Der p 23 sensitisation in patients with house dust mite respiratory allergy.

Summary: Background. The sensitization profile of patients allergic to house dust mites (HDM) and its molecular diagnosis may determine treatment and evolution of the disease. The present study investigates the prevalence of Der p 23 sensitization and its relation to asthma in a population of HDM-allergic patients. Methods. We conducted a cross-sectional study of 891 patients with HDM allergy with symptoms of rhinitis and 52.1% of them with asthma. Total and specific IgE (sIgE) was measured against Dermatophagoides pteronyssinus and its molecular components (Der p 1, Der p 2 and Der p 23) and the storage mite Lepidoglyphus destructor using ImmunoCAP. Prevalence of sensitization and levels of sIgE were analysed according to asthma diagnosis and asthma severity. Results. Der p 23 was the predominant allergen in this population (83.7%) but IgE levels were lower than those of sIgE to Der p 1 and Der p 2. A good correlation was found between sIgE to Der p 23 and the other allergens. A total of 8.2% patients were monosensitized to Der p 23. Asthma was more frequent in patients with positive sIgE against Der p 23 than in patients without this sensitization (52.8% vs 42.8%, p = 0.027). A tendency to increase both total IgE and sIgE was observed in relation to the severity of asthma from intermittent mild asthma to persistent moderate asthma but a substantial decrease in total IgE and sIgE was detected in more severe asthmatics. Conclusions. Der p 23 might be a prevalent allergen in regions with high rates of HDM exposure. Even though sIgE levels against this allergen are usually low, its presence could increase the risk of asthma.

Immunoglobulin G4-Related Disease: What an Allergist Should Know.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disorder that begins in 1 or more organs as inflammatory tumors that progress toward fibrosis. It is often accompanied by elevated serum IgG4. IgG4-RD was first described in 2003 as a new concept encompassing a number of immunoallergic diseases that had previously been considered unrelated. IgG4-RD mainly affects middleaged and older men. It consists of upregulation and expansion of CD4+ cytotoxic T lymphocytes, oligoclonal plasmablasts, and other inflammatory cells that infiltrate affected tissues and induce inflammation, organ dysfunction, and fibrosis. Symptoms depend on the location, severity, and extent of the disease. Virtually any organ can be affected, including the pancreas, salivary glands, lacrimal glands, thyroid gland, retro-orbital tissue, lymph nodes, retroperitoneum, mediastinum, lung, kidney, aorta, serosal surfaces, and meninges. Patients with widespread disease may present general symptoms. At least 30%-40% of patients are atopic or display atopic traits such as eosinophilia and elevated serum IgE levels. Additional laboratory features include increased serum IgG4 concentrations, increased blood IgG4-plasmablasts, hypergammaglobulinemia, and hypocomplementemia. Diagnosis of IgG4-RD is based on a clinicopathological correlation. Lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform-type fibrosis, obliterative phlebitis, and tissue eosinophilia are the pathological hallmarks. Therapy for IgG4-RD is based primarily on corticosteroids but may include additional immunomodulatory drugs and monoclonal antibodies such as rituximab. In individuals with allergic features, IgG4-RD should be suspected when a history of unexplained swelling is observed in 1 or more organs, particularly if they respond to corticosteroids and the patients are men in the sixth decade of life and beyond.

Anaphylaxis to Vespa velutina nigrithorax: Pattern of Sensitization for an Emerging Problem in Western Countries.

