Evaluating Sinus Microbiology by Transplant Status in Persons With Cystic Fibrosis: A Matched Cohort Study.

Objective: Sinus disease is prevalent in persons with cystic fibrosis (PwCF) and may be a reservoir of airway infection in postlung transplant (pTx) patients. The microbial composition of cystic fibrosis sinuses and its associations with chronic rhinosinusitis (CRS) is relatively unexplored. We aimed to examine the sinus and lower airway microbiome and their associations with CRS in PwCF and pTxPwCF. Study Design: Prospective single-centre study. Setting: A total of 31 sex and age (±2 years) matched PwCF and pTxPwCF. Methods: Demographic and clinical data along with sinus swabs and sputum were collected. CRS was assessed using Sinonasal Outcome Test-22 (SNOT-22) (patient reported outcome) and Lund-McKay (computed tomography sinus) scores. Samples underwent MiSeq Illumina sequencing of the universal 16S ribosomal RNA gene. Results: A total of 31 PwCF (15 pTxPwCF) were included. Aggregate airways microbiome composition was dominated by Pseudomonas (46%), Haemophilus (14%), Staphylococcus (11%), Streptococcus (10%), and Fusobacterium (6%). α-diversity was significantly lower in post-Tx samples across both sputum and sinus samples (P = .005). ß-diversity was significantly different between sputum (P = .004), but not sinus (P = .75) samples by transplant status. While there was a trend in higher ß-diversity associated with lower SNOT-22 score at time of first visit, this did not reach significance (P = .05). Conclusion: Sinus and airway microbiomes differed in PwCF and pTxPwCF, but the prevalent organisms remained consistent. Elucidating the relationship of the microbiome with clinical status to better understand when to intervene accordingly is needed to optimize sinus disease management in PwCF.

Association Between the Pulmonary Artery Pulsatility Index and Prognosis in Pulmonary Arterial Hypertension: A Multicentre Study.

Background: Risk stratification is fundamental in the management of pulmonary arterial hypertension (PAH). Pulmonary artery pulsatility index (PAPi), defined as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), is a hemodynamic index shown to predict acute right ventricular (RV) dysfunction in several settings. Our objective was to test the prognostic utility of PAPi in a diverse multicentre cohort of patients with PAH. Methods: A multicentre retrospective cohort study of consecutive adult patients with a new diagnosis of PAH on right heart catheterization between January 2016 and December 2020 was undertaken across 4 major centres in Canada. Hemodynamic data, clinical data, and outcomes were collected. The association of PAPi and other hemodynamic variables with mortality was assessed by receiver-operating characteristic curves and Cox proportional hazards modeling. Results: We identified 590 patients with a mean age of 61.4 ± 15.5 years, with 66.3% being female. A low PAPi (defined as < 5.3) was associated with higher mortality at 1 year: 10.2% vs 5.2% (P = 0.02). In a multivariable model including age, sex, body mass index, and functional class, a low PAPi was associated with mortality at 1 year (area under the curveof 0.64 (95% confidence interval 0.55-0.74). However, high RAP (> 8 mm Hg) was similarly predictive of mortality, with an area under the curve of 0.65. Conclusion: PAPi was associated with mortality in a large incident PAH cohort. However, the discriminative value of PAPi was not higher than that of RAP alone.

