Análisis de la inmunidad de las mujeres infectadas por el virus del papiloma humano y su relación con la lesión intraepitelial cervical / Immunity analysis in women infected with human papillomavirus and its link with cervical intraepithelial lesion (IMVIR study)

Introducción: El objetivo principal es estudiar los marcadores de NK memoria presentes en sangre periférica en pacientes con lesiones cervicales intraepiteliales de alto grado CIN2/3 frente a mujeres sin lesiones o con lesiones de bajo grado. Los objetivos secundarios son estudiar la relación entre el perfil de las células NK memoria y la infección o no por VPH, así como la persistencia viral en las mujeres infectadas por VPH. Material y métodos: Se trata de un estudio observacional prospectivo de una cohorte de mujeres reclutadas desde el año 2019, durante un periodo de 2años, en la unidad del tracto genital inferior en las consultas de ginecología general del Instituto de Salud de la Mujer del Hospital Clínico San Carlos. Los grupos de pacientes incluidos en el estudio son el grupo de estudio: mujeres con infección por VPH y con lesión cervical de alto grado (CIN2+); el grupo control1: mujeres con infección por el VPH sin lesión cervical de alto grado, y el grupo control2: mujeres sin infección por el VPH y sin lesión. Resultados: Durante el estudio se han reclutado 115 pacientes. Nos encontramos con un mayor número de NK «memoria» en pacientes infectadas, tanto en el grupo control1 como en el grupo de estudio, en comparación con el grupo control2. Además, cuando se analizan las pacientes no fumadoras, la expresión de NKp30 es significativamente menor en el grupo control1. Conclusiones: Los resultados ponen de manifiesto una probable menor capacidad para desarrollar funciones adaptativas por parte de las células NK en estas pacientes fumadoras frente a las no fumadoras. Un mejor conocimiento de la biología de las células NK y su papel en la infección por el VPH podría permitir el desarrollo de estrategias para manipular su funcionamiento (inmunoterapias) con un propósito pronóstico y terapéutico.(AU)

Introduction: The main objective is to study the NK markers present in circulating blood in patients with high grade intraepithelial cervical lesions compared with women without lesions or low grade lesions. The secondary objectives of the study are to understand the relationship between the NK memory like cells and the infection with HPV, as well as the persistence of the infection. Methods and materials: It is an observational prospective study that studies women from 2019 for 2years seen in ginecology rooms in Hospital Clínico San Carlos. The group of patients studied are: women with infection by HPV and high grade lesions, women with infection by HPV but no lesion or low grade lesion and women without lesion or infection. Results: We have recruited 115 patients. We have found more memory like NK cells in patients infected by HPV. And when we analyze the non-smoking patients, the expression of NKp30 is lower in patients infected without lesion. Conclusions: The results show that there could be less capacity to generate an adaptative function by NK in smoking patients than in non-smoking. A better knowledge of the NK cells biology and its role in the infection by HPV could allow us to manipulate with a therapeutic and prognostic end.(AU)

Convergence insufficiencyCentral mini-plication of medial rectusDiplopiaConsecutive esotropiaSurgical overcorrection / Detection of anti-SARS-CoV-2 antibodies in tears: Ocular surface immunity to COVID-19

Objetivos Evaluar la presencia de anticuerpos IgA e IgG específicos del SARS-CoV-2 en lágrima de sujetos no vacunados y vacunados contra la COVID-19 con antecedentes de infección SARS-CoV-2. Correlacionar los resultados en lágrima con los de saliva y sangre, datos clínicos y regímenes de vacunación. Métodos Estudio transversal que incluyó a sujetos con antecedentes de infección SARS-CoV-2, tanto no vacunados como vacunados contra la COVID-19. Se recogieron 3muestras: lágrima, saliva y sangre. Se analizaron IgA e IgG frente a S-1 SARS-CoV-2 con ELISA semicuantitativo. Resultados Treinta sujetos, con una edad media 36,4±10, varones 13/30 (43,3%) con historia de infección SARS-CoV-2 leve; 13/30 (43,3%) habían recibido un régimen de 2 dosis y 13/30 (43,3%) un régimen de 3 dosis de vacunación anti-COVID-19, 4/30 (13,3%) no estaban vacunados. Todos los sujetos con vacunación completa presentaron IgA detectable en los 3biofluidos. Entre los no vacunados, se detectó IgA en 3/4 sujetos en lágrima y saliva, mientras que no se detectó IgG. No se observaron diferencias entre la pauta de vacunación de 2 y 3 dosis según los títulos IgA-IgG. Conclusiones Anticuerpos IgA e IgG del SARS-CoV-2 están presentes en lágrimas de pacientes con antecedentes de COVID-19 leve, lo que destaca el papel de la superficie ocular como primera línea de defensa frente a la infección. La mayoría de los sujetos no vacunados presentaron IgA a largo plazo en lágrima y saliva. La inmunización híbrida (infección natural más vacunación) parece potenciar las respuestas IgG mucosas y sistémicas. No se observaron diferencias entre la pauta de 2 y 3 dosis (AU)

