Meinhard Kneussl

Predictors of Outcome in Chronic Thromboembolic Pulmonary Hypertension

Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intraluminal thrombus organization and fibrous obliteration of pulmonary arteries. Recently, associated medical conditions such as splenectomy, ventriculoatrial shunt for the treatment of hydrocephalus, permanent central intravenous lines, inflammatory bowel disease, and osteomyelitis were found to be associated with the development of CTEPH. The study aim was to define the impact of these novel risk factors on survival. Methods and Results— Between January 1992 and December 2006, 181 patients diagnosed with CTEPH were tracked with the use of our centers customized computer database. A Cox regression model was used to examine relations between survival and associated medical conditions, age, sex, hemodynamic parameters, modified New York Heart Association functional class at diagnosis, CTEPH type, pulmonary endarterectomy, and anti-cardiolipin antibodies/lupus anticoagulant. During a median observation time of 22.1 (range, 0.03 to 152) months, the clinical end point of cardiovascular death or lung transplantation occurred in 48 cases (27%). Pulmonary endarterectomy (hazard ratio, 0.14; 95% CI, 0.05 to 0.41; P=0.0003), associated medical conditions (hazard ratio, 3.17; 95% CI, 1.70 to 5.92; P=0.0003), and pulmonary vascular resistance (hazard ratio, 1.02; 95% CI, 1.00 to 1.04; P=0.04) were predictors of survival. Thirty-day postoperative mortality (24% versus 9%) and the incidence of postoperative pulmonary hypertension (92% versus 20%) were substantially higher in patients with associated medical conditions. Conclusions— CTEPH-predisposing medical conditions, such as splenectomy, permanent central intravenous lines, and certain inflammatory disorders, predict poor survival in CTEPH.

High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is an enigmatic disorder lacking signs, symptoms and classical risk factors for venous thromboembolism. The objective of the prospective case controlled study, carried out at the Pulmonary Hypertension Unit, University Hospital Vienna, Austria, was to investigate whether plasma FVIII is elevated in CTEPH patients. The study examined 122 consecutive patients diagnosed with CTEPH. Plasma FVIII was measured and compared with plasma FVIII of healthy controls (n = 82) and of patients with nonthromboembolic pulmonary arterial hypertension (PAH, n = 88). Results show that CTEPH patients had higher FVIII levels than controls (233 +/- 83IU/dl versus 123 +/- 40IU/dl, p < 0.0001) and PAH patients (158 +/- 61IU/dl, p < 0.0001). Plasma FVIII one year after surgery (212 +/- 94IU/dl) was statistically unchanged compared with preoperative values (FVIII: 226 +/- 88IU/dl, n = 25). FVIII > 230IU/dl was more prevalent in CTEPH patients (41%) than in controls (5%, p < 0.0001) and PAH patients (22%, p = 0.022). We can conclude that elevated plasma FVIII is the first prothrombotic factor identified in a large proportion of CTEPH patients.

Role for Staphylococci in Misguided Thrombus Resolution of Chronic Thromboembolic Pulmonary Hypertension

Objective—Acute pulmonary emboli usually resolve within 6 months. However, in 0.1% to 3.8% of cases thrombus transforms into fibrous masses. If vascular obstruction is severe, the resulting condition is chronic thromboembolic pulmonary hypertension (CTEPH). Patients who carry ventriculo-atrial (VA-) shunts for the treatment of hydrocephalus and report a history of shunt infection are at an increased risk for CTEPH. Because CTEPH lacks traditional plasmatic risk factors for venous thromboembolism, we hypothesized that delayed thrombus resolution rather than abnormal coagulation is important, and that bacterial infection would be important for this misguidance. Methods and Results—Human CTEPH thromboemboli were harvested during pulmonary endarterectomy. The effects of Staphylococcal infection on thrombus organization were examined in a murine model of stagnant-flow venous thrombosis. Staphylococcal DNA, but not RNA, was detected in 6 of 7 thrombi from VA shunt carriers. In the mouse model, staphylococcal infection delayed thrombus resolution in parallel with upregulation of transforming growth factor (TGF) beta and connective tissue growth factor. Conclusions—In the present work, we propose a mechanism of disease demonstrating that infection with Staphylococci enhances fibrotic vascular remodeling after thrombosis, resulting in misguided thrombus resolution. Thrombus infection appears to be a trigger in the evolution of CTEPH.

