A Case Report of Cystic Fibrosis Plus Tuberous Sclerosis: A Cautionary Tale Regarding Lung Transplantation

BackgroundCystic fibrosis (CF) and tuberous sclerosis complex (TSC) are 2 rare genetic diseases that often affect the lungs. Pulmonary compromise in TSC or CF can be severe enough to require lung transplantation. In rare instances patients with CF undergo pneumonectomy to control recurrent lung infections and lung necrosis affecting one lung more than the other. Lung transplantation in these patients is exceedingly rare because preexistent pneumonectomy increases the risk of lung transplant–associated morbidity and mortality.Case PresentationWe present the case of a young woman with co-occurrence of TSC and CF, who underwent left-sided pneumonectomy and, approximately 2 years later, right-sided single lung transplant. The posttransplant clinical course was complicated by phrenic nerve injury, ventilator dependency, Aspergillus endocarditis with embolic shower, and death. Pretransplant pneumonectomy, Aspergillus colonization, and posttransplant phrenic nerve injury contributed to the complex postoperative course, ventilatory dependence, and poor outcome.ConclusionThis cautionary case should alert physicians on the challenges associated with single lung transplant in patients with preexistent pneumonectomy.     

Pneumatosis Intestinalis After Living Donor Lung Transplantation Associated With Alpha-Glucosidase Inhibitor Treatment: A Case Report

IntroductionPneumatosis intestinalis (PI) is a rare but critical condition in which gas is found in the bowel wall. Although organ transplant recipients have an increased PI risk because of long-term immunosuppression, alpha-glucosidase inhibitors (α-GI), a standard diabetes therapy, often contribute to PI. However, little is known about the postorgan transplantation relationship between PI and α-GI. To the best of our knowledge, this is the first reported case of PI in a lung transplant recipient treated with α-GI.Case reportA 59-year-old man underwent hybrid (living-donor and cadaveric) lung transplantation (LTx). The patient was treated with prednisolone and tacrolimus as immunosuppressive therapy and α-GI for diabetes for 4 years. He developed asymptomatic PI 1031 days after transplantation without any acute abdominal finding. After excluding other possible causes of PI, his PI was attributed to α-GI. The suspected α-GI was immediately withdrawn. The patient was managed conservatively with bowel rest and oxygen therapy. After 11 days of α-GI discontinuation, PI improved, and the patient completely recovered.ConclusionPhysicians should keep this rare adverse drug reaction in mind when prescribing α-GI, particularly in patients with diabetes after organ transplantation and including LTx. The management strategy for asymptomatic PI caused by α-GI is the immediate discontinuation of α-GI therapy, followed by conservative management initiation.     

Impact of highly effective CFTR modulator therapy on digital clubbing in patients with cystic fibrosis

BackgroundThe association of certain disease processes with digital clubbing is well documented. Digital clubbing is often reversible after successful treatment of the underlying pathology, for example, after lung transplantation in patients with cystic fibrosis (CF). We examined the effect of highly effective Cystic Fibrosis Transmembrane Regulator (CFTR) modulators, defined for the purposes of this study as ivacaftor or the combination of ivacaftor, tezacaftor, and elexacaftor (ETI), on digital clubbing.Materials and MethodsClubbing index was measured on plaster of Paris casts of right index fingers obtained from 15 patients with cystic fibrosis, before and after initiation of CFTR modulator therapy. Similar measurements were made on casts for 9 cystic fibrosis patients who underwent lung transplantation. Measurements were made on the most recent casts available before treatment and the first cast available at least 3 months after initiation of treatment. The Wilcoxon signed-rank text was used to detect any significant difference in the pre- and post-treatment casts for each individual.ResultsA significant decrease in the clubbing index was found after both lung transplantation and treatment with highly effective CFTR modulator therapy.ConclusionsThese results add to the body of evidence demonstrating the efficacy of highly effective CFTR modulator therapy, the first agents that act directly at the dysfunctional chloride channel responsible for CF. By demonstrating that CFTR modulator therapy is capable of reversing digital clubbing, this study suggests a beneficial effect on lung pathology aside from air flow and gas transfer.     