Purpose To evaluate the presence of SARS-CoV-2 specific IgA and IgG antibodies in tears of unvaccinated and anti-COVID-19 vaccinated subjects with previous history of SARS-CoV-2 infection. To compare results in tears with those in saliva and serum and correlate with clinical data and vaccination regimens. Methods Cross-sectional study including subjects with a previous history of SARS-CoV-2 infection, both unvaccinated and vaccinated against COVID-19. Three samples were collected: tears, saliva and serum. IgA and IgG antibodies against S-1 protein of SARS-CoV-2 were analyzed with a semi-quantitative ELISA. Results Thirty subjects, mean age 36.4±10, males 13/30 (43.3%) with history of mild SARS-CoV-2 infection were included. 13/30 (43.3%) subjects had received a 2-dose regimen and 13/30 (43.3%) a 3-dose regimen of anti-COVID-19 vaccine, 4/30 (13.3%) subjects were unvaccinated. All the participants with full anti-COVID-19 vaccination (2-or 3-doses) presented detectable anti-S1 specific IgA in all 3biofluids, tears, saliva and serum. Among unvaccinated subjects, specific IgA was detected in 3/4 subjects in tears and saliva, whereas IgG was not detected. Considering IgA and IgG antibodies titers, no differences were observed between the 2- and 3-dose vaccination regimen. Conclusions SARS-CoV-2-specific IgA and IgG antibodies were detected in tears after mild COVID-19, highlighting the role of the ocular surface as a first line of defense against infection. Most naturally infected unvaccinated individuals exhibit long-term specific IgA in tears and saliva. Hybrid immunization (natural infection plus vaccination) appears to enhance mucosal and systemic IgG responses. However, no differences were observed between the 2- and 3-dose vaccination schedule (AU)

[Detection of anti-SARS-CoV-2 antibodies in tears: Ocular surface immunity to COVID-19]. / Detección de anticuerpos anti-SARS-CoV-2 en lágrimas: inmunidad de la superficie ocular frente a COVID-19.

Purpose: To evaluate the presence of SARS-CoV-2 specific IgA and IgG antibodies in tears of unvaccinated and anti-COVID-19 vaccinated subjects with previous history of SARS-CoV-2 infection. To compare results in tears with those in saliva and serum and correlate with clinical data and vaccination regimens. Methods: Cross-sectional study including subjects with a previous history of SARS-CoV-2 infection, both unvaccinated and vaccinated against COVID-19. Three samples were collected: tears, saliva and serum. IgA and IgG antibodies against S-1 protein of SARS-CoV-2 were analyzed with a semi-quantitative ELISA. Results: Thirty subjects, mean age 36.4 ± 10, males 13/30 (43.3%) with history of mild SARS-CoV-2 infection were included. 13/30 (43.3%) subjects had received a 2-dose regimen and 13/30 (43.3%) a 3-dose regimen of anti-COVID-19 vaccine, 4/30 (13.3%) subjects were unvaccinated. All the participants with full anti-COVID-19 vaccination (2-or 3-doses) presented detectable anti-S1 specific IgA in all 3 biofluids, tears, saliva and serum. Among unvaccinated subjects, specific IgA was detected in 3/4 subjects in tears and saliva, whereas IgG was not detected. Considering IgA and IgG antibodies titers, no differences were observed between the 2- and 3-dose vaccination regimen. Conclusions: SARS-CoV-2-specific IgA and IgG antibodies were detected in tears after mild COVID-19, highlighting the role of the ocular surface as a first line of defense against infection. Most naturally infected unvaccinated individuals exhibit long-term specific IgA in tears and saliva. Hybrid immunization (natural infection plus vaccination) appears to enhance mucosal and systemic IgG responses. However, no differences were observed between the 2- and 3-dose vaccination schedule.

Detection of anti-SARS-CoV-2 antibodies in tears: Ocular surface immunity to COVID-19.

