Recombinant human alpha 2-adrenoceptor subtypes: comparison of [3H]rauwolscine, [3H]atipamezole and [3H]RX821002 as radioligands.

Kinetic, saturation and competition binding assays were employed to optimize and validate radioligand binding methods for characterization of recombinant human alpha 2-adrenoceptor subtypes and for screening of new subtype-selective ligands. Stable transfected lines of Shionogi 115 mouse mammary tumour cells (S115) and three structurally different antagonist radioligands, [3H]rauwolscine, [3H]atipamezole and [3H]RX821002, were used. Specificity of alpha 2-adrenergic binding was defined with 100 microM (-)-adrenaline. Steady-state was reached with all three radioligands within 15-30 min at 25 degrees C, and the binding was rapidly reversible. The receptor affinities (alpha 2-C10) were highest in glycylglycine, almost equally high in K(+)-phosphate, and lowest in Tris buffer for all three [3H]-ligands. This was mainly caused by different association rates. [3H]RX821002 was bound with high affinity and similar kinetic properties to all three alpha 2-adrenoceptor subtypes in K(+)-phosphate buffer, and had the highest proportion of specific binding (96-98%). [3H]RX821002 and K(+)-phosphate buffer were subsequently used in competition assays. The rank order of affinity of compounds selective for alpha 2-adrenoceptor subtypes was alpha 2-C10 > alpha 2-C4 > alpha 2-C2 for oxymetazoline, alpha 2-C4 > alpha 2-C2 > alpha 2-C10 for prazosin and alpha 2-C2 > alpha 2-C4 > alpha 2-C10 for chlorpromazine. The drug affinities (Ki values) determined in this system were in close agreement with earlier results with [3H]rauwolscine in Tris buffer (r = 0.94). Agonist competition for [3H]RX821002 binding was biphasic in K(+)-phosphate buffer supplemented with 10 mM MgCl2, indicating functional coupling of receptors to G-proteins. Accordingly high-affinity binding of the agonists (-)-noradrenaline and UK14,304 was eliminated by 10 microM Gpp(NH)p in the assays. Our results confirm that [3H]RX821002 is a suitable radioligand for the characterization of all three human alpha 2-adrenoceptor subtypes and for the determination of the subtype-selectivity of new alpha 2-adrenoceptor agonists and antagonists.

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

Interferon maintenance therapy for small cell lung cancer: improvement in long-term survival.

Two hundred thirty-seven patients with small cell lung cancer (SCLC), who had responded to induction chemotherapy and radiotherapy, were randomly assigned to receive low-dose natural interferon-alpha (nIFN alpha) for 6 months; or 6 cycles of maintenance chemotherapy (CAP); or no maintenance therapy (control group). Although there was no difference in median survival between the groups, there was a significant difference (p = 0.04) in the long-term survival of patients with limited disease, in favour of nIFN alpha maintenance therapy. This finding is now confirmed by a further analysis of the most recent data. Ten percent of patients in the IFN group survived for five years or more, but the 5-year-survival rate in the CAP and control groups was only two percent. All long-term survivors had good performance status. The majority had limited disease and had achieved a complete response to the induction therapy. These results suggest that interferon-alpha improves the long-term survival of SCLC patients for whom other prognostic factors are favorable.

Concomitant chemotherapy and IFN-alpha for small cell lung cancer: a randomized multicenter phase III study.

Patients with any stage of small cell lung cancer were given low-dose interferon-alpha (IFN-alpha) from the first day of treatment as long as possible irrespective of changes in treatment dictated by disease progression. All patients received 6 cycles of the chemotherapy (CT): cisplatin 70 mg/m2 i.v. day 1 and etoposide 100 mg/m2 i.v. days 1, 2, 3 every 28 days. Seventy-eight patients were assigned to arm 1: CT alone, 75 patients to arm 2: CT + natural IFN-alpha (3 MU three times a week i.m.), and 66 patients to arm 3: CT + recombinant IFN alpha-2a (3 MU three times a week i.m.). There was no difference in median survival between the arms (10.2 months, 10.0 months, 10.1 months, respectively), p = 0.32. The 2-year survival rates were 15%, 3%, and 11%, respectively. Grade 3 and 4 leukopenia occurred more frequently in the IFN arms than in the CT alone arm and resulted in dose reductions. Antibodies occasionally developed to recombinant IFN. We conclude that IFN-alpha can be administered concomitantly with chemotherapy but is probably better kept for maintenance therapy so that optimal full doses of induction CT can be given.

