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Introduction Routinely, pediatric donor (PD) grafts are allocated to pediatric liver transplantation (LT) recipients; however, occasionally they can be allocated for adult recipients (ARs). Some authors reported decreased patient/graft survival and higher vascular complications, such as hepatic artery thrombosis (HAT), in LT in ARs using PDs. Methods It is a retrospective study enrolling 1202 ARs undergoing LT using whole liver grafts during the period of January 2002 to April 2019. The patients were categorized according to donor age in 2 groups: PDs and adult donors (ADs). The variables were collected from the database including the graft to recipient weight ratio (GWRW) and the incidence of HAT and graft primary nonfunction (PNF). Results The AD group had 1152 patients, and the PD group had 50 patients. PNF occurred in 68 (5.66%) patients, and the distribution between the 2 groups were similar: 65 (5.64%) in the AD group, and 3 (6%) in the PD group (P = .915). HAT was diagnosed in 30 (2.6%) patients in the AD group and in 6 (12%) patients in the PD group. HAT was significantly higher in the PD group (P = .001). In the PD group, the GWRWs among patients diagnosed with HAT were similar (P = .152). Conclusion HAT is higher in PDs, although it is a viable alternative with satisfactory results. Serial Doppler in the first week and early introduction of platelet antiaggregants and/or anticoagulants may be beneficial, albeit it is not clear if it could reduce the incidence of HAT.

A kidney-transplanted patient, unvaccinated against yellow fever (YF), developed high fever, progressed rapidly to hepatic insufficiency and coma, and died 8 days later. Real-time polymarase chain reaction for YF virus collected on the seventh day of symptoms was positive. Autopsy showed disseminated infection and midzonal hepatitis with apoptotic hepatocytes and minimal inflammatory reaction.

Summary Background Uterus transplantation from live donors became a reality to treat infertility following a successful Swedish 2014 series, inspiring uterus transplantation centres and programmes worldwide. However, no case of livebirth via deceased donor uterus has, to our knowledge, been successfully achieved, raising doubts about its feasibility and viability, including whether the womb remains viable after prolonged ischaemia. Methods In September, 2016, a 32-year-old woman with congenital uterine absence (Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome) underwent uterine transplantation in Hospital das Clinicas, University of Sao Paulo, Brazil, from a donor who died of subarachnoid haemorrhage. The donor was 45 years old and had three previous vaginal deliveries. The recipient had one in-vitro fertilisation cycle 4 months before transplant, which yielded eight cryopreserved blastocysts. Findings The recipient showed satisfactory postoperative recovery and was discharged after 8 days' observation in hospital. Immunosuppression was induced with prednisolone and thymoglobulin and continued via tacrolimus and mycophenalate mofetil (MMF), until 5 months post-transplantation, at which time azathioprine replaced MMF. First menstruation occurred 37 days post-transplantation, and regularly (every 26–32 days) thereafter. Pregnancy occurred after the first single embryo transfer 7 months post-transplantation. No blood flow velocity waveform abnormalities were detected by Doppler ultrasound of uterine arteries, fetal umbilical, or middle cerebral arteries, nor any fetal growth impairments during pregnancy. No rejection episodes occurred after transplantation or during gestation. Caesarean delivery occurred on Dec 15, 2017, near gestational week 36. The female baby weighed 2550 g at birth, appropriate for gestational age, with Apgar scores of 9 at 1 min, 10 at 5 min, and 10 at 10 min, and along with the mother remains healthy and developing normally 7 months post partum. The uterus was removed in the same surgical procedure as the livebirth and immunosuppressive therapy was suspended. Interpretation We describe, to our knowledge, the first case worldwide of livebirth following uterine transplantation from a deceased donor in a patient with MRKH syndrome. The results establish proof-of-concept for treating uterine infertility by transplantation from a deceased donor, opening a path to healthy pregnancy for all women with uterine factor infertility, without need of living donors or live donor surgery. Funding Fundacao de Amparo a Pesquisa do Estado de Sao Paulo and Hospital das Clinicas, University of Sao Paulo, Brazil.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) is an emergent microorganism of infections after liver transplant (LT). The aim of this study was to analyze the risk factors for CRE acquisition and infection after LT. METHODS: This was a prospective cohort study involving patients who underwent LT in the 2010 to 2014 period. Surveillance cultures for CRE were collected immediately before LT and weekly thereafter until hospital discharge. RESULTS: We analyzed 386 patients undergoing a total of 407 LTs. Before LT, 68 (17.6%) patients tested positive for CRE, 11 (16.2%) of those patients having CRE infection, whereas 119 (30.8%) patients acquired CRE after LT. Post-LT CRE infection was identified in 59 (15.7%) patients: Klebsiella pneumoniae was isolated in 83.2%; surgical site infection was the most common type of infection (46.7%). Multivariate analysis showed that post-LT dialysis was the only risk factor for post-LT CRE acquisition. Eighty-two percent of patients who underwent 3 or more post-LT dialysis sessions and acquired CRE before LT evolved with post-LT CRE infection. Other risk factors for CRE infection were acquisition of CRE post-LT, Model for End-Stage Liver Disease score greater than 32, combined transplantation, and reoperation. Patients who acquired CRE before LT had a high risk of developing CRE infection (P < 0.001). CONCLUSIONS: Measures for minimizing that risk, including altering the antibiotic prophylaxis, should be investigated and implemented.

