Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation

Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2–4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2–4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.

Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central / Modulation of apoptosis by cytomegalovirus, from the perspective of the central nervous system

Apoptosis is one of the most effective mechanisms against the spread of pathogens such as viruses. However, viruses have developed measures to counter the protective role of apoptosis in infected cells. Cytomegalovirus (CMV) represents the major cause of congenital infection worldwide triggering important damage in the developing central nervous system (CNS). Several mechanisms of apoptosis prevention during CMV infection have been described, among them, viral proteins and RNAs are capable of prevent apoptosis by the intrinsic and extrinsic pathways as well as the one mediated by stress in the endoplasmic reticulum. Nevertheless, the CMV pro-apoptotic effect remains enigmatic and it has been suggested as a bystander effect in non-infected cells. This review summarizes the mechanisms by which CMV modulates the signaling pathways involved in apoptosis. It also includes a brief description of the permissiveness of the CNS to CMV infection and the generated cell death after infection, which may relate to the observed damage during a congenital infection.

La apoptosis representa uno de los mecanismos de defensa más eficaces frente a la propagación de patógenos como lo son los virus. No obstante, éstos han desarrollado medidas para contrarrestar el papel protector de la apoptosis en las células infectadas. Citomegalovirus (CMV) es considerado la principal causa de infecciones congénitas a nivel mundial, afectando de forma importante el sistema nervioso central (SNC) en desarrollo. Diversos mecanismos de prevención de apoptosis durante la infección por CMV han sido descritos, entre los cuales, se encuentran proteínas y ARNs virales capaces de evitar la apoptosis por las vías intrínseca, extrínseca y la mediada por estrés del retículo endoplásmico. Sin embargo, aún representa un enigma el efecto pro-apoptótico de CMV que se sugiere actúe como un efecto espectador sobre las células no infectadas. En el presente trabajo se ofrece una revisión de los mecanismos mediante los cuales CMV modula las vías de señalización involucradas en la apoptosis. Asimismo se incluye una breve descripción de la permisividad del SNC a la infección por CMV y sobre la muerte celular generada tras la infección, que pueden relacionarse con el daño observado durante una infección congénita.

Citomegalovirus en enfermedad inflamatoria intestinal / Cytomegolavirus in inflammatory bowel disease

Cytomegalovirus (CMV) gastrointestinal infection in inflammatory bowel disease (IBD) is a diagnostic challenge with close relationship with clinical course and treatment response. This article summarizes biology, pathology, clinical manifestation and diagnosis of CMV disease and especially in IBD.

La infección gastrointestinal por citomegalovirus (CMV) en paciente con enfermedad inflamatoria intestinal (EII) constituye un desafío diagnóstico importante y se encuentra íntimamente relacionada con la evolución y respuesta a tratamiento de la EII. El presente artículo resume las características biológicas del CMV, sus características patogénicas, sus manifestaciones clínicas y sus métodos diagnósticos. Se expone con mayor detalle la implicancia de esta infección en pacientes portadores con EII y su enfrentamiento clínico.

Reactivación de Citomegalovirus en crisis de enfermedad inflamatoria intestinal: un análisis retrospectivo / Cytomegalovirus reactivation in inflammatory bowel disease: a retrospective analysis

