Withdrawal of dornase alfa increases ventilation inhomogeneity in children with cystic fibrosis

BackgroundThe lung clearance index (LCI) is increasingly used as an outcome in clinical trials of patients with mild cystic fibrosis (CF) lung disease. Yet, understanding the impact of standard CF respiratory therapy on LCI is needed. We assessed to what degree withdrawal of nebulised dornase alfa affected LCI in school-age children with CF not receiving CFTR modulators or hydrator therapy.MethodsA single-centre, randomised, controlled, parallel group study to determine effects of one month's withdrawal of nebulised dornase alfa (intervention) in 5-18 years old children with CF. Remaining chronic maintenance therapy stayed unchanged. Outcome measures were assessed at two visits one month apart. Primary outcome was absolute change in LCI. Secondary outcomes were FEV₁, FEF_25–75 and CF Questionnaire-revised (CFQ-R) respiratory symptom score. Possible harmful effects were assessed by comparing the occurrence of pulmonary exacerbations between groups.ResultsTwenty-eight children (median age 10.4 [interquartile range: 7.6; 13.5] years) with CF received standard care (n = 14) or intervention (n = 14). Compared with the control group, LCI increased (worsened) 1.74 (95% confidence interval: 0.62; 2.86) during withdrawal of dornase alfa, while FEV₁ (-6.8% predicted) and FEF_25–75 (-13.1% predicted) decreased significantly. Change in CFQ-R respiratory symptom score and the occurrence of pulmonary exacerbations did not differ significantly between groups.ConclusionsOne month's withdrawal of dornase alfa caused increasing ventilation inhomogeneity and deteriorating FEV₁ and FEF_25–75 in school-age children with mild CF. Hence, adherence to dornase alfa optimally needs to be addressed when using LCI and spirometric parameters as endpoints, even in short-term clinical trials.     

Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain‐death induced immunological injury post–lung transplant

Donor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia‐reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post‐LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post‐LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle‐treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post‐LTx in the context of donor BD.     

Risk factors and outcomes of vocal cord paralysis after lung transplantation – a retrospective cohort study

Vocal cord paralysis (VCP) may complicate thoracic surgery and is associated with increased morbidity and mortality. Among lung transplant (LTx) recipients, chronic pulmonary aspiration can contribute to chronic allograft dysfunction (CLAD). We herein assessed the unknown incidence and clinical impact of VCP in a large LTx cohort. All first‐time bilateral LTx recipients, transplanted between January 2010 and June 2015 were included in a single‐centre retrospective analysis. Bronchoscopy reports were assessed for VCP. Patients exhibiting VCP were compared to propensity score‐matched negative controls regarding CLAD onset and graft survival and secondary end‐points, including inpatient duration and complications; lower respiratory tract infections (LRTI) within 24 months. In total, 583/713 (82%) patients were included in the analysis. A total of 52 (8.9%) exhibited VCP, which was transient in 34/52 patients (65%), recovering after median 6 months (IQR 2–12). Compared to 268 controls, 3‐year graft survival and CLAD‐free survival were non‐inferior in VCP [HR 0.74 (95% CI 0.35–1.57), and HR 0.74 (95% CI 0.39–1.41)] respectively. Duration of hospitalization was similar and no differences in LRTI rates or airway complications were observed. Lower pre‐Tx BMI increased risk for VCP [HR 0.88 (95% CI 0.79–0.99)]. Overall, VCP did not adversely affect graft and CLAD‐free survival and secondary outcomes including LRTIs and hospitalizations.     