Burkholderia pyrrocinia in Cystic Fibrosis Lung Transplantation: A Case Report

Infection with Burkholderia species is typically considered a contraindication leading to transplantation in cystic fibrosis (CF). However, the risks posed by different Burkholderia species on transplantation outcomes are poorly defined. We present the case of a patient with CF who underwent lung transplantation due to a severe respiratory failure from chronic airways infection with Burkholderia pyrrocinia (B. cepacia genomovar IX) and pan-resistant Pseudomonas aeruginosa. The postoperative course was complicated by recurrent B. pyrrocinia infections, ultimately lea ding to uncontrollable sepsis and death. This is the first case report in CF of Burkholderia pyrrocinia infection and lung transplantation, providing further evidence of the high risk nature of the Burkholderia species.     

Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis

BackgroundElexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates.MethodsLung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021.ResultsAmong the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV₁) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation.ConclusionIn lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.     

Recurrent Clostridium difficile colitis in cystic fibrosis: An emerging problem

ObjectiveTo examine the incidence of recurrent Clostridium difficile infection in patients with cystic fibrosis (CF), including patients who had undergone lung transplantation, and review clinical findings in hospitalized patients with C. difficile colitis.MethodsA retrospective chart review was performed to examine the clinical presentation and management of patients with cystic fibrosis (CF) who received care at the University of Wisconsin Hospital and Clinics (UWHC) from 1994 to 2011 and were prospectively identified with C. difficile colitis.ResultsTen cases of C. difficile associated disease (CDAD) occurred in patients with CF followed by our Adult CF Center over a period of 17 years, and 4 patients were bilateral lung transplant recipients. Two of the lung transplant recipients had recurrent CDAD that lead to fulminant pancolitis, surgical intervention, and shock. Two patients in the non-transplant group experienced recurrent C. difficile infection that led to fulminant pancolitis with associated systemic inflammatory response syndrome and required colectomy.ConclusionsC. difficile colitis can cause life threatening illness in patients with CF, and symptoms may be subtle and/or atypical and lead to significant delay in diagnosis. Patients with recurrent C. difficile colitis are at high risk of fatal outcome, and empiric therapy should be considered for patients with previous C. difficile colitis even in the absence of disease when broad-spectrum antibiotics are given to treat bacterial infection.     

Lung transplant referral for individuals with cystic fibrosis: Cystic Fibrosis Foundation consensus guidelines

ObjectiveProvide recommendations to the cystic fibrosis (CF) community to facilitate timely referral for lung transplantation for individuals with CF.MethodsThe CF Foundation organized a multidisciplinary committee to develop CF Lung Transplant Referral Consensus Guidelines. Three workgroups were formed: timing for transplant referral; modifiable barriers to transplant; and transition to transplant care. A focus group of lung transplant recipients with CF and spouses of CF recipients informed guideline development.ResultsThe committee formulated 21 recommendation statements based on literature review, committee member practices, focus group insights, and in response to public comment. Critical approaches to optimizing access to lung transplant include early discussion of this treatment option, assessment for modifiable barriers to transplant, and open communication between the CF and lung transplant centers.ConclusionsThese guidelines will help CF providers counsel their patients and may reduce the number of individuals with CF who die without consideration for lung transplant.     

Lung Transplantation for Cystic Fibrosis and Non-cystic Fibrosis Bronchiectasis: A Single-Center Experience

