Risk factors for candidaemia in hospitalized patients with liver cirrhosis: a multicentre case-control-control study.

OBJECTIVES: The aim of this study was to evaluate the risk factors for candidaemia in patients with liver cirrhosis. METHODS: This was a case-control-control (1:2:2) study performed in four Italian tertiary centres from 2006 to 2015. Cases were patients with liver cirrhosis developing candidaemia. For every case of candidaemia we enrolled two additional patients undergoing blood cultures for suspected infection yielding isolation of a bacterial pathogen (control A) and two additional patients undergoing blood cultures for suspected infection yielding negative results (control B). Patients were matched according to age, sex and model for end stage liver disease at hospital admission. RESULTS: During the study period 90 cases, 180 controls A and 180 controls B were included. At multivariate analysis assessed by means of multinomial conditional regression models, factors independently associated with candidaemia were previous (<30 days) acute-on-chronic liver failure (relative risk ratio (RRR) 2.22 (95% confidence interval (CI) 1.09-4.54), p = 0.046), previous(<30 days) gastrointestinal endoscopy (RRR 2.38 (95% CI 1.19-4.78) p = 0.014), previous(<30 days) antibiotic treatment for at least 7 days (RRR 2.74 (95% CI 1.00-7.48), p = 0.049), presence of central venous catheter (RRR 2.77 (95% CI 1.26-6.09, p = 0.011), total parenteral nutrition (RRR 3.90 (95% CI 1.62-9.40), p = 0.002) at infection onset and length of in-hospital stay >15 days (RRR 4.63 (95% CI 2.11-10.18), p <0.001] Conversely, rifaximin treatment was associated with lower rate of candidaemia (RRR 0.38 (95% CI 0.19-0.77), p = 0.007). Multivariable analysis for 30-day mortality showed that patients with isolation of Candida spp. from blood cultures had worse outcome when compared with controls even though the difference did not reach a statistical significance (hazard ratio 1.64 (95% 0.97-2.75) p = 0.06). CONCLUSIONS: We identified previous antibiotic use, gastrointestinal endoscopy or acute-on-chronic liver failure and presence of central venous catheter especially for parenteral nutrition as independent factors associated with candidaemia. Surprisingly, chronic rifaximin use was a protective factor.

The impact of carbapenemase-producing Enterobacteriaceae colonization on infection risk after liver transplantation: a prospective observational cohort study.

OBJECTIVE: To investigate the impact of colonization with carbapenemase-producing Enterobacteriaceae (CPE) on the CPE infection risk after liver transplantation (LT). METHODS: Prospective cohort study of all adult patients undergoing LT at our centre over an 8-year period (2010-2017). Individuals were screened for CPE colonization by rectal swabs at inclusion onto the waiting list, immediately before LT and weekly after LT until hospital discharge. Asymptomatic carriers did not receive decolonization, anti-CPE prophylaxis or pre-emptive antibiotic therapy. Participants were followed up for 1 year after LT. RESULTS: We analysed 553 individuals who underwent a first LT, 38 were colonized with CPE at LT and 104 acquired colonization after LT. CPE colonization rates at LT and acquired after LT increased significantly over the study period: incidence rate ratios (IRR) 1.21 (95% CI 1.05-1.39) and 1.17 (95% CI 1.07-1.27), respectively. Overall, 57 patients developed CPE infection within a median of 31 (interquartile range 11-115) days after LT, with an incidence of 3.05 cases per 10 000 LT-recipient-days and a non-significant increase over the study period (IRR 1.11, 95% CI 0.98-1.26). In multivariable analysis, CPE colonization at LT (hazard ratio (HR) 18.50, 95% CI 6.76-50.54) and CPE colonization acquired after LT (HR 16.89, 95% CI 6.95-41.00) were the strongest risk factors for CPE infection, along with combined transplant (HR 2.60, 95% CI 1.20-5.59), higher Model for End-Stage Liver Disease at the time of LT (HR 1.03, 95% CI 1.00-1.07), prolonged mechanical ventilation (HR 2.63, 95% CI 1.48-4.67), re-intervention (HR 2.16, 95% CI 1.21-3.84) and rejection (HR 2.81, 95% CI 1.52-5.21). CONCLUSIONS: CPE colonization at LT or acquired after LT were the strongest predictors of CPE infection. Prevention strategies focused on LT candidates and recipients colonized with CPE should be investigated.

