Drug-Induced Lung Injury in a Liver Transplant Patient Treated With Sofosbuvir.

New direct-acting antivirals (DAAs) have dramatically improved sustained virologic response (SVR) rates in patients treated for chronic hepatitis C. Although the safety of these agents has been very good in registration trials, unexpected side effects have been reported after much broader use of DAAs on marketing. We retrospectively examined all liver transplant recipients with chronic hepatitis C that received sofosbuvir-based regimens at our clinic. A total of 24 liver transplant recipients with recurrent chronic hepatitis C had received sofosbuvir up to April 2015. Regimens were as follows: sofosbuvir+simeprevir (8), SOF+ledipasvir (6), sofosbuvir+daclatasvir (5) and sofosbuvir+ribavirin (5). Overall, treatment was very well tolerated with only mild adverse events in 42% of patients. However, a 52-year-old woman developed severe respiratory failure within 10 days after beginning sofosbuvir+daclatasvir. High-resolution computerized tomography showed areas of diffused ground-glass opacities in both lungs, suggesting drug-induced lung injury. The bronchoalveolar lavage showed marked signs of acute inflammation without recovering any infectious agent. The patient was treated with high-dose corticosteroids and steadily recovered. DAA therapy was not discontinued, but sofosbuvir was replaced by simeprevir. She reached sustained virologic response after completing 24 weeks of DAA therapy. Given the close temporal association, radiologic and bronchoalveolar lavage findings, and negative work-up for infectious agents, we postulated that sofosbuvir was the most likely explanation for drug-induced lung injury in our patient.

Treatment of severe recurrent hepatitis C after liver transplantation in HIV infected patients using sofosbuvir-based therapy.

BACKGROUND: For liver transplant recipients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection, recurrence after LT is associated with a higher risk of graft loss than for HCV mono-infected patients. Prior HCV treatment options were limited by side effects and drug-drug interactions. AIM: To evaluate treatment outcomes with sofosbuvir (SOF)-based therapy among HIV/HCV coinfected liver transplant recipients. METHODS: Access to SOF and ribavirin (RBV) prior to regulatory approval was attained via an international compassionate access program for transplant recipients with a life expectancy of 1 year or less in the absence of HCV treatment. This report focuses on the short and longer term outcomes in HCV-HIV co-infected liver transplant recipients. RESULTS: Twenty patients were treated, nine with early severe recurrence and 11 with cirrhosis. Eleven patients received SOF and RBV, one SOF, RBV and Peg-interferon, three SOF, RBV and simeprevir and five SOF, RBV and daclatasvir. Of the 18 patients who completed treatment, 16 (89%) achieved sustained virological response 12 weeks after the end of treatment (SVR12). Liver function tests (including bilirubin and albumin) improved significantly over time. Nineteen serious adverse events occurred in eight (40%) patients, none of them related to SOF. Two patients died during treatment and another, 1 year after the end of therapy, due to progressive end-stage liver disease. Importantly, HIV suppression was not compromised. No significant drug-drug interactions were reported. CONCLUSIONS: Sofosbuvir-based regimens are safe, well-tolerated and provide high rates of SVR in HCV-HIV co-infected patients with severe recurrence after-liver transplant.

Unravelling Protein-DNA Interactions at Molecular Level: A DFT and NCI Study.

Histone-DNA interactions were probed computationally at a molecular level, by characterizing the bimolecular clusters constituted by selected amino acid derivatives with polar (asparagine and glutamine), nonpolar (alanine, valine, and isoleucine), and charged (arginine) side chains and methylated pyrimidinic (1-methylcytosine and 1-methylthymine) and puric (9-methyladenine and 9-methylguanine) DNA bases. The computational approach combined different methodologies: a molecular mechanics (MMFFs forced field) conformational search and structural and vibrational density-functional calculations (M06-2X with double and triple-ζ Pople's basis sets). To dissect the interactions, intermolecular forces were analyzed with the Non-Covalent Interactions (NCI) analysis. The results for the 24 different clusters studied show a noticeable correlation between the calculated binding energies and the propensities for protein-DNA base interactions found in the literature. Such correlation holded even for the interaction of the selected amino acid derivatives with Watson and Crick pairs. Therefore, the balance between hydrogen bonds and van der Waals interactions (specially stacking) in the control of the final shape of the investigated amino acid-DNA base pairs seems to be well reproduced in dispersion-corrected DFT molecular models, reinforcing the idea that the specificity between the amino acids and the DNA bases play an important role in the regulation of DNA.

