Adriano R. Tonelli

Decreased Diversity of the Fecal Microbiome in Recurrent Clostridium difficile—Associated Diarrhea

Antibiotic-associated diarrhea due to Clostridium difficile (CDAD) is thought to reflect colonization of a disrupted microbial community by the pathogen. We profiled the fecal microbiota of patients with CDAD (both initial and recurrent episodes) by culture-independent phylogenetic analysis of 16S rRNA-encoding gene sequences. Compared with those from control subjects and patients with an initial episode, the fecal communities in patients with recurrent CDAD were highly variable in bacterial composition and were characterized by markedly decreased diversity. Preservation and restoration of the microbial diversity could represent novel strategies for prevention and treatment of recurrent CDAD, which is often recalcitrant to existing therapies.

Causes and Circumstances of Death in Pulmonary Arterial Hypertension

RATIONALE The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH). OBJECTIVES We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH. METHODS All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included. MEASUREMENTS AND MAIN RESULTS PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives. CONCLUSIONS Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.

Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) encompasses a number of diseases responsible for a specific set of hemodynamic findings during right heart catheterization. During initial workup, pulmonary vasodilator testing is performed. A positive acute pulmonary vasodilator test predicts better survival and response to calcium channel blocker (CCB) therapy. There is lack of consensus on the preferred agent for determining acute pulmonary vasoreactivity. The ACCP guidelines and the 4(th) World Symposium on Pulmonary Hypertension support the use of intravenous epoprostenol or nitric oxide (NO) as the preferred agents for pulmonary vasodilator testing. A decrease in the mean pulmonary artery pressure by at least 10 mmHg to reach an absolute value of 40 mmHg or less without a decrease in cardiac output is currently considered a positive pulmonary vasodilator test. A positive test by the current recommended criteria is observed in about 10-15% of patients with idiopathic PAH. Approximately half of these patients will experience long-term benefits with CCBs. A positive test may select patients with an earlier or less aggressive form of disease, which may carry a better prognosis. A positive vasodilator test is observed very infrequently in patients with pulmonary arterial hypertension other than idiopathic PAH or anorexigen associated PAH. This article reviews the literature regarding pulmonary vasodilator testing and use of CCB therapy in patients with PAH, while identifying the gaps in knowledge concerning this diagnostic procedure.

Prevalence and Prognostic Value of Left Ventricular Diastolic Dysfunction in Idiopathic and Heritable Pulmonary Arterial Hypertension

BACKGROUND Little is known about the association between left ventricular (LV) diastolic dysfunction and outcomes in patients with idiopathic or heritable pulmonary arterial hypertension (PAH). Our rationale was to investigate the prevalence of LV diastolic dysfunction, and its association with disease severity and outcomes, in patients with idiopathic or heritable PAH. METHODS Using the Cleveland Clinic Pulmonary Hypertension Registry, we identified subjects with heritable or idiopathic PAH who underwent Doppler echocardiography and right-sided heart catheterization. Echocardiographic diastolic parameters were assessed in each patient. RESULTS A total of 61 patients met the inclusion criteria (idiopathic 85%, heritable 15%). The age at the time of echocardiography was 48.3 ± 18 years, 84% of the subjects were women, and 48% were on PAH-targeted therapies. Normal LV diastolic function, impaired relaxation, and pseudonormalization were seen in 10%, 88%, and 2% of the patients, respectively. Peak early diastolic (peak E) velocity was directly associated with LV end-diastolic volume and cardiac index and inversely associated with the degree of right ventricular dilation, right atrial pressure, and pulmonary vascular resistance. Peak E velocity was associated with mortality adjusted for age and sex (hazard ratio [HR], 1.5; 95% CI, 1.1-2 per 10 cm/s decrease; P = .015) and age, sex, 6-min walk distance, and cardiac output (HR, 1.8; 95% CI, 1.2-2.9 per 10 cm/s decrease; P = .01). CONCLUSIONS LV diastolic dysfunction of the impaired relaxation type is observed in the majority of patients with advanced idiopathic or heritable PAH. A decrease in transmitral flow peak E velocity is associated with worse hemodynamics and outcome.

