Toxic Profile of Benznidazole in Patients with Chronic Chagas Disease: Risk Factors and Comparison of the Product from Two Different Manufacturers.

Benznidazole is considered the first-line treatment option against Chagas disease. The major drawback of benznidazole is its toxicity profile. The main objectives of this study were to describe the adverse events (AEs) in patients with chronic Chagas disease treated with benznidazole, determine the risk factors involved and compare the toxic profiles of two different preparations of the drug from ELEA and Roche. A total of 746 patients were diagnosed with Chagas disease in a 5-year period, and of these 472 were treated with benznidazole. A high proportion of patients (n = 360 [76%]) suffered AEs, the most frequent being those related to hypersensitivity (52.9% of patients), headache (12.5%), and epigastric pain (10.4%). In 72 (12.7%) cases, treatment was discontinued. Overall, women had a higher incidence of AEs compared to men (81.3% versus 66%, P = 0.001) and were subject to higher levels of hypersensitivity-related events. Dermatological events, digestive tract manifestations, and general symptoms had a greater likelihood to appear around day 10 and neurological AEs around day 40 after starting treatment. With respect to liver function and hematological tests, the majority of patients did not suffer significant perturbation of liver enzymes or altered blood cell counts. However, 14 patients suffered from neutropenia, and 14 patients had aminotransferase levels that were more than four times the upper limit of the normal range. Patients treated with the ELEA benznidazole product experienced more arthromyalgia, neutropenia, and neurological disorders (mainly paresthesias) than those treated with the Roche product. Both drug products resulted in approximately the same percentage of permanent withdrawals.

Immunosuppression and Chagas disease; experience from a non-endemic country.

Reactivation of Chagas disease in the chronic phase may occur when immunosuppression is established, sometimes resulting in high parasitaemia and severe clinical manifestations such as meningitis and meningoencephalitis. Although this situation is being increasingly described, there is still scarce information. This retrospective observational study was performed in three Tropical Medicine Units of Barcelona (Spain) included in the International Health Programme of the Catalan Health Institute (PROSICS). The objective of the study was to describe epidemiological, clinical, microbiological, prognostic and therapeutic data from patients with Chagas disease and any kind of immunosuppressive condition attended in these three institutions from January 2007 to October 2014. From 1823 patients with Chagas disease attending these three centres during the study period, 38 (2%) had some kind of immunosuppressive condition: 12 patients had human immunodeficiency virus infection, 8 patients had neoplasia, 4 patients underwent organ transplantation and 14 patients had an autoimmune disease. Eight (21.1%) patients had cardiac involvement, and six (15.8%) patients had gastrointestinal involvement. Acute Trypanosoma cruzi infection was detected in two Spanish patients. Thirty-one (81.6%) patients received treatment with benznidazole, of whom 17 (54.8%) had some kind of adverse event. No patient had a severe manifestation or reactivation of Chagas disease. Patients with Chagas disease under immunosuppressive conditions are being increasingly described, especially in non-endemic countries. More information about this topic is required and international consensus in the diagnosis, treatment and follow up of these patients must be established to reduce the morbidity and mortality.

Trypanosoma cruzi infection in a non-endemic country: epidemiological and clinical profile.

Chagas disease has been increasingly diagnosed in non-endemic countries. This is a prospective observational study performed at the Tropical Medicine Units of the International Health Program of the Catalan Health Institute, Barcelona (PROgrama de Salud Internacional del Instituto Catalán de la Salud, PROSICS Barcelona, Spain), that includes all patients with Chagas disease who attended from June 2007 to May 2012. Clinical and epidemiological data were collected. Overall, 1274 patients were included, the mean age of the patients was 37.7 years, 67.5% were women and 97% came from Bolivia. Thirteen patients had immunosuppressive conditions. The prevalence of cardiac involvement was 16.9%, lower than in previous studies performed in endemic areas (20-60%). Cardiac alterations were found in 33.8% of symptomatic and 14.1% of asymptomatic patients. The prevalence of digestive involvement was 14.8%. The rate of digestive involvement is very different among previous studies because of different diagnostic tools and strategies used. Barium enema alterations were found in 21.4% of symptomatic and 10.3% of asymptomatic patients, and oesophageal alterations were found in 3.7% of symptomatic and in 2.3% of asymptomatic patients. As shown in previous studies, Chagas disease in non-endemic countries affects younger patients and has lower morbidity.

