Evaluation of Imatinib Mesylate in the Treatment of Pulmonary Arterial Hypertension

Imatinib mesylate is a small molecule inhibitor that selectively inhibits the PDGF receptor kinase as well the cKIT and Abl kinases, among other targets. Various studies have implicated the PDGF pathway in the pathogenesis of pulmonary arterial hypertension (PAH). Inhibition with imatinib mesylate has shown efficacy in human case reports and experimental models of PAH. Results from a Phase II trial of imatinib mesylate in PAH did not meet the primary end point but showed improvement in several secondary end points and in a subgroup analysis. As suggested by this study as well as a few case reports, imatinib may be effective in a subset of patients with more severe disease. However, this remains to be further validated through a Phase III study, which is already underway. In conclusion, it appears that imatinib mesylate may hold promise as an adjunct drug in PAH therapy, especially since it is directed at a pathway not previously targeted. …

The Value of Computed Tomography Scanning for the Detection of Coronary Artery Disease in Patients with Idiopathic Pulmonary Fibrosis

BACKGROUND AND OBJECTIVE:
Patients with idiopathic pulmonary fibrosis (IPF) have a higher prevalence of coronary artery disease and this could have an impact on their outcomes. We investigated the predictive ability of coronary artery calcification, assessed by routine CT, which may predict the presence of coronary artery disease. METHODS:
The study cohort consisted of patients with IPF and with left heart catheterization data plus CT scans from July 2003 to July 2008. Grades of coronary calcification on CT were compared with left heart catheterization determination of coronary artery disease. RESULTS:
There were 57 patients in whom left heart catheterization review demonstrated significant coronary artery disease in 28.1% (16/57), mild disease in 40.3% (23/57) and none in 31.6% (18/57). The median time interval between the catheterization and the reviewed CT scan was 39 days. The sensitivity of moderate to severe calcification for significant coronary artery disease was 81%, while the specificity was 85%, with an associated odds ratio of 25.2 (4.64-166, P < 0.005). There was excellent agreement among three radiologists in the grading of coronary calcification. CONCLUSIONS: Coronary calcification, as assessed by routine CT of the chest, has very good performance characteristics in predicting underlying significant coronary artery disease in patients with IPF. The routine availability of this study enables the ready screening for coronary artery disease in IPF patients. ...

Achieving Symptom Control in Patients with Moderate Asthma

Disease severity in asthma can be classified as mild, moderate or severe based upon the frequency of symptoms or the severity of airflow obstruction. This review will focus on the treatment of youths greater than 12 years of age and adults with moderate persistent asthma. Moderate asthmatics may have daily symptoms that cause some limitation with normal daily activities and require use of a rescue inhaled short-acting beta(2)-agonist inhaler or experience nocturnal awakenings secondary to asthma that occur more than once per week. Furthermore, spirometry may reveal airflow obstruction with a reduction in FEV(1) to between 60% and 80% of predicted. Although inhaled corticosteroids (ICS) are the primary controller medication used to modify symptoms in moderate asthmatics, additional controller medications, such as inhaled long-acting beta(2)-agonists (LABA), leukotriene receptor antagonists (LTRA) or theophylline, are often needed to obtain optimal disease control. While the addition of an inhaled LABA to an ICS is very effective at improving disease control in moderate asthma, concerns have arisen over the safety of LABAs, in particular the risk of asthma-related death. Therefore, consideration may be given to initially adding a LTRA, rather than a LABA, to ICS when asthma symptoms are not adequately controlled by ICS alone. Furthermore, individualization of medication regimens, treatment of co-morbid conditions, and patient education are crucial to optimizing compliance with therapy, improving disease control, and reducing the risk of exacerbations. Lastly, the development of new asthma treatments, perhaps based upon personalized medicine, may revolutionize the future treatment of moderate asthma. …

