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The Saudi Association for Pulmonary Hypertension (previously called Saudi Advisory Group for Pulmonary Hypertension) has published the first Saudi Guidelines on Diagnosis and Treatment of Pulmonary Arterial Hypertension back in 2008.[1] That guideline was very detailed and extensive and reviewed most aspects of pulmonary hypertension (PH). One of the disadvantages of such detailed guidelines is the difficulty that some of the readers who just want to get a quick guidance or looking for a specific piece of information might face. All efforts were made to develop this guideline in an easy-to-read form, making it very handy and helpful to clinicians dealing with PH patients to select the best management strategies for the typical patient suffering from a specific condition. This Guideline was designed to provide recommendations for problems frequently encountered by practicing clinicians involved in management of PH. This publication targets mainly adult and pediatric PH-treating physicians, but can also be used by other physicians interested in PH.

Objectives: We sought to determine and compare the prevalence of nonadherence in lung, kidney, and liver transplant recipients, and identify potential risk factors for nonadherence., Materials and Methods: This cross-sectional, single-center, retrospective cohort study, evaluated 225 outpatient lung, kidney, and liver transplant recipients' adherence to immunosuppressant medication. Based on immunosuppressant dosages and dispensing records, medication possession ratio (days of medication supplied/actual days) and gaps in prescription refills (> 30-day lapse between expected depletion of supply and next refill) were used as surrogate markers in assessing adherence for 2 years. Patients were adherent to their immunosuppressant medication regimens if their medication possession ratio was ≥ 80%., Results: The mean age of the subjects was slightly greater than 50 years of age, and they were a median of 2.0, 1.3, and 1.1 years posttransplant at the start of data collection for lung, kidney, and liver recipients. Overall medication possession ratios were 95.4% ± 7.5%, 95.9% ± 7.6%, and 92.7% ± 12.3% in our lung, kidney, and liver recipients. Only 7.1% of patients had a medication possession ratio lower than 80%, which was the cutoff for nonadherence. No statistical analyses were performed to identify potential factors for nonadherence because of the small number of nonadherent patients., Conclusions: Immunosuppressant medication adherence at our center was high for all 3 organ cohorts, as measured by a medication possession ratio of 80% or better. Further study is needed to evaluate immunosuppressant adherence over time after transplant, and confirm the clinical factors that optimize adherence in high-risk patients.

Acute exacerbations of interstitial lung disease present as clinical deteriorations, with progressive hypoxemia and parenchymal consolidation not related to infection, heart failure or thromboembolic disease. Following single lung transplantation, patients receive maintenance immunosuppression, which could mitigate the development of acute exacerbations in the native lung. A 66-year-old man with fibrotic, nonspecific interstitial pneumonitis presented with fever, hypoxemia and parenchymal consolidation limited to the native lung four years after single lung transplantation. Investigations were negative for infection, heart failure and thromboembolic disease. The patient worsened over the course of one week despite broad-spectrum antimicrobial therapy, but subsequently improved promptly with augmentation of prednisone dosed to 50 mg daily and addition of N-acetylcysteine. Hence, the patient fulfilled the criteria for a diagnosis of an acute exacerbation of pulmonary fibrosis in his native lung. Clinicians should consider acute exacerbation of parenchymal lung disease of the native lung in the differential diagnosis of progressive respiratory deterioration following single lung transplantation for pulmonary fibrosis.

Background: Intravenous epoprostenol, a prostaglandin analogue, has been a mainstay of therapy for patients with advanced pulmonary arterial hypertension (PAH) since the early 1990s. This medication has multiple side effects, and sudden discontinuation is potentially associated with severe sequelae. Several recent case series have described the transition from intravenous to newer oral or subcutaneous therapies. A case series detailing the authors' experience with such transitions, and a systematic lierature review is presented., Methods: All consecutive PAH patients seen at the Vancouver Pulmonary Hypertension Clinic (Vancouver, British Columbia) between June 1995 and July 2009 were reviewed for cases in which weaning or transition from intravenous epoprostenol was attempted. The Cochrane Collaboration, Cochrane Register of Controlled Trials, Journals@Ovid, MEDLINE, EMBASE and Papers First were searched using predefined key words for publications describing transition of PAH patients from parenteral prostanoids to oral or subcutaneous agents., Results: Of the six patients who attempted, all transitioned successfully to oral or subcutaneous agents, having been on intravenous epoprostenol for a mean of 3.8 years (range 1.8 to 9.75 years). Five are living, surviving a mean of 5.5 years after transition. The literature search yielded nine studies and, of 127 patients described, 82 transitioned successfully. The length of pretransition prostanoid treatment (range 1.7 to 7.6 years) and the posttransition follow-up period (range two months to 70 months) were shorter than for patients described in the present study., Conclusions: Given the rarity of PAH, the absolute numbers of patients transitioned from intravenous epoprostenol are still low. With the advent of new therapies, these numbers will hopefully increase; continued study is necessary to identify factors that are predictive of success.