Alpha-1-antitrypsin augmentation therapy in deficient individuals enrolled in the Alpha-1 Foundation DnA and Tissue Bank

Introduction: Intravenous augmentation therapy with purified intravenous alpha-1 antitrypsin replaces the deficient protein and is the only currently approved treatment for alpha-1 antitrypsin deficiency (AATD) related lung disease. While augmentation therapy has been available for more than 20 years, there are a limited number of studies evaluating the effect of augmentation on lung function. Material and methods: We examined the decline in forced expiratory volume in one second (FEV1) in patients enrolled in the Alpha-1 Foundation DNA and Tissue Bank in relation to the use or not of alpha-1 antitrypsin augmentation therapy. For the purpose of our analysis we included 164 patients with AATD and PI ZZ genotype. Results: Mean age of the patients was 60 years, 52% were females, 94% were white and 78% ex-smokers. The mean FEV1 at baseline was 1.7 L and the mean FEV1 % of predicted was 51.3%. The mean follow-up time was 41.7 months. A total of 124 (76%) patients received augmentation therapy (augmented group) while 40 patients (24%) did not received it (non-augmented group). When adjusted by age at baseline, sex, smoking status, baseline FEV1 % of predicted, the mean overall change in FEV1 was 47.6 mL/year, favoring the augmented group (ΔFEV1 10.6 ± 21.4 mL/year) in comparison with the non-augmented group (ΔFEV1 −36.96 ± 12.1 mL/year) (P = 0.05). Beneficial ΔFEV1 were observed in ex-smokers and the group with initial FEV1 % of predicted of <50%. No differences were observed in mortality. Conclusions: In conclusion, augmentation therapy improves lung function in subjects with AATD when adjusted by age, gender, smoking status and baseline FEV1 % of predicted. The beneficial effects were noted in ex-smoker subjects with FEV1 below 50% of predicted.

Nitric oxide deficiency in pulmonary hypertension: Pathobiology and implications for therapy

Nitric oxide (NO) is a diffusible gas with diverse roles in human physiology and disease. Significant progress in the understanding of its biological effects has taken place in recent years. This has led to a better understanding of the pathobiology of pulmonary hypertension (PH) and the development of new therapies. This article provides an overview of the NO physiology and its role in the pathobiology of lung diseases, particularly PH. We also discuss current and emerging specific treatments that target NO signaling pathways in PH.

Prevalence of pulmonary hypertension in end-stage cystic fibrosis and correlation with survival

BACKGROUND Limited information is available about the prevalence of pulmonary hypertension diagnosed by right heart catheterization (RHC) in patients with cystic fibrosis being evaluated for lung transplantation. It is unclear whether there are factors that can predict the presence of pulmonary hypertension and whether the presence of pulmonary hypertension influences patient outcomes. METHODS The study included 57 unique and consecutive adult patients (33 women) with cystic fibrosis who underwent lung transplant evaluation at the University of Florida. RESULTS The average age at evaluation was 31.8 +/- 10 years. All patients were in New York Heart Association class III. The median (interquartile range) of mean pulmonary artery pressure (PAP) was 26 (24-30) mm Hg. Thirty-six patients (63.2%) had pulmonary hypertension (mean PAP >or= 25 mm Hg) and had a significantly higher degree of hypoxemia and oxygen requirements. Echocardiography evidenced limitations for the diagnosis of pulmonary hypertension. The 5-year mortality rate was similar in patients with or without pulmonary hypertension; however, it was higher in 7 patients identified by cluster analysis and in patients with a left ventricular ejection fraction < 55%. CONCLUSIONS More than half of our patients with cystic fibrosis and advanced lung disease have elevation of PAP, usually of mild degree. A lower left ventricular ejection fraction, but not the presence of pulmonary hypertension, was associated with worse outcomes.

