Impact of recipient age on mortality among Cytomegalovirus (CMV)-seronegative lung transplant recipients with CMV-seropositive donors.

BACKGROUND: Cytomegalovirus (CMV)-seronegative lung transplant recipients (LTRs) with seropositive donors (CMV D+/R-) have the highest mortality of all CMV serostatuses. Due to immunosenescence and other factors, we hypothesized CMV D+/R- status might disproportionately impact older LTRs. Thus, we investigated whether recipient age modified the relationship between donor CMV status and mortality among CMV-seronegative LTRs. METHODS: Adult, CMV-seronegative first-time lung-only recipients were identified through the Scientific Registry of Transplant Recipients between May 2005 and December 2019. We used adjusted multivariable Cox regression to assess the relationship of donor CMV status and death. Interaction between recipient age and donor CMV was assessed via likelihood ratio testing of nested Cox models and by the relative excess risk due to interaction (RERI) and attributable proportion (AP) of joint effects. RESULTS: We identified 11,136 CMV-seronegative LTRs. The median age was 59 years; 65.2% were male, with leading transplant indication of idiopathic pulmonary fibrosis (35.6%); and 60.8% were CMV D+/R-. In multivariable modeling, CMV D+/R- status was associated with 27% increased hazard of death (adjusted hazard ratio: 1.27, 95% confidence interval: 1.21-1.34) compared to CMV D-/R-. Recipient age ≥60 years significantly modified the relationship between donor CMV-seropositive status and mortality on the additive scale, including RERI 0.24 and AP 11.4% (p = 0.001), that is, the interaction increased hazard of death by 0.24 and explained 11.4% of mortality in older CMV D+ recipients. CONCLUSIONS: Among CMV-seronegative LTRs, donor CMV-seropositive status confers higher risk of posttransplant mortality, which is amplified in older recipients. Future studies should define optimal strategies for CMV prevention and management in older D+/R- LTRs.

Does community size or commute time affect severity of illness at diagnosis or quality of care in a centralized care model of pulmonary hypertension?

BACKGROUND: Centralized care models are often used for rare diseases like pulmonary hypertension (PH). It is unknown how living in a rural or remote area influences outcomes. METHODS: We identified all patients from our PH database who carried a diagnosis of WHO Group 1 or WHO Group 4 PH. Using Canadian postal code data, patients were classified as living in a rural area; or a small, medium or large community size. The commute time from patient residence to our clinic was determined using mapping software. We compared baseline catheterization data according to community size and commute time. At follow up, we evaluated the association between community size and commute time with prognostic parameters of functional class, walk distance and echocardiography. RESULTS: Of the 342 patients identified, 72(21%) patients lived in rural areas, while 26(8%), 49(14%) and 195(57%) resided in small, medium and large population centres, respectively. The commute time was <1 h for 160(47%), 1-3 h for 62(18%), and >3 h for 120(35%). There was no association seen for any catheterization parameter by either community size or commute time. At last follow up, there was no association between any prognostic parameter and community size or commute time. CONCLUSIONS: We found no association between community size or commute time with severity of illness at diagnosis, or markers of prognosis at follow up. This suggests that patients who reside in rural or remote environments are not experiencing deficiencies in care compared to urban patients.

Evolving Paradigms in the Treatment of Atrial Septal Defects With Pulmonary Arterial Hypertension.

Atrial septal defects are one of the most frequently diagnosed congenital heart defects in adulthood. The presence of concurrent moderate or severe pulmonary arterial hypertension without Eisenmenger syndrome at the time of diagnosis can make for a challenging clinical scenario. There is continually evolving literature to determine the ideal approach to this subset of patients. Here we aim to review the clinical presentation, history, medical therapy, and closure options for atrial septal defects-pulmonary arterial hypertension with predominant left-to-right shunting, in the absence of Eisenmenger syndrome.

Clinical judgment versus lung allocation score in predicting lung transplant waitlist mortality.

Canadian lung transplant centers currently use a subjective and dichotomous "Status" ranking to prioritize waitlisted patients for lung transplantation. The lung allocation score (LAS) is an objective composite score derived from clinical parameters associated with both waitlist and post-transplant survival. We performed a retrospective cohort study to determine whether clinical judgment (Status) or LAS better predicted waitlist mortality. All adult patients listed for lung transplantation between 2007 and 2012 at three Canadian lung transplant programs were included. Status and LAS were compared in their ability to predict waitlist mortality using Cox proportional hazards models and C-statistics. Status and LAS were available for 1122 patients. Status 2 patients had a higher LAS compared to Status 1 patients (mean 40.8 (4.4) vs 34.6 (12.5), P = .0001). Higher LAS was associated with higher risk of waitlist mortality (HR 1.06 per unit LAS, 95% CI 1.05, 1.07, P < .001). LAS predicted waitlist mortality better than Status (C-statistic 0.689 vs 0.674). Patients classified as Status 2 and LAS ≥ 37 had the worst survival awaiting transplant, HR of 8.94 (95% CI 5.97, 13.37). LAS predicted waitlist mortality better than Status; however, the best predictor of waitlist mortality may be a combination of both LAS and clinical judgment.