Aims The clinical spectrum of yellow fever (YF) ranges from asymptomatic to fulminant hepatitis. During the sylvatic YF epidemic in the metropolitan area of Sao Paulo, Brazil in 2018, seven orthotopic liver transplantations (OLTs) were performed in our institution to treat fulminant YF hepatitis. Three patients recovered, while four patients died following OLT. The autopsy findings of all these cases are presented herein as the first description of YF in transplanted patients. Methods and results All patients were men, aged 16-40 years, without vaccination to YF virus (YFV). All organs were examined, with tissue sampling for histopathological analysis. Detection of YF virus antigens (YFV Ag) was performed with two primary antibodies (mouse polyclonal anti-YFV antibody directed to wild strain and a goat anti-YF virus antibody), and RT-PCR assays were utilised to detect YFV-RNA. All the cases depicted typical findings of YF hepatitis in the engrafted liver. The main extrahepatic findings were cerebral oedema, pulmonary haemorrhage, pneumonia, acute tubular necrosis and ischaemic/reperfusion pancreatitis. Of the four cases, the YVF Ag was detected in the heart in one case, liver and testis in three cases, and the kidney and spleen in all four cases. All four cases had YF virus RNA detected by RT-PCR in the liver and in other organs. Conclusions Infection of the engrafted liver and other organs by YFV, possibly combined with major ischaemic systemic lesions, may have led to the death of four of the seven patients undergoing OLT.

Background Little is known about clinical characteristics and management of severe yellow fever as previous yellow fever epidemics often occurred in times or areas with little access to intensive care units (ICU). We aim to describe the clinical characteristics of severe yellow fever cases requiring admission to the ICU during the 2018 yellow fever outbreak in São Paulo, Brazil. Furthermore, we report on preliminary lessons learnt regarding clinical management of severe yellow fever. Methods Retrospective descriptive cohort study. Demographic data, laboratory test results on admission, clinical follow-up, and clinical outcomes were evaluated. Results From 10 January to 11 March 2018, 79 patients with laboratory confirmed yellow fever were admitted to the ICU in a tertiary hospital in Sao Paolo because of rapid clinical deterioration. On admission, the median AST was 7,000 IU/L, ALT 3,936 IU/L, total bilirubin 5.3 ml/dL, platelet 74 × 103/mm3, INR 2.24 and factor V 37%. Seizures occurred in 24% of patients, even without substantial intracranial hypertension. The high frequency of pancreatitis and rapidly progressive severe metabolic acidosis were notable findings. 73% of patients required renal replacement therapy. The in-hospital fatality rate was 67%. Patients with diabetes mellitus had a higher case fatality rate (CFR) of 80%, while patients without diabetes had a CFR of 65%. Leading causes of death were severe gastrointestinal bleeding, epileptic status, severe metabolic acidosis, necrohemorrhagic pancreatitis, and multi-organ failure. Conclusions Severe yellow fever is associated with a high CFR. The following management lessons were learnt: Anticonvulsant drugs in patients with any symptoms of hepatic encephalopathy or arterial ammonia levels >70 μmol/L was commenced which reduced the frequency of seizures from 28% to 17%. Other new therapy strategies included early institution of plasma exchange. Due to the high frequency of gastric bleeding, therapeutic doses of intravenous proton pump inhibitors should be administered.

Summary Background Yellow fever virus infection results in death in around 30% of symptomatic individuals. The aim of this study was to identify predictors of death measured at hospital admission in a cohort of patients admitted to hospital during the 2018 outbreak of yellow fever in the outskirts of Sao Paulo city, Brazil. Methods In this observational cohort study, we enrolled patients with yellow fever virus from two hospitals in Sao Paolo—the Hospital das Clinicas, University of Sao Paulo and the Infectious Diseases Institute “Emilio Ribas”. Patients older than 18 years admitted to hospital with fever or myalgia, headache, arthralgia, oedema, rash, or conjunctivitis were consecutively screened for inclusion in the present study. Consenting patients were included if they had travelled to geographical areas in which yellow fever virus cases had been previously confirmed. Yellow fever infection was confirmed by real-time PCR in blood collected at admission or tissues at autopsy. We sequenced the complete genomes of yellow fever virus from infected individuals and evaluated demographic, clinical, and laboratory findings at admission and investigated whether any of these measurements correlated with patient outcome (death). Findings Between Jan 11, 2018, and May 10, 2018, 118 patients with suspected yellow fever were admitted to Hospital das Clinicas, and 113 patients with suspected yellow fever were admitted to Infectious Diseases Institute “Emilio Ribas”. 95 patients with suspected yellow fever were included in the study, and 136 patients were excluded. Three (3%) of 95 patients with suspected yellow fever who were included in the study were excluded because they received a different diagnosis, and 16 patients with undetectable yellow fever virus RNA were excluded. Therefore, 76 patients with confirmed yellow fever virus infection, based on detectable yellow fever virus RNA in blood (74 patients) or yellow fever virus confirmed only at the autopsy report (two patients), were included in our analysis. 27 (36%) of 76 patients died during the 60 day period after hospital admission. We generated 14 complete yellow fever virus genomes from the first 15 viral load-detectable samples. The genomes belonged to a single monophyletic clade of the South America I genotype, sub-genotype E. Older age, male sex, higher leukocyte and neutrophil counts, higher alanine aminotransferase, aspartate transaminase (AST), bilirubin, and creatinine, prolonged prothrombin time, and higher yellow fever virus RNA plasma viral load were associated with higher mortality. In a multivariate regression model, older age, elevated neutrophil count, increased AST, and higher viral load remained independently associated with death. All 11 (100%) patients with neutrophil counts of 4000 cells per mL or greater and viral loads of 5·1 log10 copies/mL or greater died (95% CI 72–100), compared with only three (11%) of 27 (95% CI 2–29) among patients with neutrophil counts of less than 4000 cells per mL and viral loads of less than 5·1 log10 copies/mL. Interpretation We identified clinical and laboratory predictors of mortality at hospital admission that could aid in the care of patients with yellow fever virus. Identification of these prognostic markers in patients could help clinicians prioritise admission to the intensive care unit, as patients often deteriorate rapidly. Moreover, resource allocation could be improved to prioritise key laboratory examinations that might be more useful in determining whether a patient could have a better outcome. Our findings support the important role of the virus in disease pathogenesis, suggesting that an effective antiviral could alter the clinical course for patients with the most severe forms of yellow fever. Funding Sao Paulo Research Foundation (FAPESP).

