Current Respiratory Medicine Reviews

ISSN: 1573-398X

Current Respiratory Medicine Reviews
Volume 3, Number 1, February 2007

Contents


Editorial Pp. 1


Respiratory Sensation and Control of Breathing Pp. 3-6
Murray D. Altose
[Abstract] [Full text article]


Brittle Asthma Pp. 7-13
Raana Haqqee and Syed Hasan Arshad
[Abstract] [Full text article]


Cox Inhibitors as Potential Chemotherapic Drugs for Mesothelioma Pp. 15-18
Enrico P. Spugnini, Gennaro Citro and Alfonso Baldi
[Abstract] [Full text article]


The Pathophysiology of Sleep Apnoea: What We have Learned from Animal Models of Chronic Intermittent Hypoxia Pp. 19-27
Ken D. O’Halloran and Aidan Bradford
[Abstract] [Full text article]


Antioxidant Therapeutic Approaches Toward Amelioration of the Pulmonary Pathophysiological Damaging Effects of Ionizing Irradiation Pp. 29-37
Joel S. Greenberger and Michael W. Epperly
[Abstract] [Full text article]


Chlorine, Chlorination By-Products and Their Allergic and Respiratory Health Effects Pp. 39-47
Yvonne Kohlhammer and Joachim Heinrich
[Abstract] [Full text article]


A Case of Fatal Community-Acquired Necrotizing Pneumonia Caused by Panton-Valentine Leukocidin Positive Methicillin Sensitive Staphylococcus Aureus Pp. 49-51
Narimon Honarpour and Jenny T. Mao
[Abstract] [Full text article]


Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue Presenting as Multiple Pulmonary Lesions: Case Report and Review of the Literature Pp. 53-56
Bobbak Vahid, Bernadette Wildmore and Paul Marik
[Abstract] [Full text article]


Oxidative Stress, Histone Deacetylase and Corticosteroid Resistance in Severe Asthma and COPD Pp. 57-68
David Adenuga and Irfan Rahman
[Abstract] [Full text article]


Histotype in Non-Small Cell Lung Cancer Therapy and Staging: The Emerging Role of an Old and Underrated Factor Pp. 69-77
Giulio Rossi, Alessandro Marchioni, Giuliana Sartori, Lucia Longo, Silvia Piccinini and Alberto Cavazza
[Abstract] [Full text article]


Sarcoidosis in Pregnancy and Postpartum Period Pp. 79-83
Bobbak Vahid, Neil Mushlin and Sandra Weibel
[Abstract] [Full text article]


Loop Gain and Sleep Disordered Breathing Pp. 85-92
Kingman P. Strohl, Motoo Yamauchi and Thomas E. Dick
[Abstract] [Full text article]




Abstracts

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Editorial

Asthma remains a major cause of morbidity and mortality worldwide. In the United States it affects over 14 million people [1]. Acute asthma exacerbations account for almost two million emergency department (ED) visits, 500,000 hospital admissions and 5000 deaths every year [2]. Because of the significant morbidity and economic costs, clinicians are constantly searching for new interventions to treat acutely ill patients as well as more effective ways of using existing agents. Death from acute asthma, many which occur outside the hospital, reflects therapeutic failures at two different levels: failure of prophylaxis and failure in managing the acute attack.

The term brittle asthma (BA) was coined initially in 1977 to describe those patients that had wide variations in peak expiratory flow despite high doses of inhaled steroids [3]. This term has evolved to include those patients, who experience sudden, unpredictable, life-threatening asthma attacks as described by the British Thoracic Society [4, 5]. Many of these patients will have multiple visits to EDs and may eventually die. For years, the management of these patients has been a matter of debate.

In this issue of Current Respiratory Medicine Reviews, Haqqee presents a comprehensive review on BA including the role of genetics, environmental exposure as well as other factors assumed to cause this management challenge for clinicians [6].

Assessment of patients with BA, particularly when they present to the ED may be a difficult undertaking for any health care practitioner. The patient’s signs and symptoms may give a clue as to the degree of airway obstruction in some instances. However, objective measurements of pulmonary function have become the norm. Formal pulmonary function tests (spirometry), is difficult in patients presenting with acute exacerbation of asthma, and the measurement of peak expiratory flow rate has become the standard for ongoing monitoring.