Right Ventricular Echocardiographic Parameters Are Associated with Mortality after Acute Pulmonary Embolism

BACKGROUND There is limited information on the utility of certain echocardiographic measurements, such as right ventricular (RV) strain analysis, in predicting mortality in patients with acute pulmonary embolism (PE). METHODS A total of 211 patients with acute PE admitted to a medical intensive care unit (ICU) were retrospectively identified. Echocardiographic variables were prospectively measured in this cohort. The focus was on ICU, hospital, and long-term mortality. RESULTS The mean age was 61 ± 15 years. Median Acute Physiology and Chronic Health Evaluation IV and simplified Pulmonary Embolism Severity Index scores were 60 (interquartile range, 40-71) and 2 (interquartile range, 1-2), respectively. Thirty-eight patients (18%) died during the sentinel hospitalization (13% died in the ICU). A total of 61 patients (28.9%) died during a median follow-up period of 15 months (interquartile range, 5-26 months). The echocardiographic variables associated with long-term mortality (from PE diagnosis) were ratio of RV to left ventricular end-diastolic diameter (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2-4.8), tricuspid annular plane systolic excursion (HR, 0.53; 95% CI, 0.31-0.92), and RV-right atrial gradient (HR, 1.02; 95% CI, 1.01-1.4). ICU mortality was associated with ratio of RV to LV end-diastolic diameter (HR, 4.4; 95% CI, 1.3-15), RV systolic pressure (HR, 1.03; 95% CI, 1.01-1.05), tricuspid annular plane systolic excursion (HR, 0.4; 95% CI, 0.18-0.9), and inferior vena cava collapsibility < 50% (HR, 4.3; 95% CI, 1.7-11). These variables remain significantly associated with mortality after adjusting by Acute Physiology and Chronic Health Evaluation IV score, Pulmonary Embolism Severity Index score, or the use of thrombolytic agents. RV strain parameters were not correlated with hospital or long-term mortality. CONCLUSIONS Four simple parameters that measure different aspects of the right ventricle (ratio of RV to left ventricular end-diastolic diameter, RV systolic pressure, tricuspid annular plane systolic excursion, and inferior vena cava collapsibility) were independently associated with mortality in patients presenting with acute PE who were admitted to the ICU.

Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies.

Alpha-1 antitrypsin (AAT) deficiency is a hereditary condition characterized by low levels of AAT in plasma and hence diffusion into tissues. One of the most relevant characteristics of the disease is the development of panacinar emphysema due to an imbalance between proteases and antiproteases in the presence of environmental triggers. Left untreated, severe obstructive lung disease may develop. Avoidance of environmental triggers such as cigarette smoking constitutes a critical component of AAT deficiency treatment. Intravenous augmentation therapy is the only specific therapy for the condition that has been approved by the US Food and Drug Administration (FDA). While this therapy likely slows the rate of progression of emphysema and may improve survival in selected individuals with severe AAT deficiency, the gold standard for proof of efficacy is lacking. Areas where controversy exists regarding the use of AAT augmentation therapy include: (1) indications for treatment, (2) selection of specific AAT augmentation therapy, (3) appropriate dose and interval of administration, (4) cost effectiveness, (5) frequency and mode of follow up of treated patients, (6) use of augmentation therapy after lung transplantation, (7) use of recombinant AAT supplementation, (8) alternative delivery routes, and (9) genetic therapy. In this review we describe the advances in treatment and try to address some of the current controversies in AAT deficiency management.

State of the evidence: mechanical ventilation with PEEP in patients with cardiogenic shock

The need to provide invasive mechanical ventilatory support to patients with myocardial infarction and acute left heart failure is common. Despite the large number of patients requiring mechanical ventilation in this setting, there are remarkably few data addressing the ideal mode of respiratory support in such patients. Although there is near universal acceptance regarding the use of non-invasive positive pressure ventilation in patients with acute pulmonary oedema, there is more concern with invasive positive pressure ventilation owing to its more significant haemodynamic impact. Positive end-expiratory pressure (PEEP) is almost universally applied in mechanically ventilated patients due to benefits in gas exchange, recruitment of alveolar units, counterbalance of hydrostatic forces leading to pulmonary oedema and maintenance of airway patency. The limited available clinical data suggest that a moderate level of PEEP is safe to use in severe left ventricular (LV) dysfunction and cardiogenic shock, and may provide haemodynamic benefits as well in LV failure which exhibits afterload-sensitive physiology.