PURPOSE: To evaluate the presence of SARS-COV-2 specific IgA and IgG antibodies in tears of unvaccinated and anti-COVID-19 vaccinated subjects with previous history of SARS-COV-2 infection. To compare results in tears with those in saliva and serum and correlate with clinical data and vaccination regimens. METHODS: Cross-sectional study including subjects with a previous history of SARS-CoV-2 infection, both unvaccinated and vaccinated against COVID-19. Three samples were collected: tears, saliva and serum. IgA and IgG antibodies against S-1 protein of SARS-CoV-2 were analyzed with a semi-quantitative ELISA. RESULTS: 30 subjects, mean age 36.4 ±â€¯10, males 13/30 (43.3%) with history of mild SARS-CoV-2 infection were included. 13/30 (43.3%) subjects had received a 2-dose regimen and 13/30 (43.3%) a 3-dose regimen of anti-COVID-19 vaccine, 4/30 (13.3%) subjects were unvaccinated. All the participants with full anti-COVID-19 vaccination (2-or 3-doses) presented detectable anti-S1 specific IgA in all three biofluids, tears, saliva and serum. Among unvaccinated subjects, specific IgA was detected in 3/4 subjects in tears and saliva, whereas IgG was not detected. Considering IgA and IgG antibodies titers, no differences were observed between the 2- and 3-dose vaccination regimen. CONCLUSIONS: SARS-CoV-2-specific IgA and IgG antibodies were detected in tears after mild COVID-19, highlighting the role of the ocular surface as a first line of defense against infection. Most naturally infected unvaccinated individuals exhibit long-term specific IgA in tears and saliva. Hybrid immunization (natural infection plus vaccination) appears to enhance mucosal and systemic IgG responses. However, no differences were observed between the 2- and 3-dose vaccination schedule.

Causas de muerte fetal: Un revisión de 38 pacientes / Causes associated to fetal death: A review study of 38 women

INTRODUCCIÓN: La pérdida del embarazo que ocurre tras las veinte semanas de gestación, se denomina muerte fetal (MF); es un evento que causa un gran impacto psicoemocional en la pareja afectada. La literatura médica afirma que, en casi la mitad de estos casos, no hay una causa conocida. Las causas principales están relacionadas son: síndrome antifosfolípido obstétrico (SAF), otras alteraciones inmunológicas (OIA), otros factores que pueden causar infarto placentario por coagulación, rotura prematura de membranas, preeclampsia y trombosis en la circulación útero-placentaria. MÉTODOS: Revisamos cuidadosamente la historia clínica y los estudios inmunológicos de una cohorte de 38 pacientes que han sufrido MF. RESULTADOS: Treinta y ocho pacientes (edades 36-42 años) fueron estudiadas. En más de la mitad de los pacientes (57 %) se diagnosticó SAF. El hipotiroidismo autoinmune (26 %), el anticuerpo antinuclear (24 %) comprendió el grupo de OIA. Once de 38 pacientes mostraron diferentes mutaciones de trombofilias. La hiperhomocisteinemia estuvo presente en el 53 % de los pacientes. CONCLUSIÓN: Las alteraciones inmunológicas y la trombofilia se asociaron con una proporción significativa de nuestros casos de MF. El diagnóstico de las causas evitables es necesario para evitar complicaciones obstétricas en embarazos futuros

INTRODUCTION: Pregnancy loss that occurs after the twenty weeks of gestation, termed foetal death (FD), is a rare event of pregnancy causing great psycho-emotional impact on the affected couple. Medical literature states that in nearly half of these cases, there is no known cause. Leading, causes are related to obstetric antiphospholipid syndrome (APS), other immunological alterations (OIA), other factors that may cause clotting placental infarction, premature rupture of membranes, preeclampsia, and thrombosis in the utero-placental circulation with subsequent FD. METHODS: We carefully reviewed the complete medical records and immunological studies of a cohort of 38 patients that have suffered FD. RESULTS: Thirty-eight patients (ages 36 - 42 years) were studied. In more than half of the patients (57%) APS was diagnosed. Autoimmune hypothyroidism (26%), antinuclear antibody (24%) comprised the group of OIA. Eleven out of 38 patients showed different thrombophilia mutations. Hyperhomocysteinemia was present in 53% of patients. CONCLUSION: Immunological alterations and thrombophilia were associated with a significant proportion of our FD cases. Diagnosis of preventable causes of FD is necessary in order to avoid any obstetric complications in future pregnancies

Typhim vi immunization assists to discriminate primary antibody responses in hematological malignancies.

