Carles Bravo

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.

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.

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.

Isoniazid prophylaxis in lung transplantation

The incidence of tuberculous disease (TD) is higher in lung-transplant patients than in the general population. During a 7-year period, we included 61 patients who underwent lung transplantation in a prospective isoniazid prophylaxis protocol. Isoniazid was prescribed to infected and anergic patients not previously treated when added to the waiting list. Six of 61 patients (10%) developed tuberculosis. We observed no differences in tuberculous disease incidence between infected-anergic and non-infected patients. In our tuberculous-endemic area, isoniazid prophylaxis is safe and offers protection from TD to infected and anergic patients who must be enrolled in a lung transplantation program.

Estudio clínico-hemodinámico y tratamiento de 44 pacientes con hipertensión pulmonar primaria

Fundamento La hipertension pulmonar primaria es una enfermedad poco conocida y de tratamientocomplejo. Pacientes y me;todo Estudio retrospectivo de 44 pacientes con hipertension pulmonar primariaestudiados entre 1992 y 2000 en un solo centro. Resultados En el momento del diagnostico, 6 pacientes (13%) se encontraban en clasefuncional I de la NYHA, 11 (25%) en clase II, 25 (57%) en clase III y 2 (4,5%) en clase IV. Lamedia de la presion sistolica en arteria pulmonar medida por eco-Doppler fue de 92 (limites,43–154) mmHg. El cateterismo derecho basal demostro que la media (DE) de la presion en arteriapulmonar fue de 58 (18) mmHg, las resistencias pulmonares totales basales fueron de1.679 (1.071) din/cm 2 y el indice cardiaco fue de 2,2 (1) l/min/m 2 . Cinco pacientes (11%)mejoraron con anticoagulacion y antagonistas del calcio. Desde 1998, 11 pacientes fueron tratadoscon epoprostenol intravenoso continuo; de ellos, tres (27%) presentaron mejoria clinicasignificativa. La supervivencia a los 5 anos del diagnostico fue del 56%. Siete (70%) de los 10pacientes tratados mediante trasplante pulmonar estan vivos al cierre del estudio (seguimientomedio, 34 meses; limites, 3–62 meses). Conclusiones La hipertension pulmonar es una enfermedad con mal pronostico, si bien el tratamientocon prostaglandinas y el trasplante pulmonar ofrecen resultados esperanzadores.

Blood cyclosporine C0 and C2 concentrations and cytomegalovirus infections following lung transplantation

The aim of this study was to determine whether cyclosporine levels predose (C0) and at two hours postdose (C2) were higher among patients presenting with cytomegalovirus (CMV) infection or disease. Between days 40 and 365 posttransplantation serial C0 and C2 levels were measured in 15 lung transplant recipients. Nine developed 13 episodes of CMV infection or disease. Both C0 and C2 levels were higher during CMV infection or disease episodes. Eleven of the 13 CMV episodes (84%) displayed C0 >220 ng/mL and none had C0 <200 ng/mL. For C2, 11 of 13 CMV episodes (84%) showed C2 >1200 ng/mL and none had C2 <1000 ng/mL. Among determinations that did not coincide with a CMV episode, 7 of 21 (33%) showed C0 >220 and 9 of 21 (42%) showed C2 >1200, respectively (P<.05). In conclusion, cyclosporine blood levels are higher among patients presenting with CMV infection or disease.

Platelet Thromboembolism after Lung Transplantation

Lung transplant patients have an increased risk of pulmonary embolism which is often associated with hypercoagulability disorders. We present a case of sudden death resulting from pulmonary intravascular platelet thromboembolism following a single-lung transplant.