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc- mouse model.

The efficacy of IVIG in preventing GvHD has not been definitely demonstrated clinically. Using a xenogeneic model of GvHD in NOD/SCID/γc- (NSG) mice, we showed that weekly administration of IVIG significantly reduced the incidence and associated mortality of GvHD to a degree similar to CsA. Unlike CsA and OKT3, IVIG were not associated with inhibition of human T-cell proliferation in mice. Instead, IVIG significantly inhibited the secretion of human IL-17, IL-2, IFN-γ and IL-15 suggesting that IVIG prevented GvHD by immunomodulation. Furthermore, the pattern of modification of the human cytokine storm differed from that observed with CsA and OKT3. Finally, in a humanized mouse model of immune reconstitution, in which NSG mice were engrafted with human CD34(+) stem cells, IVIG transiently inhibited B-cell reconstitution, whereas peripheral T-cell reconstitution and thymopoiesis were unaffected. Together these in vivo data raise debate related to the appropriateness of IVIG in GvHD prophylaxis. In addition, this model provides an opportunity to further elucidate the precise mechanism(s) by which IVIG inhibit GvHD.

Evaluation of c4d deposition and circulating antibody in small bowel transplantation.

Antibody-mediated rejection (AMR) consensus criteria are defined in kidney and heart transplantation by histological changes, circulating donor-specific antibody (DSA), and C4d deposition in affected tissue. AMR consensus criteria are not yet identified in small bowel transplantation (SBTx). We investigated those three criteria in 12 children undergoing SBTx, including one retransplantation and four combined liver-SBTx (SBTx), with a follow-up of 12 days to 2 years. All biopsies (91) were evaluated with a standardized grading scheme for acute rejection (AR), vascular lesions and C4d expression. Sera were obtained at day 0 and during the follow-up. C4d was expressed in 37% of biopsies with or without AR, but in 50% of biopsies with severe vascular lesions. In addition, vascular lesions were always associated with AR and a poor outcome. All children with AR (grade 2 or 3) observed before the third month died or lost the graft. DSA were never found in any studied sera. We found no evidence that C4d deposition was of any clinical relevance to the outcome of SBTx. However, the grading of vascular lesions may constitute a useful marker to identify AR that is potentially resistant to standard treatment, and for which an alternative therapy should be considered.

[Rabeprazole induced acute interstitial nephritis]. / Néphropathie tubulo-interstitielle aiguë au cours d'un traitement par le rabéprazole (Pariet).

A 84-year-old women underwent renal biopsy because of rapidly progressive renal failure. Rabeprazole induced interstitial nephritis was diagnosed. Interstitial nephritis may complicate the course of any proton pump inhibitor treatment. It is a rare and serious complication. Clinician's awareness of this adverse event is essential for early diagnosis and prompt recovery.

Long-term outcome, growth and digestive function in children 2 to 18 years after intestinal transplantation.