Assessment of specific antibody (Ab) production to polysaccharide antigens is clinically relevant, identifying patients at risk for infection by encapsulated bacteria and thus enabling a more rigorous selection of patients that can benefit of immunoglobulin replacement therapy. Classically, the gold-standard test is the measurement of antibody production to pure polysaccharide pneumococcal (PPV) immunization. Several factors, including introduction of conjugate vaccination schedule, serotyping analysis, high baseline Ab levels, have hindered the evaluation of polysaccharide antigens. This is even more difficult in secondary immunodeficiencies (SID), where patients can show secondary responses despite lack of primary antibody responses and present with recurrent or severe infections. Assessment of specific Ab production to pure Salmonella typhi Vi polysaccharide (TV) immunization has been proposed as a complementary test to PPV, given its low seroprevalence. To set the optimal cut-off value for PPV and TV response in SID, we tested different biostatistical methodologies, including ROC analysis, Youden index, Union index and Closest-topleft in a cohort of 42 SID patients and 24 healthy controls. The statistically chosen cut-offs value pre-post TV Ab ratio was ≥5, (sensitivity of 90%, specificity of 100%) and a postvaccination TV concentration of 28.5 U/mL (sensitivity of 90%, specificity of 95%), showing relevant clinical correlate.

Evaluation of Polysaccharide Typhim Vi Antibody Response as a predictor of Humoral Immunodeficiency in Haematological Malignancies.

An increasing healthcare challenge in the management of haematological malignancy (HM) is secondary immunodeficiency. From January 2019, the EMA included the evaluation of specific antibody (Ab) responses to better select patients for immunoglobulin replacement therapy (IgRT). We evaluated Ab responses to pneumococcal and Salmonella typhi pure polysaccharide immunization in a cohort of 42 HM patients and 24 healthy-controls. Pre-post specific Ab concentrations were measured by ELISA at 4 weeks. Globally, significantly lower Typhim Vi (TV) seroprevalence (9%) compared to 23-valent pneumococcal polysaccharide vaccine (PPV) (76%) (p <0.001) was observed. TV non responders (88%) were higher than PPV non responders (62%) (p <0.0001) and correlated better to infectious history. By ROC analysis, pre-post 5-fold TV increase was the best cut-off to discriminate HM with recurrent infections and controls (sensitivity 91%, specificity 100%). Despite the small sample cohort, our results suggest that specific anti-S typhi Ab response is a useful complementary assay in the diagnosis and management decision of SID to HM.

Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4.

Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease that is expressed constitutively by many haematopoietic and non-haematopoietic tissues. It exists as a membrane-associated protein, as well as in an active, soluble form (herein called sDPP4), present at high concentrations in bodily fluids. Despite the proposed use of sDPP4 as a biomarker for multiple diseases, its cellular sources are not well defined. Here, we report that individuals with congenital lymphocyte immunodeficiency had markedly lower serum concentrations of sDPP4, which were restored upon successful treatment and restoration of lymphocyte haematopoiesis. Using irradiated lymphopenic mice and wild-type to Dpp4-/- reciprocal bone marrow chimeric animals, we found that haematopoietic cells were a major source of circulating sDPP4. Furthermore, activation of human and mouse T lymphocytes resulted in increased sDPP4, providing a mechanistic link between immune system activation and sDPP4 concentration. Finally, we observed that acute viral infection induced a transient increase in sDPP4, which correlated with the expansion of antigen-specific CD8+ T cell responses. Our study demonstrates that sDPP4 concentrations are determined by the frequency and activation state of lymphocyte populations. Insights from these studies will support the use of sDPP4 concentration as a biomarker for inflammatory and infectious diseases.

Screening protocols to monitor respiratory status in primary immunodeficiency disease: findings from a European survey and subclinical infection working group.

Many patients with primary immunodeficiency (PID) who have antibody deficiency develop progressive lung disease due to underlying subclinical infection and inflammation. To understand how these patients are monitored we conducted a retrospective survey based on patient records of 13 PID centres across Europe, regarding the care of 1061 adult and 178 paediatric patients with PID on immunoglobulin (Ig) G replacement. The most common diagnosis was common variable immunodeficiency in adults (75%) and hypogammaglobulinaemia in children (39%). The frequency of clinic visits varied both within and between centres: every 1-12 months for adult patients and every 3-6 months for paediatric patients. Patients diagnosed with lung diseases were more likely to receive pharmaceutical therapies and received a wider range of therapies than patients without lung disease. Variation existed between centres in the frequency with which some clinical and laboratory monitoring tests are performed, including exercise tests, laboratory testing for IgG subclass levels and specific antibodies, and lung function tests such as spirometry. Some tests were carried out more frequently in adults than in children, probably due to difficulties conducting these tests in younger children. The percentage of patients seen regularly by a chest physician, or who had microbiology tests performed following chest and sinus exacerbations, also varied widely between centres. Our survey revealed a great deal of variation across Europe in how frequently patients with PID visit the clinic and how frequently some monitoring tests are carried out. These results highlight the urgent need for consensus guidelines on how to monitor lung complications in PID patients.