The effects of source and concentration of dietary fiber, starch, and fatty acids on the daily patterns of feed intake, rumination, and rumen pH in dairy cows.

The daily patterns of feed intake and rumination influence rumen fermentation, rumen pH, and timing of absorbed nutrients in the dairy cow, but the effects of diet composition on these patterns are not well characterized. Data from 3 previously published experiments were examined to determine the influence of dietary starch, fiber, and fatty acids (FA) on daily patterns of intake, rumination, and rumen pH. Dietary neutral detergent fiber (NDF) and starch were investigated in 2 experiments, each with duplicated 4 × 4 Latin square designs with a 2 × 2 factorial arrangement of treatments in cows fed cows 1×/d at 1200 and 1400 h, respectively. To investigate fiber content and digestibility in the first experiment, brown midrib or isogenic conventional corn silage were fed in low- and high-NDF diets (29 and 38%, respectively). To investigate starch source and concentration in the second experiment, ground high-moisture corn or dry ground corn were fed in low- and high-starch diets (21 and 32%, respectively). Effect of fat concentration and saturation was investigated in the third experiment using a replicated 4 × 4 Latin square design that fed cows 1×/d at 0900 h; treatments included a control diet with no added fat and 2.5% added saturated FA, unsaturated FA, or a mixture of the saturated and unsaturated FA. In the first 2 experiments, intake followed a similar daily pattern regardless of starch and NDF concentration or digestibility. Rumination displayed a treatment by time interaction for both NDF and starch concentration, with high-fiber, low-starch diets causing greater rumination overnight but not midday. High-starch diets decreased total daily rumen pH equally across the day, but did not change the daily pattern. Type of corn silage did not affect the daily patterns of rumination or rumen pH, but pH was reduced throughout the day in brown midrib diets. In the third experiment, no interactions between fatty acid supplement and time of day were observed for intake, rumination, or rumen pH. Within all experiments, rumination fit or tended to fit a 24-h rhythm regardless of diet, with the amplitude of the rumination being reduced in low-starch diets and diets containing saturated FA or a mixture of saturated and unsaturated FA. Overall, intake, rumination, and rumen pH follow a daily pattern that was minimally modified by dietary fiber and starch type and level or fat level and fatty acid profile.

Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

Safety and efficacy of direct-acting antivirals for the treatment of chronic hepatitis C in a real-world population aged 65 years and older.

The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P=.074). Similar data were also reported in subgroup of patients aged ≥75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child-Pugh-Turcotte (CTP)-B cirrhosis and 95.4% in CTP-A (P=.013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis. In conclusions, in a real-world setting, DAAs are safe and effective in elderly patients with HCV-related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class.

Risk factors for infection with carbapenem-resistant Klebsiella pneumoniae after liver transplantation: the importance of pre- and posttransplant colonization.

Improved understanding of risk factors associated with carbapenem-resistant-Klebsiella pneumoniae (CR-KP) infection after liver transplantation (LT) can aid development of effective preventive strategies. We performed a prospective cohort study of all adult patients undergoing LT at our hospital during 30-month period to define risk factors associated with CR-KP infection. All patients were screened for CR-KP carriage by rectal swabs before and after LT. No therapy was administered to decolonize or treat asymptomatic CR-KP carriers. All patients were monitored up to 180 days after LT. Of 237 transplant patients screened, 41 were identified as CR-KP carriers (11 at LT, 30 after LT), and 20 developed CR-KP infection (18 bloodstream-infection, 2 pneumonia) a median of 41.5 days after LT. CR-KP infection rates among patients non-colonized, colonized at LT, and colonized after LT were 2%, 18.2% and 46.7% (p < 0.001). Independent risk factors for CR-KP infection identified by multivariate analysis, included: renal-replacement-therapy; mechanical ventilation > 48 h; HCV recurrence, and colonization at any time with CR-KP. Based on these four variables, we developed a risk score that effectively discriminated patients at low versus higher risk for CR-KP infection (AUC 0.93, 95% CI 0.86-1.00, p < 0.001). Our results may help to design preventive strategies for LT recipients in CR-KP endemic areas.