Histology is the gold standard for diagnosing acute rejection and hepatitis C recurrence after liver transplantation. However, differential diagnosis between the two can be difficult. We evaluated the role of C4d staining and quantification of hepatitis C virus (HCV) RNA levels in liver tissue. This was a retrospective study of 98 liver biopsy samples divided into four groups by histological diagnosis: acute rejection in patients undergoing liver transplant for hepatitis C (RejHCV+), HCV recurrence in patients undergoing liver transplant for hepatitis C (HCVTx+), acute rejection in patients undergoing liver transplant for reasons other than hepatitis C and chronic hepatitis C not transplanted (HCVTx-). All samples were submitted for immunohistochemical staining for C4d and HCV RNA quantification. Immunoexpression of C4d was observed in the portal vessels and was highest in the HCVTx- group. There was no difference in C4d expression between the RejHCV+ and HCVTx+ groups. However, tissue HCV RNA levels were higher in the HCVTx+ group samples than in the RejHCV+ group samples. Additionally, there was a significant correlation between tissue and serum levels of HCV RNA. The quantification of HCV RNA in liver tissue might prove to be an efficient diagnostic test for the recurrence of HCV infection.

Granulicatella and Abiotrophia are genera of fastidious Gram-positive cocci commensal of the oral, genitourinary, and intestinal flora. We report the first case of infective endocarditis caused by Granulicatella sp. in a kidney transplant recipient. A 67-year-old male kidney transplant recipient was admitted to the hospital for investigation of fever, abdominal pain, and diarrhea. On physical examination, he was dehydrated. Laboratory tests identified impaired renal function (creatinine level of 15.5 mg/dl; reference, 3.0 mg/dl), metabolic acidosis, and electrolyte disturbances. Cryptosporidium sp. was identified as the cause of the diarrhea, and the infection was treated with nitazoxanide. On admission, cultures of blood, urine, and stool samples were negative. Echocardiography results were normal. Despite the antimicrobial treatment, the fever persisted. A transthoracic echocardiogram revealed infective endocarditis of the mitral valve, and Granulicatella spp. were isolated in blood cultures. Although the patient was treated with penicillin and amikacin, he evolved to septic shock of pulmonary origin and died. Infective endocarditis caused by Granulicatella sp. should be suspected in cases of culture-negative endocarditis.

IntroductionAn ongoing outbreak of yellow fever (YF) has been reported in Brazil with 1261 confirmed cases and 409 deaths since July 2017. To date, there is no specific treatment available for YF. Recently published papers describing in vitro and animal models suggest a potential effect of antiviral drugs (approved for the treatment of hepatitis virus) against flaviviruses, including YF. The primary aim of this study is to analyse the effect of sofosbuvir on viral kinetics and clinical outcomes among patients presenting with YF. This is a multicentre open-label randomised controlled trial with 1:1 individual allocation, stratified by severity and by recruiting centre.Methods and analysisAdults with suspected or confirmed YF infection and symptoms lasting up to 15 days are screened. Eligible and consenting patients are randomised to receive oral sofosbuvir 400 mg daily for 10 days or to receive standard clinical care. Viral kinetics are measured daily and the reduction in YF plasma viral load from the sample at inclusion to 72 hours after randomisation will be compared between active and control groups. Clinical outcomes include severity meeting criteria for intensive care support, liver transplantation, in-hospital mortality and mortality within 60 days.Ethics and disseminationEthics approval was obtained at the participating sites and at the national research ethics committee (CAAE 82673018.6.1001.0068). The trial has been submitted for ethical approval at additional potential recruiting centres. Results of the study will be published in journals and presented at scientific meetings.Trial registrationBrazilian Clinical Trials Registry (RBR-93dp9n).

Human immunodeficiency virus (HIV) infection was considered a contraindication for solid organ transplantation (SOT) in the past. However, HIV management has improved since highly active antiretroviral therapy (HAART) became available in 1996, and the long-term survival of patients living with HIV has led many transplant programs to reevaluate their policies regarding the exclusion of patients with HIV infection. Based on the available data in the medical literature and the cumulative experience of transplantation in HIV-positive patients at our hospital, the aim of the present article is to outline the criteria for transplantation in HIV-positive patients as recommended by the Immunocompromised Host Committee of the Hospital das Clínicas of the University of São Paulo.

Objectives: To assess the virologic and immunological response of darunavir/ritonavir plus optimized background therapy in highly antiretroviral-experienced HIV-infected patients in Brazil. Methods: Prospective cohort study carried out in a tertiary center in Sao Paulo, Brazil. Three-class antiretroviral-experienced patients with confirmed virologic failure began darunavir/ritonavir plus optimized background therapy (nucleoside/tide reverse transcriptase inhibitors ± raltegravir ± enfuvirtide ± maraviroc) after performing a genotypic resistance assay. Clinical evaluation and laboratory tests were collected at baseline and at weeks 12, 24, and 48. Multivariate analysis was performed to identify predictors of virologic response at 48 weeks. Results: Ninety-two patients were included. The median of darunavir resistant mutation was 1 (range 0-6). The median genotypic sensitivity score in the optimized background therapy was 2 (interquartile range 1-2). At week 48, 83% (95% CI: 75–90%) had an HIV RNA level 100 000 copies/mL was inversely associated with virologic success at week 48 (HR: 0.22, 95% CI: 0.06-0.85, p = 0.028). Conclusions: Darunavir/ritonavir plus optimized background therapy was a highly effective salvage regimen under clinical routine conditions in a referral center in Brazil, which is similar to the reported in high-income countries. Keywords: Highly active antiretroviral therapy, Darunavir, Acquired immunodeficiency syndrome, Developing countries