Dynamic Patient Counseling: A Novel Concept in Idiopathic Pulmonary Fibrosis

BACKGROUND:
The characteristics of long-term survivors with idiopathic pulmonary fibrosis (IPF) have never been fully elucidated. We sought to illustrate the attenuated mortality and describe the characteristics of patients with IPF who survived at least 5 years beyond their initial presentation. METHODS:
Patients with IPF evaluated between 1997 and 2006 were identified through the clinic database. Patients who survived beyond 5 years from the time of their evaluation were compared with those who died or underwent lung transplantation within 5 years. Survival analyses were performed from the time of initial evaluation and contingent on annualized survival thereafter. RESULTS:
Eighty-seven patients who survived at least 5 years formed the comparator group to whom other patients were contrasted. These patients had a higher BMI, FVC % predicted, FEV1 % predicted, total lung capacity % predicted, and diffusing capacity of lung for carbon monoxide % predicted, but a lower FEV1/FVC ratio and lower mean pulmonary artery pressures. More than one-half of these patients had moderate or severe disease at the time of presentation. Our annualized contingent survival analyses revealed a progressively increasing median survival dependent on the duration of the disease. CONCLUSIONS:
Although we were able to demonstrate differences in our 5-year survivors, rather than being a distinct group, these patients appear to exist within a continuum of improving survival dependent on prior disease duration. This progressively improving time-dependent prognosis mandates the serial reevaluation of an individual patient’s projected outcomes. The implementation of dynamic counseling is an important concept in more accurately predicting life expectancy for patients…

Emergency Preparedness and Public Health: The Lessons of Hurricane Sandy

When Hurricane Sandy hit downtown Manhattan, three neighboring hospitals each made different decisions about when to evacuate. Across the metro region, more than five hospitals and over 20 nursing and assisted living facilities were evacuated, making this the central public health challenge of this calamitous event. It is a familiar story—a super storm comes ashore, infrastructure is overwhelmed, and healthcare facilities evacuate patients, with major delays in returning to normal functioning. Afterwards, policy makers evaluate lessons learned for the next disaster, but similar missteps are often repeated.
Although not identical, it is instructive to compare Hurricane Katrina with the still unfolding events of Sandy. Unlike in Katrina, New York hospitals had more detailed emergency plans. What seemed to be missing, however, were clear and consistent criteria to guide evacuation decisions. Evacuation decisions are complex—a decision to evacuate prematurely places patients at risk, while waiting too long can have devastating consequences. Public officials, in collaboration with facilities, should decide whether to shelter in place or risk transfer of fragile patients. Governors should consider early emergency declarations, including request for a formal “public health emergency declaration”, to reduce legal concerns and regulatory constraints. Federal, state, and municipal authorities can better prepare for the next disaster and have a duty to do so. …

CAT scanning for the Detection of Coronary Artery Disease in Patients with IPF

BACKGROUND AND OBJECTIVE:
Patients with idiopathic pulmonary fibrosis (IPF) have a higher prevalence of coronary artery disease and this could have an impact on their outcomes. We investigated the predictive ability of coronary artery calcification, assessed by routine CT, which may predict the presence of coronary artery disease. METHODS:
The study cohort consisted of patients with IPF and with left heart catheterization data plus CT scans from July 2003 to July 2008. Grades of coronary calcification on CT were compared with left heart catheterization determination of coronary artery disease. RESULTS:
There were 57 patients in whom left heart catheterization review demonstrated significant coronary artery disease in 28.1% (16/57), mild disease in 40.3% (23/57) and none in 31.6% (18/57). The median time interval between the catheterization and the reviewed CT scan was 39 days. The sensitivity of moderate to severe calcification for significant coronary artery disease was 81%, while the specificity was 85%, with an associated odds ratio of 25.2 (4.64-166, P < 0.005). There was excellent agreement among three radiologists in the grading of coronary calcification. CONCLUSIONS: Coronary calcification, as assessed by routine CT of the chest, has very good performance characteristics in predicting underlying significant coronary artery disease in patients with IPF. The routine availability of this study enables the ready screening for coronary artery disease in IPF patients. ...