Interferons combined with chemotherapy in the treatment of stage III-IV non-small cell lung cancer--a randomised study.

80 patients with previously untreated stage III-IV non-small cell lung cancer (NSCLC) were randomly assigned to receive chemotherapy (CT) alone (arm I: 26 patients) or the same CT combined with either interferon (IFN)-gamma (arm II: 27 patients) or with both IFN-gamma and IFN-alpha (arm III: 27 patients). The CT comprised cisplatin 60 mg/m2 intravenously (i.v.) day 1 and etoposide 100 mg/m2 i.v. days 1, 3 and 5, once every 28 days; the IFN therapy comprised either recombinant IFN-gamma 1b 0.2 mg/m2, subcutaneously, three times a week until day 25, or recombinant IFN-alpha 2c 6 x 10(6) U given according to the same schedule, and simultaneously with IFN-gamma. A maximum of six cycles were given. The treatment was discontinued if progressive disease (PD) was demonstrated. The mean numbers of cycles per patient given in the different arms were 3.6 (arm I), 3.0 (arm II) and 2.9 (arm III). The main reason for discontinuation in all arms was PD. 17 (28%) of the 61 evaluable patients achieved partial responses (35% in arm I, 29% in arm II and 35% in arm III, non-significant). No complete response was recorded. Haematological toxicity was dose-limiting in all arms: leucopenia (WHO grade 3) was observed universally, but more frequently in arm III (in 18% of cycles given). Only two episodes of grade 4 leucopenia were seen (arms II and III) and six episodes of grade 3-4 thrombocytopenia (arm III). Median survival was 6-7 months in all arms. The survival curve for arm II was slightly more favourable (non-significant) than those for other arms. The addition of IFN-gamma alone or IFN-alpha plus IFN-gamma to platinum-based CT did not improve response rates nor did it produce any significant survival benefit for patients with NSCLC. Increased haematological toxicity was observed when both IFNs were administered concomitantly with CT.

Natural alpha-interferon in combination with hyperfractionated radiotherapy in the treatment of non-small cell lung cancer.

Our previous study in patients with small-cell lung cancer indicated that natural alpha interferon might be a radiosensitiser. In this study we considered 20 patients with inoperable non-small cell lung cancer, who were randomly assigned to receive either hyperfractionation radiotherapy alone, 1.25 Gy twice a day (6 hr interval), 60 Gy/48F/32d; or the same radiotherapy concurrently with alpha interferon. Patients in the radiotherapy+alpha interferon arm received 3 x 10(6) IU natural alpha interferon intramuscularly and 1.5 x 10(6) IU inhaled via a dosimeter-equipped jet nebulizer 30 min before each radiotherapy session. Tumor response and radiation-induced lung injury were assessed by serial chest radiographs, computerized tomography scans and lung function studies, during a 1 year follow-up period. No patient in either arm achieved complete response. On the other hand, five patients in the radiotherapy arm and six in the radiotherapy+interferon arm experienced partial response, and the corresponding figures for stable disease were three and one. Combined treatment with radiotherapy and inhaled and intramuscular interferon proved feasible but laborious, for both patients and staff. Pneumonitis and/or oesophagitis in the radiotherapy+interferon arm were moderate to severe, and only two patients tolerated the treatment without any modifications. No treatment modifications were necessary in the radiotherapy arm. The early deaths in the radiotherapy+interferon arm may have been treatment-related. The optimal way to combine interferon and radiotherapy to further evaluate its role as a radiosensitiser needs further studies in larger series.

Inhaled recombinant interferon gamma in patients with lung cancer: pharmacokinetics and effects on chemiluminescence responses of alveolar macrophages and peripheral blood neutrophils and monocytes.