Avelino-Silva VI, D′Albuquerque LAC, Bonazzi PR, Song ATW, Miraglia JL, de Brito Neves A, Abdala E. Liver transplant from Anti-HBc-positive, HBsAg-negative donor into HBsAg-negative recipient: is it safe? A systematic review of the literature. Clin Transplant 2010: 24: 735–746. © 2010 John Wiley & Sons A/S. Abstract: Introduction: After liver transplant (LT) from Anti-HBc+/HBsAg− donors into HBsAg− recipients, transmission of hepatitis B virus (HBV) may occur (de novo HBV infection). This study analyzes the incidence of de novo HBV infection in HBsAg− recipients of Anti-HBc+/HBsAg− LT with respect to: (i) the recipients’ HBV serology and (ii) the type of preventive therapy adopted. Methods: A systematic review of the literature using the electronic database Medline. Results: Five hundred and fifty-two LT in 36 articles were selected. Lamivudine, Hepatitis B immune globulin (HBIG), revaccination, and combined therapies were employed in multiple strategies as preventive interventions. Naive recipients had a high risk of de novo HBV infection, with smaller incidences when HBIG and lamivudine were used, either alone or in association. Vaccinated recipients or those with isolated hepatitis B core antibodies (Anti-HBc) and previous HBV infection had lower risks of viral transmission, additionally reduced by any prophylaxis adoption. Discussion: LT from Anti-HBc+/HBsAg− donors into HBsAg− recipients is apparently safe, as long as the recipient is vaccinated or presents an isolated Anti-HBc or previous HBV infection and some prophylaxis is employed. Currently lamivudine seems the best alternative; other nucleoside analogs and revaccination strategies should be considered in future studies. Follow-up and preventive therapies should be maintained for five yr or preferably throughout the recipients’ life span.

To identify risk factors associated with survival in patients retransplanted for hepatitis C virus (HCV) recurrence and to apply a survival score to this population.We retrospectively identified 108 patients retransplanted for HCV recurrence in eight European liver transplantation centers (seven in France, one in Spain). Data collection comprised clinical and laboratory variables, including virological and antiviral treatment data. We then analyzed the factors associated with survival in this population. A recently published score that predicts survival in retransplantation in patients with hepatitis C was applied. Because there are currently no uniform recommendations regarding selection of the best candidates for retransplantation in this setting, we also described the clinical characteristics of 164 patients not retransplanted, with F3, F4, or fibrosing cholestatic hepatitis (FCH) post-first graft presenting with hepatic decompensation.Overall retransplantation patient survival rates were 55%, 47%, and 43% at 3, 5, and 10 years, respectively. Patients who were retransplanted for advanced cirrhosis had survival rates of 59%, 52%, and 49% at 3, 5, and 10 years, while those retransplanted for FCH had survival rates of 34%, 29%, and 11%, respectively. Under multivariate analysis, and adjusting for the center effect and the occurrence of FCH, factors associated with better survival after retransplantation were: negative HCV viremia before retransplantation, antiviral therapy after retransplantation, non-genotype 1, a Model for End-stage Liver Disease (MELD) score25 when replaced on the waiting list, and a retransplantation donor age60 years. Although the numbers were small, in the context of the new antivirals era, we showed that outcomes in patients who underwent retransplantation with undetectable HCV viremia did not depend on donor age and MELD score. The Andrés score was applied to 102 patients for whom all score variables were available, producing a mean score of 43.4 (SD = 6.6). Survival rates after the date of the first decompensation post-first liver transplantation (LT1) in the liver retransplantation (reLT) group (94 patients decompensated) at 3, 5, and 10 years were 62%, 59%, and 51%, respectively, among 78 retransplanted individuals with advanced cirrhosis, and 42%, 32%, and 16% among 16 retransplanted individuals with FCH. In the non-reLT group with hepatic decompensation, survival rates were 27%, 18%, and 9% at 3, 5, and 10 years, respectively (P0.0001). Compared with non-retransplanted patients, retransplanted patients were younger at LT1 (mean age 48 ± 8 years compared to 53 ± 9 years in the no reLT group, P0.0001), less likely to have human immunodeficiency virus (HIV) co-infection (4% vs 14% among no reLT patients, P = 0.005), more likely to have received corticosteroid bolus therapy after LT1 (25% in reLT vs 12% in the no reLT group, P = 0.01), and more likely to have presented with sustained virological response (SVR) after the first transplantation (20% in the reLT group vs 7% in the no reLT group, P = 0.028).Antiviral therapy before and after retransplantation had a substantial impact on survival in the context of retransplantation for HCV recurrence, and with the new direct-acting antivirals now available, outcomes should be even better in the future.

Considering the relevance of AIDS/tuberculosis comorbidity worldwide, especially in Brazil, this study was developed to describe the clinical and epidemiological features of the comorbid cases identified from 1989 to 1997 by the epidemiology service of the Hospital das Clínicas of the Universidade de São Paulo. METHODS: Databases containing information on all identified AIDS/tuberculosis cases cared for at the hospital were used to gather information on comorbid cases. RESULTS: During the period, 559 patients were identified as presenting with AIDS/tuberculosis comorbidity. Risk behavior for AIDS was primarily heterosexual contact (38.9%), followed by intravenous drug use (29.3%) and homosexual/bisexual contact (23.2%). Regarding clinical features, there were higher rates of extrapulmonary tuberculosis when compared to tuberculosis without comorbidity. There was an increase in reporting of AIDS by ambulatory units during the period. Epidemiologically, there was a decrease in the male/female ratio, a predominance in the 20 to 39 year-old age group, and a majority of individuals who had less than 8 years of schooling and had low professional qualifications. CONCLUSIONS: High rates of AIDS/tuberculosis cases at our hospital indicate the need for better attention towards early detection of tuberculosis, especially in its extrapulmonary form. Since the population that attends this hospital tends to be of a lower socioeconomic status, better management of AIDS and tuberculosis is required to increase the rates of treatment adherence and thus lower the social costs.

Cat-scratch disease, primarily caused by Bartonella henselae, typically presents with regional adenopathy, and the role of antibiotics in the treatment is debatable. We present a report of B. henselae infection transmitted by the same kitten to 4 different individuals, each with different clinical characteristics, treatment, and evolution.

