To review the spectrum and frequency of complications associated with coughing.

The anatomy and neurophysiology of cough has been reviewed in the preceding section. The objective of this section is to describe how the varied anatomic components of the respiratory system work in concert to produce an effective cough.

To describe the anatomy and neurophysiology of the cough reflex.

Anesthesia and surgery both affect the architecture of sleep. Aside from the postoperative effects of anesthesia and surgery, sleep deprivation and fragmentation have been shown to produce apneas or desaturations even in patients without presumed sleep apnea. Recent epidemiologic data have placed the prevalence of obstructive sleep apnea syndrome (OSAS) at about 5% among Western countries. The problem is further hindered by the difficulty in diagnosing OSAS, as patients with OSAS may present for surgery without a prior diagnosis. Clinical suspicion for OSAS may first be recognized intraoperatively. Adverse surgical outcomes appear to be more frequent in OSAS patients. Immediate postoperative complications may intuitively be attributed to the negative effects of sedative, analgesic, and anesthetic agents, which can worsen OSAS by decreasing pharyngeal tone, and the arousal responses to hypoxia, hypercarbia, and obstruction. Later events are, however, more likely to be related to postoperative rapid eye movement (REM) sleep rebound. In the severe OSAS patient, REM sleep rebound could conceivably act in conjunction with opioid administration and supine posture to aggravate sleep-disordered breathing. REM sleep rebound has also been suggested to contribute to mental confusion and postoperative delirium, myocardial ischemia/infarction, stroke, and wound breakdown. Although the data to guide the perioperative management of patients with moderate-to-severe OSAS is scarce, heightened awareness is recommended. The selected use of therapy with nasal continuous positive airway pressure before surgery and after extubation may be beneficial.

Much attention has been paid in recent years to optimizing the diagnosis of acute pulmonary embolism (PE). However, little is known about the changes in clot burden that occur at the level of the pulmonary arteries after documented PE. It is often problematic to distinguish between a new or residual defect on lung scintigraphy or helical CT. This may lead to falsely labeling patients with residual PE as having recurrent PE and consequent unnecessary treatment changes.

Performance measures and pay for performance are terms creating considerable angst among physicians today. Understanding the driving forces behind these concepts will help practitioners to strategically plan for their impact on individual physician practices and on health care in general. Medical societies can play a vital role in assisting physicians in the identification of appropriate performance measures used to gauge physician practices and by supporting efforts to develop equitable principles driving reimbursement based on adherence to those measures. Performance measures and pay for performance are terms evoking considerable angst across all sectors of the health services industry.

Most panels that develop clinical practice guidelines are poorly equipped to address resource allocation or cost issues associated with management options. This risks neglect, arbitrariness, lack of transparency, and methodological flaws in consideration of resource allocation. We provide recommendations for guideline panels to promote greater transparency and rigor. We suggest focusing on resource allocation issues for only a limited number of recommendations and provide criteria for selecting those in which economic considerations are likely to influence the direction or strength of the recommendation. Panels should involve a health economist to assist with the systematic review and critical interpretation of relevant economic analyses. They should carefully define the intended audience and may consider issuing alternative recommendations when available resources vary widely across target clinical settings. Targeting a limited number of recommendations for the consideration of resource allocation issues, and ensuring methodologically high-quality review, will best serve guideline panels, and the health-care providers and patients they hope to assist.

While grading the strength of recommendations and the quality of underlying evidence enhances the usefulness of clinical guidelines, the profusion of guideline grading systems undermines the value of the grading exercise. An American College of Chest Physicians (ACCP) task force formulated the criteria for a grading system to be utilized in all ACCP guidelines that included simplicity and transparency, explicitness of methodology, and consistency with current methodological approaches to the grading process. The working group examined currently available systems, and ultimately modified an approach formulated by the international GRADE group. The grading scheme classifies recommendations as strong (grade 1) or weak (grade 2), according to the balance among benefits, risks, burdens, and possibly cost, and the degree of confidence in estimates of benefits, risks, and burdens. The system classifies quality of evidence as high (grade A), moderate (grade B), or low (grade C) according to factors that include the study design, the consistency of the results, and the directness of the evidence. For all future ACCP guidelines, The College has adopted a simple, transparent approach to grading recommendations that is consistent with current developments in the field. The trend toward uniformity of approaches to grading will enhance the usefulness of practice guidelines for clinicians.