Cambios en las Subpoblaciones de Linfocitos B y T en el Título de Anticuerpos Anti-Acuaporina-4 tras el Tratamiento de un Brote Agudo con Inmunoglobulinas y Rituximab / Changes in B and T-cell subsets and NMO-IgG levels after immunoglobulins and rituximab treatment for an acute attack of neuromyelitis optica

Antecedentes: La neuromielitis óptica (NMO) es una enfermedad predominantemente humoral mediada por anticuerpos IgG-NMO/AQP-4. Sin embargo, no se conoce bien la contribución de las diferentes subpoblaciones de células B y T en su patogenia o en la respuesta a los tratamientos. Objetivos: Describir los cambios clínicos e inmunológicos asociados al tratamiento con inmunoglobulinas intravenosas (Ig-IV) y rituximab (RTX) en una paciente con un brote grave de NMO y síntesis intratecal de IgG-NMO/AQP-4 que no había respondido a metilprednisolona y recambio plasmático. Métodos: Se analizaron, de forma secuencial en el LCR y en la sangre periférica (SP), las subpoblaciones linfocitarias mediante citometría de flujo multiparamétrica y los IgG-NMO/AQP-4, antes y después del tratamiento con Ig-IV y RTX. Resultados: En el LCR antes del tratamiento, y comparado con la SP, predominaban las células T CD4+ y estaban menos representadas las T CD8+ y las B CD19+. Tras el tratamiento, el porcentaje de células T CD4+ se mantuvo alto, el de T CD8+ aumentó y el de B CD19+ disminuyó, aunque menos que en la SP. Al comparar los LCR se vio que tras la terapia el porcentaje de células T CD8+ memoria efectoras y efectoras había aumentado, y el de células B memoria IgM y el de células B con cambio de isotipos, disminuido. Los cambios observados fueron paralelos a la negativización de los IgG-NMO/AQP-4 y a la mejoría clínica. Conclusiones: Nuestros hallazgos confirman que, además de una respuesta inmunitaria humoral intratecal durante el brote de NMO, subpoblaciones específicas de células B y T participan en la modulación de la inflamación dentro y fuera del sistema nervioso central

Background: There is increasing evidence supporting that neuromyelitis optica (NMO) is an inflammatory humoral mediated disorder associated with NMO-IgG/AQP-4 antibodies. However, little is known about the subsets of B cells and T cells that contribute to the pathogenesis or therapy response. Objectives: To describe the clinical and immunological changes associated with intravenous immunoglobulins (IV-Igs) plus rituximab (RTX) in a patient with a severe acute attack of NMO and intrathecal synthesis of NMO-IgG/AQP-4, who previously did not respond to intravenous methylprednisolone and plasma exchange. Methods: We sequentially analysed the levels of NMO-IgG/AQP-4 by immunohistochemistry, and B and T cells subsets by multiparametric flow-cytometry, in the CSF and peripheral blood (PB), before and alter IV-Igs plus RTX therapy. Results: In the CSF before treatment, and compared with PB, there was a higher percentage of CD4+ T cells and a lower percentage of CD8+ T cells and CD19+ B cells. After therapy, the percentage of CD4+ T cells remained high, and that of CD8+ T cells increased. The observed decrease in the percentage of CD19+ B cells was lower than in the PB. When the CSF was compared, it was found that the percentage of effector-memory and effector CD8+ T cells had increased after therapy, and that of IgM memory B cells and switched-memory B cells decreased. The observed changes paralleled the decrease of NMO-IgG/AQP-4 results to negative and the clinical improvement. Conclusions: Our findings confirm that, besides intrathecal humoral immune response against AQP4, B and T cell subsets are involved in the modulation of inflammation within and outside the central nervous system

Changes in B and T-cell subsets and NMO-IgG levels after immunoglobulins and rituximab treatment for an acute attack of neuromyelitis optica.