Brief Education Improves Proper Metered-Dose Inhaler Use.

BACKGROUND: Inhaled ß-agonists are the cornerstone of acute treatment for asthma and chronic lung disease. Upon emergency department (ED) discharge, patients optimally receive prescriptions for metered-dose inhalers (MDIs) with instructions on their proper use. Yet prior studies suggest that ED personnel have limited knowledge of proper MDI techniques. It is unclear how effectively brief education will improve this knowledge to enable them to provide adequate patient instructions. OBJECTIVE: Our aim was to evaluate ED medical personnel's baseline knowledge of MDI use and the utility of brief education on their ability to use MDIs. METHODS: After providing written consent, a spirometry nurse evaluated emergency physicians and nurses on their ability to properly perform three (open-mouth/two-finger, spacer, and closed-mouth) MDI techniques. The same spirometry nurse then gave a short educational session demonstrating the proper MDI techniques. Two weeks later, the nurse re-evaluated the same personnel on their MDI techniques. RESULTS: All emergency medical personnel initially performed poorly in demonstrating proper MDI technique, averaging 29.8% steps done correctly. Two weeks after their educational session, they improved greatly, averaging 89.4% steps done correctly. CONCLUSIONS: This study demonstrated both that ED personnel had poor initial knowledge about MDI techniques and that a brief educational intervention improved most people's ability to use, and presumably to instruct patients/parents in proper use of, MDIs.

Lessons from lung transplantation: Cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease.

BACKGROUND: Gaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case reports of patients with GD1 receiving lung transplants. CASE PRESENTATION: We report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation. CONCLUSIONS: This is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.

Clinical and hemodynamic factors in predicting response to fluid challenge during right heart catheterization.

Fluid challenge during right heart catheterization has been used for unmasking pulmonary hypertension (PH) related to left-sided heart disease. We evaluated the clinical and hemodynamic factors affecting the response to fluid challenge and investigated the role of fluid challenge in the classification and management of PH patients. We reviewed the charts of 67 patients who underwent fluid challenge with a baseline pulmonary arterial wedge pressure (PAWP) of ≤ 18 mmHg. A positive fluid challenge (PFC) was defined as an increase in PAWP to > 18 mmHg after 500 mL saline infusion. Clinical characteristics and echocardiographic and hemodynamic parameters were compared between PFC and negative fluid challenge (NFC). PFC was associated with female sex, increased BMI, and hypertension. A greater rise in PAWP was observed in PFC (6.8 ± 2.3 vs. 3.8 ± 2.7 mmHg, P = 0.001). A larger increase in PAWP correlated with a lower transpulmonary gradient (r = -0.42, P < 0.001), diastolic pulmonary gradient (r = -0.42, P < 0.001), and pulmonary vascular resistance (r = -0.38, P < 0.001). We found 100% of the patients with PFC were classified as WHO group 2 PH compared to 49% of the NFC patients ( P < 0.001). Fewer patients with PFC were started on advanced PH therapies and more were discharged from PH clinic. A PFC and the magnitude of PAWP increase after saline loading are associated with parameters related to left heart disease. In our population, fluid challenge appeared to influence the classification of PH and whether patients are started on therapy or discharged from clinic.

Successful lung transplantation in an HIV seropositive patient with desquamative interstitial pneumonia: a case report.

BACKGROUND: Until recently, lung transplantation was not considered in patients with human immunodeficiency virus (HIV). HIV seropositive patients with suppressed viral loads can now expect long-term survival with the advent of highly active antiretroviral therapies (HAART); however, HIV remains a relative contraindication to lung transplantation. We describe, to our knowledge, the first HIV seropositive lung transplant recipient in Canada. We also review the literature of previously reported cases of solid-organ transplantation in patients with HIV with a focus on immunosuppression considerations. CASE PRESENTATION: A 48-year old man received a bilateral lung transplant for a diagnosis of desquamative interstitial pneumonia (DIP) attributed to cigarette and cannabis smoking. His control of HIV infection pre-transplant was excellent on HAART, and he had no other contraindications to lung transplantation. The patient underwent bilateral lung transplantation using basiliximab, methylprednisolone, and mycophenolate mofetil (MMF) as induction immunosuppression. He was maintained on MMF, prednisone, and tacrolimus thereafter, and restarted his HAART regimen immediately post-operatively. His post-transplant course was complicated by Grade A1 minimal acute cellular rejection, as well as an enterovirus/rhinovirus graft infection. Despite these complications, his functional status and control of HIV infection remain excellent 24 months post-transplant. CONCLUSIONS: Our patient is one of only several HIV seropositive lung transplant recipients reported globally. With growing acceptance of transplantation in this population, there is a need for clarification of prognosis post-transplantation, as well as optimal immunosuppression regimens for these patients. This case report adds to the recent literature that suggests HIV seropositivity should not be considered a contraindication to lung transplantation, and that post-transplant patients with HIV can be managed safely with basiliximab, tacrolimus, MMF and prednisone.

