Estudio de alteraciones de la inmunidad humoral y su asociación con el riesgo de infecciones en pacientes sometidos a trasplantes cardiaco, renal y pulmonar
- Autores: María Isabel Jaramillo Lopetegui
- Directores de la Tesis: Javier Alberto Carbone Campoverde (dir. tes.), Elizabeth Sarmiento Marchese (codir. tes.)
- Lectura: En la Universidad de Alcalá ( España ) en 2018
- Idioma: español
- Tribunal Calificador de la Tesis: María del Pilar Herrera Puente (presid.), José Manuel Cifrián Martínez (secret.), Carmen Rodríguez Sainz (voc.)
- Programa de doctorado: Programa de Doctorado en Ciencias de la Salud por la Universidad de Alcalá
- Materias:
- Enlaces
- Resumen
- español
Son necesarios nuevos biomarcadores para optimizar la detección de riesgo de infección en pacientes trasplantados de órgano sólido. Esta tesis doctoral contiene datos provenientes de tres estudios multicéntricos prospectivos para evaluar perfiles de repuesta humoral que podrían ser capaces de identificar riesgo de infección severa en trasplantados cardíacos, pulmonares y renales. Además, se estudió el impacto de la modificación de la inmunodeficiencia humoral secundaria en trasplante cardíaco mediante un ensayo clínico para prevenir infecciones severas mediante uso de inmunoglobulinas intravenosas (IGIV).
En el estudio de trasplante de corazón se analizaron datos de 170 receptores adultos en ocho centros de España. Evaluando parámetros inmunológicos como IgG, IgA, IgM, factores de complemento C3 y C4, título específico de anticuerpos anti neumococo (anti PN) y anti citomegalovirus (anti CMV) pre-trasplante y a día 7 y 30 post-trasplante. La variable resultado fue el desarrollo de infección severa, definida como desarrollo de infección que requirió tratamiento antimicrobiano por vía endovenosa durante los primeros 6 meses. Durante el seguimiento, 53 pacientes desarrollaron al menos una infección grave. Se confirmó que la hipogammaglobulinemia (HGG) IgG ( < 600 mg/dl) al día 7, es un factor de riesgo de las infecciones en general, así como de infecciones bacterianas y enfermedad por CMV en particular. Al día 7 después del trasplante la combinación de baja IgG ( < 600 mg/dl) y bajo C3 ( < 80 mg/dl), presentó fuerte asociación con el riesgo de infección. Se constató que valores más bajos en la cuantificación de los títulos de anticuerpos anti CMV y en las concentraciones de anticuerpos anti PN fueron predictores independientes de enfermedad por CMV y de infecciones bacterianas, respectivamente.
En el estudio de trasplante de pulmón se analizaron datos de 82 adultos de 5 centros en España. Los puntos de estudio fueron pre trasplante cuando se encontraba en lista de espera, día 7 y día 30 post-trasplante. Los parámetros inmunológicos incluidos fueron IgG, IgA, IgM y factores de complemento C3 y C4, títulos específicos de anticuerpos anti PN y anti CMV. La HGG, definida como niveles de IgG < 600 mg/dl a la semana post trasplante de pulmón, fue un factor de riesgo de enfermedad por CMV y de infección fúngica. Los niveles de anticuerpos anti PN isotipo IgM < a 5 mg/dl post trasplante pulmonar presentaron mayor asociación con infección bacteriana. Niveles pre trasplante más bajos de anti CMV se asociaron con riesgo de enfermedad CMV.
En el estudio de trasplante renal se evaluaron 264 pacientes de 5 centros con similar metodología y resultados que en los estudios previos. La prevalencia general de HGG, definida por curva ROC como IgG < 700 mg/dl, fue del 11,8% previa al trasplante, 31,4% al día 7 y 30,6% al día 30 post-trasplante. Durante el seguimiento 18 de los receptores desarrollaron al menos un episodio de infección por CMV. El nivel de IgG en el día 30 fue menor en los pacientes que desarrollaron infecciones por CMV tras el trasplante en comparación con los que no tenían esta complicación. El análisis ROC reveló una especificidad del 75% para el desarrollo de la infección por CMV del punto de corte seleccionado para la definición de HGG.
Esta tesis doctoral contribuye a la caracterización de la inmunodeficiencia secundaria asociada a trasplante de órgano sólido. Realiza la validación de la hipogammaglobulinemia, del déficit de anticuerpos específicos y de complemento como factores de riesgo inmunológicos fácilmente evaluables en la práctica clínica. Finalmente presenta una evaluación preliminar de cómo la inmunoterapia con IGIV puede corregir la HGG de manera segura aportando una posible disminución del riesgo de padecer infecciones graves.