Since 1963, when the first human liver transplantation (LT) was performed by Thomas Starzl, the world has witnessed 50 years of development in surgical techniques, immunosuppression, organ allocation, donor selection, and the indications and contraindications for LT. This has led to the mainstream, well-established procedure that has saved innumerable lives worldwide. Today, there are hundreds of liver transplant centres in over 80 countries. This review aims to describe the main aspects of LT regarding the progressive changes that have occurred over the years. We herein review historical aspects since the first experimental studies and the first attempts at human transplantation. We also provide an overview of immunosuppressive agents and their potential side effects, the evolution of the indications and contraindications of LT, the evolution of survival according to different time periods, and the evolution of methods of organ allocation.

Trichosporon species are rare etiologic agents of invasive fungal infection in solid organ transplant (SOT) recipients. We report 2 well-documented cases of Trichosporon inkin invasive infection in SOT patients. We also conducted a detailed literature review of Trichosporon species infections in this susceptible population. We gathered a total of 13 cases of Trichosporon species infections. Any type of organ transplantation can be complicated by Trichosporon infection. Bloodstream infections and disseminated infections were the most common clinical presentations. Liver recipients with bloodstream or disseminated infections had poor prognoses. Although the most common species was formerly called Trichosporon beigelii, this species name should no longer be used because of the changes in the taxonomy of this genus resulting from the advent of molecular approaches, which were also used to identify the strains isolated from our patients. Antifungal susceptibility testing highlights the possibility of multidrug resistance. Indeed, Trichosporon has to be considered in cases of breakthrough infection or treatment failure under echinocandins or amphotericin therapy. Voriconazole seems to be the best treatment option.

INTRODUÇÃO: Doença hepática avançada causada pelo vírus da hepatite C (VHC) é a principal causa de indicação de transplante de fígado. No entanto, mais da metade dos casos apresenta recidiva histológica em até um ano. A biópsia hepática tem importante papel no diagnóstico da recidiva e na orientação do manejo, porém o diagnóstico diferencial com rejeição pode ser difícil. O marcador tecidual C4d e a PCR quantitativa para o VHC têm sido propostos como métodos auxiliares nessa diferenciação diagnóstica. OBJETIVOS: O objetivo primário foi avaliar o papel da deposição de C4d e da PCR quantitativa de VHC tecidual no diagnóstico diferencial entre rejeição aguda e recidiva de hepatite C em pacientes transplantados de fígado. Os objetivos secundários foram: avaliar a associação de deposição de C4d com as características epidemiológicas, clínicas, laboratoriais e histológicas de rejeição aguda e hepatite crônica; e avaliar a associação da PCR quantitativa de VHC tecidual com as características epidemiológicas, clínicas, laboratoriais e histológicas de hepatite crônica. MÉTODO: Estudo diagnóstico retrospectivo com amostras de biópsia hepática. Os casos foram selecionados de acordo com o diagnóstico histológico, e divididos em quatro grupos: rejeição em pacientes transplantados por VHC (grupo I), recidiva do VHC pós-transplante (grupo II), rejeição em pacientes transplantados sem VHC (grupo III), e hepatite crônica em pacientes não-transplantados (grupo IV). Foi realizada revisão de prontuários e do sistema informatizado laboratorial para obtenção de dados demográficos, clínicos e laboratoriais. As amostras de biópsia hepática foram submetidas a imunohistoquímica para detecção de C4d (com graduação quantitativa dos compartimentos portal, sinusoidal e centrolobular) e quantificação de RNA do VHC. Os seguintes desfechos foram comparados entre os grupos: quantificação de C4d no tecido hepático e quantificação de RNA de VHC no tecido hepático. RESULTADOS: Foram incluídos 28 casos no grupo I, 25 casos no grupo II, 20 casos no grupo III, e 25 casos no grupo IV. O principal compartimento de deposição foi o portal, com intensa deposição no grupo de hepatite crônica não-transplantado (grupo IV), maior em relação aos demais grupos (p=0,002). O C4d portal teve intensa correlação com o grau de inflamação periportal. Não houve diferença estatística na quantificação de C4d entre os grupos de rejeição e recidiva em pacientes com hepatite C. A quantificação de RNA de VHC tecidual foi maior nas amostras de recidiva de VHC em relação ao grupo de rejeição em VHC (p

Information about resistance profile of darunavir (DRV) is scarce in Brazil. Our objectives were to estimate the prevalence of DRV resistance mutations in patients failing protease inhibitors (PI) and to identify factors associated with having more DRV resistance mutations. All HIV-infected patients failing PI-based regimens with genotyping performed between 2007 and 2008 in a referral teaching center in São Paulo, Brazil, were included. DRV-specific resistance mutations listed by December 2008 IAS-USA panel update were considered. Two Poisson regression models were constructed to assess factors related to the presence of more DRV resistance mutations. A total of 171 HIV-infected patients with available genotyping were included. The number of patients with lopinavir, saquinavir, and amprenavir used in previous regimen were 130 (76%), 83 (49%), and 35 (20%), respectively. The prevalence of major DRV resistance mutations was 50V: 5%; 54M: 1%; 76V: 4%; 84V: 15%. For minor mutations, the rates were 11I: 3%; 32I: 7%; 33F: 23%; 47V: 6%; 54L: 6%; 74P: 3%; 89V: 6%. Only 11 (6%) of the genotypes had ≥ 3 DRV resistance mutations. In the clinical model, time of HIV infection of > 10 years and use of amprenavir were independently associated with having more DRV resistance mutations. In the genotyping-based model, only total number of PI resistance mutations was associated with our outcome. In conclusion, the prevalence of DRV mutations was low. Time of HIV infection, use of amprenavir and total number of PI resistance mutations were associated with having more DRV mutations. Keywords: antiretroviral therapy, highly active, HIV protease inhibitors, acquired immunodeficiency syndrome, Brazil