Pulmonary rehabilitation services benefit patients with chronic lung disease by reducing symptoms and restoring independent function. With a multidisciplinary approach to individual patient care through education, exercise, and psychosocial interventions, health-care costs and utilization may be reduced. While pulmonary rehabilitation services have typically been provided in a facility setting, many respiratory care services can be safely provided and appropriately reimbursed in the outpatient physician office setting, with appropriate physician supervision. After reviewing the utility of pulmonary rehabilitation for patients with chronic lung disease, the supervision, documentation, coding, and reimbursement requirements for providing rehabilitative respiratory care services in the outpatient office setting are detailed.

Seroepidemiologic and virologic studies since 1889 suggested that human influenza pandemics were caused by H1, H2, and H3 subtypes of influenza A viruses. If not for the 1997 avian A/H5N1 outbreak in Hong Kong of China, subtype H2 is the likely candidate for the next pandemic. However, unlike previous poultry outbreaks of highly pathogenic avian influenza due to H5 that were controlled by depopulation with or without vaccination, the presently circulating A/H5N1 genotype Z virus has since been spreading from Southern China to other parts of the world. Migratory birds and, less likely, bird trafficking are believed to be globalizing the avian influenza A/H5N1 epidemic in poultry. More than 200 human cases of avian influenza virus infection due to A/H5, A/H7, and A/H9 subtypes mainly as a result of poultry-to-human transmission have been reported with a > 50% case fatality rate for A/H5N1 infections. A mutant or reassortant virus capable of efficient human-to-human transmission could trigger another influenza pandemic. The recent isolation of this virus in extrapulmonary sites of human diseases suggests that the high fatality of this infection may be more than just the result of a cytokine storm triggered by the pulmonary disease. The emergence of resistance to adamantanes (amantadine and rimantadine) and recently oseltamivir while H5N1 vaccines are still at the developmental stage of phase I clinical trial are causes for grave concern. Moreover, the to-be pandemic strain may have little cross immunogenicity to the presently tested vaccine strain. The relative importance and usefulness of airborne, droplet, or contact precautions in infection control are still uncertain. Laboratory-acquired avian influenza H7N7 has been reported, and the laboratory strains of human influenza H2N2 could also be the cause of another pandemic. The control of this impending disaster requires more research in addition to national and international preparedness at various levels. The epidemiology, virology, clinical features, laboratory diagnosis, management, and hospital infection control measures are reviewed from a clinical perspective.

COPD is characterized by progressive inflammation in the small airways and lung parenchyma, and this is mediated by the increased expression of multiple inflammatory genes. The increased expression of inflammatory genes is regulated by acetylation of core histones around which DNA is wound, and conversely these activated genes are switched off by deacetylation of these histones. Histone deacetylases (HDACs) suppress inflammatory gene expression, but their activity and expression (particularly of HDAC-2) is reduced in the peripheral lung and in alveolar macrophages of patients with COPD. This results in amplification of the inflammatory response as COPD progresses but also accounts for corticosteroid resistance in COPD, since HDAC-2 is required by corticosteroids to switch off activated inflammatory genes. The reduction in HDAC-2 appears to be secondary to the increased oxidative and nitrative stress in COPD lungs. Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in COPD, but this can also be achieved by low doses of theophylline, which is an HDAC activator. This mechanism is also relevant to asthmatic patients who smoke, patients with severe asthma and cystic fibrosis, in whom oxidative stress is also increased.

Despite major advances in our understanding of the pathophysiologic processes leading to pulmonary arterial hypertension and recent developments in therapeutic approaches, the long-term prognosis for patients with pulmonary arterial hypertension remains unsatisfactory. Early detection and adequate clinical classification of the disease, better assessment of patients' prognosis, and improved therapeutic strategies are important challenges for clinicians in coming years.

In vivo phage display is a screening method in which peptides homing to specific vascular beds are selected after IV administration of a random peptide library. This strategy has revealed a vascular address system that allows tissue-specific targeting of normal blood vessels and angiogenesis-related targeting of tumor blood vessels by selected peptides. Many vascular receptors or "addresses" targeted by homing peptides have been identified. One such vascular receptor of normal lung endothelium is membrane dipeptidase (MDP), which was found by in vivo phage display to bind the tripeptide motif gly-phe-glu (GFE). Our studies with GFE peptide and lung vasculature suggest that MDP mediates cancer cell adhesion to lung vasculature and the development of lung metastases, but that MDP is not present in the vasculature of lung metastases. MDP appears to occupy a vascular distribution that is similar to the pulmonary artery circulation. These results demonstrate the promise of defining critical functional and anatomic characteristics of endothelial cells in lung and other organs by in vivo phage display.

