Treatment of cytomegalovirus infection or disease in solid organ transplant recipients with valganciclovir.

Valganciclovir (VGC) has proved efficacious and safe for the prophylaxis against cytomegalovirus (CMV) in high-risk transplant recipients and for the treatment of CMV retinitis in AIDS patients. We used VGC for the treatment of CMV infection (viremia without symptoms) or disease (CMV syndrome or tissue-invasive disease) in kidney, heart, and lung transplant recipients. Fourteen transplant recipients were treated: five for asymptomatic CMV infection and nine for CMV disease. VGC was administered in doses adjusted to renal function for 4 to 12 weeks (induction and maintenance therapy). Clinically, all nine patients with CMV disease responded to treatment. Microbiologically, treatment with VGC turned blood culture negative for CMV within 2 weeks in all patients and was associated with a > or =2 log decrease in blood CMV DNA within 3 weeks in 8 of 8 tested patients. With a follow-up of 6 months (n = 12 patients), asymptomatic recurrent CMV viremia was noted in five cases, and CMV syndrome noted in one case (all cases in the first 2 months after the end of treatment). VGC was clinically well tolerated in all patients; however, laboratory abnormalities occurred in three cases (mild increase in transaminases, thrombocytopenia, and pancytopenia). This preliminary experience strongly suggests that therapy with VGC is effective against CMV in organ transplant recipients; however, the exact duration of therapy remains to be determined: a longer course may be necessary to prevent early recurrence.

Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients.

S. Gianella, L. Haeberli, B. Joos, B. Ledergerber, R.P. Wüthrich, R. Weber, H. Kuster, P.M. Hauser, T. Fehr, N.J. Mueller. Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients. Transpl Infect Dis 2009. All rights reserved Abstract: Pneumocystis jirovecii pneumonia (PCP) remains an important cause of morbidity and mortality in immunocompromised individuals. The epidemiology and pathogenesis of this infection are poorly understood, and the exact mode of transmission remains unclear. Recent studies reported clusters of PCP among immunocompromised patients, raising the suspicion of interhuman transmission. An unexpected increase of the incidence of PCP cases in our nephrology outpatient clinic prompted us to conduct a detailed analysis. Genotyping of 7 available specimens obtained from renal transplant recipients was performed using multi-locus DNA sequence typing (MLST). Fragments of 4 variable regions of the P. jirovecii genome (ITS1, 26S, mt26S, beta-tubulin) were sequenced and compared with those of 4 independent control patients. MLST analysis revealed identical sequences of the 4 regions among all 7 renal allograft recipients with available samples, indicating an infection with the same P. jirovecii genotype. We observed that all but 1 of the 19 PCP-infected transplant recipients had at least 1 concomitant visit with another PCP-infected patient within a common waiting area. This study provides evidence that nosocomial transmission among immunocompromised patients may have occurred in our nephrology outpatient clinic. Our findings have epidemiological implications and suggest that prolonged chemoprophylaxis for PCP may be warranted in an era of more intense immunosuppression.

Traitement par thoracoscopie du pneumothorax récidivant [Thoracoscopic treatment of recurrent pneumothorax].

Spontaneous pneumothorax (PNO) is usually due to rupture of a small subpleural bleb into the pleural cavity and affects mainly young men. After simple drainage, recurrence occurs in about 50% of cases. The risk of recurrence increases after each new PNO. Secondary PNO complicates an underlying pulmonary disease, especially chronic obstructive pulmonary disease with emphysema. A new form of secondary PNO has emerged in the recent years in AIDS patients with pneumocystis carinii pneumonia. We have shifted to a thoracoscopic therapy of PNO since May 1991. 25 PNO in 24 patients (1 bilateral) have been treated since that time up to April 1993. 19 PNO were primary, whereas 6 were secondary, included 3 iatrogenic PNO. Resection of the leaking parenchymal area was performed in 20 patients, and parietal partial pleurectomy was done in 20 cases. In the remaining cases, fibrin glue was applied on the lesion and in 3 cases, chemical pleurodesis was attempted using silver nitrate or talc. 1 AIDS patient died of ARDS. 3 patients had recurrent PNO and had thoracotomy without complication. 21 patients did well. Partial PNO recurred in one of them 4 months later, and was treated by simple needle aspiration. Thoracoscopy is a useful method to treat recurrent or persistent spontaneous PNO. After only 25 cases, our success rate in primary PNO is 90%. There should be a learning curve. On the basis of our experience, we believe that recognition of the lesion and its resection as well as apical parietal pleurectomy are necessary to obtain good results and a low recurrence rate.