- English
New biomarkers are necessary to improve detection of the risk of severe infection in solid organ transplantation. This doctoral thesis included data of the analysis of 3 prospective multicenter studies to evaluate humoral immunity profiles that could better enable us to identify heart, lung and kidney recipients at risk of severe infections. In addition, data of a pilot clinical trial were studied to evaluate the impact of the immunomodulation of IgG hypogammaglobulinemia (HGG) and specific antibody deficiency by use of intravenous immunoglobulin (IVIG) in heart recipients.
In the multicenter study of heart transplant data from 170 adult recipientes at 8 centers in Spain were analized. Assessment points were before transplantation, day 7 and day 30 after transplantation. Immune parameters included IgG, IgA, IgM and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti PN) and to cytomegalovirus (anti CMV). Clinical outcome was defined as an infection episode that needs intravenous anti-microbial therapy during the first 6 months after transplantation. During follow-up, 53 patients (31, 2%) developed at least one severe infection episode. It was confirmed that IgG hypogammaglobulinemia at day 7 (defined as IgG<600 mg/dl) is a risk factor of overall infection in general and of bacterial and cytomegalovirus (CMV) infections. At day 7 after transplantation, the combination of low IgG <600 mg/dl and low C3 <80 mg/dl was strongly associated with the outcome with adjusted odds ratio (OR) 7.40; 95% confidence interval (CI) 1.48 to 37.03 and p=0.014. It was shown that quantification of anti CMV antibody titers and lower anti PN antibody concentrations were independent predictors of CMV disease and bacterial infections, respectively. Thus, it was demonstrated that early immunologic monitoring of humoral immunity profiles proved to be useful for the identification of heart recipients who were at risk of severe infection. In this multicenter study of heart recipient´s it was foundw a good correlation of IgG levels among distinct participating centers.
In the clinical trial with IVIG performed to further explore of the role of HGG and the potential impact of its reconstitution 12 cardiac receptors with IgG <500 mg / dl in a screening phase of the trial were enrolled in a screening phase of the clinical trial. A 5% IVIG preparte was administered to these patients as soon as HGG was detected. IgG and specific antibody titers to different microorganisms were assayed during follow-up. The primary outcome measure was the development of a serious infection during the study period. Data on the primary outcome were compared to those of 13 transplant recipients who developed HGG that were not included in the clinical trial and those from 11 recipients who did not develop HGG during the same study period. The mean time to detection of HGG was 15 days. A significant increase of IgG and specific antibodies named anti-cytomegalovirus antibodies, anti-Haemophilus influenzae and anti-hepatitis B antibodies were observed in patients treated with IVIG. Severe infections occurred in 3 of 12 (25%) patients treated with IVIG in 10 of 13 (77%) patients with HGG without IGIV and in 2 of 11 (18%) non-HGG patients (Log-Rank, 15.31 p = 0.0005). Treated patients did not present IVIG attributable adverse events. Data from this study preliminary demonstrate that prophylactic IVIG replacement therapy safely reconstitutes HGG and specific antibodies at the same time this is associated with a lower rate of infection in patients with HGG.
In the multicenter study of lung transplantation, 82 adults were evaluated in 5 centers in Spain. Study assessment points were pre-transplant, day 7 and day 30 post-transplant. Immunological parameters included IgG, IgA, IgM and complement factors C3 and C4, specific titers of anti PN and anti CMV. HGG was defined as IgG levels <600 mg / dl a week after lung transplantation was a risk factor for CMV and fungal infection independent of the participating center. IgM anti PN below 5 mg / dl at day 7 post lung transplantation had higher association with bacterial infection. The presence of minor titers of CMV-specific antibodies in the pre-transplant period were associated with the development of CMV infection in the post-transplant period.
The multicenter prospective study of renal transplantation 264 patients from 5 centers were included and studied with similar methodology and results as in the previous studies. The overall prevalence of HGG defined as less than 700mg / dl was as follows, at baseline 11.8%, at day 7 31.4% and at day 30 29.6%. Day 30 IgG level was lower in patients who developed treated CMV infections after transplantation compared with patients without this complication (704±276 and 894±281%, respectively, p = 0.013). ROC analysis disclosed a specificity of 75% for development of CMV infection of the selected cut-off IgG <700 mg/dl. In logistic regression analysis kidney recipients with IgG <700 mg/dl at day 30 were three times more prone to develop CMV infection than patients with higher IgG values (RH 3.33, 95% CI 1.05-10.48, p =0.04).
In the multicenter studies, solid organ receptors with lower IgG levels after transplantation were at higher risk for development of severe infections. This observation suggests the rol of humoral immunity in the control of these infections. In the clinical trial, early reconstitution of hypogammaglobulinemia in heart recipients was associated with a lower rate of severe infection.
This doctoral thesis contributes to a better characterization of secondary immunodeficiency and risk factors for severe infections that develop after solid organ transplantation. This work also provides data for validation of hypogammaglobulinemia and specific antibody deficiency as risk factors easy to evaluate on the bedside. And finally, it also proposes preliminarily that immunotherapy of IgG hypogammaglobulinemia could be a save therapeutic option in these patients.
- español