OBJECTIVE: To define the sensitization pattern of patients with anaphylaxis to Vespa velutina nigrithorax (VVN). METHODS: We studied 100 consecutive Spanish patients with anaphylaxis to Hymenoptera venom and systematically determined specific IgE (sIgE) to whole venoms (Vespula species, Polistes dominula, Apis mellifera, Vespa crabro, and Dolichovespula maculata) and their molecular components (rApi m 1, rApi m 5, rApi m 10, rVes v 1, rVes v 5, rPol d 5, and cross-reactive carbohydrates). Specific IgE to VVN venom and its antigen 5 (nVesp v 5) were measured in a subsample. RESULTS: Seventy-seven patients had anaphylaxis to VVN. Of these, only 16 (20.8%) reported previous VVN stings, but were stung by other Hymenoptera. Positive sIgE (>0.35 kUA/L) to each of the whole venoms was detected in >70% of patients (Vespula species in 100%). The components showing >50% positivity were rApi m 5 (51.4%), rPol d 5 (80.0%), and rVes v 5 (98.7%). This pattern was similar to that of Vespula species anaphylaxis (n=11) but different from that of A mellifera anaphylaxis (n=10). Specific IgE to nVesp v 5 was positive in all patients (n=15) with VVN anaphylaxis and was correlated with sIgE to both rVes v 5 (R=0.931) and rPol d 5 (R=0.887). CONCLUSIONS: VVN has become the commonest cause of Hymenoptera anaphylaxis in our area. Most cases report no previous VVN stings. Their sensitization pattern is similar to that of patients with anaphylaxis to other Vespidae. Specific IgE to antigen-5 from VVN, Vespula species, and P dominula are strongly correlated in patients with VVN anaphylaxis.

Immunoglobulin G4–Related Disease: What an Allergist Should Know

Immunoglobulin G4–related disease (IgG4-RD) is a fibroinflammatory disorder that begins in 1 or more organs as inflammatory tumors that progress toward fibrosis. It is often accompanied by elevated serum IgG4. IgG4-RD was first described in 2003 as a new concept encompassing a number of immunoallergic diseases that had previously been considered unrelated. IgG4-RD mainly affects middleaged and older men. It consists of upregulation and expansion of CD4+ cytotoxic T lymphocytes, oligoclonal plasmablasts, and other inflammatory cells that infiltrate affected tissues and induce inflammation, organ dysfunction, and fibrosis. Symptoms depend on the location, severity, and extent of the disease. Virtually any organ can be affected, including the pancreas, salivary glands, lacrimal glands, thyroid gland, retro-orbital tissue, lymph nodes, retroperitoneum, mediastinum, lung, kidney, aorta, serosal surfaces, and meninges. Patients with widespread disease may present general symptoms. At least 30%-40% of patients are atopic or display atopic traits such as eosinophilia and elevated serum IgE levels. Additional laboratory features include increased serum IgG4 concentrations, increased blood IgG4-plasmablasts, hypergammaglobulinemia, and hypocomplementemia. Diagnosis of IgG4-RD is based on a clinicopathological correlation. Lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform-type fibrosis, obliterative phlebitis, and tissue eosinophilia are the pathological hallmarks. Therapy for IgG4-RD is based primarily on corticosteroids but may include additional immunomodulatory drugs and monoclonal antibodies such as rituximab. In individuals with allergic features, IgG4-RD should be suspected when a history of unexplained swelling is observed in 1 or more organs, particularly if they respond to corticosteroids and the patients are men in the sixth decade of life and beyond (AU)

Anaphylaxis to Vespa velutina nigrithorax: Pattern of Sensitization for an Emerging Problem in Western Countries

Objective: To define the sensitization pattern of patients with anaphylaxis to Vespa velutina nigrithorax (VVN). Methods: We studied 100 consecutive Spanish patients with anaphylaxis to Hymenoptera venom and systematically determined specific IgE (sIgE) to whole venoms (Vespula species, Polistes dominula, Apis mellifera, Vespa crabro, and Dolichovespula maculata) and their molecular components (rApi m 1, rApi m 5, rApi m 10, rVes v 1, rVes v 5, rPol d 5, and cross-reactive carbohydrates). Specific IgE to VVN venom and its antigen 5 (nVesp v 5) were measured in a subsample. Results: Seventy-seven patients had anaphylaxis to VVN. Of these, only 16 (20.8%) reported previous VVN stings, but were stung by other Hymenoptera. Positive sIgE (>0.35 kUA/L) to each of the whole venoms was detected in >70% of patients (Vespula species in 100%). The components showing >50% positivity were rApi m 5 (51.4%), rPol d 5 (80.0%), and rVes v 5 (98.7%). This pattern was similar to that of Vespula species anaphylaxis (n=11) but different from that of A mellifera anaphylaxis (n=10). Specific IgE to nVesp v 5 was positive in all patients (n=15) with VVN anaphylaxis and was correlated with sIgE to both rVes v 5 (R=0.931) and rPol d 5 (R=0.887). Conclusions: VVN has become the commonest cause of Hymenoptera anaphylaxis in our area. Most cases report no previous VVN stings. Their sensitization pattern is similar to that of patients with anaphylaxis to other Vespidae. Specific IgE to antigen-5 from VVN, Vespula species, and P dominula are strongly correlated in patients with VVN anaphylaxis (AU)