BACKGROUND: There is increasing evidence supporting that neuromyelitis optica (NMO) is an inflammatory humoral mediated disorder associated with NMO-IgG/AQP-4 antibodies. However, little is known about the subsets of B cells and T cells that contribute to the pathogenesis or therapy response. OBJECTIVES: To describe the clinical and immunological changes associated with intravenous immunoglobulins (IV-Igs) plus rituximab (RTX) in a patient with a severe acute attack of NMO and intrathecal synthesis of NMO-IgG/AQP-4, who previously did not respond to intravenous methylprednisolone and plasma exchange. METHODS: We sequentially analysed the levels of NMO-IgG/AQP-4 by immunohistochemistry, and B and T cells subsets by multiparametric flow-cytometry, in the CSF and peripheral blood (PB), before and alter IV-Igs plus RTX therapy. RESULTS: In the CSF before treatment, and compared with PB, there was a higher percentage of CD4(+) T cells and a lower percentage of CD8(+) T cells and CD19(+) B cells. After therapy, the percentage of CD4(+) T cells remained high, and that of CD8(+) T cells increased. The observed decrease in the percentage of CD19(+) B cells was lower than in the PB. When the CSF was compared, it was found that the percentage of effector-memory and effector CD8(+) T cells had increased after therapy, and that of IgM memory B cells and switched-memory B cells decreased. The observed changes paralleled the decrease of NMO-IgG/AQP-4 results to negative and the clinical improvement. CONCLUSIONS: Our findings confirm that, besides intrathecal humoral immune response against AQP4, B and T cell subsets are involved in the modulation of inflammation within and outside the central nervous system.

Female sex hormones regulate the Th17 immune response to sperm and Candida albicans.

STUDY QUESTION: What role do female sex hormones play in the antisperm immune response? SUMMARY ANSWER: We found that sperm induce a Th17 immune response and that estradiol down-regulates the antisperm Th17 response by dendritic cells. WHAT IS KNOWN ALREADY: Estradiol down-regulates the immune response to several pathogens and impairs the triggering of dendritic cell maturation by microbial products. STUDY DESIGN, SIZE, DURATION: Ex vivo and in vivo murine models of vaginal infection with sperm and Candida albicans were used to study the induction of Th17 and its hormonal regulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed the induction of Th17 cytokines and T cells in splenocytes obtained from BALB/c mice challenged with sperm and C. albicans. For the in vivo vaginal infection models, we used ovariectomized mice treated with vehicle, estradiol or progesterone, and we assessed the effect of these hormones on the immune response in the lymph nodes. MAIN RESULTS AND THE ROLE OF CHANCE: Th17 cytokines and T cells were induced by sperm antigens in both ex vivo and in vivo experiments. Estrus levels of estradiol down-regulated the Th17 response to sperm and C. albicans in vivo. LIMITATIONS, REASONS FOR CAUTION: This study was conducted using murine models; whether or not the results are applicable to humans is not known. WIDER IMPLICATIONS OF THE FINDINGS: Our results describe an adaptive mechanism that reconciles immunity and reproduction and further explains why unregulated Th17 could be linked to infertility and recurrent infections. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grants from the Instituto de Salud Carlos III (ISCIII) (PI10/00897) and Fundación Mutua Madrileña to M.R. M.R. holds a Miguel Servet contract from the ISCIII (CP08/00228). M.A.M.-F. was supported by (ISCIII) INTRASALUD PI09/02029. We have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not required.

Sequential combined therapy with omalizumab and rituximab: a new approach to severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common chronic skin disease, and a significant percentage of AD patients have severe forms. Inflammation based on type 2 helper T cells (T(H)2), autoantibodies, and CD8+ T cells could play a relevant role in this disease. When the patient requires systemic immunosuppressors for disease control, side effects are frequent. We propose a sequential therapeutic strategy with 2 monoclonal antibodies, omalizumab (anti-immunoglobulin [Ig] E) and rituximab (anti-CD20), which might induce clinical benefit with few side effects in selected individuals with AD. METHODS: We report 6 cases of severe AD refractory to conventional therapy. The patients underwent sequential switch therapy with omalizumab and rituximab. Clinical response was assessed by means of the decrease in body surface affected. Immunological parameters and side effects were also monitored. RESULTS: Four patients received omalizumab before a high-dose cycle of rituximab. In the case of recurrences, either low-dose cycles of rituximab or omalizumab were administered. A long-term clinical benefit was observed in 3 out of 4 patients. Two patients first received high-dose rituximab followed by either low-dose rituximab or omalizumab, and one of them achieved a response at 17 months. No severe side effects were recorded. Serum IgE level and B-cell counts decreased with therapy, the latter returning to baseline levels 10 to 11 months after treatment. Specific antibody responses remained protective during the study. CONCLUSIONS: With our proposed switch therapy, 4 out of 6 patients achieved a dramatic clinical improvement. This novel strategy targets different arms of the immune response and might be a good alternative for patients with severe AD.