Alemtuzumab plus cyclosporine treatment of the autoimmune hemolytic anemia in an adult bowel transplant.

An adult male underwent a bowel transplant for tufting enteropathy, receiving alemtuzumab, tacrolimus, and steroids as immunosuppressants. Five years later, he developed an autoimmune hemolytic anemia (AIHA), anti-IgG positive, with reduced reticulocyte count, leukopenia, and thrombocytopenia with antiplatelet antibodies. After an unsuccessful initial treatment with high dose steroids, reduction in tacrolimus dose, and intravenous immunoglobulin (IVIG), a bone marrow biopsy revealed absence of erythroid maturation with precursor hyperplasia. The patient was switched to sirolimus and received four doses of rituximab plus two courses of plasmapheresis, which decreased his transfusion requirements. After a febrile episode one month later, the AIHA relapsed with corresponding decreases in platelet and leukocyte count: cyclosporine A (CsA) was started with a second course of rituximab and IVIG without response, even though repeat bone marrow biopsy did not reveal morphology correlated to an acquired pure red cell aplasia (APRCA). Considering the similarity in his clinical and laboratory findings to APRCA, alemtuzumab was added (three doses over a week) with CsA followed by steroids. The patient was eventually discharged transfusion-independent, with increasing hemoglobin (Hb) levels and normal platelet and leukocyte count. One year later he is still disease-free with functioning graft.

Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C.

BACKGROUND: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients' survival. AIM: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. METHODS: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. RESULTS: The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11±3.5 years (range, 5-24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p=0.007), treatment duration >80% of the scheduled period (p=0.027), and early virological response (p=0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p=0.008). CONCLUSIONS: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival.

Can the dropout risk of candidates with hepatocellular carcinoma predict survival after liver transplantation?

In the last US national conference on liver transplantation for hepatocellular carcinoma (HCC), a continuous priority score, that incorporates model for end-stage liver disease (MELD), alpha-fetoprotein and tumor size, was recommended to ensure a more equitable liver allocation. However, prioritizing highest alpha-fetoprotein levels or largest tumors may select lesions at a higher risk for recurrence; similarly, patients with higher degree of liver failure could have lower postoperative survival. Data from 300 adult HCC recipients were reviewed and the proposed HCC-MELD equation was applied to verify if it can predict post-transplantation survival. The 5-year survival and recurrence rates after transplantation were 72.8 and 13.5%, respectively. Cox regression analysis confirmed HCC-MELD as predictive of both postoperative survival and recurrence (p < 0.001). The 5-year predicted survival and recurrence rates were plotted against the HCC-MELD-based dropout probability: the higher the dropout probability while on waiting list, the lower the predicted survival after transplantation, that is worsened by hepatitis C positivity; similarly, the higher the predicted HCC recurrence rate after transplantation. The HCC priority score could predict the postoperative survival of HCC recipients and could be useful in selecting patients with greater possibilities of survival, resulting in higher post-transplantation survival rates of HCC populations.

Harm and benefits of primary liver resection and salvage transplantation for hepatocellular carcinoma.

Primary transplantation offers longer life-expectancy in comparison to hepatic resection (HR) for hepatocellular carcinoma (HCC) followed by salvage transplantation; however, livers not used for primary transplantation can be reallocated to the remaining waiting-list patients, thus, the harm caused to resected patients could be balanced, or outweighed, by the benefit obtained from reallocation of livers originating from HCC patients first being resected. A Markov model was developed to investigate this issue based on literature data or estimated from the United Network for Organ Sharing database. Markov model shows that primary transplantation offers longer life-expectancy in comparison to HR and salvage transplantation if 5-year posttransplant survival remains higher than 60%. The balance between the harm for resected patients and the benefit for the remaining waiting list depends on (a) the proportion of HCC candidates, (b) the percentage shifted to HR and (c) the median expected time-to-transplant. Faced with a low proportion of HCC candidates, the harm caused to resected patients was higher than the benefit that could be obtained for the waiting-list population from re-allocation of extra livers. An increased proportion of HCC candidates and/or an increased median time-to-transplant could lead to a benefit for waiting-list patients that outweighs this harm.