Background: Severe α₁-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α₁-antitrypsin, but whether they have an increased risk of COPD is uncertain., Methods: We compared PI MZ and PI MM individuals in two large populations: a case-control study from Norway (n = 1,669) and a multicenter family-based study from Europe and North America (n = 2,707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT scan measurements of emphysema and airway disease., Results: PI MZ was associated with a 3.5% lower FEV₁/FVC ratio in the case-control study (P = .035) and 3.9% lower FEV₁/vital capacity (VC) ratio in the family study (P = .009). In the case-control study, PI MZ also was associated with 3.7% more emphysema on quantitative analysis of chest CT scans (P = .003). The emphysema result was not replicated in the family study. PI MZ was not associated with airway wall thickness or COPD status in either population. Among subjects with low smoking exposure (< 20 pack-years), PI MZ individuals had more severe emphysema on chest CT scan than PI MM individuals in both studies., Conclusions: Compared with PI MM individuals, PI MZ heterozygotes had lower FEV₁/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to the development of airflow obstruction than PI MM individuals.

Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q., Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q., Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study., Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 x 10(-5) across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5., Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.

Background: The authors of previous reports have suggested that women are more susceptible to cigarette smoke and to an airway-predominant COPD phenotype rather than an emphysema-predominant COPD phenotype. The purpose of this study was to test for sex differences in COPD phenotypes by using high-resolution CT (HRCT) scanning in male and female smokers with and without COPD., Methods: All subjects completed spirometry and answered an epidemiologic respiratory questionnaire. Inspiratory HRCT scans were obtained on 688 smokers enrolled in a family-based study of COPD. Emphysema was assessed by using a density mask with a cutoff of -950 Hounsfield units to calculate the low-attenuation area percentage (LAA%) and by the fractal value D, which is the slope of a power law analysis defining the relationship between the number and size of the emphysematous lesions. Airway wall thickness was assessed by calculating the square root of the airway wall area (SQRTWA) and the percentage of the total airway area taken by the airway wall (WA%) relative to the internal perimeter., Results: Women had a similar FEV(1) (women, 65.5% +/- 31.9% predicted; men, 62.1% +/- 30.4% predicted; p = 0.16) but fewer pack-years of cigarette smoking (women, 37.8 +/- 19.7 pack-years; men, 47.8 +/- 27.4 pack-years; p < 0.0001). Men had a greater LAA% (24% +/- 12% vs 20% +/- 11%, respectively; p < 0.0001) and larger emphysematous spaces than women, and these differences persisted after adjusting for covariates (weight, pack-years of smoking, current smoking status, center of enrollment, and FEV(1) percent predicted; p = 0.0006). Women had a smaller SQRTWA and WA% after adjusting for covariates (p < 0.0001)., Conclusion: Male smokers have more emphysema than female smokers, but female smokers do not show increased wall thickness compared with men.

Objectives: Solid organ transplantations are among the most expensive treatments yet relatively few investigators have reported well-characterized and reliable information on costs. The objective here was to compare the direct medical costs of kidney, liver, heart, and lung transplantations in British Columbia (BC), Canada., Methods: Using data from a province-wide population-based registry, resource utilization data were collated for 1333 patients who underwent solid organ transplantation between 1995 and 2003. Resource categories included hospital stays, physician fees, laboratory and diagnostic testing, and immunosuppressants. Mean costs (2003 $CDN) were derived for the index hospitalization and each of the 2 years after hospital discharge. To enable valid comparisons, the same costing methodology was applied to all four programs., Results: The mean costs of transplantation varied from $27,695 for kidney recipients to $89,942 for lung recipients, with inpatient hospital stays comprising the largest component. Mean costs for the first and second follow-up years ranged from $27,592 and $11,424 for lung recipients to $21,144 and $8086 for liver recipients. Immunosuppressants accounted for between two-thirds and three-fourths of costs by the second year. Within each program, variations in costs could not be accounted for by demographic factors., Conclusions: We observed in BC a threefold variation in mean costs of organ transplantation procedures, with the variations between programs diminishing during follow-up. Policymakers and decision-makers seeking to better understand the deployment of resources for transplantation may focus on clinical factors at the time of hospitalization and factors that influence use and costs of immunosuppressants during the induction and maintenance phases.

