Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project.

OBJECTIVE: Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. DESIGN: This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. RESULTS: Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02 × 10(-06), OR=1.90), stenosing (p=3.16 × 10(-06), OR=1.82) and penetrating (p=1.26 × 10(-02), OR=1.25) CD behaviours, and need for surgery (p=2.28 × e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86 × 10(-06), OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48 × 10(-06), OR=0.35) and surgical rate (p=1.71 × 10(-07), OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12 × 10(-03), HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01 × 10(-02), HR=1.29) among patients with low and high score. CONCLUSIONS: This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.

Tolerance of benznidazole in treatment of Chagas' disease in adults.

Chagas' disease is an emerging public health problem in areas where the disease is not endemic. Treatment with benznidazole has shown efficacy in the acute stage of the disease, but its efficacy in the chronic stage remains controversial, and unwanted side effects are more frequent and severe in adults than in children. This study describes the profile of side effects of benznidazole in a cohort of Trypanosoma cruzi-infected patients in a European country.

Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.

In the current Model for End-Stage Liver Disease allocation system, patients are at risk of suffering repeated episodes of hepatic encephalopathy (HE) while waiting for an orthotopic liver transplantation (OLT); the posttransplantation impact of these episodes has not been well explored. We evaluated the cognitive function and quality of life in a group of OLT recipients (n = 25) who had suffered from overt HE prior to their procedure (HE-PreLT group) and compared their performance to that of a similar group of patients (n = 14) without overt HE (No HE-PreLT group) as well as to controls. Patients were selected from a cohort of 280 patients who underwent OLT during this period; the presence of clinical confounders excluded many of the remaining subjects. Demographic and clinical characteristics were balanced among groups. At an average of 18 months after OLT, we administered 2 neuropsychological batteries [Psychometric Hepatic Encephalopathy Score (PHES) test battery and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]; a pyschophysiological test (critical flicker frequency); and the SF-36 quality of life score. The HE-PreLT group scored below controls in 5 of 6 cognitive domains tested by RBANS, 3 of 6 PHES subtests, as well as the critical flicker frequency test. The No HE-PreLT group scored below the controls in 1 of the 6 cognitive domains tested by RBANS. The more severe neurocognitive abnormalities seen in the HE-PreLT group did not appear to affect quality of life, as lower values than normative data were only found in 1 of the 8 SF-36 scales. In conclusion, neurocognitive abnormalities were more severe in liver transplant recipients that had suffered from overt HE prior to OLT. Prospective studies of neurocognitive function pre-OLT and post-OLT are needed to fully determine the impact of such abnormalities.

Drug exposure and pregnancy outcome in Mozambique.

BACKGROUND: The intake of medicines during pregnancy can have negative or toxic effects on the fetus, possibly leading to adverse pregnancy outcomes. OBJECTIVE: The aim of this study was to describe the level of drug exposure during pregnancy in a rural area of Mozambique and its relation to pregnancy outcome. METHODS: A total of 3105 pregnant women were interviewed in a cohort study. Information on disease, treatments received during pregnancy, and pregnancy outcome was collected. Newborns were examined at birth for clinical signs, birthweight, and presence of any congenital malformation. RESULTS: Malaria and sexually transmitted diseases were the most frequently reported diseases (30.5% and 24.1%, respectively), and 41% (1276/3105) of participants reported at least one drug exposure. The mean number of drugs taken per pregnant woman was 3.9 (SD 2.1). Antibiotics were the most commonly (41.2%) reported agents, followed by antimalarials (23.8%). There were more stillbirths (p < 0.007) among those reporting to be exposed to drugs compared with no exposure. Polydactyly was the most frequent malformation observed. CONCLUSIONS: Drug exposure during pregnancy, including drugs with recognized potential pregnancy risk, was high in this rural area of southern Africa. The association of stillbirths with drug exposure might be a consequence of the disease that led to drug administration, although a direct causality of the drugs cannot be excluded. These findings emphasize the need for reinforcing pharmacovigilance systems in rural Africa, especially, or at least, in pregnant women.