PURPOSE: A Phase I trial was conducted to investigate clinical toxicity, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AM) and peripheral blood neutrophils and monocytes after inhalation of recombinant interferon (r IFN)-gamma. METHODS AND MATERIALS: Eight patients with lung cancer inhaled r IFN-gamma as single doses of 0.1, 0.2, 0.6, 1.8, or 5.4 mg. Bronchoalveolar lavage was performed three times, 21 h before as well as 3 and 27 h after inhalation. RESULTS: Interferon-gamma was detectable in bronchoalveolar lavage fluid (BALF) samples taken 3 h after inhalation in doses of > or = 0.6 mg. Before inhalation, AM in four out of seven patients studied showed vigorous lucigenin-enhanced CL responses to N-formyl-methionyl-leucyl-phenylalanine and opsonized zymosan particles. Furthermore, the responses were markedly increased 3 h after inhalation. In three out of seven patients, AM in the pretreatment BALF samples showed low or no CL responses, and the responses did not increase after inhalation of IFN-gamma, suggesting that the patients were anergic. Postinhalation CL responses did not correlate with the dose of IFN-gamma inhaled. Circulating IFN-gamma was detected in one patient receiving the highest dose. No changes referable to IFN-gamma inhalation were found in the CL responses of blood neutrophils and monocytes. During the 24 h follow-up, two patients developed transient fever-reactions. CONCLUSIONS: The findings suggest that inhalation may provide a way to increase alveolar concentrations of IFN-gamma and to augment respiratory burst capacity of AM without any major side effects. This approach may have clinical implications for the treatment of tumors and infections of the respiratory tract.

Comparison of endobronchial and transbronchial biopsies with high-resolution CT (HRCIT) in the diagnosis of sarcoidosis.

High-resolution computed tomography (HRCT) has been shown to accurately visualise parenchymal infiltrates of sarcoidosis. The aim of this study was to compare the diagnostic yield (DY) of HRCT with that of endobronchial (EBB) and transbronchial (TBB) biopsies in establishing the diagnosis of sarcoidosis. Forty-five patients referred to Helsinki University Central Hospital with a presumptive diagnosis of sarcoidosis underwent fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL), EBB, TBB and HRCT. Thirty-seven of the patients were diagnosed as having sarcoidosis, 34 of whom showed a parenchymal infiltrate in HRCT. One of the three patients with no parenchymal findings, had positive findings in TBB, and all had lymphocytosis in BAL. The DY for sarcoidosis by EBB and TBB was 24.3% and 50.0%, respectively. The addition of EBB to TBB improved the DY by 8.3%, whereas adding TBB to EBB improved the DY by 30.6%. There were no major complications after the FOB, which was always performed under fluoroscopic control. In conclusion, HRCT is a valuable tool in diagnosing sarcoidosis. However, the HRCT findings cannot be seen in all patients with positive findings in lung biopsy, nor is the parenchymal infiltrate specific for sarcoidosis. Attempting biopsy-proven diagnosis of sarcoidosis is still recommended. Fiberoptic bronchoscopy with EBB and TBB under fluoroscopic control is a safe and well-tolerated procedure.

Paclitaxel (Taxol) and carboplatin followed by concomitant paclitaxel, cisplatin and radiotherapy for inoperable stage III NSCLC.

We assessed the efficacy and toxicity of low-dose paclitaxel (Taxol) given combined with carboplatin before radiotherapy, and with cisplatin concomitantly with radiotherapy, in 27 patients with previously untreated inoperable stage IIA/IIIB non-small cell lung cancer. The induction chemotherapy consisted of paclitaxel 135 mg/m2 given over 1 h on day 1 and carboplatin 200 mg/m2 on day 2 repeated every 3 weeks for three cycles. Patients free of progression after induction chemotherapy received megavoltage radiation (56 Gy, 2 Gy/fraction) along with paclitaxel (30 mg/m2/1 h) and cisplatin (30 mg/m2/1 h) given 2-4 h before irradiation on days, 1, 2, 3, 22, 23 and 24. A combination of antero-posterior and oblique treatment fields was used to limit the dose to the spinal cord and to the left side of the heart to 36 Gy. The overall response rate was 78% (complete response, 19%). With a median follow-up of 19 months the median survival is 12 months, the estimated 2-year survival rate is 36%, and all patients with a complete response survived for at least 12 months after starting treatment. A total of 17 deaths occurred with metastases predominantly in the brain. Major acute toxicities (> grade 3) during induction chemotherapy included leuko-/neutropenia (n = 5/27, 19%), and during chemoradiotherapy leuko-/neutropenia (n = 10/23, 43%), thrombocytopenia (n = 1, 4%), oesophagitis (n = 3, 13%) and pneumonitis (n = 7, 30%). No toxic deaths occurred. Marked renal toxicity was not observed. We conclude that this chemoradiotherapy regimen is effective and well-tolerated, and should be further evaluated in a randomised phase III trial.