ObjectivesLung transplantation is a well-established treatment for selected patients with advanced cystic fibrosis (CF)- and non-cystic fibrosis (non-CF)--related bronchiectasis. Because the number of lung transplants performed for patients with non-CF bronchiectasis is much smaller than for patients with CF, little data is available regarding patient selection, choice of procedure, and outcomes.MethodsBetween November 1997 and December 2013, 42 patients with CF and 33 patients with non-CF bronchiectasis underwent lung transplantation at the Rabin Medical Center, Israel. We analyzed and compared pretransplant evaluation data and short- and long-term results in both groups.ResultsMedian survival for the CF group in our study was 8.4 years, compared with 7.1 years for the non-CF group (P = .098), similarly to that reported by the International Society for Heart and Lung Transplantation Registry data. The main survival difference between groups was in the early postoperative period. Both groups achieved similar peak forced expiratory volume in 1 second values and had stable lung function at the 3-year follow-up. Biopsy-proven rates of acute cellular rejection were low for both groups. Rates of chronic lung allograft dysfunction development did not differ between CF and non-CF recipients.ConclusionOur institutional experience confirms that lung transplantation is feasible for non-CF bronchiectasis, and results are comparable to our CF cohort. The increased early mortality in this study occurred from 1999 to 2008 and was probably related to surgical techniques used at the time. Overall, 3-year and 5-year survival were comparable with the International Society for Heart and Lung Transplantation Registry data. Non-CF bronchiectasis patients achieved and maintained satisfactory lung function.     

Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis

Cystic fibrosis (CF) is an inherited condition that leads to respiratory failure and is the third most common indication for adult bilateral lung transplantation (LuTX). In contrast to other lung diseases, the immune system of CF patients is up‐regulated and we therefore hypothesized that these patients would benefit from induction therapy. In the current study, we investigated the impact of antithymocyte globulin (ATG) induction therapy in CF patients after LuTX. One hundred and forty six patients who underwent LuTX for CF at our centre between January 1999 and December 2010 were included in the study and retrospectively analysed. They were divided into two groups according to the immunosuppressive protocol: group‐A (n = 103) with and group‐B (n = 43) without induction therapy on top of the basic calcineurin inhibitor based triple immunosuppression with mycophenolate mofetil and steroids. Perioperative survival was significantly better in the ATG group, a benefit sustained for the entire follow‐up. ATG induction resulted in a significantly lower incidence of acute rejections without an increase in infectious complications. Taken together, our results indicate that ATG induction therapy confers a significant survival benefit in CF patients undergoing LuTX and reduces rejection. We advocate the use of induction therapy in this patient cohort.     

Long-term non-invasive ventilation in cystic fibrosis -- experience over two decades

BackgroundNon-invasive ventilation (NIV) is accepted as a bridge to lung transplantation in cystic fibrosis (CF) but there is little evidence to support its use outside this setting.MethodsWe reviewed the records of all patients with CF who received domiciliary NIV at our centre between 1991 and 2010.ResultsOf 47 patients studied, 36% underwent lung transplantation, 28% died without transplantation and 30% remain alive on NIV. Median duration of NIV was 16 months (range 2–90). Mean FEV₁ fell by 212 ml over the year before NIV but increased by 18 ml in the following year (p < 0.01). Individual response to NIV was associated with lower baseline and more rapid decline in FEV₁. From 1991 to 2000, 70% underwent lung transplantation; from 2001 to 2010 only 27% were transplanted.ConclusionsNIV may slow or reverse the decline in lung function in advanced CF. NIV is increasingly used beyond a bridge to transplantation at our centre.     

Glycemic Stability Through Islet‐After‐Kidney Transplantation Using an Alemtuzumab‐Based Induction Regimen and Long‐Term Triple‐Maintenance Immunosuppression

Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long‐term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab‐based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One‐ and 2‐year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, respectively. HbA1c dropped from 57.2 ± 13.1 (7.4 ± 1.2%) to 44.5 ± 11.8 mmol/molHb (6.2 ± 0.9%) (p = 0.003) after 2 years. Six of 13 patients suffered from severe hypoglycemia before islet transplantation. After transplantation, severe hypoglycemia was restricted to the only patient who lost graft function. Creatinine clearance was unchanged. Islet‐after‐kidney transplantation in patients with type 1 diabetes using an alemtuzumab‐based induction regimen leads to considerable islet allograft function and improvement in glycemic control.     