Background: Home-based rehabilitation is a promising approach to improve access to pulmonary rehabilitation., Objective: To assess whether self-monitored, home-based rehabilitation is as effective as outpatient, hospital-based rehabilitation in patients with chronic obstructive pulmonary disease (COPD)., Design: Randomized, multicenter, noninferiority trial., Setting: 10 academic and community medical centers in Canada., Patients: 252 patients with moderate to severe COPD., Intervention: After a 4-week education program, patients took part in home-based rehabilitation or outpatient, hospital-based rehabilitation for 8 weeks. They were followed for 40 weeks to complete the 1-year study., Measurements: The primary outcome was the change in Chronic Respiratory Questionnaire dyspnea subscale score at 1 year. The primary analysis took a modified intention-to-treat approach by using all patients who provided data at the specified follow-up time, regardless of their level of adherence. The analysis used regression modeling that adjusted for the effects of center, sex, and baseline level. All differences were computed as home intervention minus outpatient intervention., Results: Both interventions produced similar improvements in the Chronic Respiratory Questionnaire dyspnea subscale at 1 year: improvement in dyspnea of 0.62 (95% CI, 0.43 to 0.80) units in the home intervention (n = 107) and 0.46 (CI, 0.28 to 0.64) units in the outpatient intervention (n = 109). The difference between the 2 treatments at 1 year was small and clinically unimportant. The 95% CI of the difference did not exceed the prespecified noninferiority margin of 0.5: difference in dyspnea score of 0.16 (CI, -0.08 to 0.40). Most adverse events were related to COPD exacerbations. No serious adverse event was considered to be related to the study intervention., Limitation: The contribution of the educational program to the improvement in health status and exercise tolerance cannot be ascertained., Conclusion: Home rehabilitation is a useful, equivalent alternative to outpatient rehabilitation in patients with COPD.

Purpose: Exercise limitation in recipients of lung transplant may be a result of abnormalities in the skeletal muscle. However, it is not clear whether these abnormalities are merely a reflection of the changes observed in the pretransplant condition. The purpose of this paper was to compare thigh muscle volume and composition, strength, and endurance in lung transplant recipients to people with chronic obstructive pulmonary disease (COPD)., Methods: Single lung transplant recipients (n=6) and people with COPD (n=6), matched for age, sex, and BMI participated in the study. Subjects underwent MRI to determine muscle size and composition, lower extremity strength testing and an isometric endurance test of the quadriceps., Results: Lung transplant recipients had similar muscle volumes and intramuscular fat infiltration of their thigh muscles and similar strength of the quadriceps and hamstrings to people with COPD who had not undergone transplant. However, quadriceps endurance tended to be lower in transplant recipients compared to people with COPD (15 +/- 7 seconds in transplant versus 31 +/- 12 seconds in COPD, p = 0.08)., Conclusions: Recipients of lung transplant showed similar changes in muscle size and strength as people with COPD, however muscle endurance tended to be lower in people with lung transplants. Impairments in muscle endurance may reflect the effects of immunosuppressant medications on skeletal muscle in people with lung transplant.

Rationale: It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families., Objectives: To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD., Methods: Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema., Measurements and Main Results: A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD., Conclusions: Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes.

