Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal disease, based on a multifaceted and incompletely understood pathogenesis. Some of the cellular and molecular mechanisms of vascular remodeling have been experimentally explored, and it is obvious that alterations of microvessels are involved in IPF. These can, among others, lead to the development of pulmonary hypertension. In order to understand the process of vascular integrity and repair, it is necessary to identify the factors associated with angiogenesis in IPF. A delicate balance of angiogenic and angiostatic factors regulates vessel homeostasis in normal physiologic conditions in the lungs. Although earlier studies have proposed that IPF is associated with an increase of angiogenesis, there is some more recent evidence that angiogenesis in fibrotic lungs may actually be decreased, causing some controversy in the literature in this area. This review, therefore, discusses the concept of angiogenesis in pulmonary fibrosis and speculates on how the spatial and temporal heterogeneity of IPF might explain the controversial findings about vessel density in fibrotic lungs.

Adaptive servoventilation (ASV) has demonstrated efficacy in treating sleep-disordered breathing (SDB) in patients with heart failure (HF), but large randomized trials are lacking. We, therefore, sought to perform a systematic review and meta-analysis of existing data.

Obstructive sleep apnea syndrome (OSAS) is a common disorder with far-reaching health implications. One of the major consequences of OSAS is an impact on neurocognitive functioning. Several studies have shown that OSAS has an adverse effect on inductive and deductive reasoning, attention, vigilance, learning, and memory. Neurocognitive impairment can be measured objectively with tests such as the Wechsler Adult Intelligence Scale-Revised, the Psychomotor Vigilance Task, the Steer Clear Performance Test, and tests of repetitive finger tapping. In children, OSAS may cause attention-deficit hyperactivity disorder in addition to behavioral problems and learning disabilities. Risk factors for cognitive impairment include increasing age, male sex, apolipoprotein E ε4 allele positivity, current cigarette smoking, obesity, hypertension, diabetes mellitus, metabolic syndrome, Down syndrome, hypothyroidism, significant alcohol consumption, stroke, and the use of psychoactive medications. At a cellular level, OSAS likely causes cognitive impairment through intermittent hypoxia, hormonal imbalance, and/or systemic inflammation, either independently or via the resultant endothelial dysfunction that occurs. Excessive daytime sleepiness should be measured and minimized in all studies of neurocognitive impairment. Recent studies have used functional and structural neuroimaging to delineate the brain areas affected in patients with OSAS with neurocognitive dysfunction. A common finding in several of these studies is decreased hippocampal volume. Other affected brain areas include the frontal and parietal lobes of the brain, which show focal reductions in gray matter. These changes can be reversed at least partially with the use of CPAP, which highlights the importance of early recognition and treatment of OSAS. The currently available data in this field are quite limited, and more research is needed.

We report the case of a man with a history of intermittent fever and arthritis who presented with a dry cough and associated lung involvement, who was eventually given the diagnosis of Whipple disease. The pulmonary symptoms preceded the development of GI manifestations. Five years later, periodic acid-Schiff (PAS)-positive macrophages were identified in duodenal biopsy specimens and polymerase chain reaction for Tropheryma whipplei was positive in the duodenum, stools, saliva, and cerebrospinal fluid. Pulmonary T whipplei was retrospectively confirmed by positive PAS staining and immunoreactivity to specific antibodies in endobronchial biopsy specimens. Antibiotic treatment was followed by remission. A literature review identified eight other cases of Whipple disease presenting with lung parenchymal involvement, predominantly interstitial lung disease (ILD), and without initial GI symptoms. In the absence of GI symptoms, a diagnosis of Whipple disease should be considered in middle-aged men presenting with ILD or lung nodules, if the patient has a history of unexplained arthralgia and/or fever. The association of mediastinal adenopathy or pleural effusion offers additional concern. Whipple disease may be fatal in the absence of treatment, but prolonged antibiotic treatment often leads to complete remission.