Tumour response and radiation-induced lung injury in patients with recurrent small cell lung cancer treated with radiotherapy and concomitant interferon-alpha.

The aim of this study was to determine whether either natural or recombinant interferon (IFN)-alpha can improve the response to radiotherapy (RT) in patients with small cell lung cancer (SCLC), and to assess the role of IFN in radiation-induced lung injury. All patients had previously participated in a randomised trial of chemotherapy alone or in combination with IFN-alpha in three arms (arm O: no IFN, arm I: natural IFN-alpha, arm II: recombinant IFN-alpha). Patients with locally progressive disease in the lungs following chemotherapy were treated with RT and they continued with their concomitant IFN-alpha. The RT dose was 50 Gy. Radiation-induced lung injury was assessed by lung function tests, computed tomography and bronchoalveolar lavage fluid (BALF) analysis which included cell findings, Interleukin (IL)-1 alpha/-1 beta expression by alveolar macrophages and surfactant components. Seventeen patients were entered in the study, 16 of whom were evaluable. Response rates in Arms O, I and II were 50, 67 and 50%, respectively. Median survival was 18.5, 7 and 23 months respectively, and 1-year survival was 67, 29 and 75% respectively. Long-term survival as assessed by 2- and 3-year survival rates was 29% in patients receiving natural IFN-alpha as compared to 17% in patients not receiving IFN (not statistically significant findings). Every patient had abnormal results when assessed for radiation-induced lung injury. No statistically significant difference was found in toxicity between the treatment arms. A high surfactant protein (SP)-A/phospholipid ratio and a high level of SP-A in BALF before RT was associated with a high degree of radiation-induced lung injury measured by lung function tests and computed tomography in all arms of the study. Thus, we could not show that the combination of IFN-alpha and RT induced more lung toxicity than RT alone as we did in our previous study. The role of high SP-A/phospholipid ratios and high SP-A levels in BALF before RT as predictors of the development of lung injury after RT needs to be determined in the future.

The clinical importance of magnetic resonance imaging versus computed tomography in malignant pleural mesothelioma.

There is no standard therapy for malignant pleural mesothelioma (MPM), but recent reports have shown that extensive surgery combined with chemo- and radiotherapy prolongs the survival of selected patients with early stage disease. This emphasises the need for accurate staging procedures at diagnosis and reliable imaging methods to assess response to treatment. Computed tomography (CT) of the chest has been the standard imaging method for these purposes for the last decade, but it is limited in its ability to demonstrate accurately the platelike growth pattern of MPM within the thorax due to the partial volume effect on curved surfaces. In order to define the value of magnetic resonance imaging (MRI) in the imaging of MPM, we have compared the findings from 26 parallel paired CT and MRI scans of mesothelioma patients at various stages of the disease. MRI showed tumour spread into the interlobar fissures, tumour invasion of the diaphragm and through the diaphragm, and invasion of bony structures better than CT. Invasion of the chest wall and mediastinal soft tissue and tumour growth into the lung parenchyma were equally well seen on both imaging methods. CT was better for detecting the inactive pleural calcifications. MRI is a sensitive detector of the characteristic growth pattern and extension of MPM and we recommend its use more widely for the clinical management of MPM especially when evaluating tumour resectability and in research protocols when an accurate evaluation of disease extent is essential.

Phase II study of weekly gemcitabine in advanced non-small cell lung cancer.

New active agents are needed to develop effective systemic therapy against Stage IIIB-IV non-small cell lung cancer (NSCLC). The aim of the present study was to assess the efficacy and toxicity of gemcitabine, a novel nucleoside analogue with significant preclinical activity, as a single-agent therapy. Forty-three patients with previously untreated Stage IIIB-IV NSCLC were included. Gemcitabine was administered intravenously over 30 min on Days 1, 8 and 15 of each 28-day cycle at a dose of 1250 mg m-2. Thirty-seven patients were evaluable for response. There were seven partial responses giving an overall response rate of 19% (95% confidence interval 8-35%). Median duration of response was 6 months. One-year survival and median survival for all patients were 33% and 8 months, respectively. Toxicity of the treatment was mild. World Health Organization (WHO) Grade 3-4 leukopenia was detected in 11% of the patients. Mild (WHO Grade 1-2) nausea was the most frequent subjective side-effect with a rate of 82%. Mild rash and peripheral oedema were typical side-effects of gemcitabine with rates of 19 and 9%, respectively. In conclusion, single-agent gemcitabine is an active and well-tolerated treatment for Stage IIIB-IV NSCLC patients.