Peak expiratory flow rates provide a simple, quantitative and reproducible measure of the severity of airflow obstructions in most patients with asthma. Several clinical studies have found that peak expiratory flow monitoring used as a component of comprehensive asthma self-management improves health outcomes [7-9]. Although dependent on effort and technique, peak expiratory flow rate is a simple procedure that it is easily implemented in several settings. However, in the patient with BA, this commonly used objective measurement of airway obstruction may be misinterpreted and fact, in some patients may be misleading [10]. In some instances, patients may have normal flows and suddenly develop a life-threatening airway obstruction. Clinicians must be careful and recognize that the patient with BA represents a special situation with multiple risk factors, a unique pathogenesis and require very careful monitoring [11].

Even though BA is uncommon, it represents a significant management challenge for clinicians. As Haqqee notes in his review, this multifactorial illness may not respond adequately to conventional therapy.

REFERENCES

[1] Marano MA. Current Estimates from the National Health Interviewing Survey: United States, 1994. DHHS publication no. (PHS) 96-1521, Vital Health Statistics Series; 10: 193. 1996. Washington, DC, National Center for Health Statistics, US Government Printing Office.

[2] Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of Asthma in the United States. N Engl J Med 1992; 326: 862-866.

[3] Turner-Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 1977; 71: 73-86.

[4] Ayres JG, Miles JF, Barnes PJ. Brittle asthma. Thorax 1998; 53: 315-321.

[5] British Thoracic Society, British Paediatric Association, Royal College of Physicians of London, et al. Guidelines on the management of asthma. Thorax 1993; 48 (Suppl): S1-S24.

[6] Haqqee R. Brittle asthma. Curr Resp Med Rev 2007; 3: 7-13.

[7] Woolcock AJ, Yan K, Salome CM. Effect of therapy on bronchial hyperresponsiveness in the long-term management of asthma. Clin Allergy 1988; 18: 165-76.

[8] Ignacio-Garcia JM, Gonzalez-Santos P. Asthma self-management education program by home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995; 151: 353-9.

[9] Beasley R, Cushley M, Holgate ST. A self-management plan in the treatment of adult asthma. Thorax 1989; 44: 200-4.

[10] Barnes PJ. Blunted perception and death from asthma. N Engl J Med 1994; 330: 1383-1384.

[11] Varon J, Fromm RE. Acute severe asthma. Intensive Care World 1995; 11: 103-104.

Pilar Acosta
Dorrington Medical Associates, PA
Houston
Texas 77030
USA


Joseph Varon
(Editor-in-Chief)
2219 Dorrington Street
Houston
Texas 77030
USA
E-mail: Joseph.Varon@uth.tmc.edu


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Respiratory Sensation and Control of Breathing
Murray D. Altose

[Full text article]

The observation that non-chemically mediated respiratory load compensation is dependent on a state of wakefulness suggested that the perception of the load or the conscious appreciation of the ventilatory consequences of the loading is required for respiratory motor output to increase. This led to studies of respiratory sensation using a variety of psychophysical approaches. These psychophysical studies revealed that respiratory-related physical changes are consciously appreciated and indicated that sensory information from the ventilatory apparatus does reach the cerebral cortex. This was further supported by physiological studies that demonstrated respiratory-related cortical-evoked potentials over somatosensory regions of the brain. Studies utilizing chest wall vibration support an important role for chest wall muscle spindles in mediating respiratory sensation. Our studies have also shown that voluntarily reducing the level of ventilation at a constant level of chemical drive results in a progressive proportional increase in the intensity of the unpleasant sensation of respiratory discomfort and the increase in respiratory sensation is predominantly a function of the degree to which tidal volume is reduced suggesting that limiting chest expansion or thoracic displacement is the proximate cause of the unpleasant sensation. Our observations that the sensation of dyspnea intensifies with increases in ventilation as well as when ventilation is reduced below the spontaneously adopted free breathing level can be simulated by mathematical models that suggest that respiratory drive integration depends not only on the direct effects of chemical and mechanical feedback but also on the perceptual consequences of these stimuli.


