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.
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.
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 In 3 patients (2.9%), n-LAB was withdrawn due to bronchospasm in 2 and nausea in 1.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).
At the dose and frequency described, n-LAB seems effective, safe, and convenient for the prevention of Aspergillus infection in lung transplant patients.
Inhaled tobramycin treatment has been associated with nephrotoxicity in some case reports, but limited data are available about serum levels and its possible systemic absorption in lung transplant ...recipients (LTR). We conducted a single-center, observational and retrospective study of all adult (>18 years old) LTR treated with inhaled tobramycin for at least 3 days between June 2019 and February 2022. Trough serum levels were collected and >2 μg/mL was considered a high drug level. The primary outcome assessed the presence of detectable trough levels, while the secondary outcome focused on the occurrence of acute kidney injury (AKI) in individuals with detectable trough levels. Thirty-four patients, with a median age of 60 years, were enrolled. The primary indications for treatment were donor bronchial aspirate bacterial isolation (18 patients) and tracheobronchitis (15 patients). In total, 28 patients (82%) exhibited detectable serum levels, with 9 (26%) presenting high levels (>2 μg/mL). Furthermore, 9 patients (26%) developed acute kidney injury during the treatment course. Median trough tobramycin levels were significantly elevated in invasively mechanically ventilated patients compared to non-ventilated individuals (2.5 μg/mL vs. 0.48 μg/mL) (
< 0.001). Inhaled tobramycin administration in LTRs, particularly in those requiring invasive mechanical ventilation, may result in substantial systemic absorption.
Isavuconazole (ISA) is an alternative treatment for Aspergillus spp. and other fungal infections, but evidence regarding its use in solid organ transplant recipients (SOTR) is scarce. All SOTR who ...received ISA for treatment of a fungal infection (FI) at our center from December 2017 to January 2021 were included. The duration of the treatment depended on the type of infection. All patients were followed up to 3 months after treatment. Fifty-three SOTR were included, and the majority (44, 83%) were lung transplant recipients. The most frequently treated FI was tracheobronchitis (25, 46.3%). Aspergillus spp. (43, 81.1%); specially A. flavus (16, 37.2%) and A. fumigatus (12, 27.9%), was the most frequent etiology. Other filamentous fungi including one mucormycosis, and four yeast infections were treated. The median duration of treatment was 81 days (IQR 15-197). Mild gamma-glutamyltransferase elevation was the most frequent adverse event (34%). ISA was prematurely discontinued in six patients (11.3%) due to mild hepatotoxicity (2), fatigue (2), gastrointestinal intolerance (1) and myopathy (1). The mean tacrolimus dose decrease was 30% after starting ISA. Seven patients received ISA with mTOR inhibitors with good tolerability. Two patients developed breakthrough FI (3.8%). Among patients who completed the treatment, 27 (50.9%) showed clinical cure and 15 (34.1%) presented fungal persistence. Three patients (6%) died while on ISA due to FI. ISA was well tolerated and appeared to be an effective treatment for FI in SOTR.
We describe 53 solid organ transplant recipients treated with isavuconazole for fungal infections. Because its use in clinical practice, there is scarce data of its use in solid organ transplant recipients, where interactions with calcineurin inhibitors and mTOR and adverse drug events have limited the use of other triazoles. To the best of our knowledge, this is the first article describing the safety regarding adverse events and drug interactions of isavuconazole for the treatment of fungal infections in a cohort of solid organ transplant recipients. Also, although this is a noncomparative study, we report some real world effectivity data of these patients, including treatment of non-Aspergillus fungal infections.
We analyzed the effect of respiratory swings on interpreting intravascular pulmonary vascular pressures (PVPs) in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) ...candidates for lung transplantation (LTx) and the role of the alterations in pulmonary function tests on the dynamic respiratory variations. Twenty‐eight consecutive patients were included. All patients underwent a complete hemodynamic study (right atrial, mean pulmonary arterial, and pulmonary arterial occlusion pressures RAP, mPAP, and PAOP‐) and pulmonary function testing (force vital capacity FVC, forced expiratory volume in the first second FEV1, and residual volume RV). A subgroup of 10 patients underwent simultaneous esophageal pressure (PES). All hemodynamic parameters and PES were collected during apnea after an unforced expiration (ee) and during spontaneous breathing averaging five respiratory cycles (mrc). The respiratory swing (osc) was estimated as the difference between maximum–minimum values of pressures during the respiratory cycle. Intravascular RAPee, mPAPee, and PAOPee were higher than mrc values (p < 0.05), leading to 11% of pulmonary hypertension (PH) misdiagnosis and 37% of postcapillary PH misclassification. PAOPosc of COPD was higher than ILD patients and RAPosc (p < 0.05). Only PAOPosc correlated with FVC, FEV1, and RV (p < 0.05). ILD PESmrc was lower than COPD (p < 0.05), and it was associated with a significantly higher transmural than intravascular RAPmrc, mPAPmrc, and PAOPmrc. PESmrc was significantly correlated with FVC. Transmural mPAPmrc and PAOPmrc readings determined around 20% of reclassification of the patients compared to ee measurements. Candidates for LTx showed large respiratory swings in PVP, which were correlated with pulmonary function alterations. mrc PVP would be more closely approximated to the true transmural PVP leading to PH reclassification. Adjusting PVP for PES should be considered in COPD and ILD candidates of LTx with severe alterations in pulmonary functional tests and suspicion of a PESmrc far from 0. PES respiratory swings could be different in ILD to COPD patients.
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.
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.
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.
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.
Prophylaxis with inhaled liposomal amphotericin B has proven to be safe and effective for preventing infection due to Aspergillus spp in lung transplant recipients. However, the liposome contains a ...large quantity of phospholipids, and inhalation of these substances could potentially change the composition of pulmonary surfactant. The aim of this study was to determine the lipid composition of pulmonary surfactant in patients receiving inhaled liposomal amphotericin B prophylaxis.