Mycophenolate mofetil is an immunosuppressant commonly used in solid organ transplantation. Its active metabolite, mycophenolic acid (MPA), is metabolized to the inactive 7-O-mycophenolic acid glucuronide (MPAG) and the active acyl glucuronide (AcMPAG). Most pharmacokinetic (PK) studies have been focused on MPA, but not its metabolites, in kidney transplant recipients. Pharmacokinetic studies of MPA and its metabolites in thoracic transplant recipients are scarce. Because neither the heart nor lung is involved in MPA metabolism or excretion, the thoracic transplant population may exhibit unique PKs. This open-label study aimed to characterize and compare PKs of MPA and its metabolites in stable lung or heart transplant recipients. Fifty thoracic (27 lung, 23 heart) transplant recipients were recruited. Subjects were also taking cyclosporine (11 lung, 14 heart) or tacrolimus (16 lung, nine heart), and prednisone (27 lung, one heart). Blood samples were obtained at 0, 20, 40, 60, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose. Plasma was used for drug level analysis (MPA, MPAG, and AcMPAG) by a high-performance liquid chromatography-ultraviolet detection method; in a subset of subjects, free MPA concentrations were also determined. Conventional PK parameters (dose-normalized) were determined by noncompartmental methods. There was wide interpatient variability of MPA, MPAG, and AcMPAG PKs with coefficients of variation exceeding 70% for most PK parameters measured. Other findings (P < 0.05) included: lower MPA area under the curve, maximum concentration, and minimum concentration; higher apparent clearance and MPAG/MPA metabolic ratio in the lung versus heart transplant group; lower MPA area under the curve and minimum concentration, and higher apparent clearance and MPAG/MPA metabolic ratio in lung transplant recipients concurrently taking cyclosporine versus tacrolimus; and lower minimum concentration in heart transplant recipients taking cyclosporine versus tacrolimus. Despite large interpatient variability in the PKs of MPA, MPAG, and AcMPAG among thoracic transplant recipients, there appear to be significant differences between lung and heart patients, which warrant further study.

Background: Airflow limitation in COPD is due to a variable combination of small airway obstruction and centrilobular emphysema (CLE) and/or panlobular emphysema (PLE), but the relationship between these three different phenotypes is poorly understood. This study compares the severity of small airway obstruction in both forms of emphysema and determines its relationship with FEV(1)., Methods: We compared the lung histology of nonsmoking control subjects without emphysema (n = 10) to that of patients with CLE (n = 30) and PLE with (n = 8) and without alpha(1)-antitrypsin (AAT) deficiency (n = 11). The degree of airspace enlargement was measured using the mean interalveolar wall distance (IAWD) [mean linear intercept, Lm], and the evenness of airspace destruction was assessed by the coefficient of variation (CV) of the IAWD. The severity of small airway obstruction was determined by dividing total wall area by the length of the basement membrane to obtain wall thickness., Results: Lm was greater in all three subgroups of emphysema than in control subjects, and in AAT deficiency than in PLE or CLE. The CV of IAWD was greater in AAT deficiency and CLE than in control subjects and in CLE than in AAT deficiency or PLE. Although small airway wall thickness was greater in CLE and PLE with AAT deficiency than in control subjects, the association between wall thickness and both Lm and FEV(1) was observed only in CLE., Conclusions: Small airway wall thickening occurs in CLE and PLE with AAT deficiency but is more closely associated with degree of emphysema and airflow limitation in CLE.

Study Objective: To develop limited sampling strategies for estimation of mycophenolic acid exposure (by determining area under the concentration-time curve [AUC]) in lung transplant recipients by using sampling times within 2 hours after drug administration and a maximum of three plasma samples., Design: Prospective, open-label clinical study., Setting: Lung transplant clinic in Vancouver, British Columbia, Canada., Patients: Nineteen adult (mean age 48.3 yrs) lung transplant recipients who were receiving mycophenolate mofetil therapy along with cyclosporine (9 patients) or tacrolimus (10 patients)., Intervention: Eleven blood samples were collected from each of the 19 patients over 12 hours: immediately before (0 hr) and 0.3, 0.6, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after administration of mycophenolate mofetil., Measurements and Main Results: Mycophenolic acid levels in plasma were determined by a high-performance liquid chromatography-ultraviolet detection method. The 19 patients were randomly divided into index (10 patients) and validation (9 patients) groups. Limited sampling strategies were developed with multiple regression analysis by using data from the index group. Data from the validation group were used to test each strategy. Bias and precision of each limited sampling strategy were determined by calculating the mean prediction error and the root mean square error, respectively. The correlation between AUC and single concentrations was generally poor (r2= 0.18-0.73). Two single-concentration strategies, eight two-concentration strategies, and eight three-concentration strategies matched our criteria. However, the best overall limited sampling strategies (and their predictive performance) were the following: log AUC = 0.241 log C0 + 0.406 log C2 + 1.140 (bias -5.82%, precision 5.97%, r2= 0.828) and log AUC = 0.202 log C0 + 0.411 log C1.5 + 1.09 (bias -5.71%, precision 6.94%, r2= 0.791), where Cx is mycophenolic acid concentration at time x hours., Conclusion: Two-concentration limited sampling strategies provided minimally biased and highly precise estimation of mycophenolic acid AUC in lung transplant recipients. These optimal and most clinically feasible limited sampling strategies are based collectively on the number of blood samples required, r2 value, bias, and precision.