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Brittle Asthma
Raana Haqqee and Syed Hasan Arshad

[Full text article]

About 5% of asthmatics do not behave like ‘classical’ asthmatics and may not respond adequately to conventional therapy. The terms used to describe such non-responders include severe, refractory, near fatal, difficult and difficult to control asthma. Within the umbrella term of severe or refectory asthma, there are distinct sub-phenotypes including brittle asthma. Brittle asthma is rare and may occur in 0.05% of all asthmatics. Currently the diagnosis of brittle asthma is made on clinical grounds based on the variability of peak flow and uncertainty and unpredictability of sudden onset of disabling and severe symptoms despite maximal medical therapy with high dose inhaled corticosteroids, inhaled and nebulised bronchodilators and either maintenance or repeated courses of systemic corticosteroids.

The role of genetics, environmental exposure and infection is the focus of ongoing research in the development of severe asthma. Atopy, female sex and psychosocial factors are recognised to be associated with brittle asthma. Other factors, investigated as possible initiating or contributing factors in brittle asthma include nutrient deficiency, reduced antioxidants activity and immunodeficiency with low IgG subclass levels.

This review will highlight the related phenotypes, risk factors, mortality and morbidity, pathogenesis and management of patients with brittle asthma.


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Cox Inhibitors as Potential Chemotherapic Drugs for Mesothelioma
Enrico P. Spugnini, Gennaro Citro and Alfonso Baldi

[Full text article]

Malignant mesothelioma (MM) is an uncommon neoplasm that arises from the cells lining the body cavities, in particular the pleural and peritoneal cavities. The treatment of MM is a major challenge with frustrating results for clinicians and patients alike. Despite the adoption of newly developed radiotherapic and chemotherapic regimens, the prognosis remains dismal and only modest improvements have been obtained thus far. In this scenario, a better comprehension of the molecular patterns is of paramount importance. Cyclooxygenases catalyze the rate limiting step in the production of prostanoids. Accumulating data demonstrate that overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Aim of this review is to discuss the current state of the art in mesothelioma, with a particular emphasis on the recent advances in molecular pathogenesis uncovering several aspects of initiation and development of MM; in particular the role of COX-2 will be highlighted. Finally, potential novel therapeutic molecular targets will be discussed.


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The Pathophysiology of Sleep Apnoea: What We have Learned from Animal Models of Chronic Intermittent Hypoxia
Ken D. O’Halloran and Aidan Bradford

[Full text article]

Sleep apnoea is a common condition associated with significant morbidity and mortality. The English bulldog is the only animal known to have sleep apnoea. In recent years, a number of animal models have been developed which have contributed greatly to our knowledge of the condition. These models develop a number of pathophysiological changes similar to human sleep apnoea such as systemic and pulmonary hypertension, increased haematocrit, and effects on blood coaguability, cardiac rhythmogenesis and central nervous system and upper airway muscle function. This review will describe what has been learned from these models concerning the pathophysiology of sleep apnoea with special emphasis on the role played by intermittent hypoxia.


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Antioxidant Therapeutic Approaches Toward Amelioration of the Pulmonary Pathophysiological Damaging Effects of Ionizing Irradiation
Joel S. Greenberger and Michael W. Epperly

[Full text article]

There is increasing evidence that lung irradiation damage is mediated by oxidative stress responses of pulmonary vascular and parenchymal cells. The acute irradiation response involves strand breaks in nuclear DNA, then stress activated protein kinase (SAP-Kinase) transport to mitochondria where lipid peroxidation changes lead to cytochrome-c release and apoptosis. However, secondary cytokine elevations lead to a second wave of apoptosis both directly and indirectly mediated through inflammatory cell infiltrates. A recovery phase and latent period follows wherein little structural or physiological evidence of lung damage is detectable in animal models or in humans. The late effects of irradiation pulmonary fibrosis initiate by unknown triggering events thought to involve not only resident pulmonary endothelial cells, but also recruited bone marrow origin macrophages and progenitors of myofibroblasts, which contribute to the lesion of organizing alveolitis in the mouse model or pulmonary irradiation fibrosis in humans. Oxidative stress markers are elevated during formation of the late lesion in a pattern, which is reminiscent of the acute lesion. The amelioration of both the acute and late pulmonary pathophysiologic changes by administration of antioxidant therapies suggests that similar molecular mechanisms may be involved. This article reviews several bodies of evidence concerning the cause and possible therapeutic strategies, which may be of value in treating ionizing irradiation, induced lung damage.