Incidence and predictors of immune reconstitution inflammatory syndrome in a rural area of Mozambique.

BACKGROUND: There is limited data on the epidemiology of Immune Reconstitution Inflammatory Syndrome (IRIS) in rural sub-Saharan Africa. A prospective observational cohort study was conducted to assess the incidence, clinical characteristics, outcome and predictors of IRIS in rural Mozambique. METHODS: One hundred and thirty-six consecutive antiretroviral treatment (ART)-naïve HIV-1-infected patients initiating ART at the Manhiça district hospital were prospectively followed for development of IRIS over 16 months. Survival analysis by Cox regression was performed to identify pre-ART predictors of IRIS development. RESULTS: Thirty-six patients developed IRIS [26.5%, incidence rate 3.1 cases/100 persons-month of ART (95% CI 2.2-4.3)]. Median time to IRIS onset was 62 days from ART initiation (IQR 35.5-93.5). Twenty-five cases (69.4%) were "unmasking", 10 (27.8%) were "paradoxical", and 1 (2.8%) developed a paradoxical worsening followed by the unmasking of another condition. Systemic OI (OI-IRIS) accounted for 47% (17/36) of IRIS cases, predominantly of KS (8 cases) and TB (6 cases) IRIS. Mucocutaneous IRIS manifestations (MC-IRIS) accounted for 53% (19/36) of IRIS events, mostly tinea (9 cases) and herpes simplex infection (3 cases). Multivariate analysis identified two independent predictors of IRIS development: pre-ART CD4 count <50 cells/µl (HR 2.3, 95% CI 1.19-4.44, p = 0.01) and body mass index (BMI) <18.5 (HR 2.15, 95% CI 1.07-4.3, p = 0.03). The pre-cART proportion of activated T-cells, as well as the immunologic and virologic response to ART were not associated with IRIS development. All patients continued on ART, 7 (19.4%) required hospitalization and there were 3 deaths (8.3%) attributable to IRIS. CONCLUSIONS: IRIS is common in patients initiating ART in rural Mozambique. Pre-ART CD4 counts and BMI can easily be assessed at ART initiation in rural sub-Saharan Africa to identify patients at high risk of IRIS, for whom close supervision is warranted.

Rapid suppression of HIV-RNA is associated with improved control of immune activation in Mozambican adults initiating antiretroviral therapy with low CD4 counts.

The rapidity of HIV-RNA suppression after initiation of combined antiretroviral therapy (cART) may impact immune reconstitution in developing countries, where patients initiate cART at low CD4 T cell counts. One hundred and thirty-five HIV-1 Mozambican adults initiating cART were prospectively followed over 16 months within a larger observational study. Plasma HIV-RNA, CD4 counts, and CD8 T cell activation were monitored at the pre-cART visit and at 4, 10, and 16 months during cART. Of the 89 patients with available HIV-RNA data at pre-cART and 4 and 10 months post-cART, 68% (60/89) suppressed HIV-RNA at 4 months and were defined as "early virological controllers"(EC). Twenty of the 29 remaining patients who did not control HIV-RNA at 4 months did so at 10 months and were classified as "late virological controllers"(LC). Nine (10%) patients did not control HIV-RNA at either time point. Both initiating an EFV-containing cART regimen and having pre-cART tuberculosis were significantly associated with early HIV-RNA suppression if locked into a multivariate model [EFV OR: 13.6 (95% CI 1.7; 108.1) p = 0.014) tuberculosis OR: 11.0 (95% CI 1.4; 87.9) p = 0.024]. EC demonstrated significantly lower median activated CD8 T cells at 4, 10, and 16 months post-cART than did LC. Approximately 63% (12/19) of LC experienced reappearance of detectable HIV-RNA at 6 months postcontrol as compared to 15% (2/60) of EC (p = 0.001). This study suggests that rapid suppression of HIV-RNA may lead to a lower rate of reappearance of HIV-RNA, which could impact CD8 T cell activation levels in patients initiating cART at low CD4 counts.

