Rituximab and hypogammaglobulinemia

El rituximab (RTX), un anticuerpo quimérico anti-CD20 que induce la depleción de linfocitos B, es utilizado para el tratamiento de enfermedades linfoproliferativas y autoinmunes. La inmunodeficiencia humoral relacionada al tratamiento con RTX comenzó a ser un motivo de derivación a nuestro Servicio, por lo que decidimos analizar a los pacientes con el antecedente de haber sido tratados con RTX que consultaron por hipogammaglobulinemia o infecciones recurrentes desde noviembre de 2010 hasta diciembre de 2014. Evaluamos a ocho pacientes, siete mujeres y un varón. El tiempo promedio de seguimiento fue de 19.3 ± 18.8 meses, rango 1 a 54, con una mediana de 13. Tres tenían proteinogramas normales previo a la administración de RTX, tres hipogammaglobulinemia, y de dos no hay datos. A ninguno se le realizó una determinación cuantitativa de inmunoglobulinas previa al tratamiento. Cuatro recibieron RTX por linfoma B no Hodgkin, dos por leucemia linfocítica crónica, uno por púrpura trombocitopénica autoinmune y otro por poliangeítis microscópica. A seis se les diagnosticó hipogammaglobulinemia y a uno deficiencia de IgM, IgA e IgG2. Cinco presentaron infecciones, cuatro con buena respuesta al tratamiento de reemplazo con gammaglobulina. La inmunodeficiencia humoral relacionada a RTX es una causa de consulta cada vez más frecuente. Resulta fundamental disponer de los niveles de inmunoglobulinas previo al inicio de su administración para poder establecer una relación etiológica y durante el seguimiento, para disminuir el retraso diagnóstico. El tratamiento con gammaglobulina en dosis sustitutivas parece ser de utilidad en pacientes con infecciones graves o recurrentes.Rituximab, a chimeric monoclonal antibody against CD20, induces the depletion of B lymphocytes. It is used for the treatment of lymphoproliferative and autoimmune diseases. Antibody immunodeficiency associated to RTX treatment is a new motif for consultation to our service. We decided to study those patients that having been treated with RTX, consulted for hypogammaglobulinemia or recurrent infections between November 2010 and December 2014. We evaluated eight patients, seven female and one male. The average follow up time was 19.3 ± 18.8 months, range 1 to 54, median 13. Three had a normal electrophoretic proteinogram before receiving RTX, three had hypogammaglobulinemia and in two data was not available. None of them had a quantitative determination of immunoglobulins before receiving RTX. Four received RTX as a treatment of non Hodking lymphoma, two as a treatment of chronic lymphocytic leukemia, one for immune thrombocytopenic purpura and other for microscopic polyangiitis. Six were diagnosed with hypogammaglobulinemia and one with combined IgM, IgA and IgG2 deficiency. Five presented infections, four of them with good response to intravenous immunoglobulin. RTX related antibody deficiency consultations are increasing. It is important to determine the immunoglobulin levels previously to RTX use in order to establish an etiologic relationship with RTX and a quick diagnosis of antibody deficiency. The substitutive treatment with gammaglobulin seems to be useful in patients with severe or recurrent infections.Fil: Fernández Romero, Diego S.. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Torre, María Gabriela. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Larrauri, Blas J.. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Malbran, Eloisa. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Juri, María Cristina. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Malbrán, Alejandro. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

I-Move towards monitoring seasonal and pandemic influenza vaccine effectiveness: lessons learnt from a pilot multi-centric case-control study in europe, 2008-9

Within I-MOVE (European programme to monitor seasonal and pandemic influenza vaccine effectiveness (IVE)) five countries conducted IVE pilot case-control studies in 2008-9. One hundred and sixty sentinel general practitioners (GP) swabbed all elderly consulting for influenza-like illness (ILI). Influenza confirmed cases were compared to influenza negative controls. We conducted a pooled analysis to obtain a summary IVE in the age group of >or=65 years. We measured IVE in each study and assessed heterogeneity between studies qualitatively and using the I2 index. We used a one-stage pooled model with study as a fixed effect. We adjusted estimates for age-group, sex, chronic diseases, smoking, functional status, previous influenza vaccinations and previous hospitalisations. The pooled analysis included 138 cases and 189 test-negative controls. There was no statistical heterogeneity (I2=0) between studies but ILI case definition, previous hospitalisations and functional status were slightly different. The adjusted IVE was 59.1% (95% CI: 15.3-80.3%). IVE was 65.4% (95% CI: 15.6-85.8%) in the 65-74, 59.6% (95% CI: -72.6 -90.6%) in the age group of >or=75 and 56.4% (95% CI: -0.2-81.3%) for A(H3). Pooled analysis is feasible among European studies. The variables definitions need further standardisation. Larger sample sizes are needed to achieve greater precision for subgroup analysis. For 2009-10, I-MOVE will extend the study to obtain early IVE estimates in groups targeted for pandemic H1N1 influenza vaccination.European Centre for Disease Prevention and Control (ECDC