Sequential Combined Therapy With Omalizumab and Rituximab: A New Approach to Severe Atopic Dermatitis

Antecedentes: La dermatitis atópica (DA) es una enfermedad crónica de la piel. En un porcentaje elevado de pacientes con formas graves de DA, es probable que existan autoanticuerpos y linfocitos T CD8+ actuando junto con células Th2 en la fisiopatología. En los pacientes que requieren inmunosupresores sistémicos para controlar la enfermedad, los efectos adversos son frecuentes. En este trabajo proponemos la administración secuencial de dos terapias con anticuerpos monoclonales (omalizumab, anti-IgE y rituximab, anti-CD20) como estrategia terapéutica eficaz con un grado aceptable de efectos adversos. Métodos: Presentamos 6 pacientes con DA grave y recalcitrante a inmunosupresores convencionales que recibieron terapia secuencial con omalizumab (Xolair®)/Rituximab (MabThera®). La respuesta clínica se evaluó mediante la variación en la superficie corporal afectada. Se monitorizaron parámetros inmunológicos y efectos adversos. Resultados: Cuatro pacientes recibieron omalizumab seguido de un ciclo de alta dosis de rituximab (HR). En las siguientes recaídas se administró un ciclo de baja dosis de rituximab (LR) u omalizumab. Tres de los 4 pacientes consiguieron mejoría clínica prolongada. En 2 pacientes se administró primero HR seguido o bien por LR, o por omalizumab. Uno de ellos consiguió remisión durante 17 meses. No se registraron efectos adversos graves. La IgE y las células B séricas disminuyeron tras la terapia; estas últimas no recuperaron su nivel basal hasta 10-11 meses después. Las respuestas específicas de anticuerpos permanecieron en niveles protectores durante el estudio. Conclusiones: Con esta terapia, 4 de los 6 pacientes con DA grave consiguieron una mejoría significativa. Esta estrategia se dirige específicamente a varios mecanismos efectores del sistema inmunológico y podría ser una alternativa para un grupo seleccionado de pacientes con DA grave (AU)

Background: Atopic dermatitis (AD) is a common chronic skin disease, and a significant percentage of AD patients have severe forms. Inflammation based on type 2 helper T cells (TH2), autoantibodies, and CD8+ T cells could play a relevant role in this disease. When the patient requires systemic immunosuppressors for disease control, side effects are frequent. We propose a sequential therapeutic strategy with 2 monoclonal antibodies, omalizumab (anti-immunoglobulin [Ig] E) and rituximab (anti-CD20), which might induce clinical benefit with few side effects in selected individuals with AD. Methods: We report 6 cases of severe AD refractory to conventional therapy. The patients underwent sequential switch therapy with omalizumab and rituximab. Clinical response was assessed by means of the decrease in body surface affected. Immunological parameters and side effects were also monitored. Results: Four patients received omalizumab before a high-dose cycle of rituximab. In the case of recurrences, either low-dose cycles of rituximab or omalizumab were administered. A long-term clinical benefit was observed in 3 out of 4 patients. Two patients first received high-dose rituximab followed by either low-dose rituximab or omalizumab, and one of them achieved a response at 17 months. No severe side effects were recorded. Serum IgE level and B-cell counts decreased with therapy, the latter returning to baseline levels 10 to 11 months after treatment. Specific antibody responses remained protective during the study. Conclusions: With our proposed switch therapy, 4 out of 6 patients achieved a dramatic clinical improvement. This novel strategy targets different arms of the immune response and might be a good alternative for patients with severe AD (AU)

Omalizumab en el tratamiento de la dermatitis atópica / Omalizumab for the Treatment of Atopic Dermatitis