Pulmonary Vascular Reactivity and Prognosis in Patients With Chronic Thromboembolic Pulmonary Hypertension A Pilot Study

Background— Surgical pulmonary endarterectomy is the preferred treatment for chronic thromboembolic pulmonary hypertension. Persistent pulmonary hypertension after pulmonary endarterectomy has been recognized as a major determinant of poor outcome. We tested whether acute vasoreactivity identifies chronic thromboembolic pulmonary hypertension patients prone to develop persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and whether the degree of acute vasoreactivity affects survival or freedom from lung transplantation. Methods and Results— Right-sided heart catheterization at baseline and after inhalation of 40 ppm nitric oxide for 20 minutes was performed in 103 patients (56.3±15.3 years old, 53 women). Reductions in mean pulmonary arterial pressure (&Dgr;mPAP; −8.8±12.6%; P<0.0001) and pulmonary vascular resistance (−16.1±18.1%; P<0.0001) and an increase in mixed venous saturation during inhaled nitric oxide (9.1±11.6%; P<0.0001) were observed. Sixty-two patients underwent pulmonary endarterectomy after a median of 49 days (25th and 75th percentiles: 24 and 123 days). Operated patients were followed up for a median of 70.9 months (25th and 75th percentiles: 14 and 97 months). Change in mPAP during inhaled NO was identified as a predictor of persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. Patients experiencing a reduction in mPAP >10.4% with nitric oxide inhalation had a better postoperative outcome. A significant correlation was found between &Dgr;mPAP and immediate postoperative pulmonary vascular resistance (r=0.5, P<0.0001). Conclusions— A total of 80 (77.7%) of 103 patients demonstrated acute pulmonary vascular reactivity of some degree. A decrease in mPAP >10.4% under inhaled nitric oxide is a predictor of long-term survival and freedom from lung transplantation in adult patients with chronic thromboembolic pulmonary hypertension who are undergoing pulmonary endarterectomy.

Pulmonary pharmacokinetics and safety of nebulized duramycin in healthy male volunteers

Duramycin (Moli1901) is being developed for the treatment of reduced mucociliary clearance in cystic fibrosis. This study was conducted to estimate lung residence time and systemic exposure and to assess whether duramycin causes an inflammatory response. Six volunteers were administered a single dose (7.5xa0mg) of nebulized duramycin and underwent bronchoscopies to obtain a composite data set for pharmacokinetic analysis; duramycin was measured in the cellular fraction of bronchoalveolar lavage fluid (BALF) (mainly alveolar macrophages) and brush biopsies (bronchial epithelial cells). The estimated t1/2 of duramycin was ∼5xa0days in brush biopsies and 25 to 91xa0days in BALF cells. Levels of duramycin in BALF (Cmax 800xa0ng/mg) exceeded those in brush biopsies by ∼20-fold. Duramycin was absent from plasma and did not cause any detectable inflammatory response in pulmonary tissue as judged from the BALF profile of 14 relevant cytokines. Our data suggest that duramycin qualifies for intrapulmonary administration in cystic fibrosis (CF) patients.

Signal recognition particle (SRP) positive myositis in a patient with cryptogenic organizing pneumonia (COP)

We report of a 46-year-old female patient with cryptogen organizing pneumonia preceeding the rare SRP positive necrotising myositis without cardiac involvement and no sign of dysphagia. Myositis showed full regression without oral immune suppression but with extracorporeal treatment, performed as a combined therapy of plasmaexchange and immunoadsorption. After 33-month of treatment, anti-SRP antibodies were not detectable any more.