Serum Concentrations of Interleukin 6 in the General Adult Population: Possible Implications for Anti-IL-6 Therapy in SARS-Cov-2 Infection and IL-6-Related Diseases

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Assessing the relationship between markers of glycemic control through flexible copula regression models.

Glycated haemoglobin (HbA1c) is a sensitive marker of blood glucose in patients with diabetes. However, levels can vary considerably, even amongst individuals with similar mean blood glucose concentrations. Other glycated proteins, such as fructosamine, can also act as blood sugar markers, but estimating HbA1c and fructosamine via independent models may lead to errors of interpretation regarding disease severity. From a clinical standpoint, it would be of great interest to know the factors that affect the mean concentration of both HbA1c and fructosamine, which influence the variability in the concentrations of these glycated markers and cause HbA1c/fructosamine discordance. Flexible models are required to illustrate the behaviour of these variables as well as the association between them. This work reviews existing models that might serve in this regard. Flexible copula regression models using splines were used to provide a better understanding of the behaviour of both glycated proteins and the relationship between them under the possible influence of different covariates. This work shows the usefulness of this type of models in practise and provides a basis for their clinical interpretation by means of an understandable case study. Ultimately, to better understand the effects of each continuous covariate, they are represented at the true scale of the response variables.

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

Factors Influencing Serum Concentrations of Immunoglobulin D in the Adult Population: An Observational Study in Spain.

Immunoglobulin D (IgD) is the least studied of immunoglobulin classes. This study sought to investigate the potential relationship between demographic, metabolic, lifestyle and immunological factors, and serum IgD concentrations in a general adult population. We measured serum IgD concentrations by means of a commercial turbidimetric assay in 413 individuals (median age, 55 years; 45% males), randomly selected from the adult population of a Spanish municipality. Serum IgD concentrations displayed considerable variation in the population, ranging from undetectable (<6.7 mg/l) to 878 mg/l. Serum IgD concentrations were undetectable in 78 cases (18.9%) and >100 mg/l in 39 cases (9.4%). Median IgD was 21.9 mg/l. Serum IgD concentrations were negatively associated with age and positively associated with smoking, after adjustment for potential confounders. Overweight individuals showed lower concentrations of IgD than did normal-weight individuals. Atopy (positivity of skin tests to aeroallergens) was not significantly associated with IgD concentrations, although non-symptomatic atopics showed higher IgD concentrations. No consistent association was observed between serum IgD concentrations and gender, metabolic syndrome, or alcohol consumption. No significant association was found between baseline IgD concentrations and development of either allergic or immune disease after a median 11.4 years of follow-up. In conclusion, serum IgD concentrations in adults show a wide variation in the population and may be influenced by common factors, particularly age and smoking habit. These factors should be taken into account when defining reference ranges for serum IgD concentrations.

Total and honeybee venom-specific serum IgG4 and IgE in beekeepers

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Association Between Asthma and Sensitization to Allergens of Dermatophagoides pteronyssinus.