Birth weight and obstetric complications determine age at onset in first episode of psychosis.

BACKGROUND: Earlier age at onset of psychosis (AOP) has been associated with poor social adjustment and clinical outcome. Genetic and environmental factors such as obstetric complications, parental history of psychosis, advanced paternal age at time of birth, low birth weight and gestational age, and use of drugs have been described as bringing AOP forward. This study aims to evaluate the relationship between AOP and these factors in a sample of first episode of psychosis (FEP) patients. METHODS: Clinical and sociodemographic data, age at FEP, age of parents at birth, parental history of psychosis, drug-use habits of the mother during pregnancy and of the patient before psychotic onset, and Lewis and Murray obstetric complication scale were obtained from 90 patients with FEP. Statistical analysis was performed by means of Pearson correlations, Chi-square tests, Student T-test analyses and a linear regression model using SPSS version 22. RESULTS: Pre-eclampsia, need for incubator at birth, use of forceps, parental history of psychosis, and low birth weight were associated with an earlier AOP. Use of forceps and birth weight are the variables which best predict AOP in FEP. Stimulant drugs, which were mostly used together with cannabis and cocaine, were the only substances associated with an earlier AOP. CONCLUSIONS: Our findings are consistent with previous study results and underline the role of the prenatal period in the development of psychosis and the importance of careful monitoring of pregnancy and delivery, especially in cases with familial history.

Mucosal leishmaniasis mimicking squamous cell carcinoma in a liver transplant recipient.

Organ transplant recipients living in endemic regions are at increased risk of Leishmania infections. Visceral leishmaniasis is the most common kind of presentation in the Mediterranean basin. Rarely, Leishmania infantum may cause localized mucosal disease. We present the first case, to our knowledge, of a liver transplant recipient with localized mucosal leishmaniasis. Twenty-two years after transplantation, a painless, very slow growing ulcer appeared on the inner side of the patient's upper lip. A biopsy performed in the community hospital showed non-specific chronic inflammation without neoplastic signs. Because of a high suspicion of malignancy, the patient was transferred to the referral hospital to consider complete excision. The excisional biopsy revealed a granulomatous inflammatory reaction together with intracellular Leishmania amastigotes within macrophages. Leishmaniasis was confirmed by the nested polymerase chain reaction assay. The clinical and laboratory findings did not suggest visceral involvement. The patient received meglumine antimoniate for 21 days without relevant adverse effects.

TT genotype of transforming growth factor beta1 +869C/T is associated with the development of chronic kidney disease after liver transplantation.

BACKGROUND: Chronic kidney disease (CKD) is a frequent complication in patients with liver transplantation (LT), and calcineurin inhibitor chronic nephrotoxicity, mediated by transforming growth factor beta1 (TGF-ß1) is an important contributing factor. The aim of this study was to assess the influence of genetic polymorphisms of TGF-ß1 in the development of CKD at 6 months after transplantation. METHODS: One hundred sixty-four LT patients (63.4% male; overall mean age, 48.7 ± 11.6 years) were included in the analysis. CKD was considered at the 6th month after LT and was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) as calculated on the basis of Modification of Diet in Renal Disease 4-variable equation. TGF-ß1 +869 C/T and +915 G/C polymorphisms were analyzed with the use of hybridization with fluorescent probes and analysis by means of flow cytometry with the Luminex system. The association between the presence of CKD at 6 months and these polymorphisms, as well as with other known risk factors for CKD after LT, was considered. RESULTS: In the univariate analysis, the TT genotype of TGF-ß1 +869 (P = .036; odds ratio, 2.1; 95% confidence interval, 1.1-4.2), age at LT (P < .001), pre-transplantation serum creatinine levels (P = .03), eGFR (P < .001), CKD (P = .027), and immunosuppression with cyclosporine (P = .017) were associated with CKD at 6 months after transplantation. In the multivariate analysis, TGF-ß1 +869TT genotype (P = .017), immunosuppression with cyclosporine (P = .002), age at LT (P = .024), and pre-transplantation CKD (P < .001) remained as independent variables associated with the development of CKD at 6 months after transplantation. CONCLUSIONS: The genetic polymorphism TGF-ß1 +869 C/T may be an independent risk factor for CKD after liver transplantation.