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Chlorine, Chlorination By-Products and Their Allergic and Respiratory Health Effects
Yvonne Kohlhammer and Joachim Heinrich

[Full text article]

Although chlorine and most of its derivates are known toxic agents, it has been pronounced as a safe disinfectant for water treatments. More detailed analyses and extended studies concerning chlorine safety have only started recently. The objective of this article was to review data on the use of chlorine in pool environments, the resulting chlorination by-products in these environments and their potential effects on allergic and respiratory health in humans.

The MEDLINE database search comprised articles from 1966 to August 2006. Additional studies were identified by searching references of already published articles. A total of twenty-one studies evaluating effects of chlorine and its by-products on allergic or respiratory health were included in the analysis. Exposure to chlorination by-products through swimming pool attendance showed adverse health effects on children, subjects occupationally exposed, athletic swimmers and asthmatic subjects. These adverse effects were seen despite the presence of official directives in most countries to control and regulate the use of chlorine for water disinfection. Contact to chlorination by-products might not be the leading reason for poor respiratory health, but might not be as harmless as earlier thought. In particular, baby swimming in chlorinated pools is highly questionable.


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A Case of Fatal Community-Acquired Necrotizing Pneumonia Caused by Panton-Valentine Leukocidin Positive Methicillin Sensitive Staphylococcus Aureus
Narimon Honarpour and Jenny T. Mao

[Full text article]

The expression of Panton-Valentine leukocidin (PVL) has been implicated as a virulence factor for community-acquired Staphylococcus aureus pneumonia with most reported cases involving methicillin-resistant strains. Here we describe a case of community-acquired, PVL-positive methicillin-sensitive Staphylococcus aureus (MSSA) sufficiently virulent to cause rapidly progressive necrotizing pneumonia, massive pulmonary hemorrhage, sepsis, and death in a patient without conventional risk factors (diabetes, advanced age). To our knowledge, this is the first case report of a fatal necrotizing pneumonia caused by PVL-positive MSSA in Los Angeles County.


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Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue Presenting as Multiple Pulmonary Lesions: Case Report and Review of the Literature
Bobbak Vahid, Bernadette Wildmore and Paul Marik

[Full text article]

We report a case of extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT) that presented as multiple pulmonary nodules and masses. Lung lesions were found incidentally on a chest radiograph in an asymptomatic patient. Abdominal CT scan was obtained that showed asymmetric gastric mucosal thickening. Biopsy of lung masses and gastric mucosa confirmed the diagnosis of MALT lymphoma. The subject of MALT lymphoma is reviewed.


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Oxidative Stress, Histone Deacetylase and Corticosteroid Resistance in Severe Asthma and COPD
David Adenuga and Irfan Rahman

[Full text article]

Cigarette smoke-mediated oxidative stress enhances inflammation through the activation of stress kinases (JNK, ERK, p38) and redox-sensitive transcription factors such as NF-κB and AP-1 resulting in increased expression of distinct pro inflammatory mediators. Cigarette smoke and oxidants alter chromatin remodelling by targeted acetylation of histones and inhibition of histone deacetylase activity and in so doing further enhances inflammatory gene expression. Resistance to steroid therapy in patients with chronic obstructive pulmonary disease (COPD) and asthma has been attributed to the altered balance between oxidative stress and the acetylation-deacetylation states of histones. Corticosteroids/ glucocorticoids are potent anti inflammatory hormones that mediate a vast array of tissue and cell specific pathways via different tissue specific co-activators or co-repressors. Glucocorticoids exert their effect via specific glucocorticoid receptors and involve modulation of the acetylation status of histones. Histone deacetylases (HDACs) are recruited by glucocorticoids which lead to deacetylation of histones and a subsequent switching off various inflammatory genes. Cigarette smoke-mediated oxidative stress alters HDAC levels by post-translational modifications with reactive aldehydes and NO present in cigarette smoke. Pharmacological agents and polyphenolic antioxidants, especially theophylline and curcumin are now known to assist glucocorticoid recruitment of HDACs, in particular HDAC2. Various therapeutic strategies are being employed either to control the activity of NF-κB or to increase the activity of HDACs. Co-administration of theophylline, curcumin or its derivatives along with glucocorticoids could greatly overcome the resistance and enhance the therapeutic efficacy of the steroids in COPD and steroid resistant asthma.


