Antonio Roman

Survival in pulmonary hypertension in Spain: insights from the Spanish registry

A pulmonary hypertension (PH) registry (Spanish Registry of Pulmonary Arterial Hypertension) was undertaken to analyse prevalence, incidence and survival of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in Spain, and to assess the applicability of recent survival prediction equations. Voluntary reporting of previously diagnosed and incident PAH or CTEPH cases (July 2007–June 2008) was performed. Demographic, functional and haemodynamic variables were evaluated. 866 patients with PAH and 162 with CTEPH were included. PAH associated with toxic oil syndrome and pulmonary veno-occlusive disease were reported for the first time in a PAH registry. Estimated prevalences were as follows: PAH, 16 and CTEPH, 3.2 cases per million adult inhabitants (MAI). Estimated incidences were as follows: PAH, 3.7 and CTEPH, 0.9 cases per MAI per yr. 1-, 3- and 5-yr survival was 87%, 75% and 65%, respectively, with no differences between PAH and CTEPH. Male sex, right atrial pressure and cardiac index were independent predictors of death. Matching between observed survival and that predicted by different equations was closer when the characteristics of the cohorts were similar. Epidemiology and survival of PAH patients in the Spanish registry are similar to recent registries. Characteristics of the population from which survival prediction equations are derived influence their applicability to a different cohort. CTEPH is much less prevalent than PAH, although has a similar survival rate.

Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors

BACKGROUND Aspergillus infection remains a major cause of morbidity and mortality after lung transplantation. Therefore, some strategies have been attempted, one of which is nebulized amphotericin B (nAB); however, the efficacy of this prophylaxis has not been shown clearly. The aim is to study whether nAB can protect against Aspergillus infection in lung transplant recipients. PATIENTS AND METHODS A study of risk factors was conducted in 55 consecutive lung allograft recipients. Twenty-three potential risk factors were analyzed. In 44 (80%) patients, nAB was indicated as prophylaxis. Multivariate analysis using logistic regression was performed. RESULTS Eighteen of the 55 patients (33%) developed infection due to Aspergillus spp. Multivariate analysis showed nAB to be a preventive factor (odds ratio: 0.13; 95% confidence interval [CI] 0.02-0.69; p < 0.05) and cytomegalovirus (CMV) disease was an independent risk factor for developing Aspergillus infection (odds ratio: 5.1; 95% CI 1.35-19.17; p < 0.05). Only 1 patient required withdrawal of the prophylaxis owing to bronchospasm. nAB was well-tolerated in the remaining patients with only a few, mild, easily controlled side effects. CONCLUSIONS The present results show that nAB prophylaxis may be efficient and safe in preventing Aspergillus infection in lung-transplanted patients, and CMV disease increases the probability of Aspergillus infection.

Nebulized amphotericin B concentration and distribution in the respiratory tract of lung-transplanted patients.

Background. A criticism of using nebulized amphotericin B (nAB) as prophylaxis against Aspergillus infection after lung transplantation is the lack of knowledge of its pharmacokinetics and distribution in the lung. The aim of this study was to ascertain the concentrations and distribution of nAB in the respiratory tract of patients receiving lung transplantations. Methods. In the drug-concentration study, 120 bronchoscopies were performed in 39 patients receiving lung transplantions after administration of 6 mg of nAB once daily for a minimum of 7 days. Mean nAB concentration in bronchial aspirated secretions (BAS) and bronchoalveolar lavage (BAL) was determined at 4, 12, 24, and 48 hours postnebulization. In the distribution study, 17 patients inhaled 6 mg of 99mtechnetium-labeled AB, and pulmonary distribution was measured using a gamma camera. Pulmonary perfusion was also measured. Both tests were quantitatively evaluated. Results. In the drug-concentration study, mean concentrations of 1.46 &mgr;g/mL in BAS and 15.75 &mgr;g/mL in BAL were reached at 4 hours. At 24 hours, concentrations were 0.37 &mgr;g/m and 11.02 &mgr;g/mL in BAS and BAL, respectively. In the distribution study, 99mtechnetium-labeled AB distribution was uniform in 12 of 13 allografts without bronchiolitis obliterans syndrome (BOS) and in 1 of 4 allografts with BOS. A close correlation was observed between regional drug distribution and regional perfusion (r =0.82, P <0.01). Conclusions. nAB concentrations remained high for the first 24 hours in BAL and for less time in BAS, with distribution of the drug being uniform in patients without BOS. Furthermore, lung-perfusion studies appear to be useful to ascertain nAB distribution in patients receiving lung transplantions.

Mycophenolic acid plasma concentrations: influence of comedication.