Long-term survivors after pediatric liver transplatation are at increased risk for development of cardiovascular disease events: analysis of 30 cases.

BACKGROUND: Liver transplantation (LT) in adult patients is associated with a higher incidence of cardiovascular risk factors (CVRF), chronic kidney disease (CKD), and cardiovascular disease mortality than the general population. Available information about these problems in adult patients with LT from a pediatric age is limited. The aim of this study was to analyze the incidence of CVRF, risk of developing CKD, and risk of 10-year coronary event in adult patients who received LT in childhood. METHODS: Thirty adult patients (11 female, 19 male; mean age, 29.3 years) who underwent LT in childhood were analyzed, and CVRF, estimated glomerular filtration rate, and current immunosuppressive regimen were recordered. The risk of 10-year coronary event was calculated with the use of validated equations (Framingham and Regicor) and compared with the estimated risk in the general population. RESULTS: None of the patients had CVRF before LT, except 1 patient who received a transplant because of familial hypercholesterolemia. Median age of patients at the time of study was 28.6 years (range, 19.3-43.1 y), and mean follow-up after LT was 17.83 ± 5.21 years. Twenty-nine patients (96.7%) were receiving a calcineurin inhibitor (69% tacrolimus, 31% cyclosporine), along with steroids in 13 of them. The average CVRF per patient was 2, and 11 patients (43.33%) had ≥3. Thirteen patients (43.33%) had CKD. The estimated risk of developing a coronary event at 10 years according to the Framingham score was 3%, higher than expected in the general population of same age and sex. With the use of the Regicor equation, adapted to the Spanish population, the estimated cardiovascular risk was 1.6%, corresponding to Spanish men without CVRF aged 50-55 years. None of the patients had cardiovascular events during the follow-up. CONCLUSIONS: Our data show a high incidence of CVRF and CKD in young adults who received LT in childhood, resulting in an increased risk of cardiovascular disease.

CC genotype at rs12979860 of IL28B is associated with lower risk of new-onset diabetes after transplantation in adult patients with liver transplantation for hepatitis C cirrhosis.

INTRODUCTION: New-onset diabetes mellitus after transplantation (NODAT) in patients undergoing liver transplantation (LT) for hepatitis C virus (HCV)-related cirrhosis is associated with more aggressive HCV recurrence on the graft, rapid progression of fibrosis, and lower rate of sustained viral response to antiviral therapy. The CC genotype at rs12979860 of the IL28B is associated with greater rates of spontaneous clearance of HCV and response to antiviral therapy. IL28B acts on the interferon-stimulated genes through the JAK-STAT pathway, which is related to the development of insulin resistance. The aim of this study was to investigate whether IL28B rs12979860 polymorphism is associated with the development of NODAT after LT for cirrhosis owing to HCV infection. METHODS: We analyzed 99 patients (age, 52.7 ± 9.4 years; 70% male) who underwent LT for HCV-related cirrhosis, with ≥1 year of follow-up and with available DNA sample. NODAT was defined starting from the sixth month after LT, according to the international consensus guidelines. Genotyping was carried out by real-time polymerase chain reaction and analysis of the melting temperature with the LightCycler 480 system. RESULTS: Twenty-eight patients (28.3%) developed NODAT. CC genotype at rs12979860 of IL28B was associated with a lesser incidence of NODAT versus non-CC genotypes (P = .05; odds ratio, 0.31; 95% CI, 0.11-0.92). We did not find any association between NODAT and age at transplantation, gender, pretransplant body mass index, presence of hepatocellular carcinoma, type of initial immunosuppression (cyclosporine, tacrolimus or corticosteroids) or acute rejection treated with steroids. CONCLUSION: The CC genotype at rs12979860 of IL28B is a protective factor for NODAT in patients with LT for HCV-related cirrhosis.