Información para afectados por el VIH

Se trata de un protocolo que indica detalladamente cómo informar a aquellos pacientes seropositivos -infectados por el virus de la inmunodeficiencia humana- y a los que están desarrollando la enfermedad. se contempla la información pre-prueba, post-prueba, los consejos para mantenerse en salud en caso de infección, y cómo mejorar la calidad de vida en el proceso de la enfermedad.

Información para afectados por el VIH

Se trata de un protocolo que indica detalladamente cómo informar a aquellos pacientes seropositivos -infectados por el virus de la inmunodeficiencia humana- y a los que están desarrollando la enfermedad. se contempla la información pre-prueba, post-prueba, los consejos para mantenerse en salud en caso de infección, y cómo mejorar la calidad de vida en el proceso de la enfermedad.

Expression of extracellular matrix components and their receptors in the central nervous system during experimental Toxoplasma gondii and Trypanosoma cruzi infection

Alterations in extracellular matrix (ECM) expression in the central nervous system (CNS) usually associated with inflammatory lesions have been described in several pathological situations including neuroblastoma and demyelinating diseases. The participation of fibronectin (FN) and its receptor, the VLA-4 molecule, in the migration of inflammatory cells into the CNS has been proposed. In Trypanosoma cruzi infection encephalitis occurs during the acute phase, whereas in Toxoplasma infection encephalitis is a chronic persisting process. In immunocompromised individuals such as AIDS patients, T. cruzi or T. gondii infection can lead to severe CNS damage. At the moment, there are no data available regarding the molecules involved in the entrance of inflammatory cells into the CNS during parasitic encephalitis. Herein, we characterized the expression of the ECM components FN and laminin (LN) and their receptors in the CNS of T. gondii- and T. cruzi-infected mice. An increased expression of FN and LN was detected in the meninges, leptomeninges, choroid plexus and basal lamina of blood vessels. A fine FN network was observed involving T. gondii-free and T. gondii-containing inflammatory infiltrates. Moreover, perivascular spaces presenting a FN-containing filamentous network filled with a4+ and a5+ cells were observed. Although an increased expression of LN was detected in the basal lamina of blood vessels, the CNS inflammatory cells were a6-negative. Taken together, our results suggest that FN and its receptors VLA-4 and VLA-5 might be involved in the entrance, migration and retention of inflammatory cells into the CNS during parasitic infections.

Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant

The objective of this prospective study was to evaluate the efficacy and complications of the use of an intraocular sustained-release ganciclovir implant for the treatment of active cytomegalovirus (CMV) retinitis in AIDS patients. Thirty-nine eyes of 26 patients were submitted to ocular surgery. All patients underwent complete ocular examination before and after surgery. The surgical procedure was always done under local anesthesia using the same technique. The mean time for the surgical procedure was 20 min (range, 15 to 30 min). The average follow-up period was 3.7 months. Of all patient, only 4 presented recurrence of retinitis after 8, 8, 9 and 2 months, respectively. Three of them received a successful second implant. All 39 eyes of the 26 patients presented healing of retinitis as shown by clinical improvement evaluated by indirect binocular ophthalmoscopy and retinography. Retinitis healed within a period of 4 to 6 weeks in all patients, with clinical regression signs from the third week on. Six (15.4%) eyes developed retinal detachment. None of the patients developed CMV retinitis in the contralateral eye. The intraocular implant proved to be effective in controlling the progression of retinitis for a period of up to 8 months even in patients for whom systemic therapy with either ganciclovir or foscarnet or both had failed. The intraocular sustained-release ganciclovir implant proved to be a safe new procedure for the treatment of CMV retinitis, avoiding the systemic side effects caused by the intravenous medications and improving the quality of life of the patients.