Multiple breath washout in pediatric patients after lung transplantation

Forced expiratory volume in 1 second (FEV₁) from spirometry is the most commonly used parameter to detect early allograft dysfunction after lung transplantation (LTx). There are concerns regarding its sensitivity. Nitrogen‐multiple breath washout (N₂‐MBW) is sensitive at detecting early global (lung clearance index [LCI]) and acinar (S_acin) airway inhomogeneity. We investigated whether N₂‐MBW indices indicate small airways pathology after LTx in children with stable spirometry. Thirty‐seven children without bronchiolitis obliterans syndrome [BOS] at a median of 1.6 (0.6‐3.0) years after LTx underwent N₂‐MBW and spirometry, 28 of those on 2 occasions (≤6 months apart) during clinically stable periods. Additional longitudinal data (11 and 8 measurements, respectively) are provided from 2 patients with BOS. In patients without BOS, LCI and S_acin were significantly elevated compared with healthy controls. LCI was abnormal at the 2 test occasions in 81% and 71% of patients, respectively, compared with 30% and 39% of patients with abnormal FEV₁/forced vital capacity (FVC). Correlations of LCI with FEV₁/FVC (r = 0.1, P = .4) and FEV₁ (r = ?0.1, P = .6) were poor. N₂‐MBW represents a sensitive and reproducible tool for the early detection of airways pathology in stable transplant recipients. Moreover, indices were highly elevated in both patients with BOS. Spirometry and LCI showed poor correlation, indicating distinct and complementary physiologic measures.     

Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: A double-blind placebo-controlled cross-over trial

BackgroundChronic rhinosinusitis significantly impairs CF patients' quality of life and overall health. The Pari-Sinus™ device delivers vibrating aerosol effectively to paranasal sinuses. After a small pilot study to assess sinonasal inhalation of dornase alfa and placebo (isotonic saline) on potential sinonasal outcome measures, we present the subsequent prospective double-blind placebo-controlled crossover-trial.Methods23 CF patients were randomised to inhale either dornase alfa or isotonic saline for 28 days with the Pari-Sinus™ and after 28 days (wash-out) crossed over to the alternative treatment. The primary outcome parameter was primary nasal symptom score in the disease-specific quality of life Sino-Nasal Outcome-Test-20 (SNOT-20: nasal obstruction/sneezing/runny nose/thick nasal discharge/reduced smelling).ResultsPrimary nasal symptoms improved significantly with dornase alfa compared with no treatment, while small improvements with isotonic saline did not reach significance. SNOT-20 overall scores improved significantly after dornase alfa compared with isotonic saline (p = 0.017). Additionally, sinonasal dornase alfa but not isotonic saline significantly improved pulmonary function (FEF_75–25: p = 0.021).ConclusionVibrating sinonasal inhalation of dornase alfa reduces rhinosinusitis symptoms in CF.     

Neutropenia in kidney and liver transplant recipients: Risk factors and outcomes

No studies have directly compared the key characteristics and outcomes of kidney (KTx) and liver transplantation (LTx) recipients with neutropenia. In this single‐center, retrospective, cohort study, we enrolled all adult patients who received a KTx or LTx between 2000 and 2011. Neutropenia was defined as 2 consecutive absolute neutrophil count (ANC) values <1500/mm³ in patients without preexisting neutropenia. The first neutropenia episode occurring during the first year post‐transplantation was analyzed. A total of 663 patients with KTx and 354 patients with LTx met the inclusion criteria. Incidence of neutropenia was 20% in KTx and 38% in LTx, respectively. High‐risk CMV status and valganciclovir (VGCV) use were significant predictors of neutropenia for KTx recipients, but only VGCV use vs nonuse in LTx recipients. Neutropenia was associated with worse survival in KTx recipients (adjusted HR 1.95, 95% CI 1.18‐3.22, P<.01), but not in LTx recipients (adjusted HR 0.75, 95% CI 0.52‐1.10, P=.15). Sixteen acute rejection episodes were associated with preceding neutropenia in KTx recipients (HR 1.77, 95% CI 1.16‐2.68, P=.007) and 24 acute rejection episodes in LTx recipients (HR 1.41, 95% CI 0.97‐2.04, P=.07). Incidence of infection was similar in patients with and without neutropenia among KTx and LTx recipients.     