The Canadian Cardiovascular Society and the Canadian Thoracic Society requested a position statement on pulmonary arterial hypertension from leading Canadian experts. The present document is intended to act as an update for the clinician, to provide a template for the initial evaluation of patients, to enable understanding of current therapeutic paradigms based on approved indications for Canada, to highlight new therapies on the horizon, and to state the positions of the Canadian Cardiovascular Society and the Canadian Thoracic Society on resource management for pulmonary arterial hypertension in Canada.

Background: Pulmonary rehabilitation remains largely underused. Self-monitored, home-based rehabilitation is a promising approach to improving the availability of pulmonary rehabilitation., Objective: To report the rationale and methods of a trial comparing the effectiveness of self-monitored, home-based rehabilitation with hospital-based, outpatient rehabilitation in patients with chronic obstructive pulmonary disease (COPD)., Study Design: A parallel-group, randomized, noninferiority, multicentre trial will be performed with 240 patients with moderate to severe COPD., Intervention: Patients will be randomly assigned to conventional, supervised, hospital-based outpatient rehabilitation or self-monitored, home-based rehabilitation. Both interventions will include a standardized, comprehensive self-management program, in addition to the hospital-based outpatient or home-based exercise program. After the three-month intervention, patients in both groups will be encouraged to continue exercising at home. Patients will be assessed monthly with telephone interviews and in person at enrollment, three months and 12 months., Outcomes: The dyspnea domain of the Chronic Respiratory Questionnaire (CRQ) at 12 months is the primary outcome variable. Secondary outcome variables include total and domain-specific CRQ scores; exercise tolerance and activity of daily living; health service use over the one-year study period; and direct and indirect costs of COPD treatment., Analysis: An intent-to-treat approach will be used as the primary analysis. The primary analysis will focus on the change in the CRQ dyspnea score using a two-sided t distribution based on 95% CIs. The same approach will be used for secondary continuous outcome variables., Conclusion: The present trial will address two unresolved issues in pulmonary rehabilitation for patients with COPD: the short-term and long-term effectiveness of home-based pulmonary rehabilitation strategies. The authors will also determine if home-based pulmonary rehabilitation can reduce health service use (eg, hospitalizations and emergency visits) and if it can be done at a lower cost than the traditional hospital-based outpatient pulmonary rehabilitation.

Background: Circulating mediators, including thromboxane A2, the vasoconstrictor, platelet aggregant, and smooth muscle mitogen, may contribute to the progression of vascular narrowing in primary pulmonary hypertension (PPH)., Methods: To further understand the contribution of thromboxane and to provide novel therapy for PPH, we administered the potent orally active thromboxane synthetase inhibitor and thromboxane receptor antagonist terbogrel for 12 weeks to patients with New York Heart Association functional classification II and III PPH. The study had a multicenter randomized placebo-controlled design. The primary endpoint was a change in the distance walked during 6 minutes. The pharmacologic effects of terbogrel on thromboxane and prostacyclin metabolism also were studied., Results: Although the planned enrollment was 135 patients, the study was halted after only 71 patients had been randomized because of the unforeseen side effect of leg pain, which occurred almost exclusively in patients with terbogrel treatment. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. The leg pain confounded the primary endpoint of walking distance. On an intention-to-treat analysis, no improvements in 6-minute walk distance or in hemodynamics in patients with terbogrel treatment were seen. However, terbogrel was effective from a pharmacologic standpoint, reducing thromboxane metabolites by as much as 98% (P <.0001), with a modest but statistically insignificant (39%) rise in prostacyclin metabolites., Conclusion: Inhibition of thromboxane with an orally active agent is feasible in PPH, but the incidence of severe leg pain with terbogrel precludes its use in this disorder. Similar therapeutic efforts, with other thromboxane inhibitors, should be considered.