Monitoring cytomegalovirus T-cell immunity in small bowel/multivisceral transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) is a major cause of graft failure and posttransplantation mortality in intestinal/multivisceral transplantation. CMV infection exhibits a wide range of clinical manifestations from asymptomatic infection to severe CMV disease. STUDY'S PURPOSE: The purposes of this study were to assess the utility of measuring CMV-specific cellular immunity in bowel/multivisceral transplant recipients and to provide additional information on the risk of infection and development of CMV disease. METHODS: We studied 10 bowel/multivisceral transplant recipients to investigate the kinetics of CMV infection using real-time polymerase chain reaction (on blood and biopsy tissue samples) and CMV-specific T-cell reconstitution by Enzyme-linked ImmunoSPOT Assay (ELISPOT) that enumerates Interferon-gamma-secreting CMV-specific T cells upon in vitro stimulation with viral antigens (pp65 and IE-1). RESULTS: All patients were seropositive for CMV. According to the pattern of T-cell reconstitution occurring either within the first month after transplantation or later, patients were classified as early (n = 7) or late responders (n = 3). Clinically, early responder patients (3/7; 43%) experienced asymptomatic or mild CMV infections, whereas all late responders (3/3; 100%) developed moderate or severe CMV disease. A reduction in mean and peak CMV viral load was observed in early responders, whereas the onset time of infection did not differ significantly between early and late CMV responders. CONCLUSIONS: A good and early reconstitution of CMV-specific T-cell immune responses after transplantation is a critical determinant in controlling CMV infections. Simultaneous monitoring of CMV infection and CMV-specific T-cell immunity predicts T-cell-mediated control of CMV infection.

Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation.

BACKGROUND: Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates. AIM: To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response. METHODS: Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 micro/kg/week plus RBV 8-10 mg/kg/day for 24 weeks. Those with 'early virological response at week 24' (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C). RESULTS: Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02-106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR. CONCLUSIONS: Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with > or =2 log10 drop in HCV-RNA at week 24.

High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?

BACKGROUND: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. METHODS: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. RESULTS: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a "probable autoimmune hepatitis" (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). CONCLUSIONS: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.

HBV-related cutaneous periarteritis nodosa in a patient 16 years after renal transplantation: efficacy of lamivudine.

Cutaneous periarteritis nodosa (PAN) is a clinical feature characterized by chronic, benign course; its pathogenesis is unknown. In patients submitted to renal transplantation cutaneous PAN is a rare complication. We report a case of cutaneous PAN associated with the reappearance of hepatitis B antigen 16 years after kidney transplantation. A 44-year-old man underwent successful renal transplantation in June 1980. In December 1996 he presented multiple painful erythematous subcutaneous nodules on both legs. Skin lesion biopsy showed the presence of cutaneous PAN. Six months later laboratory data demonstrated the presence of HbsAg. HBeAg, HBcAb and detectable HBV-DNA serum by polymerase-chain-reaction (PCR) assay. Anti-HBs and anti-HBe proved negative. In July 1998 the laboratory tests showed an important increase of HBV-DNA (5.1 billion by Branched DNA), and so lamivudine (100 mg/day) was introduced. HBV-DNA became undetectable by PCR after 3 months of therapy. Seven months later a new skin biopsy was performed. The typical signs of PAN were no longer evident. As HBV infecion was demonstrated six months after the clinical appearance of the PAN, in a patient who was believed to be immune to the virus, it is possible that, in the early stages, the hepatitis B antigen title was methodologically indeterminable, but sufficient to form circulating immune complexes responsible for vasculitis primer. Lamivudine therapy resulted efficacious in favouring the regression of cutaneous PAN, but its long-term efficacy requires further evaluation as regards potential selection of drug resistant hepatitis B virus (HBV) mutants during treatment.

Severe and relapsing upper gastrointestinal bleeding in a patient with Glanzmann's thrombasthenia.

Glanzmann's thrombasthenia (GT) is a rare familial thrombocytic disease inherited as an autosomal recessive disorder that can induce hemorrhages due to a defect of platelet aggregation, resulting from the absence or reduced concentration of the membrane glycoproteic receptor binding the fibrinogen (integrin alpha(IIb)beta3). The gastrointestinal tract is the site of bleeding in only about 10% of cases but the related mortality is high (12.8%). Among the deaths due to hemorrhage, digestive bleeding causes 57.1%. According to reported data, the source of bleeding may be from preexisting gastroduodenal chronic and acute lesions. We report a case of severe and relapsing upper digestive bleeding in a woman with GT and coexisting thrombocytopenia (from HCV-related liver cirrhosis) and H. pylori-positive duodenal ulcer.

Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group.

OBJECTIVES: This study was designed to compare the effects of a 6-month treatment with budesonide 100 microg bid (low dose) and 400 microg bid (standard reference dose) in controlling symptoms and lung function in a group of asthmatics with moderate asthma (baseline FEV(1) > or = 50% and < or = 90% of predicted values) previously treated with inhaled beclomethasone dipropionate (500 to 1,000 microg/d). Moreover, we investigated whether or not asthma exacerbations could be treated by a short-term increase in the daily dose of budesonide. METHODS: After a 2-week run-in period and 1-month treatment with a high dose of budesonide (800 microg bid), 213 patients with moderate asthma were assigned to randomized treatments. Daily treatment included budesonide (bid) plus an additional treatment in case of exacerbation (qid for 7 days). Treatments were as follows: budesonide 400 microg plus placebo (group 1); budesonide 100 microg plus budesonide 200 microg (group 2); and budesonide 100 microg plus placebo (group 3). Symptoms and a peak expiratory flow (PEF) diary were recorded and lung function was measured each month. An exacerbation was defined as a decrease in PEF > 30% below baseline values on 2 consecutive days. RESULTS: We found that that 1-month treatment with a high budesonide dose remarkably reduced all asthma symptoms. Moreover, symptoms were under control in all treatment groups throughout the study period. Similarly, lung function improved and remained stable, and no relevant differences between groups were observed. In each treatment group, the majority of patients had no exacerbations. In patients treated with the standard budesonide dose (group 1), the number of exacerbations and days with exacerbations were significantly lower than in group 3 (intention-to-treat analysis). Additionally, patients treated with low budesonide dose plus budesonide (group 2) experienced a significantly lower number of exacerbations and days with exacerbations compared to group 3 (per-protocol analysis). CONCLUSIONS: This study demonstrates that when patients with moderate asthma had reached a stable clinical condition with a high dose of budesonide, a low dose of budesonide (200 microg/d) is as effective as the standard dose (800 microg/d) in the control of symptoms and lung function over a period of several months. Furthermore, results showed that the addition of inhaled budesonide (800 microg/d) at onset of an asthmatic exacerbation has a beneficial clinical effect.

Functional, life-threatening disorders and splenectomy following liver transplantation.

UNLABELLED: Splenectomy (SPL) in cirrhotic patients undergoing liver transplantation (LTx) may resolve specific problems related to the procedure itself, in case of functional and life-threatening clinical situations often occurring as a result of liver cirrhosis and portal hypertension. METHOD: A single-center experience of ten splenectomies in a series of 180 consecutive adult liver transplant patients over a period of 6 yr is reported. The mean patient age was 46.8 +/- 9.5 yr (range 25 57 yr). Indications for SPL were post-operative massive ascitic fluid loss (n = 3), severe thrombocytopenia (n = 3), acute intra-abdominal hemorrhage (n = 2), infarction of the spleen (n = 1), and multiple splenic artery aneurysms (n = 1). RESULTS: Extreme ascites production due to functional graft congestion disappeared post-SPL, with an improvement of the hepatic and renal functions. SPL was also effective in cases of thrombocytopenia persistence post-LTx, leading to an increase in the platelet count after about 1 wk. Bleeding episodes related to left-sided portal hypertension or trauma were also resolved. The rejection rate during hospitalization was 0%, and no other episodes were recorded in the course of the long-term follow-up. However, sepsis with a fatal outcome occurred in 4 patients, i.e. between 2 and 3 wk post-SPL in three cases and 1 yr after the procedure as a result of pneumococcal infection in the last case. Fatal traumatic cranial injury occurred 3 yr post-LTx in another case. Five patients (50%) are still alive and asymptomatic after a median follow-up period of 36 months. CONCLUSION: The lowering of the portal flow appears to resolve unexplained post-operative ascitic fluid loss as a result of functional graft congestion following LTx. However, because of the enhanced risk of SPL-related sepsis, a partial splenic embolization (PSE) or a spleno-renal shunt could be used as an alternative procedure because it allows us to preserve the immunological function of the spleen. SPL is indicated in case of post-transplant bleeding due to left-sided portal hypertension and trauma, spleen infarction, and to enable prevention of hemorrhage in liver transplant patients with multiple splenic artery aneurysms. Severe and persistent thrombocytopenia could be treated with PSE. Because the occurrence of fatal sepsis post-SPL is a major complication in LTx, functional disorders, such as ascites and thrombocytopenia, should be treated with a more conservative approach.

