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Osteopontin in Patients With Idiopathic Pulmonary Hypertension

Background:

Osteopontin (OPN) is a pleiotropic cytokine that has been postulated to play a role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). OPN plasma levels may be related to disease severity and mortality in patients with PAH.

 Methods:

OPN plasma levels obtained during right-sided heart catheterization were assessed by a commercially available enzyme-linked immunosorbent assay and related to hemodynamics, exercise capacity, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, uric acid level, C-reactive protein level, and survival in two cohorts of patients with IPAH: a 4-year retrospective cohort (n = 70) and a prospective cohort (n = 25) followed for 3 months after initiation of therapy. Forty apparently healthy individuals served as control subjects.

 Results:

Baseline OPN levels were elevated in patients with IPAH compared with healthy control subjects (50.2 ± 35.9 vs 23.7 ± 2.8 ng/mL, P < .0001). In the retrospective as well as in the prospective cohort, OPN levels correlated with mean right atrial pressure and NT-BNP. In the retrospective cohort, OPN levels also correlated with age (r = 0.3, P = .02), 6-min walking distance (r=–0.4, P = .05), and New York Heart Association class (r = 0.4, P = .001). Multivariate Cox analysis demonstrated that baseline OPN levels were independent predictors of mortality (P = .02). When patients were divided according to their baseline OPN values, being normal or elevated at baseline (below or above 34.5 ng/mL), proportional survival rates were 100% vs 80% after 1 year and 77% vs 51% after 3 years, respectively.

 Conclusion:

Circulating OPN predicts survival in patients with IPAH and is associated with a higher New York Heart Association class. OPN, thus, may be useful as a biomarker in IPAH.

Interaction Between Adaptive and Innate Immune Pathways in the Pathogenesis of Atopic Asthma: Operation of a Lung/Bone Marrow Axis

Atopic asthma is the most common form of asthma, particularly during childhood, and in many cases it persists into adult life. Although atopy is clearly a risk factor for development of this disease, only a small subset of subjects sensitized to aeroallergens express persistent symptoms, suggesting that additional pathogenic mechanisms are involved. Recent studies have implicated respiratory viral infections as key cofactors in asthma development in atopic patients. In relation to initial expression of the asthma phenotype in early childhood, it has been shown that although both atopic sensitization and early severe lower respiratory tract infections can operate as independent asthma risk factors, the persistence of asthma is most frequent among children who experience both insults, suggesting that the relevant inflammatory pathways interact to maximally drive disease pathogenesis. Importantly, it has been established that both these factors must be operative contemporaneously for these interactions to occur (ie, the interactions are likely to be direct). Recent studies on viral-induced asthma exacerbations in atopic children have provided a plausible mechanism for these interactions. Notably, it has been demonstrated that signals triggered during the innate immune response to the virus can lead to the release of large numbers of migrating high-affinity IgE receptor-bearing bone marrow-derived precursors of mucosal dendritic cells into the blood. The subsequent trafficking of these cells to the infected airway mucosa where dendritic cell turnover is very high provides a potential mechanism for recruitment of underlying aeroallergen-specific T-helper 2 immunity into the already inflamed milieu in the infected airway mucosa.

The Utility of Cardiopulmonary Exercise Testing in Difficult Asthma

Background:

Unexplained persistent breathlessness in patients with difficult asthma despite multiple treatments is a common clinical problem. Cardiopulmonary exercise testing (CPX) may help identify the mechanism causing these symptoms, allowing appropriate management.

 Methods:

This was a retrospective analysis of patients attending a specialist-provided service for difficult asthma who proceeded to CPX as part of our evaluation protocol. Patient demographics, lung function, and use of health care and rescue medication were compared with those in patients with refractory asthma. Medication use 6 months following CPX was compared with treatment during CPX.