Whole exome sequencing analysis in severe chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value < 2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value = 0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

Comparison of thermodilution and indirect Fick cardiac outputs in pulmonary hypertension.

BACKGROUND: The accurate measurement of cardiac output (CO) is required in patients with pulmonary hypertension (PH).While both the thermodilution (TDCO) and indirect Fick (IFCO) methods are commonly used, there is little data comparing them in patients with PH. METHODS: We performed a retrospective analysis of patients evaluated at our center. All patients who had right heart catheterization (RHC) within 3 months of an echocardiogram, and CO assessment by both TDCO and IFCO methods were included. Bland-Altman analysis was used to assess agreement between the two methods. We further evaluated their agreement in each sex, and within tertiles of age, BMI and TR severity. We investigated the correlation between each method of CO and objective parameters of right ventricular function on echocardiography. RESULTS: In a cohort of 168 patients, the correlation between IFCO and TDCO was modest at (r = 0.61). On average, values for CO were lower with IFCO than with TDCO, by 0.62 L/min (95% CI -0.82, -0.40). This difference was greater for females: 0.86 L/min (95% CI -1.08, -0.63) and in the highest tertile of BMI: 0.97 L/min (95% CI -1.4, -0.55). Moderate and severe TR did not in general result in lower TDCO values. Echocardiographic parameters of right ventricular function were correlated more strongly with TDCO than with IFCO. CONCLUSION: In PH patients, IFCO was substantially lower than TDCO on average, suggesting that these two techniques cannot be used interchangeably. TDCO correlated more strongly with echocardiographic measures of RV function, suggesting that it may be preferred over IFCO.

Organizing Pneumonia in an Adult With Chronic Recurrent Noninfectious Osteomyelitis: A Case Report and Literature Review.

Chronic recurrent multifocal osteomyelitis (CRMO) is an idiopathic inflammatory disorder primarily of children and adolescents that is characterized by multifocal nonpyogenic relapsing and remitting inflammatory bone lesions. Pulmonary abnormalities are rarely associated with CRMO, with two reported cases of consolidation on chest CT that occurred in children. We present a case of organizing pneumonia in an adult patient with CRMO. The concurrent worsening of pulmonary and bone disease suggests that CRMO may be a rare cause of organizing pneumonia.

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10-8) and PPP4R4/SERPINA1 (P = 1.01 × 10-8) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility. OBJECTIVES: To identify coding variants associated with COPD. METHODS: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts. MEASUREMENTS AND MAIN RESULTS: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. CONCLUSIONS: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

Family physician access to specialist advice by telephone: Reduction in unnecessary specialist consultations and emergency department visits.

PROBLEM ADDRESSED: Timely access to specialist care is an important issue for patients with mild to moderate symptoms, and wait times for referrals are currently quite long. OBJECTIVE OF PROGRAM: To provide FPs with quick telephone access to other specialists for treatment advice for patients with nonserious conditions that they would otherwise refer to specialist care. PROGRAM DESCRIPTION: The RACE (Rapid Access to Consultative Expertise) program is a telephone hot-line providing FPs and nurse practitioners in the Vancouver, BC, area with timely access to specialist consultations. An evaluation of data from RACE found 60% of RACE calls prevented patients from visiting a specialist and 32% of calls prevented FP referrals to hospital emergency departments. CONCLUSION: Supported by RACE, FPs can more effectively remain the locus of patient care, calling on other specialist expertise when appropriate and providing better coordination of care for their patients. Evaluations to date suggest RACE helps reduce system costs by reducing unnecessary emergency department visits and face-to-face specialist consultations.

Unclassifiable interstitial lung disease: an unresolved diagnostic dilemma.

Interstitial lung disease (ILD) classification requires a multidisciplinary review that includes input from an ILD clinician, chest radiologist, and lung pathologist. We report a case of ILD that remained unclassifiable due to discordant clinical, radiological, and pathological findings despite a thorough evaluation that included examination of explanted lung tissue. This case demonstrates that ILD can remain unclassifiable even with a complete evaluation and illustrates one approach to the management of such patients.

Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: 2014 updates.

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.