BACKGROUND AND OBJECTIVE: Little is known about the role of molecular diagnosis in house dust mite (HDM) allergy. In this study, we investigated the association between the sensitization profile of adolescent and adult HDM-allergic patients and asthma in a region with high rates of exposure to HDM. METHODS: We conducted a cross-sectional study of 384 HDM-allergic patients (38.5%, males; median age, 28 years). A total of 368 patients (95.8%) had rhinitis, and 175 (45.6%) had asthma. Specific IgE (sIgE) to Dermatophagoides pteronyssinus, nDer p 1, rDer p 2, and rPen a 1 was measured in all patients. sIgE to Lepidoglyphus destructor was measured in patients (n=301) with a positive skin test result. RESULTS: Significantly higher concentrations of sIgE to Der p 1 and sIgE to Der p 2 were observed in patients with asthma than in those without asthma. The proportion of asthmatic patients was higher among individuals who reacted (≥0.35 kUA/L) to both Der p 1 and Der p 2 (147/291, 50.5%) than among those who reacted to only 1 allergen (either Der p 1 or Der p 2, 18/55, 32.7%) or neither allergen (10/38, 26.3%, P=.002). Reactivity to both allergens was associated with asthma after adjusting for age and sex (OR, 2.87; 95%CI, 1.32-6.20). Higher concentrations of sIgE to L destructor were observed in patients with asthma than in patients without asthma. Tropomyosin sIgE ≥0.35 kUA/L was detected in only 6 individuals (1.6%). CONCLUSIONS: L destructor may be a relevant allergen in high-exposure areas. Dual sensitization (ie, IgE to both Der p 1 and Der p 2) may help to identify HDM-allergic patients who are at risk of asthma.

Association between asthma and sensitization to allergens of dermatophagoides pteronyssinus

Background: Little is known about the role of molecular diagnosis in house dust mite (HDM) allergy. Objective: In this study, we investigated the association between the sensitization profile of adolescent and adult HDM-allergic patients and asthma in a region with high rates of exposure to HDM. Methods: We conducted a cross-sectional study of 384 HDM-allergic patients (38.5%, males; median age, 28 years). A total of 368 patients (95.8%) had rhinitis, and 175 (45.6%) had asthma. Specific IgE (sIgE) to Dermatophagoides pteronyssinus, nDer p 1, rDer p 2, and rPen a 1 was measured in all patients. sIgE to Lepidoglyphus destructor was measured in patients (n=301) with a positive skin test result. Results: Significantly higher concentrations of sIgE to Der p 1 and sIgE to Der p 2 were observed in patients with asthma than in those without asthma. The proportion of asthmatic patients was higher among individuals who reacted (≥0.35 kU A /L) to both Der p1 and Der p 2 (147/291, 50.5%) than among those who reacted to only 1 allergen (either Der p 1 or Der p 2, 18/55, 32.7%) or neither allergen (10/38, 26.3%, P=.002). Reactivity to both allergens was associated with asthma after adjusting for age and sex (OR, 2.87; 95%CI, 1.32-6.20). Higher concentrations of sIgE to L destructor were observed in patients with asthma than in patients without asthma. Tropomyosin sIgE ≥0.35 kUA L was detected in only 6 individuals (1.6%). Conclusions: L destructor may be a relevant allergen in high-exposure areas. Dual sensitization (ie, IgE to both Der p 1 and Der p 2) may help to identify HDM-allergic patients who are at risk of asthma (AU)

