Clinical-haematological changes and predictors of severity in acute food protein-induced enterocolitis syndrome reactions at oral food challenge: a multicentre observational study.

BACKGROUND: Oral food challenge (OFC) is the gold standard for diagnosis of acute Food Protein-Induced Enterocolitis Syndrome (FPIES). No diagnostic/prognostic biomarkers are available, and OFC assessment criteria are not validated. OBJECTIVE: To assess clinical-haematological changes and predictors of severity of FPIES reactions at OFC. METHODS: Observational multicentre prospective study. Children aged 0-18 years diagnosed with acute FPIES were recruited at follow-up OFC in 12 tertiary centres in Spain and Italy. OFC Outcomes (as positive/negative/inconclusive and mild/moderate/severe) were assessed based on published '2017 FPIES Consensus' criteria. Clinical characteristics were recorded, and full blood count was done at baseline, reaction onset and 4 hours later. Regression analysis was performed to assess predictors of severe reactions at OFC. RESULTS: 81 children had positive OFC (mild in 11% (9/81), moderate in 61% (49/81), severe in 28% (23/81)). Increase in neutrophils and reduction in eosinophils, basophils and lymphocytes was observed (P-value<0.05). OFC was inconclusive in 19 cases despite objective signs or neutrophilia. Regression analysis showed a 2-day OFC protocol where only 25% of an age-appropriate portion is given on day 1 (not gender, age, culprit food, cumulative dose and previous reaction severity) was associated with reduced odds of severe reaction compared to giving multiple doses in a single day. CONCLUSION: Distinct haematological changes may help support FPIES diagnosis. Current OFC assessment criteria may not capture the broad spectrum of acute FPIES presentations. This 2-day protocol may associate a reduced risk of severe reactions. Future work should aim to develop safer OFC and non-OFC diagnostics for FPIES.

Case Report: Everolimus reduced bone turnover markers but showed no clinical benefit in a patient with severe progressive osseous heteroplasia.

Background: Progressive osseous heteroplasia (POH) is an ultrarare genetic disorder characterized by an inactivating mutation in the GNAS gene that causes heterotopic ossification. Inhibition of the mammalian target of the rapamycin (mTOR) signalling pathway has been proposed as a therapy for progressive bone fibrodysplasia and non-genetic forms of bone heteroplasia. Herein, we describe the impact of using Everolimus as a rescue therapy for an identical twin girl exhibiting an aggressive clinical phenotype of POH. Methods: Clinical evaluation of the progression of the disease during Everolimus treatment was performed periodically. Cytokine markers involved in bone metabolism and protein markers related to bone activity were analyzed to explore bone turnover activity. Results: The patient received Everolimus therapy for 36 weeks. During treatment, no clinical improvement of the disease was perceived. Analysis of biochemical parameters, namely, ß-CTX (r 2 = -0.576, P-value = 0.016) and PNIP (r 2 = -0.598, P-value = 0.011), indicated that bone turnover activity was significantly reduced. Additionally, bone metabolism-related biomarkers showed only a significant positive correlation with PTH levels. Conclusions: Everolimus treatment did not modify the clinical progression of the disease in an aggressive form of POH, although an impact on the protein markers studied was observed.

Rotavirus and autoimmunity.

Rotavirus, a major etiological agent of acute diarrhea in children worldwide, has historically been linked to autoimmunity. In the last few years, several physiopathological approaches have been proposed to explain the leading mechanism triggering autoimmunity, from the old concept of molecular mimicry to the emerging theory of bystander activation and break of tolerance. Epidemiological and immunological data indicate a strong link between rotavirus infection and two of the autoimmune pathologies with the highest incidence: celiac disease and diabetes. The role for current oral rotavirus vaccines is now being elucidated, with a so far positive protective association demonstrated.

Routine infant vaccination of pneumococcal conjugate vaccines has decreased pneumonia across all age groups in Northern Spain.