OBJECTIVE: Small bowel (SB) transplantation (Tx), long considered a rescue therapy for patients with intestinal failure, is now a well recognised alternative treatment strategy to parental nutrition (PN). In this retrospective study, we analysed graft functions in 31 children after SBTx with a follow-up of 2-18 years (median 7 years). PATIENTS: Twelve children had isolated SBTx, 19 had combined liver-SBTx and 17 received an additional colon graft. Growth, nutritional markers, stool balance studies, endoscopy and graft histology were recorded every 2-3 years post-Tx. RESULTS: All children were weaned from PN after Tx and 26 children remained PN-free. Enteral nutrition was required for 14/31 (45%) patients at 2 years post-Tx. All children had high dietary energy intakes. The degree of steatorrhoea was fairly constant, with fat and energy absorption rates of 84-89%. Growth parameters revealed at transplantation a mean height Z-score of -1.17. After Tx, two-thirds of children had normal growth, whereas in one-third, Z-scores remained lower than -2, concomitant to a delayed puberty. Adult height was normal in 5/6. Endoscopy and histology analyses were normal in asymptomatic patients. Chronic rejection occurred only in non-compliant patients. Five intestinal grafts were removed 2.5-8 years post-Tx for acute or chronic rejection. CONCLUSIONS: This series indicates that long-term intestinal autonomy for up to 18 years is possible in the majority of patients after SBTx. Subnormal energy absorption and moderate steatorrhoea were often compensated for by hyperphagia, allowing normal growth and attainment of adult height. Long-term compliance is an important pre-requisite for long-term graft function.

Collagen alpha5 and alpha2(IV) chain coexpression: analysis of skin biopsies of Alport patients.

Alport syndrome is a collagen type IV disease caused by mutations in the COL4A5 gene with the X-linked form being most prevalent. The resultant alpha5(IV) collagen chain is a component of the glomerular and skin basement membranes (SBMs). Immunofluorescent determination of the alpha5(IV) chain in skin biopsies is the procedure of choice to identify patients. In 30% of patients, however, the mutant protein is still found in the SBM resulting in a normal staining pattern. In order to minimize or eliminate false results, we compared the distribution of the alpha2(IV) chain (another SBM component) and the alpha5(IV) chain by standard double label immunofluorescence (IF) and by confocal laser scanning microscopy. The study was performed on 55 skin biopsies of patients suspected of Alports and five normal control specimens. In normal skin, IF showed the classical linear pattern for both collagens along the basement membrane. Additionally, decreased alpha5(IV) was found in the bottom of the dermal papillary basement membrane. Confocal analysis confirmed the results and show alpha5(IV) focal interruptions. In suspected patients, both techniques showed the same rate of abnormal alpha5(IV) expression: segmental in women and absent in men. Our results show a physiological variation of alpha5(IV) location with focal interruptions and decreased expression in the bottom of the dermal basement membrane. Comparison of alpha5(IV) with alpha2(IV) expression is simple and eliminates technical artifacts.

Duodenal intraepithelial lymphocytosis during Helicobacter pylori infection is reduced by antibiotic treatment.

AIM: To evaluate clinical, biological and immunological features of patients with increased duodenal intraepithelial lymphocytes (IELs), and its relation to Helicobacter pylori (HP) and coeliac disease (CD). METHODS: We have studied all patients accrued over a 4-year period with increased duodenal IELs. Those patients were recalled for biological and immunological evaluation and a second endoscopy. RESULTS: Twenty-three from a total of 639 patients were identified and 17 of them were included in the study. The median duodenal IEL count was 59 per 100 epithelial cells. Twelve (71%) patients were HP+; eight of them received HP eradication. At the second endoscopy the duodenal IEL count was significantly lower 2 months after HP eradication (73 versus 28), while the IEL count was unchanged in those patients seronegative for HP (n = 5) or those in whom it was not eradicated (n = 4) (55 versus 55). No patient had coeliac antibodies, four expressed HLA-DQ2, lower than in the general population, and the prevalence of CD was 2% (12/639 patients). CONCLUSION: In some cases an increased duodenal IEL count may be due to an inappropriate host response to HP. HP screening and eradication should be considered before recommending a gluten-free diet.

Refractory coeliac sprue is a diffuse gastrointestinal disease.

