Rodrigo de Carvalho Santana

IL‐18, TNF, and IFN‐γ alleles and genotypes are associated with susceptibility to chronic hepatitis B infection and severity of liver injury

This study evaluated the association of polymorphisms in the IL‐18 (−607C/A and −137C/G), IFNγ (+874 A/T), and TNF (−238 A/G and −308 A/G) genes with susceptibility to HBV infection and severity of liver injury. A total of 259 chronic HBV‐infected patients followed at the University Hospital, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil, and 202 healthy individuals were studied. Four Single Nucleotide Polymorphisms (SNPs) were amplified by Polymerase Chain Reaction (PCR). Liver biopsy was performed in 212 HBV‐infected patients and classified according to severity of liver fibrosis (scores 0–4) and necroinflammatory activity (HAI scores 0–18). TNF‐308*A allele (P < 0.001; OR = 2.16) and TNF −308 AA genotype (P = 0.026; OR = 5.43) were associated with susceptibility to HBV infection. An association was found between severe liver fibrosis when compared to mild fibrosis and the following polymorphisms: Alleles IL‐18 ‐137*G (P = 0.004; OR = 3.45), TNF −308*A (P < 0.001; OR = 3.39), and IFNγ +874*T (P = 0.029; OR = 1.85) and IL‐18 −137 GG genotype (P = 0.009; OR = 3.70). No significant association was found between IL‐18 (−607 A/C) polymorphism and severity of liver fibrosis. Alleles IL‐18 −137*G (P = 0.028; OR = 2.64) and TNF‐308*A (P = 0.002; OR = 3.06) and IL‐18 −137 GG genotype (P = 0.011; OR = 4.20) were associated with severe necroinflammatory activity (HAI>12) when compared to mild necroinflammatory activity (HAI 1–8). The results suggest that IL‐18 −137C/G, TNF‐308 G/A and IFNγ +874 A/T SNPs were associated to more severe liver injury in chronic HBV infection. TNF −308*A allele and TNF −308 AA genotype could play a role in the susceptibility to HBV infection. J. Med. Virol. 87:1689–1696, 2015.

Histoplasmosis in immunocompetent individuals living in an endemic area in the Brazilian Southeast.

INTRODUCTION The distribution of infection by Histoplasma capsulatum in Brazil is heterogeneous, and the number of cases affecting immunocompetent individuals is relatively small. This study reports the epidemiological and clinical data regarding histoplasmosis in non-immunosuppressed individuals. METHODS The study included only the immunocompetent patients with histoplasmosis who were diagnosed between 1970 and 2012 at a university hospital located in Ribeirão Preto, State of São Paulo, Brazil. Clinical and epidemiological data were collected retrospectively from the patient records. RESULTS Of the 123 patients analyzed, 95 had an active disease that manifested in the different clinical forms of histoplasmosis. Men were the predominant gender, and most patients resided in the Northeast of the State of São Paulo and in the nearby municipalities of the State of Minas Gerais. The risk factors for acquiring histoplasmosis and prolonged contact in a rural environment were recorded in 43.9% and 82.9% of cases, respectively. Smoking, alcoholism, and comorbidity rates were high among the patients with the chronic pulmonary and subacute/chronic disseminated forms of histoplasmosis. Many patients achieved clinical cure spontaneously, but 58.9% required antifungals; the disease lethality rate was 5.3%. CONCLUSIONS Immunocompetent individuals manifested the diverse clinical forms of histoplasmosis over a period of 4 decades, revealing an additional endemic area of this fungal disease in the Brazilian Southeast.