Improving medication adherence and outcomes in adult kidney transplant patients using a personal systems approach: SystemCHANGE™ results of the MAGIC randomized clinical trial

This study determined if a SystemCHANGE? intervention was more efficacious than attention control in increasing immunosuppressive medication adherence and improving outcomes in adult kidney transplant recipients during a 6‐month intervention phase and subsequent 6‐month (no intervention) maintenance phase. The SystemCHANGE? intervention taught patients to use person‐level quality improvement strategies to link adherence to established daily routines, environmental cues, and supportive people. Eighty‐nine patients (average age 51.8 years, 58% male, 61% African American) completed the 6‐month intervention phase. Using an intent‐to‐treat analysis, at 6 months, medication adherence for SystemCHANGE? (median 0.91, IQR 0.76‐0.96) and attention control (median 0.67, IQR 0.52‐0.72) patients differed markedly (difference in medians 0.24, 95% CI 0.13‐0.30, P < .001). At the conclusion of the subsequent 6‐month maintenance phase, the gap between medication adherence for SystemCHANGE? (median 0.77, IQR 0.56‐0.94) and attention control (median 0.60, IQR 0.44‐0.73) patients remained large (difference in medians 0.17, 95% CI 0.06‐0.33, P = .004). SystemCHANGE? patients evidenced lower mean creatinine and BUN at 12 months and more infections at 6 and 12 months. This first fully powered RCT testing SystemCHANGE? to improve and maintain medication adherence in kidney transplant recipients demonstrated large, clinically meaningful improvements in medication adherence. Clinical Trial Registration: NCT02416479.     

Calcineurin Inhibitor–Based Maintenance Immunosuppression in Lung Transplant Recipients: Optimal Serum Levels for Managing Acute Rejection and Renal Function

BackgroundAlthough effective for curtailing alloimmune responses, calcineurin inhibitors (CNIs) have an adverse-effect profile that includes nephrotoxicity. In lung transplant (LTx) recipients, the optimal serum levels of the CNI tacrolimus necessary to control alloimmune responses and minimize nephrotoxicity are unknown.MethodsThis retrospective, single-center study reviewed tacrolimus whole blood trough levels (BTLs), grades of acute cellular rejection (ACR), acute rejection scores, and creatinine clearance (CrCl) obtained in LTx recipients within the first year after their transplant procedure. Comparisons were made between the first 90 days post LTx (when tacrolimus BTLs were maintained >10 µg/L) and the remainder of the post-LTX year (when BTLs were <10 µg/L).ResultsDespite tacrolimus mean BTLs being higher during the first 90 days post LTx compared with the remainder of the first post-LTx year (10.4 ± 0.3 µg/L vs 9.5 ± 0.3 µg/L, P < .0001) there was no association with lower grades of ACR (P = .24). The intensity of ACR (as determined by acute rejection scores) did not correlate with tacrolimus mean BTLs at any time during the first posttransplant year (P = .79). During the first 90 days post LTx there was a significant decline in CrCl and a correlation between increasing tacrolimus mean BTLs and declining CrCl (r = −0.26, P = .03); a correlation that was not observed during the remainder of the year (r = −0.09, P = .52).ConclusionsIn LTx recipients, maintaining BTLs of the CNI tacrolimus >10µg/L did not result in superior control of acute rejection responses but was associated with declining renal function.     

Epidemiology and Outcomes of Deep Surgical Site Infections Following Lung Transplantation

We conducted a retrospective study of deep surgical site infections (SSIs) among consecutive patients who underwent lung transplantation (LTx) at a single center from 2006 through 2010. Thirty‐one patients (5%) developed SSIs at median 25 days after LTx. Empyema was most common (42%), followed by surgical wound infections (29%), mediastinitis (16%), sternal osteomyelitis (6%), and pericarditis (6%). Pathogens included Gram‐positive bacteria (41%), Gram‐negative bacteria (41%), fungi (10%) and Mycobacterium abscessus, Mycoplasma hominis and Lactobacillus sp. (one each). Twenty‐three percent of SSIs were due to pathogens colonizing recipients' native lungs at time of LTx, suggesting surgical seeding as a source. Patient‐related independent risk factors for SSIs were diabetes and prior cardiothoracic surgery; procedure‐related independent risk factors were LTx from a female donor, prolonged ischemic time and number of perioperative red blood cell transfusions. Mediastinitis and sternal infections were not observed among patients undergoing minimally invasive LTx. SSIs were associated with 35% mortality at 1 year post‐LTx. Lengths of stay and mortality in‐hospital and at 6 months and 1 year were significantly greater for patients with SSIs other than empyema. In conclusion, deep SSIs were uncommon, but important complications in LTx recipients because of their diverse microbiology and association with increased mortality.     