Lung transplantation in cystic fibrosis normalizes essential fatty acid profiles

BackgroundCystic fibrosis (CF) can be a devastating disease. Disorders in essential fatty acid state are increasingly reported and various supplementation trials have been performed in an attempt to improve outcomes. However, the mechanisms leading to these disturbances remain elusive.We wanted to investigate the role of the diseased CF lung on fatty acid profiles.MethodsWe compared fatty acid profiles in patients with CF after lung transplantation (n = 11) to age-matched healthy controls and homozygous F508del patients (n = 22 each).ResultsCompared to healthy controls, in patients with CF, there are decreased levels of docosahexaenoic, linoleic and arachidonic acid and increased levels of mead acid. In patients that underwent a lung transplantation, levels of docosahexaenoic, linoleic and arachidonic acid were normal. Mead acid did not decrease significantly.ConclusionsThe diseased CFTR deficient lung is a major determinant in the disturbed fatty acid profile in CF.     

Posterior reversible encephalopathy syndrome after lung transplantation: Risk factors and management

Introduction : Posterior reversible encephalopathy syndrome is a rare neurologic complication that can occur under immunosuppressive therapy with CNI after organ transplantation. Methods : We retrospectively reviewed medical records of 545 patients who underwent lung transplantation between 2012 and 2019. Within this group, we identified 30 patients with neurological symptoms typical of PRES and compared the characteristics of patients who were diagnosed with PRES (n = 11) to those who were not (n = 19). Results : The incidence of PRES after lung transplantation was 2%. Notably, 73% of the patients with PRES were female and the mean age was 39.2. Seizure (82% vs. 21%, p = .002) was the most common neurological presentation. The risk of developing PRES was significantly associated with age (OR = .92, p < .0001) and having cystic fibrosis (CF) (OP = 10.1, p < .0001). Creatinine level (1.9 vs. 1.1 mg/dl, p = .047) and tacrolimus trough level (19.4 vs. 16.5 ng/ml, p = .048) within 1 week prior to neurological symptoms were significantly higher in patients with PRES. Conclusion : Renal insufficiency and high tacrolimus levels are associated with PRES. A change of immunosuppressive drug should be done after confirmed PRES diagnosis or immediately in case of severe neurological dysfunction to improve neurological outcomes and minimize the risk of early allograft rejection.     

P. aeruginosa in the paranasal sinuses and transplanted lungs have similar adaptive mutations as isolates from chronically infected CF lungs

BackgroundPseudomonas aeruginosa cells are present as biofilms in the paranasal sinuses and the lungs of chronically infected cystic fibrosis (CF) patients. Since different inflammatory responses and selective antibiotic pressures are acting in the sinuses compared with the lungs, we compared the adaptive profiles of mucoid and non-mucoid isolates from the two locations.MethodsWe studied the genetic basis of phenotypic diversification and gene expression profiles in sequential lung and sinus P. aeruginosa isolates from four chronically infected CF patients, including pre- and post-lung transplantation isolates.ResultsThe same phenotypes caused by similar mutations and similar gene expression profiles were found in mucoid and non-mucoid isolates from the paranasal sinuses and from the lungs before and after transplantation.ConclusionBilateral exchange of P. aeruginosa isolates between the paranasal sinuses and the lungs occurs in chronically infected patients and extensive sinus surgery before the lung transplantation might prevent infection of the new lung.     

Recommended shielding against COVID-19 impacts physical activity levels in adults with cystic fibrosis

BackgroundSevere acute respiratory syndrome – coronavirus-2 (SARS-CoV-2) has caused a pandemic threatening the life of people with chronic respiratory diseases including cystic fibrosis (CF). This study was designed to investigate health-related aspects of individuals with CF, with and without lung transplantation (LTX), their communication with their specialist healthcare providers during the pandemic, potential changes in peoples’ individual therapy regimes and daily physical activity levels.MethodsA web-based survey was conducted among Swiss adults with CF with and without LTX, study period from March 16th, 2020 – the day the “extraordinary situation” was officially declared in Switzerland introducing stringent measures protecting the public – until May 16^th, 2020.Results327 individuals (25% LTX recipients) were included, 45 individuals reported coronavirus-2019 disease (COVID-19) like symptoms. Of 28 subjects tested, only three subjects were tested positive, all with mild symptoms, no hospitalization required. Almost half of the survey respondents (45%) reported undertaking less physical activity during the lockdown, while 79% and 91% of participants reported no change in traditional airway clearance and inhalation therapies, respectively. Distress regarding a potential SARS-CoV-2 infection or worsening of lung disease were no major concerns for subjects.ConclusionsOur study reveals that the direct impact of SARS-CoV-2 on clinical outcomes of individuals with CF was mild although people with chronic lung diseases like CF are considered a high-risk population; overall, this is reassuring. However, strict lockdown measures substantially affected peoples’ physical activity levels, a vital cornerstone of CF therapy; and this is worrisome.     