Clinical and laboratory findings related to a favorable evolution of hantavirus pulmonary syndrome

The medical records of 27 patients with hantavirus pulmonary syndrome were analyzed according to the need for invasive mechanical ventilation in relation to the following data up on hospital admission: age, gender, fever, cough, dyspnea, systolic arterial blood pressure, heart rate, levels of hemoglobin, hematocrit, leukocytes, lymphocytes, platelets, creatinine and arterial blood gases. The volume infused during the first 24 hours after admission, the use of inotropic agents, the use of corticosteroids and the patient outcomes were also evaluated. A favorable outcome was related to systolic blood pressure(3) 100 mmHg, heart rate lower than 100 beats per minute, creatinine below 1.6 mg/dl, arterial blood pH(3) 7.35, bicarbonate higher than 15 mEq/dl, oxygen saturation higher than 84.1%, lower rehydration volume in the first 24 hours of hospitalization and no use of inotropic agents. Absence of clinical and laboratory signs of circulatory shock up on admission was associated with a favorable outcome of the patients.

The HLA-G 14-base pair deletion allele and the deletion/deletion genotype are associated with persistent HBe antigenemia in chronic hepatis B infection

BACKGROUND AND AIMS HLA-G has well-recognized immunomodulatory properties, and this molecule is frequently expressed in the livers of hepatitis B virus (HBV)-infected patients. Because the HLA-G 14 bp-insertion/deletion polymorphism (rs371194629) has been associated with the magnitude of HLA-G expression, we evaluated this polymorphism in the recognized evolutionary forms of chronic HBV infection. METHODS We studied 196 chronic HBV-infected patients (118 HBeAg-negative chronic hepatitis, 53 HBeAg-positive chronic hepatitis and 25 inactive carriers exhibiting low levels of serum HBVDNA and persistently normal ALT levels), and 202 healthy individuals. Chronic hepatitis HLA-G typing was performed using PCR-amplified DNA hybridized with specific primers. RESULTS The frequencies of the insertion/deletion alleles and genotypes were very similar in patients and controls. After patient stratification according to the evolutionary form of the chronic HBV infection, the frequencies of the deletion allele (P=0.0460; OR=1.26; 95%CI=1.01-1.45) and of the deletion/deletion genotype (P=0.0356; OR=2.08; 95%CI=1.05-4.09) were overrepresented in HBeAg-positive patients when compared to HBeAg-negative patients. No differences were observed when HBV inactive carriers were compared to HBeAg-negative chronic hepatitis patients. CONCLUSIONS Because the 14-bp deletion allele has been associated with increased HLA-G production and because HLA-G may down regulate the cytotoxic activity of TCD8 and NK cells, patients exhibiting the 14-bp deletion allele at single or double doses are at increased risk for developing chronic forms of HBV associated with persistent viremia and worse prognoses.

Secular trends in Klebsiella pneumoniae isolated in a tertiary-care hospital: increasing prevalence and accelerated decline in antimicrobial susceptibility

UNLABELLED INTRODUCTION Klebsiella pneumoniae has become an increasingly important etiologic agent of nosocomial infections in recent years. This is mainly due to the expression of virulence factors and development of resistance to several antimicrobial drugs. METHODS This retrospective study examines data obtained from the microbiology laboratory of a Brazilian tertiary-care hospital. To assess temporal trends in prevalence and antimicrobial susceptibility, K. pneumoniae isolates were analyzed from 2000 to 2013. The relative frequencies of K. pneumoniae isolation were calculated among all Gram-negative bacilli isolated in each period analyzed. Susceptibility tests were performed using automated systems. RESULTS From 2000-2006, K. pneumonia isolates comprised 10.7% of isolated Gram-negative bacilli (455/4260). From 2007-2013, this percentage was 18.1% (965/5331). Strictly considering isolates from bloodstream infections, the relative annual prevalence of K. pneumoniae increased from 14-17% to 27-32% during the same periods. A progressive decrease in K. pneumoniae susceptibility to all antimicrobial agents assessed was detected. Partial resistance was also observed to antimicrobial drugs that have been used more recently, such as colistin and tigecycline. CONCLUSIONS Our study indicates that K. pneumoniae has become a major pathogen among hospitalized patients and confirms its recent trend of increasing antimicrobial resistance.