Investigative bronchoscopy and endobronchial biopsy is well tolerated in hyperreactive asthma patients.

The tolerability of 57 non-smoking asthma patients inhaling salbutamol as needed (ATS, 18--60 years, 60% < or = FEV1 < or =100%, PD15FEV1 <0.4 mg histamine) to fibreoptic bronchoscopy (FOB) and endobronchial biopsy was studied. The FOB was done in local Lignocaine anaesthesia, and from five to eight biopsy specimens were taken from the bronchial mucosa of the right lung. The tolerability was measured as cough/bronchospasm during the procedure (from 0 = normal to 3 = interrupted procedure), success of the procedure, and untoward occurrences. Twenty-seven of the 57 patients (48%) had no cough or bronchospasm during the FOB (score 0). Few coughs of no importance (score 1) were documented in 23 patients (40%). Seven patients (12%) had cough and/or bronchospasm interfering with the FOB procedure (score 2). The FOB procedure was not interrupted because of cough and/or bronchospasm (score 3) in any patient. Scores of cough and/or bronchospasm diminished progressively with the increase of PD15FEV1 histamine. The success of the procedure was 100%. Two patients had untoward medical occurrences requiring additional rescue medication (3.5%). In conclusion, we found that hyperreactivity predicts cough and/or bronchospasm during the FOB. Cough and/or bronchospasm are frequently observed during the bronchial procedure, but they are mild and of minor clinical importance. An investigational endobronchial procedure can be successfully performed in mildly or moderately obstructive asthmatic patients, even in cases with severe bronchial hyperreactivity.

Airway inflammation and basement membrane tenascin in newly diagnosed atopic and nonatopic asthma.

Previous studies have shown both similar and distinct inflammatory changes in atopic and nonatopic asthma. This study was set to investigate the bronchial inflammatory cell infiltrate and subepithelial basement membrane (BM) tenascin deposition in subjects with newly diagnosed asthma and bronchial hyperresponsiveness (BHR). Seventy-nine asthmatic subjects (age 18-60 years) were recruited and 58 were atopic according to skin prick testing. The patients recorded asthma symptoms and peak flow measurements for 14 days. Lung function and BHR were measured by spirometry and histamine challenge. Serum eosinophil cationic protein (ECP) and blood eosinophils were assessed. Fiberoptic bronchoscopy was performed to obtain bronchial biopsies. Serum ECP was higher in the atopic group but eosinophil counts did not differ. There were no differences in inflammatory cells studied (activated eosinophils, T-lymphocytes, mast cells or macrophages) between nonatopic and atopic subjects. BM tenascin layer was significantly thicker in atopic compared with nonatopic subjects (7.6 vs 6.3 microm, P = 0.007). The thickness of tenascin correlated with eosinophil, T-lymphocyte, and macrophage counts, as well as with IL-4-positive cell counts and the correlation was seen only in atopic asthmatics. These findings suggest that inflammatory cells may have a regulatory role in tenascin expression in atopic asthma.

Vitamin E and selenium supplementation in geriatric patients : A double-blind preliminary clinical trial.

Sodium selenate (8 mg/d), organic selenium (50 µg/d) andd-alpha-tocopherol acetate (400 mg/d) were administered for 1 yr to 15 geriatric patients. Fifteen comparable controls received placebo. The mean age of both groups was 76 yr. The patients were assessed every 2 mo independently by two nurses using the Sandoz Clinical Assessment Geriatric-scale (SCAG). The propositae, showed significant improvement in the following SCAG parameters: depression, anxiety, self-care, mental alertness, emotional lability, motivation and initiative, hostility, interest in the environment, fatigue, anorexia, and general impression. A distinct improvement of the general condition was noticed after only 2 mo and the improvement continued up to the end of the 1-yr study period. The high selenium and vitamin E doses were well tolerated; there were no side effects whatsoever.