All-cause versus cause-specific excess deaths for estimating influenza-associated mortality in Denmark, Spain, and the United States

Background: Seasonal influenza-associated excess mortality estimates can be timely and provide useful information on the severity of an epidemic. This methodology can be leveraged during an emergency response or pandemic. Method: For Denmark, Spain, and the United States, we estimated age-stratified excess mortality for (i) all-cause, (ii) respiratory and circulatory, (iii) circulatory, (iv) respiratory, and (v) pneumonia, and influenza causes of death for the 2015/2016 and 2016/2017 influenza seasons. We quantified differences between the countries and seasonal excess mortality estimates and the death categories. We used a time-series linear regression model accounting for time and seasonal trends using mortality data from 2010 through 2017. Results: The respective periods of weekly excess mortality for all-cause and cause-specific deaths were similar in their chronological patterns. Seasonal all-cause excess mortality rates for the 2015/2016 and 2016/2017 influenza seasons were 4.7 (3.3-6.1) and 14.3 (13.0-15.6) per 100,000 population, for the United States; 20.3 (15.8-25.0) and 24.0 (19.3-28.7) per 100,000 population for Denmark; and 22.9 (18.9-26.9) and 52.9 (49.1-56.8) per 100,000 population for Spain. Seasonal respiratory and circulatory excess mortality estimates were two to three times lower than the all-cause estimates. Discussion: We observed fewer influenza-associated deaths when we examined cause-specific death categories compared with all-cause deaths and observed the same trends in peaks in deaths with all death causes. Because all-cause deaths are more available, these models can be used to monitor virus activity in near real time. This approach may contribute to the development of timely mortality monitoring systems during public health emergencies.This study was conducted as part of Sebastian Schmidt's research fellowship, which was financially supported by the Novo Nordic Foundation and A.P. Møller Fonden. The EuroMOMO network has received financial support from the European Centre for Disease Prevention and Control (ECDC) and from the World Health Organization (WHO) Regional Office for Europe.S

Influenza vaccine effectiveness estimates in Europe in a season with three influenza type/subtypes circulating: the I-MOVE multicentre case–control study, influenza season 2012/13

In the fifth season of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE), we undertook a multicentre case–control study (MCCS) in seven European Union (EU) Member States to measure 2012/13 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory confirmed as influenza. The season was characterised by substantial co-circulation of influenza B, A(H1N1)pdm09 and A(H3N2) viruses. Practitioners systematically selected ILI patients to swab ≤7 days of symptom onset. We compared influenza-positive by type/subtype to influenza-negative patients among those who met the EU ILI case definition. We conducted a complete case analysis using logistic regression with study as fixed effect and calculated adjusted vaccine effectiveness (AVE), controlling for potential confounders (age, sex, symptom onset week and presence of chronic conditions). We calculated AVE by type/subtype. Study sites sent 7,954 ILI/acute respiratory infection records for analysis. After applying exclusion criteria, we included 4,627 ILI patients in the analysis of VE against influenza B (1,937 cases), 3,516 for A(H1N1)pdm09 (1,068 cases) and 3,340 for influenza A(H3N2) (730 cases). AVE was 49.3% (95% confidence interval (CI): 32.4 to 62.0) against influenza B, 50.4% (95% CI: 28.4 to 65.6) against A(H1N1)pdm09 and 42.2% (95% CI: 14.9 to 60.7) against A(H3N2). Our results suggest an overall low to moderate AVE against influenza B, A(H1N1)pdm09 and A(H3N2), between 42 and 50%. In this season with many co-circulating viruses, the high sample size enabled stratified AVE by type/subtype. The low estimates indicate seasonal influenza vaccines should be improved to achieve acceptable protection levels

Lockdown measures and relative changes in the age-specific incidence of SARS-CoV-2 in Spain