A prospective, open, controlled multicenter study was conducted in 2 groups: 19 lung transplant recipients who received regular prophylaxis with inhaled amphotericin B (study group) and 19 recipients who did not receive inhaled prophylaxis (control group). From both groups, 15 ml of the third aliquot of bronchoalveolar lavage fluid was obtained and phospholipid content determined in the active fraction of surfactant (large aggregates) and in the inactive fraction (small aggregates). Large aggregate cholesterol content was also determined.
Patient demographic data and characteristics were similar in the 2 groups. No between-group differences in median phospholipid content were found for large aggregates (study group, 0.4 range, 0.18-1.9 μmol vs controls, 0.36 range 2.15-0.12 μmol; p = 0.69) or small aggregates (study group, 0.23 range, 0.1-0.58 μmol vs controls, 0.29 range, 0.18-0.65 μmol; p = 0.33). The small aggregate-to-large aggregate phospholipid ratio, commonly used as a marker of alveolar injury, showed no differences between the groups (study group, 0.56 vs controls, 0.69; p = 0.28). Nor were there differences in the cholesterol content of large aggregates (study group, 0.04 μmol range 0.01-0.1 vs controls, 0.04 μmol range 0.02-0.27); p = 0.13).
These results seem to indicate that prophylaxis with nebulized liposomal amphotericin B does not cause changes in the lipid content of pulmonary surfactant.
The relationship between community-acquired respiratory viruses (CARVs) and chronic lung allograft dysfunction (CLAD) in lung transplant recipients is still controversial.
We performed a prospective ...cohort study (2009-2014) in all consecutive adult patients (≥18 years) undergoing lung transplantation in the Hospital Universitari Vall d'Hebron (Barcelona, Spain). We systematically collected nasopharyngeal swabs from asymptomatic patients during seasonal changes, from patients with upper respiratory tract infectious disease, lower respiratory tract infectious disease (LRTID), or acute rejection. Nasopharyngeal swabs were analyzed by multiplex polymerase chain reaction. Primary outcome was to evaluate the potential association of CARVs and development of CLAD. Time-dependent Cox regression models were performed to identify the independent risk factors for CLAD.
Overall, 98 patients (67 bilateral lung transplant recipients; 63.3% male; mean age, 49.9 years) were included. Mean postoperative follow-up was 3.4 years (interquartile range IQR, 2.5-4.0 years). Thirty-eight lung transplant recipients (38.8%) developed CLAD, in a median time of 20.4 months (IQR, 12-30.4 months). In time-controlled multivariate analysis, CARV-LRTID (hazard ratio HR, 3.00 95% confidence interval {CI}, 1.52-5.91; P = .002), acute rejection (HR, 2.97 95% CI, 1.51-5.83; P = .002), and cytomegalovirus pneumonitis (HR, 3.76 95% CI, 1.23-11.49; P = .02) were independent risk factors associated with developing CLAD.
Lung transplant recipients with CARVs in the lower respiratory tract are at increased risk to develop CLAD.
This study describes the clinical presentation, treatment, and outcomes of SARS‐CoV‐2 infection in lung transplant recipients (LTRs). This is a multicenter, retrospective study of all adult LTRs with ...confirmed SARS‐CoV‐2 infection from March 4 until April 28, 2020 in six Spanish reference hospitals for lung transplantation. Clinical and radiological data, treatment characteristics, and outcomes were reviewed. Forty‐four cases were identified in that period. The median time from transplantation was 4.2 (interquartile range: 1.11–7.3) years. Chest radiography showed acute parenchymal abnormalities in 32 (73%) cases. Hydroxychloroquine was prescribed in 41 (93%), lopinavir/ritonavir (LPV/r) in 14 (32%), and tocilizumab in 19 (43%) patients. There was a strong interaction between tacrolimus and LPV/r in all cases. Thirty‐seven (84%) patients required some degree of respiratory support and/or oxygen therapy, and 13 (30%) were admitted to intermediate or intensive critical care units. Seventeen (39%) patients had died and 20 (45%) had been discharged at the time of the last follow‐up. Deceased patients had a worse respiratory status and chest X‐ray on admission and presented with higher D‐dimer, interleukin‐6, and lactate dehydrogenase levels. In this multicenter LTR cohort, SARS‐CoV‐2 presented with high mortality. Additionally, the severity of disease on presentation predicted subsequent mortality.
A national cohort of lung transplant recipients with SARS‐CoV‐2 infection shows high severity and mortality.
Abstract
Monitoring cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) is useful in predicting late-onset CMV infection after solid organ transplantation, but few data have been reported ...after lung transplantation (LT). CMV CMI against 2 CMV antigens (IE-1, pp65) was evaluated in 60 seropositive LT at 6-month prophylaxis withdrawal. LT with late-onset CMV infection showed significantly lower (IE-1)CMV CMI than patients without (P = .045), and was more evident in patients developing high viral loads (P = .010). (IE-1)CMV CMI independently predicted high first late-onset viral replication (odds ratio, 4.358; 95% confidence interval, 1.043–18.215). CMV-specific CMI may be useful in CMV preventive strategies after LT.
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isolates cause infections with high mortality in lung transplant recipients. Treatment is challenging due to antimicrobial resistance. We describe two cases of
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tracheobronchitis in lung ...transplant recipients successfully treated with nebulized micafungin. This antifungal was well tolerated and achieved high concentrations in epithelial lining fluid up to 14 h after nebulization without significant plasma concentrations. Nebulized micafungin may be a safe and effective option for the treatment of fungal tracheobronchitis.
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