After liver transplant (LT) from Anti-HBc+/HBsAg- donors into HBsAg- recipients, transmission of hepatitis B virus (HBV) may occur (de novo HBV infection). This study analyzes the incidence of de novo HBV infection in HBsAg- recipients of Anti-HBc+/HBsAg- LT with respect to: (i) the recipients' HBV serology and (ii) the type of preventive therapy adopted.A systematic review of the literature using the electronic database Medline.Five hundred and fifty-two LT in 36 articles were selected. Lamivudine, Hepatitis B immune globulin (HBIG), revaccination, and combined therapies were employed in multiple strategies as preventive interventions. Naïve recipients had a high risk of de novo HBV infection, with smaller incidences when HBIG and lamivudine were used, either alone or in association. Vaccinated recipients or those with isolated hepatitis B core antibodies (Anti-HBc) and previous HBV infection had lower risks of viral transmission, additionally reduced by any prophylaxis adoption.LT from Anti-HBc+/HBsAg- donors into HBsAg- recipients is apparently safe, as long as the recipient is vaccinated or presents an isolated Anti-HBc or previous HBV infection and some prophylaxis is employed. Currently lamivudine seems the best alternative; other nucleoside analogs and revaccination strategies should be considered in future studies. Follow-up and preventive therapies should be maintained for five yr or preferably throughout the recipients' life span.

Settings Despite a now codified antibiotic treatment for Lyme disease, a significant proportion of patients treated according to recommendations complain of persistent signs and symptoms. The pathophysiological mechanisms which underlie this syndrome of post-treatment chronic systemic illness remain unclear. For some physicians post-treatment symptoms indicate a persistent infection requiring prolonged antibiotic therapy. For others, there is no benefit from antimicrobial therapy. The difficulty of assessment encountered in studies is significant because many symptoms are subjective. We think that the term “chronic Lyme disease” is not appropriate and should be replaced by chronic “tick associated poly-organic syndrome” (TAPOS). Objective This open-label prospective study was made on a group of 100 patients having followed a medical treatment for a chronic TAPOS and to evaluate their evolution under prolonged antibiotic treatment. Results The medical management was found to be effective for symptoms, especially for patients with a high probability of chronic TAPOS (NEJM score). Patients with post tick-bite symptoms, which often worsens their quality of life, deserve particular attention. Conclusion This study had methodological limitations but could help in terms of feasibility, choice of inclusion criteria, and design of follow-up for a future randomized, double blind study to test for an optimal management of TAPOS.

Mycophenolate mofetil (MMF) is currently used for prophylaxis of acute rejection in solid organ transplantation. There have been diverging reports regarding an association between MMF and the risk of cytomegalovirus (CMV) infection. We reviewed the main published studies in an attempt to clarify the association between the use of MMF and the risk, frequency and severity of CMV infections. In a search of the Medline database with the terms "mycophenolate" and "cytomegalovir*", 42 articles were found to be relevant; among these, 29 articles were thoroughly analyzed. The first studies on MMF in renal transplantation already showed a tendency towards an association between this drug and the occurrence of CMV disease. Further studies were designed specifically to study this association; with the conclusion that an immunosuppressive regimen containing MMF increases the likelihood of CMV disease. Most studies were performed with kidney transplant recipients. We conclude that the use of MMF apparently increases the incidence of CMV disease in renal transplant patients; however, further studies are needed to confirm this association.