Prevalence of antibodies to human herpesvirus-8 in populations with and without risk for infection in São Paulo State

Human herpesvirus 8 (HHV-8) is a newly described herpesvirus that is etiologically associated with all forms of Kaposi's sarcoma (KS). Seroepidemiological studies have shown high prevalence rates of HHV-8 antibodies among men who have sex with men (MSM) and AIDS patients, African children, Brazilian Amerindians, and elderly individuals in certain regions of Europe. The aim of the present study was to determine the prevalence of HHV-8 antibodies in healthy children and young adults from different cities in São Paulo State, and in a population at high risk for HHV-8 infection: HIV-negative MSM, and AIDS patients with and without KS. Antibodies to HHV-8 latency-associated nuclear antigen and lytic-phase antigens were detected by immunofluorescence assays. In 643 healthy children and young adults from the general population attending a vaccination program for yellow fever in ten different cities in São Paulo State, the prevalence of HHV-8 antibodies detected by the presence of latent or lytic antigens ranged from 1.0 to 4.1% in the different age groups (mean = 2.5%). In the MSM group, the prevalence was 31/95 (32.6%). In the group of patients with AIDS, the prevalence was 39.2% (51/130) for non-KS patients and 98.7% (77/78) for AIDS patients with the diagnosis of KS confirmed by histopathological examination. We conclude that HHV-8 has a restricted circulation among healthy children and young adults in the general population of São Paulo State and a high prevalence among MSM and AIDS patients.

A multiplex PCR assay able to simultaneously detect Torque teno virus isolates from phylogenetic groups 1 to 5

Torque teno virus (TTV) is a circular, single-stranded DNA virus that chronically infects healthy individuals of all ages worldwide. TTV has an extreme genetic heterogeneity which is reflected in its current classification into five main phylogenetic groups (1-5). Using specific PCR assays, it has been shown that many individuals are co-infected with TTV isolates belonging to different phylogenetic groups. Here, a multiplex PCR assay was developed, using five recombinant plasmids. Each plasmid carried an insert of different size issued from a TTV isolate belonging to a different group. The assay was able to simultaneously amplify DNAs of TTV isolates belonging to all five phylogenetic groups. Multiplex PCR was then tested satisfactorily on DNAs extracted from 55 serum samples (47 health care workers and 8 AIDS patients). All individuals but nine were infected with at least one TTV isolate. Co-infection with multiple isolates was found in 29/47 (62%) health care workers and in 8/8 (100%) AIDS patients. A number of discrepancies were observed when results obtained with three thermostable DNA polymerases were compared. For example, four TTV phylogenetic groups were detected in a particular serum sample by using one of the three DNA polymerases, whereas the other two enzymes were able to detect only three TTV groups. However, none of the three enzymes used could be broadly considered to be more efficient than the others. Despite its limitations, the assay described here constitutes a suitable tool to visualize the degree of co-infection of a given population, avoiding time-consuming experiments.

Is arterial stiffness in HIV-infected individuals associated with HIV-related factors?

We investigated the association between pulse wave velocity (PWV) and HIV infection, antiretroviral treatment-related characteristics, viral load, immune status, and metabolic changes in a cross-sectional study nested in a cohort of HIV/AIDS patients who have been followed for metabolic and cardiovascular changes since 2007. The study included patients recruited from the cohort (N = 261) and a comparison group (N = 82) of uninfected individuals, all enrolled from April to November 2009. Aortic stiffness was estimated using the carotid-femoral PWV (Complior-Artech, Paris, France). The groups were similar with respect to age, metabolic syndrome, diabetes mellitus, Framingham score, and use of antihypertensive and hypolipidemic medications. Hypertension was more frequent among the controls. Individuals with HIV had higher triglyceride, glucose and HDL cholesterol levels. Among individuals with HIV/AIDS, those with a nadir CD4+ T-cell count <200 cells/mm³ had a higher PWV (P = 0.01). There was no statistically significant difference when subjects were stratified by gender. Heart rate, age, male gender, and blood pressure were independently correlated with PWV. Nadir CD4+ T-cell count did not remain in the final model. There was no significance difference in PWV between HIV-infected individuals and uninfected controls. PWV was correlated with age, gender, and blood pressure across the entire population and among those infected with HIV. We recommend cohort studies to further explore the association between inflammation related to HIV infection and/or immune reconstitution and antiretroviral use and PWV.