Underweight and obesity increase the risk of mortality after lung transplantation: a systematic review and meta‐analysis

Many studies have found an association between abnormal body mass index (BMI) and poor outcomes among lung transplant recipients. We performed a systematic review and meta‐analysis to identify outcomes associated with an abnormal pretransplant BMI after lung transplantation (LTx). The MEDLINE and EMBASE databases were searched from inception to May 2015 with focus on original observational studies with post‐transplant survival data in candidates with abnormal BMI (underweight, overweight, or obese). We performed meta‐analyses examining survival and primary graft dysfunction after LTx. We identified 866 citations; 13 observational cohort studies involving 40 742 participants met our inclusion criteria for systematic review. Seven of the 13 were included in the meta‐analysis. There was a significant risk of mortality after LTx in candidates with underweight and obesity (underweight versus normal, relative risk [RR] 1.36, 95% confidence interval [CI] 1.11–1.66, I² = 0%; obesity vs. normal, RR 1.90, 95% CI 1.45–2.56, I² = 0%; overweight vs. normal, RR 1.36, 95% CI 1.11–1.66, I² = 0). There was also a significant risk of primary graft dysfunction in obese (RR 1.92, 95% CI 1.39–2.65, I² = 0%) and overweight (RR 1.72, 95% CI, 1.32–2.24, I² = 0%) candidates. Lung transplant candidates who are underweight or obese have a higher risk of post‐transplant mortality than recipients with a normal BMI.     

Evaluation of adherence and tolerability of prolonged‐release tacrolimus (Advagraf™) in kidney transplant patients in Germany: A multicenter,noninterventional study

This study assessed adherence to prolonged‐release tacrolimus (PR‐T)‐based immunosuppression during routine maintenance of renal transplant recipients in Germany. Patients had received PR‐T for ≥1 month at inclusion. Data were collected during four visits (V): baseline (V1), 6 (V2), 12 (V3), and 18 (V4) months. Composite primary endpoint: nonadherence at V4, defined as self‐reported nonadherence on the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS^©), investigator‐rated nonadherence, and/or V4 tacrolimus trough level outside a predefined range. Secondary endpoints: individual BAASIS items, incidence of rejection, kidney function, and safety. Overall, 153 adult kidney recipients (mean [standard deviation] time post‐transplant 5.8 [4.6] years) were included. Nonadherence was high at V4 (67.7% [95% confidence interval 58.9%, 75.6%]). Medication‐taking adherence was 86.9% and 91.3% at V1 and V4, respectively; adherence to timing of medication intake was 58.2% and 58.3%, with little evidence of missed doses/drug holidays. Investigators rated adherence “good” in 85.6% of patients (V4). Two (1.3%) patients had acute rejection episodes. Kidney function remained stable (mean creatinine clearance, V1: 62.1 mL/min; V4: 65.3 mL/min). Investigators rated effectiveness of PR‐T as “very good”/“good” in 91.5% of patients. Most patients (94.7%) found PR‐T dosing more convenient than immediate‐release tacrolimus. PR‐T was well tolerated with high medication persistence.     