Chronic Stenotrophomonas maltophilia infection and mortality or lung transplantation in cystic fibrosis patients

BackgroundChronic Stenotrophomonas maltophilia infection is an independent risk factor for severe pulmonary exacerbations in cystic fibrosis (CF) patients. The goal of this study was to determine the effect of chronic S. maltophilia infection on mortality and the need for lung transplantation in a longitudinal study of children and adults with CF.MethodsThis was a cohort study of CF patients from the Hospital for Sick Children and St Michael's Hospital (Toronto, Canada) from 1997 to 2008. A Cox Regression model was used to estimate the hazard ratio (HR) to time of death or lung transplantation adjusting for age, gender, genotype, pancreatic status, CF related diabetes (CFRD), forced expiratory volume in 1 s (FEV₁), body mass index, number of pulmonary exacerbations, Pseudomonas aeruginosa, Burkholderia cepacia complex, Aspergillus and chronic S. maltophilia infection.ResultsA total of 687 patients were followed over the 12 year study period; 95 patients underwent a lung transplantation (of which 26 died) and an additional 49 patients died (total 144 events). In a Cox Regression model adjusting for baseline FEV₁, baseline infection with B. cepacia complex (HR 1.72, 95% CI 1.09–2.71) and baseline chronic S. maltophilia infection (HR 2.80, 95% CI 1.65–4.76) were significantly associated with death or lung transplant. However, in a time-varying model, infection with B. cepacia complex and chronic S. maltophilia infection were no longer significant.ConclusionsBaseline chronic S. maltophilia infection is associated with an almost three-fold increased risk of death or lung transplant in CF patients. It is still unclear, however, whether chronic S. maltophilia infection is simply a marker of severity of disease and ultimate mortality or whether it is causally related to disease progression.     

Alopecia in Children Following Living Related Liver Transplantation

IntroductionAlopecia is a common complication in patients following kidney transplantation; however, reports regarding liver transplantation patients are still few.MethodsThis study followed 111 children who underwent living related liver transplantation. Alopecia patients and its possible risk factors were analyzed.ResultsAlopecia occurred in 3 patients (2.7%). Underlying diseases were biliary atresia and Alagille syndrome. Clinically significant alopecia (universal alopecia) occurred in 1 patient with Alagille syndrome. All patients received tacrolimus as their immunosuppression drug. None of the patients who received cyclosporine experienced alopecia. The onset of alopecia ranged from 7 to 28 months after transplantation. Alopecia was treated with a topical corticosteroid and topical tacrolimus, but 1 patient with clinically severe alopecia required conversion from tacrolimus to cyclosporine A.ConclusionsAlopecia is 1 complication seen in children receiving tacrolimus therapy following living donor liver transplant. Prompt management of this cosmetic complication should be done to ensure patients’ compliance to medication regimen.     