Hypercoagulability biomarkers in Trypanosoma cruzi -infected patients.

There is a current controversy over the hypothesis that a number of thromboembolic events could be related to hypercoagulable state in patients with chronic Chagas disease. This study was designed to determine whether a prothrombotic state existed in chronic Trypanosoma cruzi-infected patients and, if so, to describe its evolution after treatment with Benznidazole. Twenty-five patients with chronic Chagas disease and 18 controls were evaluated. The markers used were prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin, plasminogen, protein C, total protein S, free protein S, factor VIII, D-dimer, activated factor VIIa, tissue-type plasminogen activator inhibitor-1, prothrombin fragment 1+2 (F1+2), plasmin-antiplasmin complexes, soluble P-selectin and endogenous thrombin potential (ETP). Despite statistically significant differences between cases and controls in several markers, only ETP (which quantifies the ability of plasma to generate thrombin when activated through tissue factor addition) (p<0.0001) and F1+2 (a marker of thrombin generation in vivo) (p<0.0001) showed values outside the normal levels in patients compared with controls. Similar results were obtained in these markers six months after treatment in the cohort of cases (p<0.0008 and p<0.004, respectively). These results may be relevant in clinical practice. Though current treatment for Chagas disease is still controversial, if it were considered as a thromboembolic risk factor the antiparasitic treatment strategy could be reinforced. The results also support further research on haemostasis parameters as candidates for early surrogate biomarkers of cure or progression of Chagas disease.

Distinguishing malaria from severe pneumonia among hospitalized children who fulfilled integrated management of childhood illness criteria for both diseases: a hospital-based study in Mozambique.

Malaria and severe pneumonia in hospitalized young children may show striking clinical similarities, making differential diagnosis challenging. We investigated ways to increase diagnostic accuracy in patients hospitalized with clinical symptoms compatible with malaria and severe pneumonia, in an area with high a prevalence of infection with human immunodeficiency virus. A total of 646 children admitted at the Manhiça District Hospital in Manhiça, Mozambique who met the World Health Organization clinical criteria for severe pneumonia and malaria were recruited for 12 months and thoroughly investigated to ascertain an accurate diagnosis. Although symptom overlap between malaria and severe pneumonia was frequent among hospitalized children, true disease overlap was uncommon. Clinical presentation and laboratory determinations were ineffective in reliably distinguishing between the two diseases. Infection with human immunodeficiency virus differentially influenced the epidemiology and clinical presentation of these two infectious diseases, further challenging their discrimination on clinical grounds, and having a greater impact on the current burden and prognosis of severe pneumonia.

Predictors of immune reconstitution inflammatory syndrome-associated with kaposi sarcoma in mozambique: a prospective study.

BACKGROUND: The impact and relevance of immune reconstitution inflammatory syndrome-associated with Kaposi sarcoma (IRIS-KS) has not been assessed in sub-Saharan African countries, where the bulk of HIV-1 and KS-associated herpesvirus (KSHV) coinfection occurs. Understanding the risk factors for developing IRIS-KS would aid in the identification and in the improvement of clinical management for high-risk patients. METHODS: Sixty-nine consecutive HIV-1 and KSHV coinfected Mozambican adults initiating cART were prospectively followed for development of IRIS-KS over 10 months as part of a larger prospective observational study. Plasma HIV RNA, CD4 counts, anti-KSHV lytic antibodies, and plasma KSHV DNA viral load were assessed at the pre-cART visit and at 4 and 10 months after cART initiation. A survival analysis was performed to assess potential risk factors for developing IRIS-KS. RESULTS: During the first 10 months of combined antiretroviral therapy (cART), 8 patients (8/69, 11.6%) experienced IRIS-KS at a median time of 13.8 weeks after cART initiation. Multivariate analysis identified 4 independent IRIS-KS predictors: clinical pretreatment KS [hazard ratio (HR) 91.7], detectable plasma KSHV DNA (HR 24.4), hematocrit <30% (HR 26.5), and plasma HIV-1 RNA viral load (HR 34.6 per log viral load increase). Treatment with either cART alone or with a combination of cART and systemic chemotherapy led to partial or complete clinical response in 62.5% (5/8) of IRIS-KS cases. CONCLUSIONS: This study identified 4 independent predictors of IRIS-KS, which may help to develop screening tools aiding in the identification of patients at high risk of IRIS-KS for whom close clinical supervision is warranted.