Post‐transplant lymphoproliferative disease in lung transplantation: A nested case‐control study

Post‐transplant lymphoproliferative disorder (PTLD) may compromise long‐term outcome of lung transplant (LTx) recipients. A case‐control study was performed, comparing LTx recipients with PTLD (n=31) to matched recipients without PTLD (Controls, n=62). Risk factors for PTLD and post‐transplant outcomes were assessed. PTLD prevalence was 3.9%, time to PTLD 323 (166‐1132) days; and 54.8% had early‐onset PTLD versus 45.2% late‐onset PTLD. At LTx, more Epstein‐Barr virus (EBV)‐seronegative patients were present in PTLD (42%) compared to Controls (5%) (P<.0001); most of whom had undergone EBV seroconversion upon PTLD diagnosis. EBV viral load was higher in PTLD versus Controls (P<.0001). Overall, lower hemoglobin and higher C‐reactive protein levels were present in PTLD versus Controls (P<.0001). EBV status at LTx (P=.0073) and EBV viral load at PTLD (P=.0002) were the most important risk determinates for later PTLD. Patients with PTLD demonstrated shorter time to onset of chronic lung allograft dysfunction (CLAD) (P=.0006) and poorer 5‐year survival post‐LTx (66.6% versus 91.5%), resulting in worse CLAD‐free survival (HR 2.127, 95%CI 1.006‐4.500; P=.0483) and overall survival (HR 3.297 95%CI 1.473‐7.382; P=.0037) compared to Controls. Late‐onset PTLD had worse survival compared to early‐onset PTLD (P=.021). Primary EBV infection is a risk for PTLD; which is associated with worse long‐term outcome post‐LTx.     

Hypogammaglobulinemia in the early period after liver transplantation in children

Data, on the kinetic and serum levels of immunoglobulins in the immediate post‐liver transplantation (LTx) period, are sparse with existing studies limited to adults or case reports of children. The aim of this study is to describe the phenomenon of hypogammaglobulinemia (HGG) in the immediate post‐transplantation period among children undergoing LTx. A retrospective 10‐yr chart review was conducted of all children who underwent LTx at a fourth‐level pediatric medical center. Fifty‐seven, of the 76 children who underwent LTx, were included in the study. Seventeen (29.8%) (mean age, 6.8 ± 5.2 yr) had HGG (11‐IgG, 1‐IgG+IgA, 1‐IgG+IgM, 4‐IgG+IgA+IgM), detected at 2 to 25 d after transplantation. Abdominal fluid was drained for 5 to 42 d; the amount drained until detection of HGG measured 27–668 mL/kg. HGG was associated with increased infection rate 0.9 episodes/patient vs. 0.17 episodes/patient (p < 0.01) in children without detected HGG. In conclusion, HGG is not rare in the immediate post‐LTx period in children, and it may place patients at increased risk of infection. Further studies are needed to delineate the rate of occurrence, risk factors, and clinical implications of hypogammaglobulinemia in this patient population.     

Hospital admissions and emergency department visits among kidney transplant recipients

Reducing acute care utilization is a means of improving long‐term patient outcomes. We sought to assess high inpatient (IP) admission and standalone emergency department (ED) utilization within a 9‐month period post‐kidney transplantation and to identify mutable factors to reduce utilization. In this ten‐year retrospective study, 1599 adult kidney transplant recipients were identified. A previous transplant, graft loss, or death within 3 months post‐transplantation excluded 319 patients. Comprehensive resource utilization data were obtained from a statewide database. Those with ≥2 IP admissions or standalone ED visits 4‐12 months post‐transplantation were classified as high utilizers. Multivariable logistic regression models were used for examining associations of predictors with high IP or ED utilization. Of 1280 kidney recipients, 209 and 183 were categorized as IP and ED high utilizers, respectively. Factors significantly associated with high IP utilization included valvular disease, body mass index ≥35, and IP or ED use <3 months post‐transplantation; while factors associated with high ED utilization included IP or ED use <3 months post‐transplantation, younger age, female, smoker, congestive heart failure, depression, and IP or ED use 1 year pre‐transplantation. Inpatient and standalone ED utilization within a 9‐month period after kidney transplantation is high and associated with sociodemographic factors, mutable comorbidities, and healthcare utilization.     