Contexte: La stratification des risques est fondamentale dans la prise en charge de l'hypertension artérielle pulmonaire (HTAP). L'indice de pulsatilité des artères pulmonaires (iPAP), défini comme la pression différentielle dans les artères pulmonaires divisée par la pression auriculaire droite (PAD), est un indice hémodynamique qui s'est révélé prédictif d'une dysfonction ventriculaire droite (VD) aiguë dans plusieurs situations. Notre objectif était d'évaluer l'utilité pronostique de l'iPAP dans une cohorte multicentrique diversifiée de patients atteints d'HTAP. Méthodologie: Une étude de cohorte multicentrique rétrospective de patients adultes consécutifs atteints d'une HTAP nouvellement diagnostiquée par cathétérisme cardiaque droit entre janvier 2016 et décembre 2020 a été effectuée dans quatre grands centres au Canada. Les données hémodynamiques, les données cliniques et les résultats ont été recueillis. La corrélation de l'iPAP et d'autres va-riables hémodynamiques avec la mortalité a été évaluée par les courbes caractéristiques opérationnelles du receveur et des modèles à risques proportionnels de Cox. Résultats: Nous avons recensé 590 patients dont l'âge moyen était de 61,4 ± 15,5 ans; la proportion de femmes était de 66,3 %. Un faible iPAP (défini comme une valeur < 5,3) a été associé à une hausse de la mortalité à 1 an : 10,2 % contre 5,2 % (p= 0,02). Dans un modèle multivarié comprenant l'âge, le sexe, l'indice de masse corporelle et la classe fonctionnelle, un faible iPAP a été associé à la mortalité à 1 an (aire sous la courbe de 0,64 [intervalle de confiance à 95 %; de 0,55 à 0,74]). Cependant, une PAD élevée (> 8 mmHg) a aussi été un facteur prédictif de mortalité, l'aire sous la courbe étant de 0,65. Conclusions: L'iPAP a été associé à la mortalité dans une vaste cohorte de patients atteints d'une HTAP. Toutefois, la valeur discriminante de l'iPAP n'a pas été supérieure à celle de la PAD seule.

Reproductive health after thoracic transplantation: An ISHLT expert consensus statement.

Pregnancy after thoracic organ transplantation is feasible for select individuals but requires multidisciplinary subspecialty care. Key components for a successful pregnancy after lung or heart transplantation include preconception and contraceptive planning, thorough risk stratification, optimization of maternal comorbidities and fetal health through careful monitoring, and open communication with shared decision-making. The goal of this consensus statement is to summarize the current evidence and provide guidance surrounding preconception counseling, patient risk assessment, medical management, maternal and fetal outcomes, obstetric management, and pharmacologic considerations.

Upfront riociguat and ambrisentan combination therapy for newly diagnosed pulmonary arterial hypertension: A prospective open-label trial.

BACKGROUND: Initial combination therapy with an endothelin receptor antagonist (ERA) and riociguat in pulmonary arterial hypertension (PAH) has limited supporting data. METHODS: We performed a prospective, single-arm, open-label trial of riociguat, and ambrisentan for incident PAH patients in functional class III. The primary endpoint was pulmonary vascular resistance (PVR) at 4-months. RESULTS: Twenty patients (59 ± 13 years old, 85% female) enrolled and 1 died before their 4-month follow-up. Fifteen patients completed a 4-month and 13 completed the 12-month follow-up. At 4-months PVR decreased 54% with an absolute change of -5.8 Wood units (95% CI -4.0; -7.5, p < 0.001). Other hemodynamic variables and risk scores also improved. Six patients discontinued riociguat and 8 discontinued ambrisentan, with 5 (25%) discontinuing both. CONCLUSIONS: These results do not support the routine use of riociguat plus ambrisentan in initial regimens. Future studies are needed to compare this strategy with phosphodiesterase-5 inhibitors and an ERA with respect to tolerability and long-term outcomes.

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era.

BACKGROUND: The evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH. METHODS: We performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy). RESULTS: There was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53). CONCLUSIONS: There was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

ANOTHER syndrome-Familial presentations of progressive lung disease leading to double lung transplantation: A case report and literature review.

Ectodermal dysplasias (EDs) are a heterogeneous rare group of disorders with an incidence at 1/100,000 live births. Currently, there are limited case reports of patients requiring lung transplantation. Here, we report two brothers who present with a constellation of features including alopecia, nail dystrophy, ophthalmic complications, thyroid disease, hypohidrosis, ephelides, enteropathy and recurrent respiratory tract infections, known as ANOTHER syndrome, a rare autosomal recessive variant of ED. Both presented in early childhood with progressive respiratory decline and eventual failure. Chronic respiratory decline was refractory to standard therapy. Both patients required lung transplantation for sequelae of end-stage lung disease. Pathology demonstrated multifocal bronchiectasis with areas of fibrosis and small airway obstruction. ANOTHER syndrome is rare with a paucity of data in the literature. Given the limited therapeutic options available with natural progression towards respiratory failure, lung transplantation may be considered.