Since the early 2000s, pneumococcal conjugate vaccines (PCVs) have been shown to be effective in the prevention of pneumonia and invasive pneumococcal diseases. In 2011, the Galician region incorporated PCV in the routine infant immunization, the very first stable program in Spain. We aim to assess direct and indirect benefits of PCV vaccination on all-cause pneumonia in the region across different age groups using an ecological study design. For this, we calculated the annual hospitalization rates using a hospital-based disease registry. We identified all-cause pneumonia, pneumococcal pneumonia and pneumococcal invasive diseases within the registry. Hospitalization rates were computed and compared across three study periods: pre-vaccination (1998-2003), early-vaccination (2005-2009) and routine-vaccination (2011-2015). Across Northern Spain, we identified 114,873 all-cause pneumonia hospitalizations, of which 24,808 were further diagnosed with pneumococcal pneumonia. The majority were elderly > 64 years (67.3%). Hospitalizations from all-cause pneumonia had a net increase from 20.6 (pre-PCV) and 21.4/10,000 (early) to 28.4/10,000 (routine) (+32.7%, p < .0001), this is attributed to the huge number of cases in the elderly age group. In contrast, a net reduction of incidence of hospitalized pneumococcal pneumonia was observed from 6.3/10,000 (pre-PCV) and 5.7/10,000 (early) to 2.4/10,000 (routine) cases (-57.9%, p < .0001). Thus, routine infant vaccination may have resulted to an overall decline of pneumococcal pneumonia in infants, as well as in elderly age groups. However, a paradoxical increase on all-cause pneumonia was observed in Galicia, mostly attributed to the growing number of cases in the elderly population.

Impact of rotavirus vaccination on childhood hospitalizations for seizures: Heterologous or unforeseen direct vaccine effects?

There is a growing interest in the possible relationship between rotavirus (RV) vaccine and hospitalizations due to childhood seizures. We explored variation in hospitalization rates after 9 years of vaccination against pre-vaccination period for children <5 years of age from Galicia (Northwest Spain) before and after the introduction of the RV vaccines. Hospitalization rates for childhood seizures in Galician children were compared before and after RV vaccine introduction (in 2007) using different statistical approaches, including time series analyses. Our study cohort totaled 7,712 children <5 years of age admitted to hospital between 2002 and 2015 for "all kind of childhood seizures". Hospitalization rates decreases steadily with reductions ranging from 22.3% (95% CI: 15.0-29.1) in 2008, to 50.9% (95% CI: 45.5-55.7) in 2014, and significant results were also observed for <1, 1, and 2-year-old children in comparison with pre-vaccination period hospitalization rate. Regression models indicate a negative association between RV vaccination and hospitalizations for all kind of seizures. In addition, time series analyses are consistent with this finding and predict that vaccination coverage will affect hospitalization rates for "all kind of seizures" after 9 months. The results strongly support that RV vaccination has significantly reduced hospitalization rates due to childhood seizures.

False-Positive Results of Serological Tests for Allergy in Alcoholic Patients.

BACKGROUND AND OBJECTIVE: Alcohol consumption is associated with enhanced TH2 immune responses. Objective: To investigate the frequency of false-positive results in serological tests for allergy in alcoholic patients. METHODS: A total of 138 alcoholic patients consecutively admitted to hospital underwent a panel of allergy tests that included serum total IgE, a multiallergen IgE test (UniCAP Phadiatop), and skin prick tests to relevant aeroallergens in the area, which were considered the standard reference for atopy. In selected cases with positive specific IgE (sIgE) to cross-reactive carbohydrate determinants (CCDs) on ImmunoCAP, we determined sIgE to hymenoptera venom components (ADVIA Centaur) and a microarray of 103 allergen components (ISAC). RESULTS: Increased serum total IgE (>170 IU/mL) was observed in 59/110 (54%) of nonatopic (skin prick test-negative) patients. The result of the multiallergen IgE test was positive in 46 nonatopic patients (42%). This finding was closely associated with high serum concentrations of total IgE and sIgE to CCDs. The vast majority of patients with positive CCD-sIgE showed positivity to glycosylated plant and hymenoptera allergen components on ISAC and ADVIA Centaur. Only 1 out of 26 patients with positive sIgE to CCD and hymenoptera venom developed honeybee venom allergy after a median follow-up of 166 months. Correlations between measurements of sIgE to CCD markers on ImmunoCAP, ADVIA Centaur, and ISAC were imperfect. CONCLUSIONS: Serological tests for allergy should be interpreted with caution in alcoholic patients, who frequently have increased levels of total IgE and CCD-sIgE and subsequent positivity of sIgE to glycosylated allergen components, irrespective of the method used.