Mycophenolate mofetil (MMF) in combination with cyclosporine (CsA) or Tacrolimus (TAC) has been show to be a potent immunosuppressive agent. The authors assessed the mycophenolic acid (MPA) plasma levels achieved in clinical practice and evaluated the effect of concomitant administration of CsA and TAC . One hundred forty transplant patients (kidney: 120 and lung: 20) received a triple immunosuppression regimen of CsA or TAC, prednisone and MMF. Twenty-two renal transplant patients received double therapy with MMF and prednisone. There was no correlation between MMF dose and MPA trough concentrations (r = -0.0657). The medians (range) of the MPA dose-to-concentration ratio (D/C) in the CsA and TAC groups were 0.90 (0.11–8.33) and 0.56 (0.11–14.3), respectively (p < 0.0001). According to the post transplant period (1–3, 4–6 and >6 months), D/C values were significantly lower in patients receiving MMF and TAC than those receiving MMF and CsA in all three periods. MPA levels in patients treated with MMF and CsA were significantly lower than those obtained in double therapy. The D/C ratio in CsA-treated patients, increased significantly (p = 0.0005) when CsA level increased. There was no relationship between D/C ratio and TAC blood concentrations. These results suggest that CsA exerts an influence on MPA trough levels, although further work is required to characterize the mechanism of interaction.

Nebulized liposomal amphotericin B prophylaxis for Aspergillus infection in lung transplantation: pharmacokinetics and safety.

BACKGROUND The main problem with using nebulized liposomal amphotericin (n-LAB) as prophylaxis for Aspergillus infection after lung transplantation is the lack of knowledge of its pharmacokinetics and its possible adverse effects. The aim of this study was to measure post-inhalation amphotericin B concentration in the respiratory tract and serum of lung transplant patients and assess the effects of n-LAB on respiratory function. METHODS Thirty-two consecutive bronchoscopies were performed on 27 lung transplant patients at two hospitals. Amphotericin B concentration in the first and third aliquot of bronchoalveolar lavage material was measured in steady state. The first aliquot approximates most closely the true amphotericin B concentrations in the proximal airway, whereas the third aliquot provides an optimum sample from the distal airway. RESULTS At 2 days, mean amphotericin B concentrations were 11.1 microg/ml (95% confidence interval [CI]: 16.5 to 5.7 microg/ml) and 9.0 microg/ml (95% CI: 14.3 to 3.8 microg/ml) in the first and third aliquot, respectively. Thereafter, concentrations declined progressively. At 14 days, concentrations were 3.0 microg/ml (95% CI: 4.4 to 1.5 microg/ml) in the first aliquot and 4.1 microg/ml (95% CI: 6.1 to 2.1 microg/ml) in the third aliquot (p = not statistically significant). Traces of amphotericin B (0.1 microg/ml) were found in serum samples from only 1 of 27 patients. Mean value of forced expiratory volume in the first second (FEV(1)) was similar before and after n-LAB. CONCLUSIONS Amphotericin B concentrations after n-LAB remained high for 14 days, at adequate concentrations for prophylaxis of Aspergillus infection. No significant systemic absorption of amphotericin B was detected and no effect was observed on respiratory function. This promising prophylactic regimen warrants assessment in future clinical studies.

Estándares asistenciales en hipertensión pulmonar* Documento de consenso elaborado por la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) y la Sociedad Española de Cardiología (SEC)

En los ultimos anos se han producido importantes avances en el diagnostico y tratamiento de la hipertension pulmonar que han logrado una mejoria significativa en la supervivencia de esta enfermedad. Estas innovaciones se han recogido en guias de practica clinica basadas en la evidencia elaboradas por las sociedades cientificas. Sin embargo, no se incluyen en ellas, por falta de evidencia cientifica concluyente, algunos aspectos que inciden en la practica asistencial. Conscientes de ello, la Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) y la Sociedad Espanola de Cardiologia (SEC) han promovido la elaboracion de un documento de consenso para definir en nuestro medio los estandares de calidad adecuados para el diagnostico y tratamiento de la hipertension pulmonar en sus diversas formas de presentacion, asi como la via clinica y las directrices basicas de la organizacion asistencial del cuidado de estos pacientes, haciendo especial hincapie en los requisitos y funciones de las unidades de referencia. Para su redaccion la SEPAR y la SEC designaron a un grupo de trabajo formado por expertos en los distintos aspectos de la enfermedad. Para la elaboracion del documento se han utilizado las guias clinicas internacionales existentes, la revision de la evidencia cientifica disponible y el debate en panel entre los expertos. El documento final, aprobado por todos los participantes, ha sido evaluado por revisores externos.

Donor-to-host transmission of bacterial and fungal infections in lung transplantation.

The purpose of this study was to evaluate the incidence and etiology of bacterial and fungal infection or contamination in lung allograft donors and to assess donor‐to‐host transmission of these infections. Recipients who survived more than 24 h and their respective donors were evaluated. The overall incidence of donor infection was 52% (103 out of 197 donors). Types of donor infection included isolated contamination of preservation fluids (n = 30, 29.1%), graft colonization (n = 65, 63.1%) and bacteremia (n = 8, 7.8%). Donor‐to‐host transmission of bacterial or fungal infection occurred in 15 lung allograft recipients, 7.6% of lung transplants performed. Among these cases, 2 were due to donor bacteremia and 13 to colonization of the graft. Twenty‐five percent of donors with bacteremia and 14.1% of colonized grafts were responsible for transmitting infection. Excluding the five cases without an effective prophylactic regimen, prophylaxis failure occurred in 11 out of 197 procedures (5.58%). Donor‐to‐host transmission of infection is a frequent event after lung transplantation. Fatal consequences can be avoided with an appropriate prophylactic antibiotic regimen that must be modified according to the microorganisms isolated from cultures of samples obtained from donors, grafts, preservation fluids and recipients.

Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation.

BACKGROUND Nebulized amphotericin B deoxycholate (n-ABD) is used to prevent Aspergillus infection in lung transplantation. Nebulized liposomal amphotericin B (n-LAB) is another option; however, no clinical data are available on the results of n-LAB for this purpose. METHODS In an observational study performed in 2 centers to assess the feasibility, tolerability, and outcomes of n-LAB prophylaxis, 104 consecutive patients undergoing prophylaxis with n-LAB were compared with 49 historical controls who received n-ABD. Patient follow-up lasted 12 months. The n-LAB prophylaxis regimen was 25 mg thrice weekly starting on the first post-operative day and continuing to 60 days, 25 mg once weekly from 60 to 180 days, and the same dose once every 2 weeks thereafter. RESULTS Aspergillus infection developed in 8 of 104 patients (7.7%) with n-LAB prophylaxis (5 colonization, 1 simple tracheobronchitis, 1 ulcerative tracheobronchitis, and 1 invasive pulmonary infection). Ulcerative tracheobronchitis and invasive pulmonary aspergillosis were regarded as invasive disease; hence, the rate of invasive disease was 1.9% (2 patients). The control group had similar rates of Aspergillus infection (10.2%; p = 0.6) and invasive disease (4.1%; p = 0.43). In 3 patients (2.9%), n-LAB was withdrawn due to bronchospasm in 2 and nausea in 1. In the control group, prophylaxis was stopped in 2 patients (4.1%) because of bronchospasm (p = 0.7). CONCLUSIONS At the dose and frequency described, n-LAB seems effective, safe, and convenient for the prevention of Aspergillus infection in lung transplant patients.

Infliximab Rescue Therapy after Cyclosporin Failure in Steroid-Refractory Ulcerative Colitis

Background: Cyclosporin (CsA) and infliximab (IFX) have proven efficacy in avoiding colectomy in patients with steroid-refractory ulcerative colitis (UC). Aim: To assess the clinical outcome of patients treated with IFX after CsA failure for acute steroid-refractory flares of UC. Methods: Medical records of patients with a steroid-refractory UC flare who did not respond to CsA or relapsed soon after hospital discharge, and who followed rescue therapy with IFX, were reviewed retrospectively. Results: Sixteen patients were included, 69% with extensive UC. Thirteen patients had moderate-to-severe disease activity at the time IFX was started. Median time between CsA discontinuation and the first IFX infusion was 19 days. Thirteen patients completed an induction regimen, and 6 of them followed scheduled maintenance treatment with IFX. After a median time of follow-up from the first IFX infusion of 195 days, 6 patients (37.5%) required colectomy. Median time for colectomy was 47 days. There were no deaths or malignancies, and only one septic complication was recorded. Conclusions: IFX rescue therapy might avoid short-term colectomy in a proportion of steroid-refractory UC patients who do not respond to CsA, but systematic use of sequential rescue therapy is not recommended until more data about its safety profile is available.

Acute and chronic pleural complications in lung transplantation

BACKGROUND Lung transplant recipients may have pleural complications. However, the influence of these complications on the prognosis is not well known. METHODS We analyzed pleural complications and clinical and radiologic data from 100 patients who underwent lung transplantation in a general hospital in a 9-year period. Pre-operative evaluation, surgical protocol, immunosuppressive regimen, and follow-up were carried out systematically. Chest computerized tomography (CT) was performed at 3 and 12 months after transplantation. RESULTS All patients had early post-operative pleural effusion ipsilateral to the graft, which required drainage for a mean of 19.3 days (range, 5-52 days). Thirty-four patients had 43 acute pleural complications: 15 hemothoraxes, 10 persistent air leaks, 8 pneumothoraxes, 7 transient air leaks, and 3 empyemas. Multivariate analysis showed hemothorax and persistent air leak were associated with increased post-operative mortality (p = 0.024, p = 0.011, respectively). Post-operative mortality was not associated with any pre-transplant variable. Chest CT findings at 3 months revealed > or =1 pleural alteration in 58 of 70 patients (83%): 34 post-operative residual ipsilateral pleural effusions; 36 pleural thickenings; and 3 residual pneumothoraxes, 1 with a coexisting bronchial dehiscence. Chest CT at 12 months showed pleural alterations in 50 of 58 patients (86%): pleural thickening in 48, calcification in 4, and residual pleural effusion in 4. CONCLUSIONS Pleural complications are common in lung transplant recipients. Hemothorax and persistent air leak are associated with increased post-operative mortality. Chest CT showed pleural alterations in most patients 12 months after transplantation.