Études sur le rôle d’IL-18 dans l’immunopathogénèse du SIDA

Le virus de l’immunodéficience humaine ou VIH est l’agent qui cause le SIDA. Le VIH donne lieu à une dérégulation dans la production de certaines cytokines qui ont un rôle immunologique très important chez les patients infectés. L’IL-18, autrement nommé facteur inducteur d’IFN-γ, est une cytokine pro-inflammatoire qui affecte le système immunitaire de façon importante. Son activité est régulée par l’"IL-18 Binding Protein" (IL-18BP), une autre cytokine qui se lie avec l’IL-18 et inhibe son activité biologique. Des études ultérieures ont montré des niveaux élevés d’Il-18 chez les patients infectés par le VIH par rapport aux personnes saines. Cependant, aucune étude n’a été réalisée concernant la production d’IL-18BP chez ces patients. Due à sa relevance dans la régulation de l’IL-18, nous avons étudié l’effet de l’infection par le VIH sur l’équilibre entre ces deux facteurs et l’impact de cet équilibre sur l’homéostasie des cellules NK. Nous avons mesuré les taux de l’IL-18 et de l’IL-18BP circulantes dans les sérums des patients infectés par le VIH en les comparants avec le même nombre de personnes saines et séronégatives. Nous avons aussi déterminé le nombre total des différents sous-types de cellules NK et analysé l’activité des cellules NK (Natural Killer). Finalement nous avons cherché à déterminer si l’IL-18 pouvait induire l’apoptose des cellules NK en activant l’expression de Fas ligand. Nos résultats nous démontrent que les patients infectés par le VIH ont trois fois plus d’IL-18 que les donneurs sains. Cependant les niveaux d’IL-18BP sont plus bas chez les patients infectés comparés aux donneurs sains. Alors, le ratio IL-18/IL-18BP est augmenté chez les patients infectés, ce qui entraîne une grande quantité d’IL-18 libre et biologiquement active circulante dans leur organisme. Nos études démontrent que chez ces patients, les concentrations d’IL-18 sont en corrélation négative avec l’activité cytotoxique de leurs cellules NK. Nos études in vitro démontrent que le traitement des cellules NK par l’IL-18 induit de façon fratricide leur apoptose en augmentant l’expression de Fas ligand. Finalement, cette production non coordonnée de ces deux facteurs pourrait contribuer à une immunopathologie induite par l’IL-18 en entraînant une apoptose fratricide des cellules NK qui possèdent un rôle important dans la réponse antivirale. Le dérèglement de l’homéostasie des cellules NK pourrait donc contribuer à la pathogenèse induite par le VIH.

Études des mécanismes d’induction de l’immunosuppression par le virus Herpès Humain 6

HHV-6 is a ubiquitous human herpesvirus. Most individuals become infected at the age of 2 years. Primary infection by the virus causes a self-limiting febrile illness called exanthem subitum or roseola. In adults, primary infection may cause mononucleosis-like illnesses. The infection usually remains latent in healthy individuals, but often reactivates in immunocompromised individuals, for example, transplant patients and AIDS patients. The virus has also been associated with cancers and lymphoproliferative disorders. The virus encodes two proteins that interact with p53. However, little is known concerning the impact of the virus on cell cycle progression in human cells. The investigations reported in the thesis were focused on this issue. We show here that that HHV-6 infection delays the cell cycle progression in human T cell line HSB-2, as well as in primary human T cells and causes their accumulation in S and G2/M phase. By degrading the viral DNA in the virus-infected cells, we show that the infected cells accumulate in the G2/M and not in the S phase. We observed an increase in the kinase activity of cdc2 in virus-infected cells despite lower levels of its catalytic partners, cyclin A and cyclin B. We show here that the viral early antigen p41 associates with, and increases the kinase activity of, CDK1. Our studies have shown that there is a drastic reduction of p21 protein, despite the virus-induced stabilization and activation of p53 suggesting that p53 may be transcriptionally inactivated in the virus-infected cells. This decrease of p21 in infected cells was partially restored by proteasome inhibitors. These results suggest that HHV-6 causes perturbations in the normal progression of cell cycle in human T cells. Autophagy is a physiological cell process during which old cellular constituents and long-lived proteins in cells are degraded. This process is regulated in a cell cycle-dependent manner. We show here that infection with HHV-6 induces autophagy in HSB-2 cells. This was shown by the induction of LC-3 II as well as by the appearance of autophagic vacuoles in the virus-infected cells. However, we found that the virus inhibits fusion between autophagic vacuoles and lysosomes formed in infected cells, thus evading the autophagic response of infected host cells. Finally we tried to investigate replication of the virus in human cells in the absence of P53; a tumor suppressor gene which is also known as "the guardian of the genome ". During these investigations, we found that that inhibition of p53 gene expression mediated by siRNA as well as its inhibition by pharmacological inhibitors leads to massive cell death in human T cell line HSB-2 that carries a wild-type p53. We show that this death also occurs in another cell line CEM, which carries a transcriptionally mutated p53. Interestingly, the cell death could be prevented by pharmacological inhibitors of autophagy and necroptosis. Taken together, our results provide important novel insights concerning the impact of HHV-6 on cell cycle regulation and autophagy as well as of basal level p53 in cell survival.