Usefulness of oral beclometasone dipropionate in the treatment of active ulcerative colitis in clinical practice: the RECLICU Study.

BACKGROUND: Beclometasone dipropionate (BDP) is a relatively new topically acting oral steroid to treat mild to moderately active ulcerative colitis (UC). We estimate that 20,000 patients have received oral BDP in Spain in the last two years. Our aim was to evaluate the efficacy and safety of oral BDP in clinical practice. METHODS: Retrospective and multicenter study that included 434 patients with active UC treated with BDP. The partial Mayo Clinic score (pMS, 0-9) was used to measure disease activity. Remission was defined as post-treatment pMS of 0 or 1; response as a decrease in pMS of 3 points or 2 points and >30%, and failure as lack of remission or response. RESULTS: BDP dose was 5 mg/day in 88% of patients and mean treatment duration was 6.2 weeks. BDP achieved remission in 44.4%, response in 22.3% and failed in 33.2% of patients. Mean pMS decreased from 4.9 ± 1.3 to 2.4 ± 2.3 (p<0.0001). Remission rate was higher in mild and moderate than in severe UC (p<0.043) and tended to be higher in left-sided and extensive UC than in proctitis (p<0.06). Failure was less frequent in patients treated for >4 weeks (p<0.02). Mild adverse events were reported in 7.6% of patients. CONCLUSION: BDP induces response or remission in two thirds of active UC patients, with a good safety profile. Patients with mild to moderate, left-sided or extensive UC, receiving BDP for more than 4 weeks are most likely to benefit from this treatment.

Human papillomaviruses are identified in a subgroup of sinonasal squamous cell carcinomas with favorable outcome.

BACKGROUND: The role of human papillomavirus (HPV) in the pathogenesis of squamous cell carcinomas (SCCs) of the sinonasal tract and its clinicopathological implications were evaluated. METHODS: All SCCs of the sinonasal tract diagnosed in the Hospital Clinic of Barcelona from 1981 to 2006 were retrospectively evaluated (N = 60). Clinical and pathological data were reviewed. HPV infection was determined and typed by amplification of HPV DNA by polymerase chain reaction using the SPF-10 primers. p16(INK4a) expression was determined by immunohistochemistry. Overall and progression-free survival for HPV-positive and -negative patients was estimated by Kaplan-Meier analysis and by the use of a multivariate Cox proportional hazards model. RESULTS: HPV DNA was detected in tumor tissue of 12 of 60 (20%) patients. HPV16 was identified in 11 tumors and HPV35 in 1. Immunohistochemistry for p16(INK4a) stained all HPV-positive and no HPV-negative tumors (P < .001). No differences were observed in terms of site and histological grade or stage at presentation between HPV-positive and -negative tumors. However, HPV-positive patients had a significantly better 5-year progression-free survival (62%; 95% confidence interval [CI], 23%-86% vs 20%; 95% CI, 9%-34%; P = .0043, log-rank test) and overall survival (80%; 95% CI, 20%-96% vs 31%; 95% CI, 15%-47%; P = .036, log-rank test) than patients with HPV-negative tumors. In multivariate analysis, HPV-positive tumors were associated with improved progression-free survival (hazard ratio, 0.21; 95% CI, 0.17-0.98; P = .012). CONCLUSIONS: A subgroup of sinonasal SCCs is associated with HPV infection. These tumors have a significantly better prognosis.