A Prospective Evaluation of the Diagnostic Accuracy of the Physical Examination for Pulmonary Hypertension.

BACKGROUND: The usefulness of physical examination findings for pulmonary hypertension (PH) is not well established. The purpose of this study was to evaluate prospectively the diagnostic performance of the physical examination for detecting PH. METHODS: Consecutive patients undergoing right-sided heart catheterization (n = 116) were examined by an attending physician, medical resident, and medical student in a blinded fashion. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) were calculated for each physical finding. Jugular venous pulsation (JVP) height was compared with right atrial pressure (RAP) by using linear regression. The association between physical findings and PH was assessed using univariate and multivariate logistic regression. RESULTS: The prevalence of PH was 87%. Only a JVP > 3 cm (positive LR, 2.5; 95% CI, 1.2-5.4) and pulmonic regurgitation murmur (specificity, 100%; 95% CI, 79%-100%) helped rule in PH. The absence of JVP > 3 cm (negative LR, 0.4; 95% CI, 0.3-0.6) and absence of loud pulmonic component of the second heart sound (negative LR, 0.5; 95% CI, 0.3-0.9) had modest usefulness in excluding PH. JVP correlated with RAP (r = 0.59; P < .001) but tended to lead to underestimation of RAP (mean bias, -3.4 cm H2O; 95% limits of agreement, -14.0 to 7.2). The presence of JVP > 3 cm and a parasternal heave discriminated PH (area under the curve [AUC] = 0.75). The combination of JVP > 3 cm, heave, and peripheral edema discriminated severe PH (mean pulmonary arterial pressure ≥ 45 mm Hg; AUC = 0.82). CONCLUSIONS: Individual physical examination findings have inadequate diagnostic usefulness for PH. No combination of findings can be used to exclude PH, but the presence of high JVP, peripheral edema, and parasternal heave suggests severe PH.

Characterization of Right Ventricular Deformation in Pulmonary Arterial Hypertension Using Three-Dimensional Principal Strain Analysis.

BACKGROUND: Pulmonary arterial hypertension (PAH) can cause maladaptive right ventricular (RV) functional changes associated with adverse prognosis that are challenging to accurately quantify noninvasively. The aim of this study was to explore principal strain (PS) with contraction angle analysis using three-dimensional echocardiography to characterize RV deformation changes in patients with PAH. METHODS: Three-dimensional echocardiography was performed in 37 patients with PAH and 20 healthy control subjects with two-component (primary and secondary) PS and principal contraction angle analysis. Patients were stratified according to World Health Organization (WHO) functional class. RESULTS: Primary PS differed significantly between patients with PAH and healthy control subjects (-20.2 ± 3.3% vs -26.8 ± 3.3%, P = .01), while secondary PS was not significantly different (3.6 ± 5.1% vs -2.5 ± 4.7%, P = .12). Principal contraction angle was significantly lower in patients with PAH (63 ± 22° vs 71 ± 7°, P = .01), with the greatest reduction for the RV free wall. Primary PS and principal contraction angle differed significantly between WHO class I and II and class III and IV patients (-23.9 ± 4.7% vs -18.1 ± 4.8% [P = .03] and 69 ± 9° vs 58 ± 14° [P = .03], respectively), while secondary PS was not significantly different between groups (P = .13). Compared with healthy control subjects, septal principal contraction angle was not different in patients with WHO class I and II PAH (P = .62), but it was significantly reduced in those with WHO class III and IV PAH (P < .01). The area under the curve for primary PS to differentiate patients with PAH by WHO functional class was 0.81 (95% CI, 0.77-0.89; P = .01). Primary PS intraclass correlation coefficients for intraobserver and interobserver variability were 0.91 (95% CI, 0.88-0.93) and 0.86 (95% CI, 0.81-0.88), respectively. CONCLUSIONS: PS analysis using three-dimensional echocardiography provides comprehensive quantification of RV deformation and characterizes alterations occurring in PAH that are associated with WHO functional class.