Late emergence of A594V and L595W mutations related to ganciclovir resistance in a patient with HCMV retinitis and long-term HIV progression.

The emergence of ganciclovir (GCV) resistance during the treatment of human cytomegalovirus (HCMV) infection is a serious clinical challenge, and is associated with high morbidity and mortality. In this case report, we describe the emergence of two consecutive mutations (A594V and L595W) related to GCV resistance in a patient with HCMV retinitis and long-term HIV progression after approximately 240 days of GCV use. Following the diagnosis of retinitis, the introduction of GCV did not result in viral load reduction. The detected mutations appeared late in the treatment, and we propose that other factors (high initial HCMV load, previous GCV exposure, low CD4+ cell count), in addition to the presence of resistance mutations, may have contributed to the treatment failure of HCMV infection in this patient.

Orbital tuberculosis presenting as proptosis and fever: the risk of empiric corticosteroids

Tuberculosis (TB) remains an important public health problem worldwide, with a progressive increase in the absolute number of cases during recent years. The overall disease incidence has been estimated at 9.4 million cases, which occurred mostly in Asia and Africa [1]. Acquired primarily by inhalation, the disease manifests predominantly in the pulmonary form, although extra-pulmonary presentations have been detected more frequently in recent years. Data from the Centers for Disease Control and Prevention (CDC) [2] indicate that the percentage of TB cases with extrapulmonary manifestations increased from 16 % in 1993 to 21 % in 2009. According to the World Health Organization (WHO) [1], in 2009, approximately 0.9 million new cases of extrapulmonary TB were reported in the world. The epidemic of human immunodeficiency virus (HIV) infection and the greater use of different types of immunosuppressive therapies have contributed to the re-emergence of pulmonary TB as well as the increase in extrapulmonary presentations. Among these, orbital involvement is a rare ocular manifestation of TB [3]. This condition usually presents in one of five forms—classic periostitis, orbital soft tissue tuberculoma or cold abscess with or without bony involvement, spread from the paranasal sinuses, and tuberculous dacryoadenitis [4]. Diagnosing orbital TB is challenging and often delayed, especially in the absence of pulmonary signs or symptoms typical of TB. In fact, concomitant respiratory symptoms are often absent, and the tuberculin skin test (TST) may be negative [5]. Moreover, infections of extra-pulmonary sites are frequently paucibacillary, which complicates the identification and culture of tubercle bacilli from non-pulmonary samples [6]. The objective of this article is to alert physicians by presenting a case report of proptosis and fever that was initially approached as an idiopathic ocular inflammatory myositis but was finally diagnosed as orbital TB based on systemic manifestations of the disease after empiric corticosteroid treatment. R. de Carvalho Santana (&) V. R. Bollela B. A. L. da Fonseca Division of Infectious Diseases, Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes, 3900, Bairro Monte Alegre, Ribeirão Preto, São Paulo 14049-900, Brazil e-mail: santanacrod@yahoo.com.br

Lipodystrophy diagnosis in people living with HIV/AIDS: prediction and validation of sex-specific anthropometric models