Identifying patients with impaired renal function is crucial in the setting of critical illness. Serum creatinine serves as the gold standard for assessing steady-state renal function, helping to define those with chronic kidney disease (CKD). Although these baseline creatinine values are often not available in the setting of critical illness, CKD, whether defined by serum creatinine or proteinuria, increases the risk of developing acute kidney injury (AKI). Despite delays in elevations following renal insults, serum creatinine remains the standard for assessing acute changes in renal function. Standardized definitions of AKI, using changes in serum creatinine and urine output, have informed the epidemiology of ICU-acquired AKI and have helped define the long-term outcomes in patients who experience AKI. A complex cyclical interplay exists between AKI and CKD, in which CKD predisposes patients to an increased risk of AKI, whereas those with AKI, regardless of baseline renal function, are more likely to suffer from post-AKI CKD. The clarification of the AKI-CKD dynamic remains a work in progress and will be aided by the implementation of novel measures of renal function. Several novel biomarkers of renal function have been proposed to augment serum creatinine in the diagnosis of AKI and CKD. These biomarkers, taken with recent clinical investigations, have laid the groundwork for the impending paradigm shift in risk stratifying and in diagnosing changes in renal function in the ICU.

Despite regular use of drugs for critically ill patients, overall data are limited regarding the impact of critical illness on pharmacokinetics (PK). Designing safe and effective drug regimens for patients with critical illness requires an understanding of PK. This article reviews general principles of PK, including absorption, distribution, metabolism, and elimination, and how critical illness can influence these parameters. In the area of drug absorption, we discuss the impact of vasopressor use, delayed gastric emptying and feeding tubes, and nutrient interactions. On the topic of drug distribution, we review fluid resuscitation, alterations in plasma protein binding, and tissue perfusion. With drug metabolism, we discuss hepatic enzyme activity, protein binding, and hepatic blood flow. Finally, we review drug elimination in the critically ill patient and discuss the impact of augmented renal clearance and acute kidney injury on drug therapies. In each section, we highlight select literature reviewing the PK impact of these conditions on a drug PK profile and, where appropriate, provide general suggestions for clinicians on how to modify drug regimens to manage PK challenges.

Allergen-specific immunotherapy (SIT) involves the repeated administration of allergenic extracts to atopic individuals over a period of 3 to 5 years either subcutaneously (SCIT) or sublingually (SLIT) for the treatment of allergic respiratory diseases, including asthma and allergic rhinitis (AR). In studies, SCIT and SLIT have been shown to improve existing symptoms of asthma and AR and to also have the capability to cause disease-modifying changes of the underlying atopic condition so as to prevent new allergic sensitization as well as arrest progression of AR to asthma. Recent evidence suggests that immunotherapy brings about these effects through actions that use T-regulatory cells and blocking antibodies such as IgG(4) and IgA(2,) which can then result in an "immune deviation" from a T-helper (Th) 2 cell pattern to a Th1 cell pattern. Numerous meta-analyses and studies have been performed to evaluate the existing data among these studies, with the consensus recommendation favoring the use of immunotherapy because of its potential to modify existing diseases. Significant adverse reactions can occur with immunotherapy, including anaphylaxis and, very rarely, death. A primary factor in considering SIT is its potential to provide long-lasting effects that are able to be sustained well after its discontinuation. Given the significant burden these allergic diseases impose on the health-care system, SIT appears to be a cost-effective adjunctive treatment in modifying the existing disease state.

Asthma is one of the most common chronic illnesses, especially in children. Reaching the diagnosis of asthma and its management are more difficult than for other chronic illnesses. For example, asthma is a heterogeneous syndrome with many clinical classifications based on patient symptoms, lung function, and response to therapy. The symptoms and objective measurements of lung function, often used to guide therapy, are largely based on the inflammation of the airways. Because measuring airway dysfunction and inflammation in a typical clinical setting is difficult, it is often not done. Metabolomics is the study of small molecules generated from cellular metabolic activity. It is possible that the metabolic profile of a patient with a chronic illness such as asthma is different from that of a healthy patient or from a patient with another respiratory illness. Furthermore, if this metabolome could be measured, it might also vary with disease severity. The pattern of metabolites becomes the diagnostic representing the disease. This article outlines the more recent work that has been done to develop the metabolomic profile of asthma.