Cytomegalovirus (CMV) is considered an agent involved in reactivation of inflammatory bowel disease (IBD). In our country there are no studies or guidelines to standardize CMV search in that setting. Objective: To describe the prevalence of CMV infection in hospitalized patients with IBD. Methods: Retrospective analysis of patients hospitalized due to IBD crisis from June 2007 to June 2009 at a university health center. Electronic cards, laboratory data, and endoscopic study were reviewed. CMV reactivation was diagnosed by means of antigenemia assay, and/or histopathology. Results: 88 IBD crises were identified (74 patients), in 52 a CMV study was requested (47 with antigenemia assay). Mean age was 38.5 years-old, 54 percent female, ulcerative colitis 67.3 percent, Crohn disease 32.7 percent. IBD crisis were classified as follows; severe 57.7 percent, moderate or mild 42.3 percent. The CMV diagnosis test was positive in 5 cases (9.6 percent), all of them were severe crisis (16.6 percent in severe crisis versus 0 percent in moderate/mild crisis, p = 0.055). In the group of steroid resistant disease the CMV antigenemia was positive in 66.6 percent versus 2.17 percent of non-steroid resistant patients (p = 0.0002). Test to detect CMV performed after the third day of hospitalization were positive in 36.36 percent versus those performed earlier, which were positive in 2.43 percent (p = 0.004). Conclusion: High prevalence of CMV infection in cases of severe IBD crisis was detected, specifically in a subgroup of steroid-resistant patients and three days after hospital admission. These findings suggest the importance to search CMV in this subgroup of patients.

Introducción: El citomegalovirus (CMV) puede participar en la reactivación de la enfermedad inflamatoria intestinal (EII). En nuestro medio no se ha estudiado el rol de CMV en pacientes hospitalizados por crisis de EII. Objetivo: Estimar la prevalencia de la reactivación de CMV en crisis de EII que requirieron hospitalización. Métodos: Análisis retrospectivo de pacientes hospitalizados en un centro de salud universitario por EII entre junio de 2007 y junio de 2009. Se revisaron registros clínicos electrónicos, laboratorio y estudio endoscópico. La reactivación de CMV se diagnosticó mediante antigenemia y/o histología. Resultados: Se identificaron 88 crisis de EII (74 pacientes), en 52 se solicitó estudio de CMV (47 con antigenemia). 67,3 por ciento fueron colitis ulcerosa; 32,7 por ciento enfermedad de Crohn. Edad promedio 38,5 años, 54 por ciento sexo femenino. La exacerbación fue catalogada como grave en 57,7 por ciento de los casos, moderada o leve en 42,3 por ciento. Se detectó reactivación de CMV en 5 pacientes (9,6 por ciento), los que se caracterizaron por presentar crisis grave (16,6 por ciento en crisis grave versus 0 por ciento en crisis leve/moderada, p = 0,055), refractariedad a corticoides (66,6 por ciento en corticorrefractarios versus 2,17 por ciento en sensibles a corticoides, p = 0,0002) y hospitalización mayor de 3 días (36,36 por ciento en hospitalización > 3 días versus 2,43 por ciento en estudio temprano, p = 0,004). Conclusión: En pacientes hospitalizados por crisis de EII es frecuente detectar evidencia de reactivación de CMV, la que se concentra en las crisis graves, corticorrefractarias y con hospitalización mayor de 3 días. Estos datos sugieren que la búsqueda de CMV debiera ser dirigida a este subgrupo de pacientes.

Comparison of immunoperoxidase and immunofluorescence assays for pp65 cytomegalovirus antigen in immunocompromised patients

We compared the pp65 antigen detection by an in house method (immunoperoxidase assay) and by a commercial kit (immunofluorescence assay) available for cytomegalovirus infection diagnosis in immunocompromised patients. Sixty-four blood samples were analyzed in duplicate for both techniques. Eight-six percent of the samples had concordant qualitative results. The discordant results occurred more frequently in samples with low quantity of positive cells. There were no significant differences with qualitative and quantitative results of the methods.