Toll-like receptor 3 L412F polymorphism may protect against acute graft rejection in adult patients undergoing liver transplantation for hepatitis C-related cirrhosis.

Liver transplantation activates the innate immune system by toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. The aim of this study was to evaluate the possible association of different single nucleotide polymorphisms (SNPs) in several TLR genes with the incidence of acute graft rejection in liver transplant recipients for hepatitis C virus (HCV)-related cirrhosis. This is a single-center study of 100 adult patients who received a first whole only liver graft from deceased donors at our institution between 1988 and 2009 for cirrhosis due to HCV infection. We examined 10 SNPs in the TLR1 (S6021), TLR2 (R753Q), TLR3 (L412F), TLR4 (D299G and T399I), TLR5 (R392X), TLR6 (S249P), TLR7 (Q11L), and TLR9 (-1237T/C and -1486C/T) genes. Genotyping was carried out with the LightSNiP typing assay (TIB-MolBiol, Berlin, Germany) by analyzing the melting curves with the LightCycler 480 system (Roche Applied Science, Mannheim, Germany). Recipient allelic and genotypic distributions for each SNP were compared among patients with and without acute rejection within the first 3 months after transplantation. We found the homozygous mutant TT genotype for TLR3 L412F was associated with a lower rate of acute rejection when compared with the homozygous wild-type genotype [odds ratio (OR) = 0.1, 95% confidence interval (95% CI) = 0.01-0.86; P = .017], and showed a trend toward a lower graft rejection rate when compared with patients carrying one or two C alleles (OR = 0.15, 95% CI = 0.02-1.2, P = .05). No other associations with acute rejection rates were found for any other SNP evaluated. This preliminary study suggests an important role for SNP TLR3 L412F in acute rejection in liver transplant patients for HCV-related cirrhosis. Nevertheless, these findings must be prospectively validated in other cohorts of patients as well as in patients after liver transplantation for other etiologies than HCV.

Breakthrough rhinocerebral mucormycosis in a liver transplant patient receiving caspofungin.

Zygomycetes are among the most frequent causes of non-Aspergillus mycelial fungal infections in transplant recipients. We have described a single case of breakthrough zygomycosis. A young Japanese woman presented because of idiopathic fulminant hepatitis and renal failure. On the third day of admission, she underwent orthotopic liver transplantation. A considerable amount of red blood cells and fresh frozen plasma were transfused during surgery. On posttransplant day 2, Candida albicans was isolated from respiratory secretions; prophylactic caspofungin was prescribed. During the next 6 days, C albicans was isolated from tracheal secretions, surgical wound, and exudates and stools. Ventilator-associated pneumonia was diagnosed day 4. Her renal function did not improve during the postoperative period; the patient continued on hemodialysis. On day 28, a dark blue eschar due to zygomycosis was detected on the skin of the nose. Tracheal and nasal exudates yielded Rhizopus sp. The patient died 12 hours later due to multiorgan failure with hypothermia. The fatal evolution in this case may be related to a presumed brain infarction after progressive vessel fungal invasion. The presented case had 2 risk factors related to zygomycosis. A high index of suspicion is required in transplant recipients with risk factors for zygomycosis. Early diagnosis and surgery with appropriate systemic fungal drugs (amphotericin B) are mandatory to improve the prognosis.

Quantitation of atherosclerosis by magnetic resonance imaging and 3-D morphology operators.

The objective was to ascertain whether MRI and image processing can be used to quantify atherosclerosis by measuring wall thickness in rabbit aorta. The abdominal aortas of 2 healthy and 5 atherosclerotic rabbits were examined with a gradient-echo inflow angiography sequence (2DI) and a proton density weighted turbo-spin-echo sequence (PDW). Using thresholding by four observers and 3D morphology operators, segmentation of the artery and vein lumina was performed from the 2DI sequence, and of surrounding fat and muscle from the PDW sequence. Remaining voxels adjacent to the aortic lumen were classified as vessel wall. By measuring the vessel wall volume and the lumen volume, the wall percentage was calculated. The values were significantly higher for the diseased animals than for unaffected individuals (p < 0.01). It is concluded that aortic wall thickening in atherosclerotic rabbits can be measured quantitatively by using MRI combined with 3D morphology image processing operators.