False-positive results of serological tests for allergy in alcoholic patients

Background: Alcohol consumption is associated with enhanced TH2 immune responses. Objective: To investigate the frequency of false-positive results in serological tests for allergy in alcoholic patients. Methods: A total of 138 alcoholic patients consecutively admitted to hospital underwent a panel of allergy tests that included serum total IgE, a multiallergen IgE test (UniCAP Phadiatop), and skin prick tests to relevant aeroallergens in the area, which were considered the standard reference for atopy. In selected cases with positive specific IgE (sIgE) to cross-reactive carbohydrate determinants (CCDs) on ImmunoCAP, we determined sIgE to hymenoptera venom components (ADVIA Centaur) and a microarray of 103 allergen components (ISAC).Results: Increased serum total IgE (>170 IU/mL) was observed in 59/110 (54%) of nonatopic (skin prick test-negative) patients. The result of the multiallergen IgE test was positive in 46 nonatopic patients (42%). This finding was closely associated with high serum concentrations of total IgE and sIgE to CCDs. The vast majority of patients with positive CCD-sIgE showed positivity to glycosylated plant and hymenoptera allergen components on ISAC and ADVIA Centaur. Only 1 out of 26 patients with positive sIgE to CCD and hymenoptera venom developed honeybee venom allergy after a median follow-up of 166 months. Correlations between measurements of sIgE to CCD markers on ImmunoCAP, ADVIA Centaur, and ISAC were imperfect. Conclusions: Serological tests for allergy should be interpreted with caution in alcoholic patients, who frequently have increased levels of total IgE and CCD-sIgE and subsequent positivity of sIgE to glycosylated allergen components, irrespective of the method used

Antecedentes: El consumo de alcohol se asocia con respuestas inmunes aumentadas de tipo Th2.Objetivo: Investigar la frecuencia de falsos positivos en los tests serológicos de alergia en alcohólicos. Métodos: En un total de 138 pacientes alcohólicos ingresados en el hospital de forma consecutiva se realizó un panel de pruebas de alergia que incluyó la determinación de IgE sérica total, un test de IgE específica multialergeno (UniCAP Phadiatop) y pruebas cutáneas en prick a una batería de aeroalérgenos relevantes en el área, cuya positividad se consideró la referencia para clasificar a los pacientes como atópicos. En casos seleccionados con positividad de IgE específica (sIgE) frente a carbohidratos con reactividad (CCDs) en el ImmunoCAP, se determinó la sIgE a componentes del veneno de hymenópteros (ADVIA Centaur) y a un microarray de 103 componentes alergénicos (ISAC).Resultados: Se observó un aumento de las concentraciones de IgE sérica total (>170 IU/mL) en 59/110 (54%) de los alcohólicos no atópicos (prick test-negativos). Cuarenta y seis alcohólicos no atópicos (42%) presentaban un test de IgE específica multialérgeno positivo. Este hallazgo estuvo estrechamente asociado con la presencia de concentraciones elevadas de IgE total y de sIgE a CCDs. La gran mayoría de los alcohólicos con positividad de sIgE a CCDs mostraron positividad con componentes moleculares glicosilados de plantas e himenópteros en el ISAC y el ADVIA Centaur. Sólo uno de los 26 pacientes con positividad de sIgE a CCDs e himenópteros desarrolló alergia clínica a picadura de abeja tras un seguimiento mediano de 166 meses. La correlación de las determinaciones de sIgE a marcadores de CCD en ImmunoCAP, ADVIA Centaur e ISAC fue imperfecta. Conclusiones: Los tests serológicos de alergia se deben interpretar con precaución en pacientes alcohólicos, que frecuentemente muestran elevación de IgE total, positividad de sIgE a CCDs y, consecuentemente, positividad de sIgE a componentes alergénicos glicosilados, independientemente del método utilizado

Salivary epidermal growth factor correlates with hospitalization length in rotavirus infection.