 Results:

Of 302 sequential referrals, 39 patients underwent CPX. A single explanatory feature was identified in 30 patients and two features in nine patients: hyperventilation (n = 14), exercise-induced bronchoconstriction (n = 8), submaximal test (n = 8), normal test (n = 8), ventilatory limitation (n = 7), deconditioning (n = 2), cardiac ischemia (n = 1). Compared with patients with refractory asthma, patients without "pulmonary limitation" on CPX were prescribed similar doses of inhaled corticosteroid (ICS) (median, 1,300 µg [interquartile range (IQR), 800-2,000 µg] vs 1,800 µg [IQR, 1,000-2,000 µg]) and rescue oral steroid courses in the previous year (median, 5 [1-6] vs 5 [1-6]). In this group 6 months post-CPX, ICS doses were reduced (median, 1,300 µg [IQR, 800-2,000 µg] to 800 µg [IQR, 400-1,000 µg]; P < .001) and additional medication treatment was withdrawn (n = 7). Patients with pulmonary limitation had unchanged ICS doses post CPX and additional therapies were introduced.

 Conclusions:

In difficult asthma, CPX can confirm that persistent exertional breathlessness is due to asthma but can also identify other contributing factors. Patients with nonpulmonary limitation are prescribed inappropriately high doses of steroid therapy, and CPX can identify the primary mechanism of breathlessness, facilitating steroid reduction.

Pneumonia Due to Pseudomonas aeruginosa: Part II: Antimicrobial Resistance, Pharmacodynamic Concepts, and Antibiotic Therapy

Pseudomonas aeruginosa carries a notably higher mortality rate than other pneumonia pathogens. Because of its multiple mechanisms of antibiotic resistance, therapy has always been challenging. This problem has been magnified in recent years with the emergence of multidrug-resistant (MDR) pathogens often unharmed by almost all classes of antimicrobials. The objective of this article is to assess optimal antimicrobial therapy based on in vitro activity, animal studies, and pharmacokinetic/pharmacodynamic (PK/PD) observations so that evidence-based recommendations can be developed to maximize favorable clinical outcomes. Mechanisms of antimicrobial resistance of P aeruginosa are reviewed. A selective literature review of laboratory studies, PK/PD concepts, and controlled clinical trials of antibiotic therapy directed at P aeruginosa pneumonia was performed. P aeruginosa possesses multiple mechanisms for inducing antibiotic resistance to antimicrobial agents. Continuous infusion of antipseudomonal β-lactam antibiotics enhances bacterial killing. Although the advantages of combination therapy remain contentious, in vitro and animal model studies plus selected meta-analyses of clinical trials support its use, especially in the era of MDR. Colistin use and the role of antibiotic aerosolization are reviewed. An evidence-based algorithmic approach based on severity of illness, Clinical Pulmonary Infection Score, and combination antibiotic therapy is presented; clinical outcomes may be improved, and the emergence of MDR pathogens should be minimized with this approach.

Can Chest Ultrasonography Replace Standard Chest Radiography for Evaluation of Acute Dyspnea in the ED?

Background:

We examined the concordance between chest ultrasonography and chest radiography in patients with dyspnea, using chest CT scanning as the gold standard in case of mismatch between the two modalities.

 Methods:

A prospective, blinded, observational study was conducted in the ED of a university-affiliated teaching hospital. All consecutive patients presenting for dyspnea during a single emergency physician shift were enrolled independently from the underlying disease. Only patients with trauma were excluded.

 Results:

Both ultrasonography and radiography were performed in 404 patients; CT scanning was performed in 118 patients. Ultrasound interpretation was completed during the scan, whereas the average time between radiograph request and its final interpretation was 1 h and 35 min. Ultrasonography and radiography exhibited high concordance in most pulmonary diseases, especially in pulmonary edema ( = 95%). For lung abnormalities such as free pleural effusion, loculated pleural effusion, pneumothorax, and lung consolidation, the concordance was similar for both left- and right-side lungs (all P not significant). When ultrasound scans and radiographs gave discordant results, CT scans confirmed the ultrasound findings in 63% of patients (P < .0001). Particularly, ultrasonography exhibited greater sensitivity than radiography in patients with free pleural effusion (P < .0001).

 Conclusions:

When performed by one highly trained physician, our study demonstrated high concordance between ultrasonography and radiography. When ultrasound scans and radiographs disagreed, ultrasonography proved to be more accurate in distinguishing free pleural effusion. Thus, considering the short time needed to have a final ultrasound report, this technique could become the routine imaging modality for patients with dyspnea presenting to the ED.

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