Antifungal Prophylaxis in Lung Transplantation—A World‐wide Survey

While variations in antifungal prophylaxis have been previously reported in lung transplant (LTx) recipients, recent clinical practice is unknown. Our aim was to determine current antifungal prophylactic practice in LTx centers world‐wide. One nominated LTx clinician from each active center was invited by e‐mail to participate in a web‐based survey between September 2009 and January 2010. Fifty‐seven percent (58/102) responded. The majority of responses were from medical directors of LTx centers (72.4%), and from the United States (44.8%). Within the first 6 months post‐LTx, most centers (58.6%) employed universal prophylaxis, with 97.1% targeting Aspergillus species. Voriconazole alone, and in combination with inhaled amphotericin B (AmB), were the preferred first‐line agents. Intolerance to side effects of voriconazole (69.2%) was the main reason for switching to alternatives. Beyond 6 months post‐LTx, most (51.8%) did not employ antifungal prophylaxis. Fifteen centers (26.0%) conducted routine antifungal therapeutic drug monitoring during prophylactic period. There are differences in strategies employed between U.S. and European centers. Most respondents indicated a need for antifungal prophylactic guidelines. In comparison to earlier findings, there was a major shift toward prophylaxis with voriconazole and an increased use of echinocandins, posaconazole and inhaled lipid formulation AmB.     

Prolonged Mechanical Ventilation After Lung Transplantation—A Single‐Center Study

This single‐center study examines the incidence, etiology, and outcomes associated with prolonged mechanical ventilation (PMV), defined as time to definite spontaneous ventilation >21 days after double lung transplantation (LTx). A total of 690 LTx recipients between January 2005 and December 2012 were analyzed. PMV was necessary in 95 (13.8%) patients with decreasing incidence during the observation period (p < 0.001). Independent predictors of PMV were renal replacement therapy (odds ratio [OR] 11.13 [95% CI, 5.82–21.29], p < 0.001), anastomotic dehiscence (OR 8.74 [95% CI 2.42–31.58], p = 0.001), autoimmune comorbidity (OR 5.52 [95% CI 1.86–16.41], p = 0.002), and postoperative neurologic complications (OR 5.03 [95% CI 1.98–12.81], p = 0.001), among others. Overall 1‐year survival was 86.0% (90.4% for LTx between 2010 and 2012); it was 60.7% after PMV and 90.0% in controls (p < 0.001). Conditional long‐term outcome among hospital survivors, however, did not differ between the groups (p = 0.78). Multivariate analysis identified renal replacement therapy (hazard ratio [HR] 3.55 [95% CI 2.40–5.25], p < 0.001), post‐LTx extracorporeal membrane oxygenation (HR 3.47 [95% CI 2.06–5.83], p < 0.001), and prolonged inotropic support (HR 1.95 [95% CI 1.39–2.75], p < 0.001), among others, as independent predictors of mortality. In conclusion, PMV complicated 14% of LTx procedures and, although associated with increased in‐hospital mortality, outcomes among patients surviving to hospital discharge were unaffected.     

Evaluation of rejection,infection, and malignancy outcomes in elderly liver transplant recipients receiving a similar level of immunosuppression compared to a younger group

Elderly liver transplant (LTx) recipients at a lower risk of acute rejection compared to younger recipients due to immunosenescence. As such, they may benefit from reduced immunosuppression (IS) to minimize infectious and malignant complications. We aimed to evaluate outcomes in LTx recipients ≥60 years compared to a younger group of LTx recipients aged 18–59 years maintained on a similar level of IS. This was a single-center retrospective evaluation of adult LTx recipients from 2013 to 2018 who received methylprednisolone induction and were maintained on tacrolimus, mycophenolate mofetil (MMF), and a prednisone taper. A total of 143 LTx recipients were evaluated. Mean age in the older group was 65 ± 3.8 compared to 49 ± 10.4 years in the younger group (p < 0.0001). Mean tacrolimus levels and the duration of MMF and steroids were comparable. Both groups had a similar incidence of first rejection within 1 year (19.2% in the elderly group vs. 23.1% in the younger group, p = 0.57). There were no statistical difference in terms of infection, malignancy, or patient survival. In conclusion, our data suggests that elderly LTx recipients, when treated with a similar level of IS, had similar 1 year incidence of rejection, infection, malignancy, and patient survival as younger LTx recipients.     