A febre amarela é uma febre hemorrágica, viral e endêmica de regiões tropicais na América Central e do Sul e no continente Africano, afetando principalmente humanos e primatas não-humanos, causada pelo vírus da Febre Amarela (YFV). O recente surto de Febre amarela no Brasil foi um dos mais graves nos tempos atuais disseminando-se para áreas com baixa cobertura vacinal. Durante os picos dos surtos, foi possível observar uma diferença na evolução clínica dos pacientes que trouxe o questionamento se o vírus poderia ter apresentado mutações que levassem a uma alteração no quadro clínico. O presente estudo avaliou a diversidade genética do vírus da Febre Amarela dos casos internados no Hospital das Clínicas da Faculdade de Medicina de São Paulo, que sobreviveram à infecção durante o surto ocorrido em São Paulo nos anos de 2018 e 2019 e determinou a carga viral bem como o genótipo da cepa viral circulante. Para a realização deste estudo foram utilizadas amostras de soro e/ou urina positivas para o vírus da Febre Amarela, que foram submetidas à extração do RNA viral e em seguida à amplificação de cDNA. O sequenciamento de nova geração foi realizado e posteriormente feita a análise de dados utilizando ferramentas de bioinformática próprias para gerar as informações sobre a qualidade e cobertura das sequências a fim de realizar a montagem do genoma viral, análises das variantes e análises filogenéticas. Utilizando essa estratégia, foram obtidos 39 genomas quase completos, sendo possível a análise da diversidade genética viral entre os grupos de 2018 e 2019. Foram encontradas 46 substituições nucleotídicas (nt), sendo 20 delas substituições não sinônimas, com destaque para as posições 195 nt (presente em 60% das amostras de 2019) e 218 nt no capsídeo (presente em 28,6% das amostras de 2018), 5055 nt na NS3 presente em 100% das amostras deste estudo e 10.104 nt na NS5 (42,85% de 2018 e 96% de 2019), proteína polimerase do vírus. A única substituição nucleotídica encontrada neste estudo previamente publicada foi na posição 5055 nt da proteína NS3. Analisando as árvores filogenéticas, os genomas foram classificados como genótipo Sul Americano I subgrupo E, sendo este resultado comparado com estudos previamente publicados e de acordo com o descrito. É possível observar que 85,7% da casuística deste estudo é composta por pacientes do sexo masculino. Mapeamentos geográficos do provável local de infecção dos pacientes incluídos no estudo, demonstraram que o surto de 2018 teve uma maior concentração na região da Grande São Paulo, chegando ao litoral paulista, e o surto de 2019 concentrou-se, em sua maior parte, no Vale do Ribeira. Este estudo sugere que os vírus circulantes nos surtos de 2018 e 2019 são distintos, porém para um melhor entendimento do impacto das variantes sobre a patogênese viral, é necessária uma análise in silico. Em geral, as análises aqui realizadas permitem um melhor entendimento do genoma do YFV circulante em São Paulo e contribui para futuros estudos virológicos e epidemiológicos Yellow fever is a viral and endemic hemorrhagic fever from tropical regions in the Central and South Americas and Africa, affecting mainly humans and nonhuman primates, caused by the Yellow Fever virus (YFV). The recent outbreak of yellow fever in Brazil has been one of the most severe in the last decades, spreading to areas with low vaccine coverage. During the peak of the 2018-2019 outbreak, it was possible to observe a difference in the clinical evolution of the patients and it raised questions of whether the virus could have had mutations that led to milder clinical symptoms. The present study aimed to evaluate the genetic diversity of Yellow fever virus of Hospital das Clinicas da Faculdade de Medicina de Sao Paulo, hospitalized cases that survived the infection during the recent outbreak, in order to determine the viral load and genotype of the circulating viral strain in Sao Paulo. YFV-positive serum and / or urine samples were subjected to viral RNA extraction and then cDNA amplification. New generation sequencing and data analyses were carried out using bioinformatics tools for quality and coverage analysis for genome assembly, variant and phylogenetic analyses. Almost thirty-nine nearly complete YFV genomes were obtained and genetic diversity analysis comparing the circulating virus strains during 2018 and 2019, allowed us to find 46 nucleotides (nt) substitutions, and 21 of them were non-synonymous substitutions, highlighting the positions 195nt (60% of samples from 2019) and 218nt (28.6% of samples from 2018) in capsid protein, 5055nt (100% of samples) in NS3 protein and 10.104 in NS5 protein (42.85% of samples from 2018 and 96% samples from 2019). Phylogenetic analysis demonstrated that all YFV strains circulating during the outbreak form a unique major clade with the South American IE genotype. This finding was compared with previously published studies and is in accordance with what has been described so far. In conclusion, it was possible to describe that 85.7% of all patients enrolled in this study are male and the peak from 2018 YFV outbreak was concentrated in Greater Sao Paulo, going to the coast but the peak from 2019 outbreak was more concentrated in Vale do Ribeira. Our findings suggest that 2018 and 2019 circulating viruses were distinct from each other however for a better understanding of how these variants affect the viral pathogenesis it is necessary to perform an in silico analysis. Overall, our findings provide an overview of YFV genome characterization in Sao Paulo and contribute for future virological and epidemiological studies

INTRODUÇÃO: A hepatite B é uma das principais patologias hepáticas e uma das doenças infecciosas mais desafiadoras à saúde pública mundial, com altos índices de morbidade e mortalidade relacionadas à evolução da infecção pelo vírus da hepatite B (HBV). Dez diferentes genótipos (A-J) do HBV já foram caracterizados até o presente momento, sendo os genótipos F e H os que apresentam maior divergência e estão associados com casos de hepatite B nas Américas. OBJETIVOS: O objetivo deste trabalho foi sequenciar genomas completos de amostras dos genótipos F e H do HBV provenientes do Brasil e do México utilizando a metodologia de sequenciamento de nova geração; e analisar características genéticas relevantes para a compreensão da história natural das infecções associadas com esses genótipos. MATERIAIS E MÉTODOS: Foram incluídas 90 amostras de plasma com DNA do HBV detectável pertencentes aos genótipos F (n = 59) e H (n = 31), as quais foram submetidas à extração do DNA viral e posteriormente à amplificação do genoma completo do HBV. As amostras amplificadas foram submetidas à fragmentação do DNA, marcação e finalmente sequenciamento de última geração na plataforma MiSeq (Illumina). A análise dos dados foi desenvolvida por meio de ferramentas de bioinformática, nas quais foram avaliadas a qualidade das leituras obtidas e a cobertura de diferentes regiões do genoma. Os dados de sequenciamento foram analisados usando ferramentas de biotecnologia considerando qualidade e cobertura para alinhar os fragmentos e criar contigs mais longos. Sequências curadas e editadas foram então alinhadas com sequências de referência para determinar o subgenótipo viral e para detectar variantes de sequência em posições relevantes nos diferentes genes virais. Uma árvore filogenética foi construída usando métodos Bayesianos. Para a análise de variantes foi utilizada a ferramenta Freebayes. RESULTADOS: Foi possível amplificar o genoma completo do HBV de 31 amostras e dessas 18 foram sequenciadas com sucesso (HBV/F=16 e HBV/H=2).. A análise das sequências geradas mostrou que uma das amostras genótipo F apresentava co-infeccção com os subgenótipos F1b e F3, enquanto as demais amostras eram todas subgenótipo F2a. Não foram observados eventos de recombinação nos genomas de HBV/F e H sequenciados. As principais variantes observadas nesse estudo foram aquelas com alterações nos genes Pré-S e S que levam à interrupção prematura da síntese ou não produção das proteínas de superfície (7/18); e mutações no códon de iniciação do gene pré-core que resultam na falta de síntese da proteína HBeAg (11/18). Essas variantes foram observadas em alguns casos compondo a população viral majoritária e em outros a minoritária. CONCLUSÕES: Neste trabalho, desenvolvemos uma metodologia de NGS aplicada para os genótipos F e H, característicos da América Latina em amostras obtidas no México e no Brasil. Estas amostras tiveram seus genomas completos sequenciados e encontrou-se 15 amostras do subgenótipo F2a, uma amostra apresentando co-infecção com os subgenótipos F1b e F3 e 2 amostras do genótipo H INTRODUCTION: Hepatitis B is one of the main liver diseases and one of the most challenging infectious diseases to public health worldwide, with high rates of morbidity and mortality related to the evolution of hepatitis B virus (HBV) infection. Ten different genotypes (A-J) of HBV have been characterized to date, with the F and H genotypes showing the greatest divergence and being associated with cases of hepatitis B in the Americas. OBJECTIVES: The aim of this work was to sequence complete genomes of samples of HBV F and H genotypes from Brazil and Mexico using the next-generation sequencing methodology; and analyze genetic characteristics relevant to understanding the natural history of infections associated with these genotypes. MATERIALS AND METHODS: 90 plasma samples with detectable HBV DNA belonging to the F (n = 59) and H (n = 31) genotypes were included. The amplified samples were submitted to DNA fragmentation, labeling and finally sequencing of the latest generation in the MiSeq platform (Illumina). Data analysis was carried out using bioinformatics tools, in which the quality of the readings obtained and the coverage of different regions of the genome were evaluated. Sequencing data was analyzed using biotechnology tools considering quality and coverage to align fragments and create longer contigs. Cured and edited sequences were then aligned with reference sequences to determine viral subgenotype and to detect sequence variants at relevant positions in the different viral genes. A phylogenetic tree was constructed using Bayesian methods. For the analysis of variants, the Freebayes tool was used. RESULTS: It was possible to amplify the complete HBV genome of 31 samples and of these 18 were successfully sequenced (HBV/F=16 and HBV/H=2). The analysis of the generated sequences showed that one of the F genotype samples presented co- infection with F1b and F3 subgenotypes, while the other samples were all F2a subgenotype. No recombination events were observed in the sequenced HBV/F and H genomes. The main variants observed in this study were those with alterations in the Pre-S and S genes that lead to premature interruption of the synthesis or non-production of surface proteins (7/18); and mutations in the pre-core gene start codon that result in lack of HBeAg protein synthesis (11/18). These variants were observed in some cases making up the majority viral population and in others the minority. CONCLUSIONS: In this work, we developed an NGS methodology applied to F and H genotypes, characteristic of Latin America, in samples obtained from Mexico and Brazil. These samples had their complete genomes sequenced and 15 samples of the F2a subgenotype were found, one sample showing co-infection with the F1b and F3 subgenotypes and 2 samples of the H genotype