Pulmonale Hypertension bei rheumatischen Erkrankungen

Zusammenfassung. Die pulmonale Hypertension (PH) ist durch Steigerung des pulmonal-arteriellen Druckes und Erhöhung des Lungengefäßwiderstandes charakterisiert. Die pulmonale Hypertension bei rheumatischen Erkrankungen stellt eine Sonderform der pulmonal arteriellen Hypertension dar, die sich aber sowohl in der klinischen Präsentation als auch histologisch von allen anderen Formen wenig unterscheidet. Durch einen progressiven Verlauf kommt es beim Unbehandelten innerhalb von zwei bis drei Jahren nach Diagnosestellung zu Rechtsherzversagen und Tod. Diagnostisch ist entscheidend, die chronisch thromboembolische PH (CTEPH) von der Primären PH (PPH) abzugrenzen. Beide Formen findet man assoziiert mit dem Spektrum rheumatischer Erkrankungen. Während für die CTEPH die pulmonale Thromboendarterektomie eine kausale Therapieform darstellt, steht für die PPH in erster Linie die medikamentöse Therapie zur Verfügung. Da Vasokonstriktion und thrombotischer Verschluss der Widerstandsgefäße der Lunge den Krankheitsprozess beschleunigen, werden derzeit Vasodilatatoren mit verschiedenen Angriffspunkten am glatten Gefäßmuskel und Antikoagulierung eingesetzt. Noch vor wenigen Jahren wurde die medikamentöse Therapie der PH nur als Überbrückung zur Lungen- oder Herz-Lungen-Transplantation betrachtet, heute ist sie eine Alternative zur Transplantation. Die wenigen verfügbaren Subgruppenanalysen großer Vasodilatatorstudien lassen aber vermuten, dass subjektive PH-Symptome, Leistungsfähigkeit und Hämodynamik bei PH assoziiert mit rheumatischen Erkrankungen weniger verbesserbar sind als bei der klassischen PPH. In den kommenden Jahren werden verschiedene Kombinationstherapien erprobt werden.Summary. Pulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature characterized by increased vascular resistance and pressure overload of the right ventricle. Histologically, PH lungs demonstrate medial hypertrophy of small pulmonary arteries and proliferation of endothelial cells resulting in plexiform lesions. Recent studies have identified mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene and the activin-receptor-like kinase 1 (ALK1) gene, that affect the transforming growth factor beta (TGF-beta) receptor superfamily, a group of transmembrane signaling molecules with serine-threonine kinase activity that are involved in the regulation of cell growth. Several lines of evidence indicate that the development of PH is a multi-hit process, where one of the events is having a gene mutation and another might be a circumstantial condition or other disease-modifying genes. It is unknown which mechanism that is critical in rheumatic diseases causes pulmonary vascular disease. PH is most frequently associated with systemic sclerosis (SS), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), however, it is still a rare manifestation of these disorders. For example, approximately 10% of SS cases manifest pulmonary vascular disease. In recent years symptomatic vasodilator therapies have been employed and have been able to improve exercise capacity and survival in these patients.

Liver disease in adults with α1-antitrypsin deficiency

Background The natural history of adult liver disease due to α1-antitrypsin deficiency (A1AD) remains poorly understood. Objective We investigated whether heterozygosity for the Z-allele predisposes for the development of clinically significant portal hypertension (CSPH). Moreover, we aimed to non-invasively assess the prevalence of liver fibrosis and hepatic steatosis in adults with A1AD treated by pulmonologists. Methods SERPINA1 rs28929474 (Z-allele) was genotyped in 315 patients with CSPH (hepatic venous pressure gradient ≥10u2009mmHg; cases) and 248 liver donors (controls). In addition, 31 adults with A1AD (Pi*ZZ/Pi*SZ) and 11 first-degree relatives (Pi*MZ/Pi*MS) underwent liver stiffness and controlled attenuation parameter (CAP) measurement. Results Heterozygosity for the Z-allele was observed in 6.7% of patients with CSPH and 2.8% of liver donors. Thus, harboring the Z-allele was associated with increased odds of CSPH (odds ratio: 2.47; 95% confidence interval: 1.03–5.9; Pu2009=u20090.042). Among Pi*ZZ/Pi*SZ patients, 23%/3% had liver stiffness values indicative of liver fibrosis (u2009≥F2/u2009≥F3). Interestingly, 65%/52% of Pi*ZZ/Pi*SZ patients had CAP values indicative of hepatic steatosis (u2009≥S1/u2009≥S2). Conclusions Heterozygosity for the Z-allele predisposes for the development of CSPH, confirming its role as a genetic (co)factor in liver disease. Pi*ZZ/SZ patients rarely develop liver fibrosisu2009≥F3 during adulthood; however, liver fibrosisu2009≥F2 is common. Elevated CAP values hint at underlying hepatic steatosis, which might promote liver fibrosis progression.

J.A.P. Paré

On February 24, 2013, Jules Arthur Peter Pare MDCM, BSc, FACP, Professor Emeritus of Medicine, McGill University (Montreal, QC, Canada) died at 95 years of age in Montreal after a long and full life.nnDr Pare grew up in Montreal and received his MD degree from McGill University in 1943. He trained in Internal Medicine and Respiratory Medicine at McGill and in 1948–1949 was a postdoctoral fellow in Chest Medicine at the Massachusetts General Hospital, Harvard Medical School in Boston, MA, USA. He then returned to Montreal, where he spent the duration of his career. In 1975, he became Professor of Medicine at McGill, and between 1975 and 1983 was the combined Respiratory Division Head of all McGill teaching hospitals (Royal Victoria Hospital, Montreal General Hospital, Montreal Chest Hospital and Jewish General Hospital).nnnnJ.A.P. ParennnnProfessor Pare was a masterful clinician and teacher and influenced two generations of respiratory physicians at McGill and these have, in turn, affected Respiratory Medicine across all parts of the globe. With his friend, Dr Robert Fraser, a chest radiologist at McGill, he published their textbook, …