Recurrent hepatitis C after liver transplantation: A nonrandomized trial of interferon alfa alone versus interferon alfa and ribavirin

Liver transplant recipients with recurrent hepatitis C virus (HCV) infection often have histological hepatitis, and in some patients, graft failure develops. The aim of this nonrandomized study is to determine the efficacy and tolerability of interferon alfa (IFN alfa) alone and IFN alfa and ribavirin combination therapy in such patients. Forty transplant recipients with recurrent hepatitis were initiated on therapy with IFN alfa-2b at 3 million units (MU) three times weekly for 1 month followed by 5 MU three times weekly for 5 months. Twenty patients were administered IFN alfa-2b, 3 MU three times weekly for 1 month followed by 5 MU three times weekly for 11 months, and ribavirin, 600 mg, twice daily orally for 12 months concurrently. The primary end point was sustained clearance of serum HCV RNA, and secondary end points were serum alanine aminotransferase (ALT) level normalization and histological improvement. Thirty patients completed 6 months of IFN-alfa monotherapy and 15 patients completed 12 months of IFN alfa and ribavirin combination therapy. End-of-treatment biochemical responses were similar in the two groups (IFN alfa, 20% v combination therapy, 25%); however, viral clearance was greater in the combination-therapy group (40% v 15%; P = .04). Six months after the completion of therapy, only 1 patient (2.5%) in the IFN-alfa group and 4 patients (20%) in the combination-therapy group were HCV RNA negative (P = .03). Serum ALT and HCV RNA levels declined significantly in both groups during therapy. There was no improvement in inflammatory grade, and fibrosis score was worse in both groups. Ten patients (25%) in the IFN-alfa group and 5 patients (20%) in the combination-therapy group withdrew because of adverse effects. We conclude that in liver allograft recipients with recurrent hepatitis C, combination therapy with IFN alfa and ribavirin is more efficacious than treatment with IFN alfa alone. However, the efficacy is limited by tolerability. (Liver Transpl 2001;7:863-869.)     

The efficacy and safety of cyclosporine reduction in de novo renal allograft patients receiving sirolimus and corticosteroids: results from an open‐label comparative study

This study evaluated the safety and efficacy of a sirolimus, corticosteroid, and cyclosporine reduction regimen in an open‐label, 12‐month trial of 420 de novo renal allograft recipients at 49 European transplant centers. One month post‐transplantation, 357 patients were randomized to receive standard‐dose cyclosporine (sCsA, n = 179) or reduced‐dose cyclosporine (rCsA, n = 178). All patients also received sirolimus and corticosteroids. The primary end points were the rate of biopsy‐confirmed acute rejection (BCAR) and renal function, as measured by serum creatinine. Baseline demographic and donor characteristics were similar between groups. BCAR rates at 12 months were not significantly different: 11.2% for rCsA patients and 16.2% for sCsA patients. Mean serum creatinine (±SEM) was significantly lower (1.75 ± 0.10 vs. 1.97 ± 0.07 mg/dl, P < 0.001), and creatinine clearance (±SEM; Nankivell method) was significantly higher (57.8 ± 1.78 vs. 49.5 ± 2.46 ml/min, P < 0.001) in patients receiving rCsA versus sCsA at 1 year, respectively. Patient and graft survival exceeded 98% in both groups. No significant differences in infection or malignancy were noted between groups. The rCsA with sirolimus and corticosteroid regimen resulted in excellent 12‐month patient and graft survival, a low incidence of BCAR, and improved renal function in renal allograft recipients. Sirolimus administered with rCsA and corticosteroids provided adequate immunosuppression while reducing the potential for the nephrotoxic effects of cyclosporine. These findings may help to improve long‐term renal allograft outcomes.     

Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: Results from the prospect study

The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV₁% predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population.