BACKGROUND: Refractory coeliac sprue (RCS) with an immunophenotypically aberrant clonal intraepithelial lymphocyte (IEL) population is considered a cryptic form of intestinal T cell lymphoma. AIMS: To investigate the distribution of the abnormal and monoclonal IEL population in the digestive tract of RCS patients. PATIENTS AND METHODS: We compared the frequency of lymphocytic gastritis (LG) and lymphocytic colitis (LC), together with IEL phenotype and T cell clonality, in gastric and colonic samples from 15 adults with RCS (all with aberrant CD3 intracytoplasmic(+) surface(-) CD8(-) clonal IELs on duodenojejunal biopsies), 18 patients with active coeliac disease (ACD), and 10 patients with coeliac disease (CD) on a gluten free diet (GFD-CD) by means of immunohistochemistry and multiplex polymerase chain reaction amplification of the T cell receptor gamma gene (TCR-gamma) rearrangement. Blood samples of nine RCS patients were also tested for clonality. RESULTS: LG was found in 9/14 (64%), 11/18 (61%), and 3/10 (30%) patients with RCS, ACD, and GFD-CD, respectively, while LC was found in 6/11 (55%), 3/4 (75%), and 2/3 (66%) patients. Contrary to CD, all samples from patients with LG and LC showed an aberrant IEL phenotype. Monoclonal TCR-gamma rearrangements were detected in 8/13 (62%), 8/10 (80%), and 4/9 (44%) of gastric, colonic, and blood samples, respectively, from RCS patients, while in CD patients such rearrangements were only found in 2/25 (8%) gastric samples. CONCLUSION: The immunophenotypically aberrant monoclonal IEL population present in the small intestine of patients with RCS frequently disseminates to the blood and the entire gastrointestinal epithelium, suggesting that this is a diffuse gastrointestinal disease.

Chronic intestinal graft-versus-host disease: clinical, histological and immunohistochemical analysis of 17 children.

Graft-versus-host disease (GVHD) can be acute or chronic. The pathogenesis of chronic GVHD is unclear. Chronic GVHD affects mainly skin, liver and digestive tract. Intestinal involvement is uncommon and histological features are poorly described. We report here the clinical, histological and immunohistochemical features of chronic GVHD with intestinal involvement. Intestinal biopsies from children with chronic GVHD (n=17) were compared to control children (n=21: 10 non-transplant cases, four non-GVHD transplant cases, seven acute GVHD). We evaluated clinical outcome, histological features and characterized immunohistochemically the immune cells involved locally. Chronic GVHD with intestinal involvement was usually multisystemic (88.2%) and preceded by acute GVHD in 88.2% of cases. The outcome was severe with complete recovery in only 58.8% of cases, and death related to chronic GVHD in 17.6% of cases. Histological features were characterized by (1) villous atrophy and (2) glandular lesions, mainly apoptotic with variable intensity and (3) lamina propria infiltrate with cytotoxic T lymphocytes (CD3+, CD8+, TiA1+, granzyme B-) which were significantly (P<0.001) increased compared to non-GVHD transplant and non-transplant controls. Therefore in chronic intestinal GVHD, the apoptotic process could be related to cytotoxic T lymphocytes.

[Etiological diagnosis of villous atrophy]. / Diagnostic étiologique d'une atrophie villositaire.

Villous atrophy may have various etiologies. The diagnosis of villous atrophy relies on an intestinal biopsy which necessitates a perfect histological technique to assert the villous atrophy and its degree. The most frequent etiology is coeliac disease. Villous atrophy regresses with gluten free diet. The failure of a strict gluten free diet implies to exclude a refractory sprue thought to be the earliest form of enteropathy associated T cell lymphoma. The other etiologies of villous atrophy are unusual and could be observed in alpha chain disease, inflammatory and infectious diseases, immune disorders, and primitive ileal villous atrophy. Other etiologies characterize villous atrophy in children as cow milk allergy and epithelial abnormalities.