Introdução - A colonização intestinal prévia por bactérias multirresistentes (BMR) é um fator de risco para infecções da corrente sanguínea (ICS) e uma das principais complicações na fase inicial do Transplante de Células-Tronco Hematopoiéticas (TCTH). Avaliamos o impacto do Lactobacillus plantarum na modulação do microbioma intestinal em candidatos ao TCTH colonizados por BMR. Métodos - Amostras de fezes foram obtidas previamente à introdução de L. plantarum e ao TCTH, na segunda semana de uso do L. plantarum, na neutropenia, na semana anterior a infecção e na enxertia do TCTH. Foram incluídos 42 candidatos a TCTH autólogo ou alogênico com diagnósticos oncohematológicos. Os participantes foram alocados em um grupo de intervenção (n=22) que recebeu cápsulas de L. plantarum (5x109 UFC) duas vezes ao dia antes do TCTH até o início da neutropenia e um grupo controle (n=20). A região V4 do gene rRNA bacteriano 16S foi sequenciada em 93 amostras de fezes de um subconjunto de 33 pacientes. Colonização por MDRO foi avaliada por cultura em meio seletivo e PCR para identificação de genes de resistências. Clonalidade dos isolados foi avaliada por PFGE. Resultados A média da adesão à intervenção foi de 86% (±11%) por cerca de 43(±29) dias de consumo. L. plantarum foi seguro, tolerável e associado a um aumento na abundância de Lactobacillales (p = 0,004). Aumento de Lactococcus e redução de Turicibacter foram identificados na segunda semana de uso de L. plantarum. Não houve diferença na redução de BMR entre os grupos, nem um mesmo perfil clonal dos isolados foi identificado entre os pacientes. Foi encontrado maior abundância de Enterococcus no grupo controle na enxertia do TCTH. Diversidades alfa e beta foram alteradas ao longo do procedimento de TCTH, independentemente do uso de L. plantarum. Conclusões - L. plantarum foi seguro e pode, potencialmente, reduzir os níveis fecais do gênero Enterococcus em candidatos a TCTH. No entanto, não mostrou impacto significativo na descolonização por BMR Background - Previous gut colonization by multidrug resistant organisms(MDROs) is a risk factor for bloodstream infections(BSI) and a major complication in the early phase of Hematopoietic Stem Cell Transplantation(HSCT). We evaluated, in an exploratory study, the impact of Lactobacillus plantarum on modulation of the gut microbiome in HSCT patients colonized by MDROs. Methods - Stool samples were obtained at timed intervals from 42 oncohematological candidates undergoing autologous or allogeneic HSCT. Participants were allocated to na intervention group(IG = 22) who received capsules of L. plantarum(5x109 CFU) twice a day before the HSCT until the onset of neutropenia and a control group(CG= 20). The V4 region of the 16S bacterial rRNA gene in 93 stool samples from a subset of 33 patients was sequenced. Colonization by MDRO was evaluated by culture in a selective medium and PCR to identify resistance genes. Clonality of the isolates was assessed by PFGE. Results - L. plantarum had an average 86%(±11%) drug-target engagement at 43(±29) days of consumption and it was safe, tolerable and associated with an increase in the abundance of the Lactobacillales(p=0.004). Differently abundant bacteria were investigated by LefSe and na increase of Lactococcus and reduction of Turicibacter were identified on the second-week of L. plantarum use. Both the IG and CG exhibited a similar reduction in MDROs; there was not the same clonal profile of the isolates identified among the patients; except Enterococcus abundance which had a greater rise in the CG Alpha and beta diversity measures were altered throughout the HSCT procedure, regardless of L. plantarum usage. Conclusions L. plantarum was safe and may potentially reduce fecal levels of Enterococcus genus in HSCT candidates; however, it has not showed a significant impact on MDRO decolonization