BackgroundBody composition alterations, or lipodystrophy, can lead to serious health problems in people living with HIV/AIDS (PLWHA). The objectives of this study are to predict and validate sex-specific anthropometric predictive models for the diagnosis of lipodystrophy in PLWHA.MethodsA cross-sectional design was employed to recruit 106 PLWHA (men = 65 and women = 41) in Brazil during 2013–2014. They were evaluated using dual-energy X-ray absorptiometry, and 19 regions of body perimeters and 6 skinfold thicknesses were taken. Sex-specific predictive models for lipodystrophy diagnosis were developed through stepwise linear regression analysis. Cross-validations using predicted residual error sum of squares was performed to validate each predictive model.ResultsResults support the use of anthropometry for the diagnosis of lipodystrophy in men and women living with HIV/AIDS. A high power of determination with a small degree of error was observed for lipodystrophy diagnosis for men in model six (r2 = 0.77, SEE = 0.14, r2PRESS = 0.73, SEE PRESS = 0.15), that included ratio of skinfold thickness of subscapular to medial calf, skinfold thickness of thigh, body circumference of waist, formal education years, time of diagnosis to HIV months, and type of combined antiretroviral therapy (cART) (with protease inhibitor “WI/PI = 1” or without protease inhibitor “WO/PI = 0”); and model five for women (r2 = 0.78, SEE = 0.11, r2PRESS = 0.71, SEE PRESS = 0.12), that included skinfold thickness of thigh, skinfold thickness of subscapular, time of exposure to cART months, body circumference of chest, and race (Asian) (“Yes” for Asian race = 1; “No” = 0).ConclusionsThe proposed anthropometric models advance the field of public health by facilitating early diagnosis and better management of lipodystrophy, a serious adverse health effect experienced by PLWHA.

Assessment of indicators of vitamin A status in non-cirrhotic chronic hepatitis C patients

Subjects with chronic liver disease are susceptible to hypovitaminosis A due to several factors. Therefore, identifying patients with vitamin deficiency and a requirement for vitamin supplementation is important. Most studies assessing vitamin A in the context of hepatic disorders are conducted using cirrhotic patients. A cross-sectional study was conducted in 43 non-cirrhotic patients with chronic hepatitis C to evaluate markers of vitamin A status represented by serum retinol, liver retinol, and serum retinol-binding protein levels. We also performed the relative dose-response test, which provides an indirect estimate of hepatic vitamin A reserves. These vitamin A indicators were assessed according to the stage of liver fibrosis using the METAVIR score and the body mass index. The sample study was predominantly composed of male subjects (63%) with mild liver fibrosis (F1). The relative dose-response test was <20% in all subjects, indicating vitamin A sufficiency. Overweight or obese patients had higher serum retinol levels than those with a normal body mass index (2.6 and 1.9 µmol/L, respectively; P<0.01). Subjects with moderate liver fibrosis (F2) showed lower levels of serum retinol (1.9 vs 2.5 µmol/L, P=0.01) and retinol-binding protein levels compared with those with mild fibrosis (F1) (46.3 vs 67.7 µg/mL, P<0.01). These results suggested an effect of being overweight on serum retinol levels. Furthermore, more advanced stages of liver fibrosis were related to a decrease in serum vitamin A levels.

Comparison of the effectiveness of initial combined antiretroviral therapy with nelfinavir or efavirenz at a university-based outpatient service in Brazil

Since there are some concerns about the effectiveness of highly active antiretroviral therapy in developing countries, we compared the initial combination antiretroviral therapy with zidovudine and lamivudine plus either nelfinavir or efavirenz at a university-based outpatient service in Brazil. This was a retrospective comparative cohort study carried out in a tertiary level hospital. A total of 194 patients receiving either nelfinavir or efavirenz were identified through our electronic database search, but only 126 patients met the inclusion criteria. Patients were included if they were older than 18 years old, naive for antiretroviral therapy, and had at least 1 follow-up visit after starting the antiretroviral regimen. Fifty-one of the included patients were receiving a nelfinavir-based regimen and 75 an efavirenz-based regimen as outpatients. Antiretroviral therapy was prescribed to all patients according to current guidelines. By intention-to-treat (missing/switch = failure), after a 12-month period, 65% of the patients in the efavirenz group reached a viral load <400 copies/mL compared to 41% of the patients in the nelfinavir group (P = 0.01). The mean CD4 cell count increase after a 12-month period was also greater in the efavirenz group (195 x 10(6) cells/L) than in the nelfinavir group (119 x 10(6) cells/L; P = 0.002). The efavirenz-based regimen was superior compared to the nelfinavir-based regimen. The low response rate in the nelfinavir group might be partially explained by the difficulty of using a regimen requiring a higher patient compliance (12 vs 3 pills a day) in a developing country.