During the first months of the SARS-CoV-2 epidemic in 2020, Spain implemented an initial lockdown period on March 15 followed by a strengthened lockdown period on March 30 when only essential workers continued to commute to work. However, little is known about the epidemic dynamics in different age groups during these periods. We used the daily number of COVID-19 cases (by date of symptom onset) reported to the National Epidemiological Surveillance Network (RENAVE) among individuals aged 15-19y through 65-69y. For each age group g, we computed the proportion PrE(g) of individuals in age group g among all reported cases aged 15-69y during the pre-lockdown period (March 1-10, 2020) and the corresponding proportion PrL(g) during two lockdown periods (initial: 25 March-3 April; strengthened: 8-17 April, 2020). For each lockdown period, we computed the proportion ratios PR(g)= PrL(g)/PrE(g). For each pair of age groups g1,g, PR(g)>PR(g) implies a relative increase in the incidence of detected SARS-CoV-2 infection in the age group g compared with g for the lockdown period vs. the pre-lockdown period. For the initial lockdown period, the highest PR values were in age groups 50-54y (PR=1.21; 95% CI: 1.12,1.30) and 55-59y (PR=1.19; 1.11,1.27). For the second lockdown period, the highest PR values were in age groups 15-19y (PR=1.26; 0.95,1.68) and 50-54y (PR=1.20; 1.09,1.31). Our results suggest that different outbreak control measures led to different changes in the relative incidence by age group. During the initial lockdown period, when non-essential work was allowed, individuals aged 40-64y, particularly those aged 50-59y, had a higher relative incidence compared with the pre-lockdown period. Younger adults/older adolescents had an increased relative incidence during the later, strengthened lockdown. The role of different age groups during the epidemic should be considered when implementing future mitigation efforts

Identification and quantification of phenolic compounds in bambangan (Mangifera pajang Kort.) peels and their free radical scavenging activity.

Phenolic compounds and antioxidant capacity of acidified methanolic extract prepared from fully ripe bambangan (Mangifera pajang K.) peel cultivated in Sarawak, Malaysia, were analyzed. The total phenolic content (98.3 mg GAE/g) of bambangan peel powder (BPP) was determined by the Folin-Ciocalteu method. BPP showed a strong potency of antioxidant activity and was consistent with that of BHT and vitamin C as confirmed by the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity and FRAP (ferric-reducing antioxidant power) assays. Gallic acid, p-coumaric acid, ellagic acid, protocatechuic acid, and mangiferin were the major compounds among the 16 phenolics that have been identified and quantified in M. pajang peels with 20.9, 12.7, 7.3, 5.4, and 4.8 mg/g BPP, respectively. Peak identities were confirmed by comparing their retention times, UV-vis absorption spectra, and mass spectra with authentic standards. The 16 phenolic compounds identified in M. pajang K. using HPLC-DAD and TSQ-ESI-MS are reported here for the first time

Using surveillance data to estimate pandemic vaccine effectiveness against laboratory confirmed influenza A(H1N1)2009 infection : two case-control studies, Spain, season 2009-2010

Background: Physicians of the Spanish Influenza Sentinel Surveillance System report and systematically swab patients attended to their practices for influenza-like illness (ILI). Within the surveillance system, some Spanish regions also participated in an observational study aiming at estimating influenza vaccine effectiveness (cycEVA study). During the season 2009-2010, we estimated pandemic influenza vaccine effectiveness using both the influenza surveillance data and the cycEVA study. Methods: We conducted two case-control studies using the test-negative design, between weeks 48/2009 and 8/2010 of the pandemic season. The surveillance-based study included all swabbed patients in the sentinel surveillance system. The cycEVA study included swabbed patients from seven Spanish regions. Cases were laboratory-confirmed pandemic influenza A(H1N1)2009. Controls were ILI patients testing negative for any type of influenza. Variables collected in both studies included demographic data, vaccination status, laboratory results, chronic conditions, and pregnancy. Additionally, cycEVA questionnaire collected data on previous influenza vaccination, smoking, functional status, hospitalisations, visits to the general practitioners, and obesity. We used logistic regression to calculate adjusted odds ratios (OR), computing pandemic influenza vaccine effectiveness as (1-OR *100. Results: We included 331 cases and 995 controls in the surveillance-based study and 85 cases and 351 controls in the cycEVA study. We detected nine (2.7%) and two (2.4%) vaccine failures in the surveillance-based and cycEVA studies, respectively. Adjusting for variables collected in surveillance database and swabbing month, pandemic influenza vaccine effectiveness was 62% (95% confidence interval (CI): -5; 87). The cycEVA vaccine effectiveness was 64% (95%CI: -225; 96) when adjusting for common variables with the surveillance system and 75% (95%CI: -293; 98) adjusting for all variables collected. Conclusion: Point estimates of the pandemic influenza vaccine effectiveness suggested a protective effect of the pandemic vaccine against laboratory-confirmed influenza A(H1N1)2009 in the season 2009-2010. Both studies were limited by the low vaccine coverage and the late start of the vaccination campaign. Routine influenza surveillance provides reliable estimates and could be used for influenza vaccine effectiveness studies in future seasons taken into account the surveillance system limitations