Antecedentes: El papel del diagnóstico molecular en la alergia a los ácaros no ha sido estudiado en profundidad. Objetivo: Investigar el perfil molecular de sensibilización de pacientes adolescentes y adultos alérgicos a los ácaros del polvo doméstico y su relación con asma en una región en donde la exposición a los ácaros es importante. Métodos: Estudio transversal en 384 pacientes alérgicos a los ácaros (38,5% varones; edad media, 28 años) de los que 368 (95,8%) padecían rinitis y 175 (45,6%), asma. Se determinó la IgE específica (sIgE) frente a D. pteronyssinus, nDer p 1, rDer p 2, y rPen a 1 en toda la muestra. Además, se midió la sIgE frente a L. destructor en 301 con una prueba positiva frente a este ácaro. Resultados: Los pacientes con asma presentaron niveles significativamente más altos de sIgE frente a Der p 1 y a Der p 2 que aquellos que no padecían asma. La prevalencia de asma fue mayor en los pacientes con sIgE positiva (≥0,35 kU A /L) frente a ambos Der p 1 y Der p 2 (147/291, 50,5%) que entre los sujetos que tan solo presentaron sIgE frente a uno de estos alérgenos (Der p 1 o Der p 2, 18/55, 32,7%) o ninguno de ellos (10/38, 26,3%, p=0,002). La detección de sIgE frente a ambos alérgenos se asoció con asma aún después de ajustar por edad o sexo (OR 2,87, 95% CI 1,32-6,20). Los pacientes con asma presentaron, asimismo, títulos más altos de IgE total y sIgE frente a L. destructor-sIgE. Solo 6 pacientes (1,6%) presentaron niveles de sIgE frente a la tropomiosina superiores a 0,35 kUA /L. Conclusiones: L. destructor puede ser un alérgeno relevante en áreas en las que se encuentre presente. La doble sensibilización a Der p 1 y Der p 2 podría ser de utilidad para identificar sujetos con riesgo de asma (AU)

Sensitization pattern of crustacean-allergic individuals can indicate allergy to molluscs.

This study investigated the sensitization pattern of crustacean-allergic patients according to tolerance to molluscs. Thirty-one patients with anaphylaxis to crustaceans (14 with mollusc allergy and 17 with mollusc tolerance) were studied using skin prick tests (SPTs), specific IgEs (sIgEs) and SDS-PAGE immunoblotting. IgE-reactive shrimp proteins were identified by proteomic analyses. Patients with mollusc allergy presented more frequently SPTs positive to molluscs and higher sIgE titres in response to both molluscs and crustaceans. Shrimp-sIgE and rPen a1-sIgE values of 1.57 kUA /l and 4.38 kUA /l, respectively, showed positive likelihood ratios of 4.3 and 10.9 for the identification of mollusc allergy. Patients with mollusc allergy reacted more frequently to tropomyosin in immunoblots than did patients without it (93% vs 35%, respectively, P = 0.004). Reactivity to proteins other than tropomyosin (n = 14) was not different between the two groups. Among patients with crustacean anaphylaxis, patients with mollusc allergy and mollusc tolerance show a different pattern of sensitization, something that may help identify them.

The impact of poor psychosocial work environment on non-work-related sickness absence.

PURPOSE: We aimed to analyse the impact of psychosocial work environment on non-work-related sickness absence (NWRSA) among a prospective cohort study, stratified using a random sampling technique. METHODS: Psychosocial variables were assessed among 15,643 healthy workers using a brief version of the Spanish adaptation of Copenhagen Psychosocial Questionnaire. A one year follow-up assessed the total count of NWRSA days. Zero-inflated negative binomial regression was used for multivariate analyses. RESULTS: After adjusting for covariates, low levels of job control and possibilities for development (Odds Ratio [OR]: 1.17; 95% CI: 1.01-1.36 [men]; OR: 1.39 95% CI: 1.09-1.77 [women]), poor social support and quality of leadership (OR: 1.29; 95% CI: 1.11-1.50 [men]; OR: 1.28; 95% CI: 1.01-1.63 [women]), and poor rewards (OR: 1.34; 95% CI: 1.14-1.57 [men]; OR: 1.30; 95% CI: 1.01-1.66 [women]) predicted a total count of sickness absence greater than zero, in both men and women. Double presence was also significantly associated with NWRSA different than 0, but only among women (OR: 1.40; 95% CI: 1.08-1.81). Analyses found no association between psychosocial risk factors at work and the total count (i.e., number of days) of sickness absences. CONCLUSIONS: The results suggest that work-related psychosocial factors may increase the likelihood of initiating an NWRSA episode, but were not associated with the length of the sickness absence episode. Among our large cohort we observed that some associations were gender-dependent, suggesting that future research should consider gender when designing psychosocial interventions aimed at decreasing sickness absences.