Lung cancer is the leading cause of cancer-related mortality in the United States and around the world. There are > 90 million current and ex-smokers in the United States who are at increased risk of lung cancer. The published data from the National Lung Screening Trial (NLST) suggest that yearly screening with low-dose thoracic CT scan in heavy smokers can reduce lung cancer mortality by 20% and all-cause mortality by 7%. However, to implement this program nationwide using the NLST inclusion and exclusion criteria would be extremely expensive, with CT scan costs alone > $2 billion per annum. In this article, we offer a possible low-cost strategy to risk-stratify smokers on the basis of spirometry measurements and emphysema scoring by radiologists on CT scans.

Given the current lack of effective vaccines against TB, the accuracy of screening tests for determining or excluding latent TB infection (LTBI) is decisive in effective TB control. This meta-analysis critically appraises studies investigating the positive and the negative predictive value (PPV and NPV, respectively) from a test-determined LTBI state for progression to active TB of interferon-γ release assays (IGRAs) and the tuberculin skin test (TST).

Pneumothorax in critically ill patients remains a common problem in the ICU, occurring in 4% to 15% of patients. Pneumothorax should be considered a medical emergency and requires a high index of suspicion, prompt recognition, and intervention. The diagnosis of pneumothorax in the critically ill patient can be made by physical examination findings or radiographic studies including chest radiographs, ultrasonography, or CT scanning. Ultrasonography is emerging as the diagnostic procedure of choice for the diagnosis and management guidance and management of pneumothoraces, if expertise is available. Pneumothoraces in unstable, critically ill patients or in those on mechanical ventilation should be managed with tube thoracostomy. If there is suspicion for tension pneumothorax, immediate decompression and drainage should be performed. With widespread use of CT scanning, there have been more occult pneumothoraces diagnosed, and the most recent literature suggests that drainage is preferred. In patients with a persistent air leak or failure of the lung to expand, current guidelines suggest that an early thoracic surgical consultation be requested within 3 to 5 days.

It is estimated that 350,000 people suffer a cardiac arrest each year in the United States, with one-half occurring out-of-hospital and the other half in-hospital. Overall survival is < 10% and has not changed significantly for decades. CPR is the umbrella term for attempts to restore organized cardiac contractility and functional blood flow. Physicians have studied resuscitation techniques for millennia. In 1964, Peter Safar published the first ABCs of Heart-Lung Resuscitation, which included: (1) first aid, (2) start spontaneous circulation, and (3) support recovery. Many of these principles were incorporated into the first official CPR guidelines developed by the American Heart Association in 1966. These guidelines have been updated periodically since then, with the most recent iteration developed in November 2010. Fundamental principles, such as early defibrillation, chest compressions performed at the appropriate rate and depth, and delivery of postarrest care, are affirmed in the recent guidelines update. In addition, a greater emphasis has been placed on quality of CPR, with the need to minimize interruptions, the reordering of CPR priorities to place chest compressions before ventilations, and the need for comprehensive postarrest care that includes both targeted temperature and hemodynamic management. Whether a cardiac arrest occurs out-of-hospital or in-hospital, the basic approach to CPR and postarrest care is identical. Documentation should be performed in a standardized fashion, using a consensus set of data elements known as the Utstein format, and can contribute to quality improvement, research, and billing efforts.

Respiratory infections remain the most common reason why patients seek medical care in ambulatory and hospital settings, and they are the most frequent precursor of sepsis. In light of the limitations of clinical signs and symptoms and traditional microbiologic diagnostics for respiratory infections, blood biomarkers that correlate with the presence and extent of bacterial infections may provide additional useful information to improve diagnostic and prognostic efforts and help with therapeutic decisions in individual patients. A growing body of evidence supports the use of procalcitonin (PCT) to differentiate bacterial from viral respiratory diagnoses, to help risk stratify patients, and to guide antibiotic therapy decisions about initial need for, and optimal duration of, therapy. Although still relatively new on the clinical frontier, a series of randomized controlled trials have evaluated PCT protocols for antibiotic-related decision making and have included patients from different clinical settings and with different severities of respiratory infection. In these trials, initial PCT levels were effective in guiding decisions about the initiation of antibiotic therapy in lower-acuity patients, and subsequent measurements were effective for guiding duration of therapy in higher-acuity patients, without apparent harmful effects. Recent European respiratory infection guidelines now also recognize this concept. As with any other laboratory test, PCT should not be used on a stand-alone basis. Rather, it must be integrated into clinical protocols, together with clinical, microbiologic data and with results from clinical risk scores. The aim of this review is to summarize recent evidence about the usefulness of PCT in patients with lower respiratory tract infections and to discuss the potential benefits and limitations of this marker when used for clinical decision making.