Transjugular intrahepatic portosystemic shunt after adult liver transplantation: experience in eight patients.

BACKGROUND: Transjugular intrahepatic portosystemic shunting (TIPS) has become an effective treatment for the complications of portal hypertension. We assessed the feasibility and outcome of TIPS in liver transplant recipients. METHODS: During the period from December 1992 to January 1998, eight adults presenting recurrent hepatitis C virus (five patients) and hepatitis B virus (one patient) infection, veno-occlusive disease (one patient), and secondary biliary cirrhosis (one patient) had TIPS because of refractory ascites (five patients), bleeding esophageal varices (one patient), refractory hepatic hydrothorax (one patient), retransplantation (two patients), and redo-biliary surgery (one patient). RESULTS: In two patients, the procedure was difficult due to cavo-caval implantation. Ascites, hydrothorax, and variceal bleeding were controlled in all patients. Moderate to severe encephalopathy developed in four patients; two patients had worsening of their existing encephalopathy. Three of five patients treated with cyclosporine needed a drastic dose reduction due to the development of severe side effects. No long-term survivor developed shunt stenosis or occlusion. Two patients did moderately well at 6 and 14 months, respectively; the former died due to chronic rejection while waiting for a retransplantation. Three did well at 14, 36, and 28 months, respectively; the latter patient died of liver failure 32 months after TIPS. One jaundiced patient died after 1.5 months due to necrotic pancreatitis. Two patients died after 4 and 8.5 months, respectively, due to liver failure; the latter was doing well until 7 months after TIPS. CONCLUSIONS: TIPS is feasible in transplant recipients in cases of decompensated allograft cirrhosis, of allograft veno-occlusive disease or when retransplantation or redo-biliary surgery are scheduled in the presence of portal hypertension. At transplantation, the surgeon should keep in mind the eventuality of a later TIPS procedure. Close immunosuppression monitoring is warranted because modified metabolization of cyclosporine (and probably tacrolimus) may cause serious side effects.

Budesonide down-regulates eosinophil locomotion but has no effects on ECP release or on H2O2 production.

Treatment of allergic asthma with inhaled corticosteroids results in local down-regulation of proinflammatory cytokine synthesis and in marked decrease in tissue eosinophilia. Blood concentrations of inhaled corticosteroids, although significantly lower than those measured in the lung, may still have antiinflammatory effects on circulating eosinophils, reducing their ability to migrate. The aim of our study was to evaluate in vitro the activity of budesonide on blood eosinophils by measuring their chemotactic response, eosinophil cationic protein (ECP) release, and hydrogen peroxide (H2O2) production in the presence of different drug concentrations similar to those obtained at airway level (10(-8) and 10(-7) M) and at blood level (10(-10) and 10(-9) M). Partially purified blood eosinophils, isolated from 23 asthmatic subjects, were used to evaluate the activity of budesonide on: (1) chemotaxis toward the activated fifth component of complement (C5a, 0.1 microg/ml) or recombinant human (rh) interleukin (IL)-5 (200 pg/ml), (2) ECP release by cells stimulated with tetradecanoylphorbol acetate (TPA) and (3) H2O2 production by TPA-activated cells. The chemotactic response to C5a was down-regulated significantly by budesonide only by the highest concentrations tested (10(-8) and 10(-7) M); differently, budesonide was effective in inhibiting eosinophil migration toward rhIL-5, at all concentrations tested (p < 0.01, each comparison). By contrast, no drug-induced modifications were observed in ECP release or in H2O2 production (p > 0.05, each comparison). We conclude that concentrations of budesonide similar to those obtained in vivo are effective in inhibiting eosinophil locomotion but not in down-regulating the release of reactive oxygen species and granule-associated proteins.