC), which is a potency of the drug. There is an increasing need to identify new therapeutic approaches which improve the chance to reduce the morbidity and obtain successful outcomes. So far, antibiotic dosing has been focused on PK concepts, mainly the penetration of drug into sites of infection and its elimination half-life. Recently, a new appealing approach integrating PK and PD features has been suggested to implement optimal antibiotic dosing regimens, since several studies in animals and humans found a striking correlation between bacteriological outcome and specific PK/PD indices. It appears it would lead to better results not only in terms of clinical and bacteriological cure but also in the whole patient care.