Ideación suicida y algunos factores biopsicosociales asociados con estas en pacientes adultos con leucemia, linfomas, cáncer gástrico o cáncer colorrectal Informe de investigación

El cáncer es una de las enfermedades con mayor impacto en la población mundial, debido a que genera alteraciones en las áreas de ajuste de los individuos, su núcleo familiar y social circundante. El presente estudio tiene como objetivo establecer la prevalencia de ideación suicida en pacientes con cáncer de tejidos blandos (leucemias y linfomas) y cáncer gástrico (colorectal). Fue un estudio exploratorio descriptivo, de la línea de investigación en Psicooncología y Cuidado Paliativo a la cual pertenece el proyecto: “Conducta suicida (ideación suicida, intención suicida y suicidio frustrado) y factores biopsicosociales asociadas a esta en pacientes con cáncer”. La población que participó en este estudio fueron pacientes adultos del Centro de Investigaciones oncológicas de la clínica San Diego CIOSAD. De esta investigación se puede concluir que la prevalencia de ideación suicida en pacientes con estos tipos de cáncer es de 4.9% (N=10). Los factores asociados a la ideación suicida fueron: número de hijos, dolor y ansiedad en la última semana y estrato socioeconómico

Ansiedad, depresión y calidad de vida en personas adultas con VIH/SIDA y deterioro cognitivo leve

El Virus de la Inmunodeficiencia Humana (VIH) y el Síndrome de Inmunodeficiencia Adquirida (SIDA) han tenido a lo largo de los años un comportamiento epidemiológico que muestra la tendencia al aumento, de tal forma que ha llegado a considerarse como un problema de salud pública a nivel mundial. Sin embargo los tratamientos antiretrovirales han permitido que las personas con esta infección tengan una tasa de supervivencia mayor; pero ligado a esto, se han presentado efectos secundarios tales como problemas con la memoria y el funcionamiento cognitivo de estas personas. Además se ha encontrado que las personas con VIH/SIDA tienen algunas alteraciones en su área afectiva y generalmente ven afectada su calidad de vida. Este es un estudio exploratorio descriptivo que tuvo por objeto describir la ansiedad, depresión y percepción de calidad de vida en 35 pacientes con VIH/SIDA con deterioro cognitivo leve, seleccionados por conveniencia. Se aplicaron tres cuestionarios, el BDI-II para evaluar la sintomatología depresiva; el BAI para evaluar la sintomatología ansiosa y el MOS-SF30 para evaluar la calidad de vida. Además, se realizó una entrevista semiestructurada para profundizar en la evaluación de estas tres variables. Dentro de los resultados se evidenció que todos los paciente presentan algún nivel de ansiedad y de depresión, evalúan su calidad de vida en un punto medio; ni óptima ni baja. Se discuten estos y otros resultados.

Chronic colitis associated with HIV infection can be related to intraepithelial infiltration of the colon by CD8+T lymphocytes

Gastrointestinal complications in AIDS patients with diarrhoea are common clinical manifestations, frequently diagnosed by colonoscopy as non-specific colitis. We retrospectively study colon biopsies diagnosed as chronic colitis associated with HIV (CCH). Biopsies were sorted as patients with AIDS (serum CD4 < 200 cell/mm(3)) but without any clear infectious process (n = 12) and patients without HIV infection (n = 24). There are low numbers of CD4+ T lymphocytes in lamina propria of AIDS patients, but CD8+ T populations in this area appear to be similar in all studied groups, regardless of HIV infection or laboratory evidence of a specific agent. We found the clear evidence of CD8+ T cells infiltration in colonic mucosa in HIV patients with microscopic colitis. An imbalance of lymphocyte subpopulations in the colon, both in the lamina propria and epithelium, could result in an intraepithelial CD8 infiltration, involved in the pathogenesis of CCH in AIDS patients.