Impairment of cytomegalovirus-specific cellular immune response as a risk factor for cytomegalovirus disease in transplant recipients: [review]

Human cytomegalovirus (CMV) infection is common in most people but nearly asymptomatic in immunocompetent individuals. After primary infection the virus persists throughout life in a latent form in a variety of tissues, particularly in precursor cells of the monocytic lineage. CMV reinfection and occurrence of disease are associated with immunosuppressive conditions. Solid organ and bone marrow transplant patients are at high risk for CMV disease as they undergo immunosuppression. Antiviral treatment is effective in controlling viremia, but 10-15 percent of infected patients can experience CMV disease by the time the drug is withdrawn. In addition, long-term antiviral treatment leads to bone marrow ablation and renal toxicity. Furthermore, control of chronic CMV infection in transplant recipients appears to be dependent on the proper recovery of cellular immunity. Recent advances in the characterization of T-cell functions and identification of distinct functional signatures of T-cell viral responses have opened new perspectives for monitoring transplant individuals at risk of developing CMV disease.

Uma nova técnica para avaliar a lesão endotelial na arteriosclerose / A new technique to evaluate the endotelium lesion in atheroesclerosis

Os autores propõem uma nova técnica para avaliar a relação entre infecção e aterosclerose pela coleta de sangue da artéria coronária depois da lesão ou do seio coronariano em casos de insuficiência coronariana aguda durante a angioplastia, buscando bactérias, vírus e fragmentos de DNA virais

Citomegalovirose / Cytomegalovirus Disease

As infecçöes por CMV vêm assumindo papel de destaque cada vez maior em imunodeprimidos tais como pacientes com AIDS, transplantados renais e outros com déficit da imunidade celular. Também o CMV é considerado a causa mais comum de infecçäo congênita. Objetivamos com esta revisäo abordar os aspectos gerais das citomegaloviroses: histórico, características do vírus, patogênese, epidemiologia, incidência, quadro clínico, métodos diagnósticos e tratamento. Com isso, pretendemos ressaltar a importância desta infecçäo, que tem frequência subestimada devido a dificuldades diagnósticas e às vezes pelo desconhecimento de suas características. O diagnóstico da citomegalovirose propicia ao clínico tomada de medidas tais como: evitar uso abusivo de antibióticos em casos de febre prolongada, seleçäo de doadores de sangue e ou órgäos, detecçäo das crianças com infecçäo congênita e das gestantes de risco, assim como o uso de drogas antivirais específicas em pacientes imunodeprimidos

Citomegalovirus: diseminación de la infección en relación con los avances científicos y cambios sociales / Cytomegalovirus: infection's disemination in relation to the Scientific advances and social changes

Se comenta cómo el acentuado peligro y poco empleo de las transfusiones antes de 1900, año en que se descubrieron los grupos sanguíneos, mantuvo en cero la frecuencia de la enfermedad citomegálica. La generación de las transfusiones después de ese momento inición la diseminación del agente viral, acelerándose durante las guerras por el incremento en las necesidades de recambio del vital líquido. Los notables avances ulteriores en la cirugía, como fueron la práctica de los trasplantes de órganos y el invento de la bomba de perfusión sanguínea, aunados a la industrialización de concentrados del factor VIII, hicieron que la curva de la frecuencia de la infección citomegálica se tornase vertical, e incontables los casos informados a partir de 1955. También en el mismo decenio, un cambio social importante disminuyó considerablemente la represión en materia sexual y dio mayor libertad para expresar sus preferencias a la población homosexual, favoreciendo la promiscuidad y acrecentando la morbilidad por infecciones de transmisión sexual. El citomegalovirus, como se sabe, es capaz de provocar varias infecciones agudas y en cada una de ellas ocasionar en el individuo infectado un estado de inmunodeficiencia celular que lo torna una medida inerme ante infecciones oportunistas. La coincidencia de la diseminación del citomegalovirus, la extensión de la homosexualidad y otras costumbres sexuales promiscuas y la posible presencia, en esas infecciones, de una cepa que se ha asociado con el sarcoma de Kaposi, podrían en cierto modo explicar lo que acontece en el sídrome de inmunodeficiencia adquirida (SIDA), que aqueja mayormente a grupos hasta ahora considerados de alto riesgo: homosexuales masculinos, farmacodependientes que utilizan la vía intravenosa, hemofílicos y bisexuales promiscuos...