La atopia se acompaña de forma casi constante de una producción elevada de inmunoglobulina E (IgE). Omalizumab es un anticuerpo monoclonal anti-IgE, que actualmente está indicado en pacientes con asma que cumplen determinados criterios. Se han publicado algunos estudios sobre la utilidad del omalizumab en el tratamiento de la dermatitis atópica (DA), con resultados variables. Presentamos nuestra experiencia en 9 pacientes con dermatitis atópica grave, refractaria al menos a dos fármacos sistémicos. Todos los pacientes tratados referían una disminución del prurito y una mejoría en su calidad de vida. Los que presentaban asma consiguieron un buen control desde el punto de vista respiratorio, sin precisar otros tratamientos adicionales. En dos casos se consiguió un buen control en monoterapia, apreciándose una discreta mejoría de las lesiones de eccema en 4 de ellos. El omalizumab es un fármaco bien tolerado y seguro. Puede ser útil en el tratamiento de pacientes con DA grave, refractaria a otros tratamientos sistémicos. Este anticuerpo monoclonal anti-IgE abre la puerta a los tratamientos inmunomoduladores sistémicos para el manejo de la DA, lo que supone un gran avance terapéutico (AU)

Atopy is almost always associated with an elevated immunoglobulin (Ig) E production. Omalizumab is a monoclonal anti-IgE antibody that is currently indicated for the treatment of cases of asthma that satisfy certain criteria. A number of studies have been published on the usefulness of omalizumab in the treatment of atopic dermatitis, and the results have been variable. We present our experience in the treatment of 9 patients with severe atopic dermatitis refractory to at least 2 systemic drugs. All patients reported a decrease in pruritus and an improvement in quality of life. Good control of the skin disease was achieved with omalizumab in monotherapy in 2 patients, and there was a slight improvement in the eczematous lesions in 4 patients. Those patients who also had asthma achieved good control of their respiratory symptoms and did not require additional therapy. Omalizumab is a well-tolerated and safe drug that can be useful for the treatment of severe atopic dermatitis refractory to other systemic therapies. This monoclonal anti-IgE antibody is a major therapeutic advance as it opens the door to the management of atopic dermatitis using systemic immunomodulating therapies (AU)

Omalizumab for the treatment of atopic dermatitis.

Atopy is almost always associated with an elevated immunoglobulin (Ig) E production. Omalizumab is a monoclonal anti-IgE antibody that is currently indicated for the treatment of cases of asthma that satisfy certain criteria. A number of studies have been published on the usefulness of omalizumab in the treatment of atopic dermatitis, and the results have been variable. We present our experience in the treatment of 9 patients with severe atopic dermatitis refractory to at least 2 systemic drugs. All patients reported a decrease in pruritus and an improvement in quality of life. Good control of the skin disease was achieved with omalizumab in monotherapy in 2 patients, and there was a slight improvement in the eczematous lesions in 4 patients. Those patients who also had asthma achieved good control of their respiratory symptoms and did not require additional therapy. Omalizumab is a well-tolerated and safe drug that can be useful for the treatment of severe atopic dermatitis refractory to other systemic therapies. This monoclonal anti-IgE antibody is a major therapeutic advance as it opens the door to the management of atopic dermatitis using systemic immunomodulating therapies.

Sublingual therapeutic immunization with a polyvalent bacterial preparation in patients with recurrent respiratory infections: immunomodulatory effect on antigen-specific memory CD4+ T cells and impact on clinical outcome.

Recurrent respiratory tract infections (RRTIs) are common clinical conditions in individuals with alterations of the immune function. A prospective open pilot study in a cohort of patients with RRTIs has been performed to assess whether sublingual immunization with a polyvalent bacterial vaccine could exert an immunomodulatory effect on the antigen-specific immunological responses and have an impact on the clinical outcome. Seventeen patients with RRTIs were recruited. An oral polyvalent bacterial preparation (Bactek®) was administered to all patients daily for 6 months. Immunological assessment was performed at baseline and at the end of immunization. Immunological measurements included: T cell-specific proliferations of CD3+CD4+ and CD3+CD8+ to Bactek® antigens, total immunoglobulin levels, antibodies to pneumococcal polysaccharide and tetanus toxoid and B, T and natural killer (NK) cell subsets. There was a significant increase in the proliferative capacity of CD3+CD4+ T cells specific to Bactek® antigens at month 6 in comparison to baseline (P < 0·0001). A significant increase in total CD3+ T cells was also observed (P < 0·05). No significant differences were observed between baseline and month 6 in levels of total immunoglobulins, specific antibodies and B, T or NK cell subsets. A significant reduction in the patient's rate of RRTIs was observed compared with 1 year prior to initiation of therapy (P < 0·0001). The results demonstrate that long-term administration of a sublingual polyvalent bacterial preparation in patients with RRTIs exerts an immune stimulating effect on CD4+ T helper cell responses to bacterial antigens which could be associated with clinical benefit.