Supranormal Expiratory Airflow after Bilateral Lung Transplantation is Associated with Improved Survival

RATIONALE:
flow volume loops (FVL) in some bilateral lung transplant (BLT) and heart-lung transplant (HLT) patients suggest variable extrathoracic obstruction in the absence of identifiable causes. These FVLs usually have supranormal expiratory and normal inspiratory flow rates (SUPRA pattern). OBJECTIVES:
characterize the relationship of the SUPRA pattern to predicted donor and recipient lung volumes, airway size, and survival. METHODS:
we performed a retrospective review of adult BLT/HLT patients. We defined the SUPRA FVL pattern as: (1) mid-vital capacity expiratory to inspiratory flow ratio (Ve50:Vi50) > 1.0, (2) absence of identifiable causes of extrathoracic obstruction, and (3) Ve50/FVC ≥ 1.5 s(-1). We calculated predicted total lung capacity (pTLC) ratio by dividing the donor pTLC by the recipient pTLC. We measured airway luminal areas on thoracic computer tomographic scans. We compared survival in patients with and without the SUPRA pattern. MEASUREMENTS AND MAIN RESULTS:
the SUPRA FVL pattern occurred in 56% of the 89 patients who qualified for the analysis. The pTLC ratio of SUPRA and non-SUPRA patients was 1.11 and 0.99, respectively (P = 0.004). A higher pTLC ratio was correlated with increased probability of the SUPRA pattern (P = 0.0072). Airway luminal areas were larger in SUPRA patients (P = 0.009). Survival was better in the SUPRA cohort (P = 0.009). CONCLUSIONS:
the SUPRA FVL pattern was frequent in BLT/HLT patients. High expiratory flows in SUPRA patients could result from increased lung elastic recoil or reduced airway resistance, both of which could be caused by the pTLC mismatch. Improved survival in the SUPRA cohort suggests…

Heart Rate Recovery after 6MWT Predicts Pulmonary Hypertension in Patients with IPF

BACKGROUND AND OBJECTIVE:
In patients with IPF, we sought to validate that abnormal heart rate recovery at 1 min (HRR1) after six-minute walk test (6MWT) predicts mortality and to explore the relationship between abnormal HRR1 and pulmonary hypertension (PH). METHODS:
We identified IPF patients who performed a 6MWT as part of their clinical evaluation between 2006 and 2009 and were followed to lung transplantation or death. Right heart catheterization (RHC) data were collated and analysed for the subgroup who had this procedure. RESULTS:
There were 160 subjects who qualified for the survival analysis, and those with an abnormal HRR1 had worse survival than subjects with normal HRR1 (log-rank P = 0.01). Eighty-two subjects had a right heart catheter (RHC); among them, abnormal HRR1 was associated with RHC-confirmed PH (χ(2) = 4.83, P = 0.03) and had a sensitivity, specificity, positive predictive value and negative predictive value of 52%, 74%, 41% and 82%, respectively, for PH. In bivariate and multivariable analyses, abnormal HRR1 appeared to be the strongest predictor of RHC-confirmed PH (odds ratio (OR) = 4.0, 95% CI: 1.17-13.69, P = 0.02 in the multivariable analysis). CONCLUSIONS:
This study adds to data that support the validity of abnormal HRR1 as a predictor of mortality and of RHC-confirmed PH in IPF. Research is needed to further investigate the link between abnormal HRR1 and PH and to elucidate heart-lung interactions at work during exercise and recovery in patients with IPF. …

The HLA Class II Allele Allele DRB1*15 is over-represented in patients with Idiopathic Pulmonary Fibrosis

BACKGROUND:
Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. METHODS/PRINCIPAL FINDINGS:
HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DL(CO)) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). CONCLUSIONS/SIGNIFICANCE:
DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in…