Hypoxia-inducible factor (HIF)-1 is a transcription factor that is activated in response to hypoxia and growth factor/cytokine signaling via regulation of the HIF-1alpha subunit. HIF-1 has been implicated in the pathogenesis of pulmonary hypertension based on both experimental and clinical data. In a mouse model of pulmonary hypertension, hypoxia-induced increases in right ventricular mass, right ventricular pressure, and medial wall thickness of pulmonary arterioles were impaired in mice that were heterozygous for a null allele at the locus encoding HIF-1alpha compared to wild-type littermates. Electrophysiologic analyses revealed that the hypoxia-induced hypertrophy and depolarization of pulmonary arterial smooth muscle cells from wild-type mice was significantly impaired in heterozygotes. In clinical studies, immunohistochemical analyses of plexiform lesions within the lungs of patients with severe pulmonary hypertension revealed dramatic overexpression of HIF-1alpha within proliferating endothelial cells. These cells also expressed vascular endothelial growth factor (VEGF), which is the product of a known HIF-1 target gene, indicating that autocrine VEGF-VEGF receptor signaling may contribution to the pathogenesis of plexiform lesions. These studies implicate HIF-1 in pathophysiologic alterations of both smooth muscle and endothelial cell biology in patients with pulmonary hypertension.

Transforming growth factor (TGF)-beta is a multifunctional protein that initiates its diverse cellular responses by binding to and activating specific type I and type II serine/threonine kinase receptors. TGF-beta can act as a regulator of proliferation, migration, survival, differentiation, and extracellular matrix synthesis in endothelial cells and vascular smooth muscle cells, as well as in the maintenance of vascular homeostasis. Importantly, genetic studies in humans have revealed the pivotal role of TGF-beta as well as its signaling components in angiogenesis. Mutations in two TGF-beta receptors (ie, the activin receptor-like kinase (ALK) 1 and the accessory TGF-beta receptor endoglin) have been linked to vascular disorders named hereditary hemorrhagic telangiectasia. In addition, knockout mice for the different components of the TGF-beta signaling pathway have shown that TGF-beta is indispensable for angiogenesis. Recent studies have revealed that TGF-beta can regulate vascular homeostasis by balancing the signaling between two distinct TGF-beta type I receptors (ie, the endothelial-restricted ALK1 and the broadly expressed ALK5 receptors). The activation of these receptors has been shown to induce opposite effects on endothelial cell behavior and angiogenesis. In this review, we will present recent advances in understanding the role of TGF-beta signaling in endothelial cells as well as the underlying molecular mechanisms by which perturbation of this pathway can lead to vascular disorders.

Idiopathic pulmonary arterial hypertension is a progressive and potentially fatal disease with a limited number of therapeutic options. Two key lesions underlie the pathophysiology of this disease. The principal lesion is found in large- and intermediate-sized blood vessels and is characterized by medial and adventitial hypertrophy/hyperplasia, with distal extension of smooth-muscle layers into normally nonmuscularized vessels. The second lesion, found prominently in severe forms of pulmonary hypertension, originates in small precapillary vessel segments, commonly at blood vessel bifurcations. This "plexiform lesion" is a lumen-obliterative lesion comprised, at least in part, of cells that share endothelial cell attributes, but that have lost the "law of the monolayer." Indeed, the endothelial contribution to the (mal-)adaptive response in pulmonary hypertension is becoming increasingly apparent, with evidence that endothelium plays an important role in promoting the vasoconstriction and hyperproliferation of medial and adventitial cell layers in large- and intermediate-vessel sizes, and lumen obliteration in the plexiform lesion. Recent evidence indicates endothelial cells along the pulmonary artery and precapillary segments are phenotypically distinct and may fulfill different roles in these site-specific lesions. Thus, the present review summarizes our current understanding of pulmonary endothelial cell heterogeneity and discusses the potential role(s) of endothelial cell heterogeneity in the pathogenesis of pulmonary hypertension.