Epidemic Pseudomonas aeruginosa infection in patients with cystic fibrosis is not a risk factor for poor clinical Outcomes following lung transplantation.

BACKGROUND: Epidemic strains of Pseudomonas aeruginosa (ePA) causing infection in cystic fibrosis (CF) have been commonly identified from clinics around the world. ePA disproportionally impacts CF patient pre-transplant outcomes manifesting in increased exacerbation frequency, worsened treatment burden and increased rate of lung function decline, and disproportionally leads to death and/or transplantation. As other CF factors such as pre-transplant infection with multi-resistant organisms, and isolation of P. aeruginosa in the post transplant graft, may impact post-transplant outcomes, we sought to determine if infection with ePA similarly adversely impact post-transplant outcomes. METHODS: Between 1991-2014, 53 CF patients from our center received lung transplants. Bacterial strain typing was performed retrospectively on isolates collected prior to transplantation. Comprehensive chart reviews were performed to obtain baseline patient characteristics and post-transplant outcomes. RESULTS: Of the 53 transplanted patients, 57% of patients were infected with ePA prior to transplant; the other 43% of patients had unique strains of P. aeruginosa. Mean age at transplant was 29.0years for ePA and 33.3years for unique (p=0.04). There were no differences in overall survival (HR=0.75, 95% CI 0.31-1.79), bronchiolitis obliterans syndrome (BOS) free survival (HR 1.43, 95% CI 0.54-4.84) or all other assessed outcomes including exacerbation frequency, chronic renal failure, acute cellular rejections, Aspergillus infection, airway stenosis, and post-transplant lymphoproliferative disorder. CONCLUSION: Unlike pre-transplant outcomes, CF patients infected with ePA do not experience worse post-transplant outcomes than those infected with unique strains. Therefore, lung transplantation should be considered for all patients with P. aeruginosa infection and end stage lung disease, irrespective of infection with ePA.

Pregnancy after lung and heart-lung transplantation.

BACKGROUND: Advances in lung transplantation have enabled women to successfully undertake pregnancies. This study explored outcomes in this group, including changes in lung function, kidney function, and calcineurin inhibitor (CNI) levels. METHODS: A retrospective review identified 19 transplant recipients who had ever become pregnant at our center, and manual reviews of their medical records were completed for 14. Results of spirometry, serum creatinine, CNI doses and trough levels, and comorbidities were collected. RESULTS: Eight births occurred (42% success rate). Six patients have since died, with pregnancy contributing to 1 death. Five pregnancies were unplanned, with only 1 resulting in birth. Six pregnancies ended with spontaneous termination, and 2 were terminated for medical reasons. Mean age was 31.4 years (range, 22-39 years), and mean time from transplant was 76.2 months (range, 26-139 months). Complications included preeclampsia in 2, diabetes of pregnancy in 1, and abnormal liver enzymes in 1. Within 6 months of delivery, there were 2 cases of pneumonia, 2 cases of obliterative bronchiolitis, 1 case of tuberculosis, and 1 case of mild acute rejection. Forced expiratory volume in 1 second was stable at 3 (-1.5%; p = 0.55) and 12 months (1.4%; p = 0.84) after pregnancy. Mean change in Forced expiratory volume in 1 second during full-term pregnancies was -2.4% (p = 0.29), and the mean change in forced vital capacity was -0.8% (p = 0.55). In the first trimester, 83% of patients had a fall in creatinine, and a universal fall in CNI trough levels was seen. CONCLUSIONS: In carefully selected patients, planned pregnancy after lung transplant can be successful. Complications are common, and close monitoring of immunosuppression and renal function is needed.