Cytotoxic T cells in AIDS colonic cryptosporidiosis.

BACKGROUND/AIMS: It is not known how enteric cryptosporidiosis induces severe intestinal impairment despite minimal invasion by the parasite. The aim of this study was to analyse the histological features and locally implicated immune cells in colonic biopsies of AIDS related cryptosporidiosis. PATIENTS/METHODS: Colonic biopsies from patients with AIDS related cryptosporidiosis (n = 10, group I), patients with AIDS but without intestinal infection (n = 9, group II), and human seronegative controls (n = 9, group III) were studied. Using immunohistochemistry the infiltrating mononuclear cells were analysed in both the epithelium and lamina propria for the expression of CD3, CD8, TiA1, granzyme B, and CD68 and for glandular expression of human major histocompatibility complex DR antigen (HLA-DR). RESULTS: Severe histological changes, resulting in abundant crypt epithelial apoptosis and inflammatory infiltrate in the lamina propria, were seen in all biopsies from group I. A significant increase of CD8+, TiA1+, and granzyme B+ T cells in the lamina propria and HLA-DR glandular expression was noted in group I compared with groups II and III. However, the number of intraepithelial lymphocytes, lamina propria CD3+ T cells, and macrophages was not significantly increased in cryptosporidiosis specimens compared with controls. CONCLUSION: Epithelial apoptosis mediated by granzyme B+ cytotoxic host T cells might play a major role in the development of colonic lesions in AIDS related cryptosporidiosis.

[Efficacity of treatment with lamivudine in two patients with severe reactivation of hepatitis B after withdrawal of chemotherapy]. / Efficacité du traitement par lamivudine chez deux malades ayant eu une réactivation sévère d'une hépatite B induite par l'arrêt d'un traitement chimiothérapique.

Reactivation of chronic infection is a serious complication during and especially after the withdrawal of cancer chemotherapy in hepatitis B virus carriers. Mortality is high, ranging from 4 to 20%. We report two cases of severe reactivation, after withdrawal of chemotherapy for chronic lymphocytic leukemia in one case and for a bladder tumor in the other. Recovery occurred with lamivudine therapy. Morbidity and mortality are common in these cases, especially when intensive chemotherapy and/or chronic hepatitis and/or precore mutants viruses are involved. Although lamivudine seems to be effective in these cases, prophylactic use has not been clearly defined and must be evaluated.

Distinction between coeliac disease and refractory sprue: a simple immunohistochemical method.

AIMS: We recently showed that refractory sprue is distinct from coeliac disease, the former being characterized by abnormal intraepithelial T-lymphocytes expressing a cytoplasmic CD3 chain (CD3c), lacking CD3 and CD8 surface expression, and showing TCRgamma gene rearrangements. To take advantage of the abnormal phenotype of CD3c + CD8 - intraepithelial lymphocytes (IEL) in refractory sprue we developed a simple method to distinguish coeliac disease from refractory sprue. METHODS AND RESULTS: Comparative immunohistochemical studies using anti-CD3 and anti-CD8 antibodies were applied on paraffin-embedded and frozen biopsy specimens in refractory sprue (n = 6), coeliac disease (n = 10), healthy controls (n = 5) and suspected refractory sprue (n = 6). Comparable results were obtained on fixed and frozen biopsy specimens. In four of the six patients with suspected refractory sprue, abnormal CD3c + CD8 - IEL and TCRgamma gene rearrangements were found, as in refractory sprue; the remaining two patients had normal (CD3 + CD8 +) IEL and no TCRgamma gene rearrangements. Both patients had coeliac disease, as one failed to comply with a gluten-free diet, while the other was a slow responder. CONCLUSION: This simplified immunostaining method using anti-CD3 and anti-CD8 antibodies on paraffin sections can distinguish active coeliac disease from refractory sprue and should prove useful in clinical practice.

Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger's disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice.

The pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN), the most prevalent form of glomerulonephritis worldwide, involves circulating macromolecular IgA1 complexes. However, the molecular mechanism(s) of the disease remain poorly understood. We report here the presence of circulating soluble FcalphaR (CD89)-IgA complexes in patients with IgAN. Soluble CD89 was identified as a glycoprotein with a 24-kD backbone that corresponds to the expected size of CD89 extracellular domains. To demonstrate their pathogenic role, we generated transgenic (Tg) mice expressing human CD89 on macrophage/monocytes, as no CD89 homologue is found in mice. These mice spontaneously developed massive mesangial IgA deposition, glomerular and interstitial macrophage infiltration, mesangial matrix expansion, hematuria, and mild proteinuria. The molecular mechanism was shown to involve soluble CD89 released after interaction with IgA. This release was independent of CD89 association with the FcRgamma chain. The disease was induced in recombination activating gene (RAG)2(-/-) mice by injection of serum from Tg mice, and in severe combined immunodeficiency (SCID)-Tg mice by injection of patients' IgA. Depletion of soluble CD89 from serum abolished this effect. These results reveal the key role of soluble CD89 in the pathogenesis of IgAN and provide an in vivo model that will be useful for developing new treatments.

Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease.

BACKGROUND & AIMS: Celiac disease is a gluten-induced enteropathy characterized by the presence of gliadin-specific CD4(+) T cells in the lamina propria and by a prominent intraepithelial T-cell infiltration of unknown mechanism. The aim of this study was to characterize the subset(s) of intraepithelial lymphocytes (IELs) expanding during active celiac disease to provide insights into the mechanisms involved in their expansion. METHODS: Flow-cytometric analysis of isolated IELs and/or immunohistochemical staining of frozen sections were performed in 51 celiac patients and 50 controls with a panel of monoclonal antibodies against T-cell and natural killer (NK) receptors. In addition, in vitro studies were performed to identify candidate stimuli for NK receptor expression. RESULTS: In normal intestine, different proportions of IELs, which were mainly T cells, expressed the NK receptors CD94/NKG2, NKR-P1A, KIR2D/3D, NKp46, Pen5, or CD56. During the active phase of celiac disease, the frequency of CD94(+) IELs, which were mostly alphabeta T cells, was conspicuously increased over controls. In contrast, the expression of other NK markers was not modified. Furthermore, expression of CD94 could be selectively induced in vitro by T-cell receptor activation and/or interleukin 15, a cytokine produced by intestinal epithelial cells. CONCLUSIONS: The gut epithelium favors the development of T cells that express NK receptors. In active celiac disease, there is a specific and selective increase of IELs expressing CD94, the HLA-E-specific NK receptor that may be related to T-cell receptor activation and/or interleukin 15 secretion.

Push enteroscopy in celiac sprue and refractory sprue.

BACKGROUND: The aim of this study was to determine in patients with sprue whether jejunal endoscopy improves the diagnostic yield or provides information that may modify management, when compared with evaluation limited to the duodenum. METHODS: From January 1994 to June 1998, a total of 31 patients (6 men, 25 women, mean age 41 years) were prospectively evaluated by push enteroscopy. They were divided into two groups: (1) celiac disease at different stages of activity (n = 23) and (2) refractory sprue (n = 8). The endoscopic and histologic findings in the duodenum and in the jejunum were compared. RESULTS: Celiac disease: In 19 patients, endoscopic and histologic findings in the duodenum and jejunum were similar; in four patients villous atrophy was more severe in the duodenum than in the jejunum. Refractory sprue: In 5 of 8 patients, enteroscopy revealed ulcerative jejunitis, whereas ulcerations were found in the duodenum in only one case. CONCLUSION: In refractory sprue, push enteroscopy with jejunal biopsies was of diagnostic value in 50% of cases demonstrating ulcerative jejunitis, whereas it did not modify the management of patients with responsive celiac disease.