Alternating patterns of seasonal influenza activity in the WHO European Region following the 2009 pandemic, 2010-2018

Background: Influenza virus infections are common and lead to substantial morbidity and mortality worldwide. We characterized the first eight influenza epidemics since the 2009 influenza pandemic by describing the distribution of viruses and epidemics temporally and geographically across the WHO European Region. Methods: We retrospectively analyzed laboratory-confirmed influenza detections in ambulatory patients from sentinel sites. Data were aggregated by reporting entity and season (weeks 40-20) for 2010-2011 to 2017-2018. We explored geographical spread using correlation coefficients. Results: There was variation in the regional influenza epidemics during the study period. Influenza A virus subtypes alternated in dominance, except for 2013-2014 during which both cocirculated, and only one season (2017-2018) was B virus dominant. The median start week for epidemics in the Region was week 50, the time to the peak ranged between four and 13 weeks, and the duration of the epidemic ranged between 19 and 25 weeks. There was evidence of a west-to-east spread across the Region during epidemics in 2010-2011 (r = .365; P = .019), 2012-2013 (r = .484; P = .001), 2014-2015 (r = .423; P = .006), and 2017-2018 (r = .566; P < .001) seasons. Variation in virus distribution and timing existed within reporting entities across seasons and across reporting entities for a given season. Conclusions: Aggregated influenza detection data from sentinel surveillance sites by season between 2010 and 2018 have been presented for the European Region for the first time. Substantial diversity exists between influenza epidemics. These data can inform prevention and control efforts at national, sub-national, and international levels. Aggregated, regional surveillance data from early affected reporting entities may provide an early warning function and be helpful for early season forecasting efforts.WHO Regional Office for Europe was supported for work on influenza by a cooperative agreement from the United States Centers for Disease Control and Prevention (NU511P000876); the funder had no role in the analysis or interpretation of the data.S

Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study

Within the Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) project we conducted a multicentre case–control study in eight European Union (EU) Member States to estimate the 2011/12 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory-confirmed as influenza A(H3) among the vaccination target groups. Practitioners systematically selected ILI / acute respiratory infection patients to swab within seven days of symptom onset. We restricted the study population to those meeting the EU ILI case definition and compared influenza A(H3) positive to influenza laboratory-negative patients. We used logistic regression with study site as fixed effect and calculated adjusted influenza vaccine effectiveness (IVE), controlling for potential confounders (age group, sex, month of symptom onset, chronic diseases and related hospitalisations, number of practitioner visits in the previous year). Adjusted IVE was 25% (95% confidence intervals (CI): -6 to 47) among all ages (n=1,014), 63% (95% CI: 26 to 82) in adults aged between 15 and 59 years and 15% (95% CI: -33 to 46) among those aged 60 years and above. Adjusted IVE was 38% (95%CI: -8 to 65) in the early influenza season (up to week 6 of 2012) and -1% (95% CI: -60 to 37) in the late phase. The results suggested a low adjusted IVE in 2011/12. The lower IVE in the late season could be due to virus changes through the season or waning immunity. Virological surveillance should be enhanced to quantify change over time and understand its relation with duration of immunological protection. Seasonal influenza vaccines should be improved to achieve acceptable levels of protection.ECD

Esophageal Granular Cell Tumor and Eosinophilic Esophagitis: Two Interesting Entities Identified in the Same Patient

We illustrate the case of a 41-year-old male with allergic manifestations since childhood. He sought medical attention for intermittent, progressive dysphagia from which he had been suffering for a number of years, having felt the sensation of a retrosternal lump and a self-limited obstruction to the passage of food. Endoscopy detected a submucosal tumor in the upper third of the esophagus, which was typified, via biopsy, as a granular cell tumor with benign characteristics and probably responsible for the symptoms. Two years later, the patient sought medical attention once again as these symptoms had not abated, hence digestive endoscopy was repeated. This revealed stenosis of the junction between the middle and lower thirds of the organ which had not been detected previously but was passable under gentle pressure. Eosinophilic esophagitis was detected after biopsies were taken. Esophageal manometry identified a motor disorder affecting the esophageal body. Following three months of treatment using fluticasone propionate applied topically, the symptoms went into remission, esophageal stenosis disappeared and the esophageal biopsies returned to normal. This is the first documented case of the link between granular cell tumors and Eosinophilic esophagitis, two different disorders which could cause dysphagia in young patients