BACKGROUND: The IFI27 interferon gene expression has been found to be largely increased in rotavirus (RV)-infected patients. IFI27 gene encodes for a protein of unknown function, very recently linked to epidermal proliferation and related to the epidermal growth factor (EGF) protein. The EGF is a low-molecular-weight polypeptide that is mainly produced by submandibular and parotid glands, and it plays an important physiological role in the maintenance of oro-esophageal and gastric tissue integrity. Our aim was to determine salivary EGF levels in RV-infected patients in order to establish its potential relationship with IFI27 increased expression and EGF-mediated mucosal protection in RV infection. METHODS: We conducted a prospective comparative study using saliva samples from 27 infants infected with RV (sampled at recruitment during hospital admission and at convalescence, i.e. at least 3 months after recovery) and from 36 healthy control children. RESULTS: Median (SD) EGF salivary concentration was 777 (529) pg/ml in RV-infected group at acute phase and 356 (242) pg/m at convalescence, while it was 337 (119) pg/ml in the healthy control group. A significant association was found between EGF levels and hospitalization length of stay (P-value = 0.022; r2 = -0.63). CONCLUSIONS: The salivary levels of EGF are significantly increased during the acute phase of natural RV infection, and relate to length of hospitalization. Further assessment of this non-invasive biomarker in RV disease is warranted.

Influence of experimental alcohol administration on serum immunoglobulin levels: contrasting effects on IgE and other immunoglobulin classes.

In humans, alcoholic liver disease is associated with hypergammaglobulinemia, particularly with high serum concentrations of IgA. Furthermore, alcohol consumption is associated with high concentrations of IgE and low concentrations of IgG. However, there is little experimental evidence to corroborate these observational findings. The objective of the present study was to investigate the potential short-term effects of alcohol administration on serum immunoglobulin concentrations in mice, and the potential influence of sex and strain on these effects. Eight mouse groups were defined by strain (Swiss vs C57BL/6), sex (male vs female), and experimental procedure (alcohol administration vs control diet). Alcohol was administered in a semi-liquid diet (6.5%v/v); control animals received an isocaloric semi-liquid diet. Immunoglobulin concentrations (IgE, IgA, IgM, IgG1, IgG2a, IgG2b, and IgG3) were measured at baseline and weekly thereafter for 4 weeks. Serum Th1 (interferon-gamma) and Th2 (IL-4 and IL-13) cytokines were measured at week 4. We found significant variations in baseline immunoglobulin concentrations depending upon mouse sex and strain. Alcohol administration was quickly followed by an increase in serum IgE concentrations in all experimental groups. IgE increase was correlated with serum IL-13 increase. In contrast, alcohol administration was not associated with significant changes in serum IgA and IgM concentration, and appeared to decrease IgG subclass concentrations. Alcohol effects on immunoglobulin concentrations were independent of mouse strain and sex. In conclusion, alcohol administration in mice had contrasting effects on IgE and other immunoglobulin classes. This experimental evidence confirms observational results in humans.

Immunoglobulin-E reactivity to a glycosylated food allergen (peanuts) due to interference with cross-reactive carbohydrate determinants in heavy drinkers.