Maintaining an airway clear of inhaled particles, pathogens, and cellular debris is paramount for lung homeostasis. In healthy individuals, the phagocytes of the innate immune system act as sentinels to patrol the airway and ensure sterility. However, in airways diseases, including asthma, COPD, and cystic fibrosis, there is a propensity for bacterial colonization that may contribute to disease worsening. Evidence suggests that this may be due to dysfunctional phagocytosis. In patients with COPD, phagocytosis of several bacterial species and removal of apoptotic cells (efferocytosis) by alveolar macrophages are significantly reduced; however, these cells can remove inert beads normally. Attenuated phagocytosis is also apparent in monocyte-derived macrophages from the same patients, suggesting an inherent defect in these cells. Reduced expression of cell surface recognition receptors has been suggested as one mechanism for these observations; however, the literature is currently contradictory and requires further clarification. In cystic fibrosis, a similar defect is also observed in both airway neutrophils and macrophages, leading to ineffective bacterial uptake and subsequent killing. In asthma and other airways diseases, there are also reports of defective phagocytosis of bacterial pathogens, although the relevance to disease pathophysiology is not understood. Oxidative stress is emerging as a common mechanism that may be altering both macrophage and neutrophil functions that can be reversed by various antioxidant strategies. The identification of this and other mechanisms underlying phagocyte dysfunction may present novel therapeutic opportunities for the treatment of many of these intractable diseases and improve patient morbidity and mortality.

Although atrial fibrillation (AF) is accepted as the most common sustained cardiac arrhythmia, most published epidemiologic studies focus on predominantly white populations in North America or Europe, and information on AF in nonwhite populations is scarce. The objective of this study was to undertake a systematic review of the published literature on the epidemiology of AF in other regions.

The purpose of our study was to conduct a systematic review and meta-analysis of all randomized controlled trials to date comparing fibrinolytics with placebo to clarify their current role in the management of parapneumonic effusions and empyemas.

Sleep-disordered breathing (SDB) comprises a diverse set of disorders marked by abnormal respiration during sleep. Clinicians should realize that SDB may present as acute cardiopulmonary failure in susceptible patients. In this review, we discuss three clinical phenotypes of acute cardiopulmonary failure from SDB: acute ventilatory failure, acute congestive heart failure, and sudden death. We review the pathophysiologic mechanisms and recommend general principles for management. Timely recognition of, and therapy for, SDB in the setting of acute cardiopulmonary failure may improve short- and long-term outcomes.

Ubiquitination is a posttranslational modification that regulates a variety of cellular functions depending on timing, subcellular localization, and type of tagging, as well as modulators of ubiquitin binding leading to proteasomal or lysosomal degradation or nonproteolytic modifications. Ubiquitination plays an important role in the pathogenesis of acute lung injury (ALI) and other lung diseases with pathologies secondary to inflammation, mechanical ventilation, and decreased physical mobility. Particularly, ubiquitination has been shown to affect alveolar epithelial barrier function and alveolar edema clearance by targeting the Na,K-ATPase and epithelial Na(+) channels upon lung injury. Notably, the proteasomal system also exhibits distinct functions in the extracellular space, which may contribute to the pathogenesis of ALI and other pulmonary diseases. Better understanding of these mechanisms may ultimately lead to novel therapeutic modalities by targeting elements of the ubiquitination pathway.

Bronchodilators are central to the symptomatic management of patients with COPD.Previous data have shown that inhaled indacaterol improved numerous clinical outcomes over placebo.

The article describes the mechanisms of action, pharmacokinetics, and pharmacodynamics of aspirin, dipyridamole, cilostazol, the thienopyridines, and the glycoprotein IIb/IIIa antagonists. The relationships among dose, efficacy, and safety are discussed along with a mechanistic overview of results of randomized clinical trials. The article does not provide specific management recommendations but highlights important practical aspects of antiplatelet therapy, including optimal dosing, the variable balance between benefits and risks when antiplatelet therapies are used alone or in combination with other antiplatelet drugs in different clinical settings, and the implications of persistently high platelet reactivity despite such treatment.