Anti-oxidant supplementation decreases TBA reactants in serum of elderly.

An "anti-oxidant cocktail" consisting of betacarotene, vitamins B6, C, E, zinc, and selenium or corresponding placebos were given for one y as daily dietary supplements to 45 elderly residents of a nursing home. Initially, the serum TBA reactant levels were higher (2.7 +/- 0.7 mumol/L) than those of an ad hoc control group of healthy younger adults (2.3 +/- 0.6 mumol/L), p less than 0.01. After three mo supplementation, the levels among the verum elderly had decreased to 2.2 +/- 0.6 mumol/L, and they remained at this lower level until the end of the study period, whereas the placebo group showed no change. A significant inverse correlation (r = -0.428, p less than 0.01) existed between the concentrations of serum TBA reactants and whole blood selenium (B-Se), but only B-Se levels above 200 micrograms/L were associated with a decrease in serum lipid peroxides. Serum alpha-tocopherol concentration also correlated inversely with serum TBA reactants but this correlation (r = -0.273, p less than 0.76) was not as strong as that of B-Se. Deficient vitamin B6 status, in biochemical terms, was observed in 25% of the elderly; a daily supplement of 2 mg B6 fully cured all cases of deficiency. The verum group improved slightly in several psychological tests, whereas subjects on placebo remained unchanged or deteriorated during the follow-up period. Clinical amelioration among the verum subjects was reported by the nurses; no toxic side effects were reported. In conclusion, the elderly benefited biochemically and clinically of dietary antioxidant supplements.

Vitamin B6 status of Finnish elderly. Comparison with Dutch younger adults and elderly. The effect of supplementation.

About 25% of Finnish and Dutch elderly appeared to be more or less deficient in vitamin B6 as compared to younger adults. Deficiency was observed at the cellular (PLP, EGOT and alpha-EGOT) as well as at the plasma level (PLP). The benefit of a one-year daily supplementation with 2 mg of pyridoxine-HCl was investigated at the biochemical and psychological level as compared to a placebo group. After one year, none of the supplemented elderly was deficient in biochemical terms. At the psychological level and at the level of general well-being, the elderly supplemented with vitamin B6 showed slight improvements. However, for the psychological variables significant correlations with the vitamin B6 parameters were not observed. Plasma fatty acids (e.g. gamma-linolenic acid) showed no correlation with the vitamin B6 status.

Control of early Aspergillus mortality after lung transplantation: outcome and risk factors.

Historic treatment strategies in our institute had resulted in 10% Aspergillus mortality within the first posttransplant year. Despite nebulized amphotericin B (nAmB) prophylaxis, a significant incidence of Aspergillus infection, usually with poor outcome, is still reported. The aim of this single-center retrospective study was to evaluate the outcomes of patients receiving either standard nAmB or additional systemic caspofungin prophylaxis for selected high-risk patients. We also tried to define independent risk factors for either fungal infection or death. We followed 76 consecutive lung transplant patients performed at our center between 2002 and 2010 from the day of transplantation. The median follow-up duration was 953 days (2.6 years; range, 16-2,751 days). The endpoints were postoperative Aspergillus colonization or disease or death due to any cause. All patients received either nAmB deoxycholate (nAmBd, 15 patients) or nAmB lipid complex (nAmBLC, 61 patients). In addition, 33 patients also received short-term caspofungin prophylaxis. The overall cumulative mortality during the entire follow up was 14.5%. No clinically confirmed invasive Aspergillus infections (IPA) occurred during the first 2 postoperative years; however, there was 1 possible and 1 probable IPA. One patient died of bronchiolitis obliterans and IPA at 2 years 3 months. Twelve patients showed transient Aspergillus colonization. The antifungal prophylactic regimens were well tolerated. The risk factors for death were age >55 years and postoperative Aspergillus detection (P = .011 and P = .015, respectively). Preoperative Aspergillus colonization/disease was not a risk factor for death (P = 1.000). The strongest predictor of death was age >55 years, due to the elder probably being more susceptible to the adverse effects of immunosuppressants. Postoperative detection of Aspergillus still seems to be an indicator of a poorer outcome. Preoperative Aspergillus colonization is not necessarily a threat with prompt institution of antifungal prophylaxis.