BACKGROUND: N-glycans in plant and invertebrate glycoproteins can induce extensive IgE cross-reactivity therefore limiting the specificity of in vitro allergy tests. IgE sensitization to N-glycans (cross-reactive carbohydrate determinants, CCDs) may be increased in heavy drinkers, who therefore show IgE reactivity to aeroallergens, latex, and Hymenoptera venoms. The peanut, a CCD-bearing allergen, is the leading cause of severe food allergic reactions in many populations. AIM OF THE STUDY: To investigate the potential interference of CCDs with determinations of IgE to peanuts in heavy drinkers. METHODS: We determined IgE to peanuts and IgE to a CCD marker (MUXF(3), the N-glycan from bromelain) in 41 heavy drinkers admitted to the hospital and 54 healthy controls. None of the participants reported symptoms of peanut allergy. In cases with positive (>or=0.35 kU/l) IgE to peanuts, we performed inhibition assays with a neoglycoprotein consisting of MUXF(3) molecules coupled to bovine serum albumin (MUXF(3)-BSA) and a similar neoglycoprotein lacking xylose and fucose (MM-BSA). In the same cases, we screened for IgE to a panel of recombinant nonglycosylated peanut allergens. SDS-PAGE immunoblotting and inhibition assays were performed in selected cases. RESULTS: The prevalence of positive IgE to peanuts was 22 and 3.7% in heavy drinkers and healthy controls, respectively (p < 0.001). Peanut-IgE positivity was closely related to the presence of IgE to CCDs. In most (8/9) heavy drinkers with positive IgE to peanuts, reactivity was inhibited by preincubation with MUXF(3)-BSA, but not with MM-BSA. IgE binding to multiple bands on immunoblotting studies was also inhibited by MUXF(3)-BSA preincubation. IgE to nonglycosylated recombinant peanut allergens was uniformly negative. CONCLUSION: Heavy drinking is associated with clinically asymptomatic IgE reactivity to peanuts, a relevant food allergen, in relation to CCD interference.

Lipid-specific immunoglobulin M in CSF predicts adverse long-term outcome in multiple sclerosis.

BACKGROUND AND OBJECTIVE: The presence of lipid-specific immunoglobulin M bands in the cerebrospinal fluid (CSF) predicts an aggressive course in patients with relapsing-remitting multiple sclerosis (MS) during early stages of the disease. This study examined whether it is also a predictor of long-term prognosis in MS. METHODS: Eighty-one patients with MS and 22 headache controls were analyzed for anti-lipid IgM reactivity in CSF samples. The correlation between the presence of lipid-specific immunoglobulin M bands in CSF and disease progression was assessed in patients with MS who had been followed longitudinally for, on average, more than 11 years. RESULTS: Lipid-specific immunoglobulin M bands were detected in the CSF of 24 of 81 patients with MS and were absent in the CSF of all headache controls. Median time to conversion to a secondary progressive course was 11 years in patients with bands and 22 years in patients without bands. Median time to an Expanded Disability Status Scale score of 4 was 14 years in patients with bands and 24 years in patients without bands. CONCLUSION: The presence of lipid-specific immunoglobulin M bands in CSF predicts a more adverse long-term outcome in patients with MS; it may thus define a subset of patients who might benefit from aggressive treatment during the early phase of the disease.

Influence of oligoclonal IgM specificity in multiple sclerosis disease course.

Oligoclonal IgM bands (OCMB) against myelin lipids predict an aggressive multiple sclerosis (MS) course. However, the clinical significance of OCMB without lipid specificity, present in other MS patients, remains unknown. We describe here a characterization of these antibodies and study their role in MS progression. Fifty-four MS patients showing CSF-restricted OCMB were included in this study at disease onset and followed-up during 61.1 +/- 2.7 months. The specificity of OCMB and the CSF B-cell profile were investigated. A second CSF IgM study was performed in a group of eight patients. Thirty-eight patients showed OCMB against myelin lipids (M+L+) and other sixteen had OCMB lacking this specificity (M+L-). The CD5+ B cell subpopulation, responsible for most persistent IgM responses, was considerably higher in M+L+ than in M+L- patients (3.3 +/- 0.6% versus 0.8 +/- 0.2, P = 0.009). In addition, M+L+ bands persisted during disease course, while M+L- disappeared during follow-up. M+L+ patients suffered more relapses (4.2 +/- 0.6 versus 1.6 +/- 0.3, P = 0.002) and reached higher disability (EDSS score of 2.2 +/- 0.2 versus 1.2 +/- 0.2, P = 0.02) than M+L- group. These data corroborate that anti-lipid OCMB associate with an aggressive MS course and show that OCMB that do not recognize myelin lipids represent a transient immune response related to a more benign disease course.