Nasal polyposis in lung transplant recipients with cystic fibrosis

BackgroundChronic rhinosinusitis with nasal polyposis is common in patients with cystic fibrosis (CF). There are still many open questions regarding factors related to this condition. Furthermore, the prevalence of nasal polyposis and its implications for the outcomes in lung transplant recipients with cystic fibrosis are unknown.MethodsAll CF patients who underwent lung transplantation at our centre between November 1992 and December 2009 were included. Nasal polyp status was determined endoscopically at time sinus surgery and its relationships to gender, age at lung transplantation, Liou raw score, body mass index, FEV₁%predicted, diabetes mellitus, pre-transplant pseudomonas colonisation of the sinuses and the lungs, pre-transplant corticosteroid use and type of mutation of the CFTR gene were analysed. The post-transplant survival times and the incidence of bronchiolitis obliterans syndrome in patients with or without nasal polyposis were compared.ResultsNasal polyps were found in 19% (17 patients) of the 89 lung transplant recipients, whose data was available for statistical analysis. None of the factors analysed was related to the nasal polyp status. The post-transplant survival times and the incidence of bronchiolitis obliterans syndrome did not significantly differ between patients with or without nasal polyposis.ConclusionsCF-related nasal polyposis occurs in a relevant fraction of lung transplant recipients. A specific effect of nasal polyposis on post-transplant outcome could not be confirmed. Nevertheless, there was a trend to NP recurrence in patients with post‐transplant sinonasal pseudomonas colonisation and is a tendency of less chronic rejection in CF patients with nasal polyps.     

Case Report: Cystic Fibrosis, Lung Transplantation, and the Novel H1N1 Flu

The H1N1 pandemic flu is a significant risk factor for both patients with chronic disease who need organ transplantation and transplant recipients. This population needs special care regarding comorbidities and related complications. MB, a 38-year-old Italian cystic fibrosis male patient with lung and pancreatic involvement, was referred to our division in July 2009 for fever-associated arthromyalgia, headache, and rhinitis. Lung transplantation had been performed in September 2005, and he was subsequently treated with immunosuppressive therapy: tacrolimus, everolimus, and prednisolone. In the past, chronic respiratory colonization with Pseudomonas aeruginosa and intermittent infection with Aspergillus flavus, chronic renal failure, hypertension, and diabetes mellitus complicated his clinical history. He started antiviral treatment with oseltamivir despite no travel history and no respiratory symptoms. H1N1 swab was positive. Three days later, the patient was admitted to the hospital for the persistence of fever and the onset of cough. Chest x-ray showed a left lower pneumonia, which was confirmed by computerized tomography. Broad-spectrum antibiotic therapy led to an improvement of the clinical condition. The patient was discharged 8 days later; a control swab was negative. This case report suggests some general considerations regarding solid organ recipients: 1) Flu-related complications require early treatment (both antiviral and antibiotic); 2) active microbiologic surveillance is important to prevent lethal infections (ie, invasive aspergillosis); 3) evaluation of immunosuppressant blood levels is necessary for drug-drug interactions. Active prevention is the best option for decreasing morbidity and mortality in the transplanted patient.     

Factors influencing the progression of fibrosis in patients with recurrent hepatitis C after liver transplantation under antiviral therapy: a retrospective analysis of 939 liver biopsies in a single center.

Recurrent hepatitis C after liver transplantation (LT) is a major problem, since up to 30% of patients develop cirrhosis only 5 years after LT in the absence of antiviral therapy. The aim of this study was to examine the rate of progression of fibrosis and its associated risk factors in patients submitted to an early antiviral treatment post-LT. Included in the study were 105 patients submitted to LT between September 1990 and December 2004, 70 of whom were treated with interferon and/or ribavirin. A total of 939 liver biopsies were studied. The median fibrosis stage was 0.8 after 1 year post-LT, 1.1 after 3 years, 1.3 after 5 years, and 1.5 after 10 years. LT recipients with fibrosis >2 (13% at 10 years) had a significantly reduced survival rate (63% vs. 87% at 10 years, P = 0.03). Univariate analysis disclosed that recipient male gender, antiviral therapy before LT, LT after 1998, induction immunosuppressive regimen including tacrolimus, induction immunosuppressive regimen including mycophenolate (or without azathioprine), and short duration of prednisolone (<12 months) were significantly associated with progression of fibrosis. In a multivariate analysis, recipient male gender (P = 0.04), antiviral treatment before LT (P = 0.001), and initial immunosuppressive regimen without azathioprine (P = 0.03) were associated with progression of fibrosis. In conclusion, our study has documented that fibrosis progression is not linear over time and that occurrence of severe fibrosis is related to previously described factors related to immunosuppressive regimen or donor age and also to a past history of pre-LT antiviral therapy.