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Histotype in Non-Small Cell Lung Cancer Therapy and Staging: The Emerging Role of an Old and Underrated Factor
Giulio Rossi, Alessandro Marchioni, Giuliana Sartori, Lucia Longo, Silvia Piccinini and Alberto Cavazza

[Full text article]

Therapeutic management of lung cancer is mainly based on a dichotomic distinction between small cell (SCLC) and non-small cell lung cancer (NSCLC), tumour stage and patient performance status. However, crossing the recent data emerging from molecular studies of gene expression profiling, from the new 2004-WHO histopathological classification of lung tumours as well as from clinical trials with newl targeted therapies against EGFR (gefitinib/erlotinib/cetuximab), it seems that a better definition of tumour histotype in NSCLC might somehow be helpful in predicting clinical response and patient outcome. In addition, lung tumours histotype may deeply influence the tumour stage when assessing parameters (i.e., pulmonary atelectasis, pleural invasion, tumour dimension) defining the current lung tumours staging system. Thus, in this review we analyze the possible future role of histotype as an important influencing factor in the clinical management of patients with NSCLC.


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Sarcoidosis in Pregnancy and Postpartum Period
Bobbak Vahid, Neil Mushlin and Sandra Weibel

[Full text article]

Sarcoidosis is a multisystemic disease of unknown etiology, characterized by granulomatous inflammation. It typically presents between the ages of 20 to 40 years old. An estimated 0.02% to 0.05% of pregnancies occur in patients with sarcoidosis. Although fetal loss has been reported in mothers with sarcoidosis, limited studies do not suggest an increase risk of fetal or neonatal complications. Several reports suggest an improvement of sarcoidosis during pregnancy. Sarcoidosis, a Th1-mediated disease, seems to follow the same course as rheumatoid arthritis during pregnancy and post-partum. Estrogen levels increase during pregnancy, resulting in a decreased Th1-mediated immune response, which can improve active sarcoidosis. Free plasma cortisol concentrations increase in pregnancy, with plasma levels 2- to 3-fold higher than those of non-pregnant controls, suggesting greater tissue exposure to glucocorticoids during pregnancy. This may result in decreased granulomatous inflammation with improvement in symptoms and clinical findings. During the postpartum period, when free cortisol levels return to the prior non-pregnant levels, reactivation of sarcoidosis can occur. The majority of patients with sarcoidosis will either have a stable disease or will experience improvement in their symptoms. A small group of pregnant mother with active sarcoidosis, however, may develop more progressive disease during pregnancy. The manifestations, course of disease, and treatment options during pregnancy and postpartum period are discussed.


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Loop Gain and Sleep Disordered Breathing
Kingman P. Strohl, Motoo Yamauchi and Thomas E. Dick

[Full text article]

There is a close relationship among the types of sleep apnea (central, obstructive, and mixed) in regard to both the pathogenesis and in the clinical management of sleep apnea syndromes. This review will recount the rationale for the use of animal models in understanding intermediate traits, such as the ventilatory responses to hypoxia and reoxygenation, seen with human sleep apnea. One feature of particular interest will be the dynamic responses of the control system, specifically the instability over time that could operate to produce repetitive apneas. The recurrent nature of clinically significant sleep apnea can be understood in terms of feedback control, or “loop gain”. We will discuss findings in a mouse model for recurrent apneas and propose that there exist genetic mechanisms that could determine loop gain in the respiratory control system.