Anti-IL-5/5Ra biologics improve work productivity and activity in severe asthma: a RAPSODI registry-based cohort study.

INTRODUCTION: Severe asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment. AIMS AND OBJECTIVES: This study aims to relate treatment with biologics targeting IL-5/5Ra to work productivity and activity in the long term in a real-world context. MATERIAL AND METHODS: This is a registry-based multi-center cohort study evaluating data from adults with severe eosinophilic asthma included in the Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management (RAPSODI). Patients that started with anti-IL-5/5Ra biologics and completed the work productivity and activity improvement questionnaire, were included. Study and patient characteristics were compared between the employed and unemployed patients. Work productivity and activity impairment are related to accompanying improvements in clinical outcomes. RESULTS: At baseline, 91 of 137 patients (66%) were employed which remained stable throughout the follow-up period. Patients in the working age category were younger and had significantly better asthma control (p = 0.02). Mean overall work impairment due to health decreased significantly from 25.5% (SD2.6) to 17.6% (SD 2.8) during 12 months anti-IL-5/5Ra biologics treatment (P = 0.010). There was a significant association between ACQ6 and overall work improvement after targeted therapy (ß = 8.7, CI 2.1-15.4, P = 0.01). The improvement of asthma control of 0.5 points on the asthma Control Questionnaire was associated with an overall work impairment of -9%. CONCLUSIONS: Work productivity and activity in severe eosinophilic asthma improved after starting anti-IL-5/5Ra biologics. Clinically relevant improvement in asthma control was associated with an overall work impairment score of -9% in this study.

[Work-related asthma in clinical practice]. / Werkgerelateerd astma in de klinische praktijk.

Work-related asthma is an underestimated problem. More awareness is needed for early identification of work-related lung diseases to prevent permanent damage in patients with lung diseases. Work-related asthma can lead to an increase in the burden of disease, the number of exacerbations and hospital admissions. Therefore, exposure to substances with irritating and/or sensitizing properties should be regarded as an additional treatable trait in asthma treatment. The number of occupations where such exposures plays a role is large and diverse. Inquiring about the profession, activities or future career choice of the (asthma) patient during the first consultation is of great importance for the correct diagnosis and treatment. Cooperation between pulmonologist, lung nurse, ENT specialist, dermatologist, company doctor and occupational hygienist can contribute to this. A regional organization with a 'multidisciplinary consultation' for occupational lung diseases is important to guarantee optimal care and advice. The clinical case series demonstrate work-related asthma in clinical practice.

Case-control study of patient characteristics, knowledge of the COVID-19 disease, risk behaviour and mental state in patients visiting an emergency room with COVID-19 symptoms in the Netherlands.

BACKGROUND: Coronavirus disease 2019 is a serious respiratory virus pandemic. Patient characteristics, knowledge of the COVID-19 disease, risk behaviour and mental state will differ between individuals. The primary aim of this study was to investigate these variables in patients visiting an emergency department in the Netherlands during the COVID-19 pandemic and to compare the "COVID-19 suspected" (positive and negative tested group) with the "COVID-19 not suspected" (control group) and to compare in the "COVID-19 suspected" group, the positive and negative tested patients. METHODS: Consecutive adult patients, visiting the emergency room at the Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands, were asked to fill out questionnaires on the abovementioned items on an iPad. The patients were either "COVID-19 suspected" (positive and negative tested group) or "COVID-19 not suspected" (control group). RESULTS: This study included a total of 159 patients, 33 (21%) tested positive, 85 (53%) negative and 41 (26%) were COVID-19 not suspected (control group). All patients in this study were generally aware of transmission risks and virulence and adhered to the non-pharmaceutical interventions. Working as a health care professional was correlated to a higher risk of SARS-Cov-2 infection (p- value 0.04). COVID-19 suspected patients had a significantly higher level of anxiety compared to COVID-19 not suspected patients (p-value < 0.001). The higher the anxiety, the more seriously hygiene measures were followed. The anxiety scores of the patients with (pulmonary) comorbidities were significantly higher than without comorbidities. CONCLUSION: This is one of the first (large) study that investigates and compares patient characteristics, knowledge, behaviour, illness perception, and mental state with respect to COVID-19 of patients visiting the emergency room, subdivided as being suspected of having COVID-19 (positive or negative tested) and a control group not suspected of having COVID-19. All patients in this study were generally aware of transmission risks and virulence and adhered to the non-pharmaceutical interventions. COVID-19 suspected patients and patients with (pulmonary) comorbidities were significantly more anxious. However, there is no mass hysteria regarding COVID-19. The higher the degree of fear, the more carefully hygiene measures were observed. Knowledge about the coping of the population during the COVID-19 pandemic is very important, certainly also in the perspective of a possible second outbreak of COVID-19.

[A dyspnoeic woman with an abnormal chest image]. / Een benauwde vrouw met een afwijkende thoraxfoto.

A 19-year-old woman presented with a productive cough, fever and chest pain. Clinical and chest X-ray findings prompted us to do a CT-scan, which revealed a mediastinal mass extending in the left thoracic cavity, suggestive of a teratoma with an obstructive pneumonia. The patient was successfully treated with intravenous antibiotics and surgical removal of the tumour.

Low percentage of clinically relevant pistachio nut and mango co-sensitisation in cashew nut sensitised children.

BACKGROUND: Cashew nut, pistachio nut and mango belong to the Anacardiaceae family and are botanically related. Therefore, cashew nut sensitised children are frequently advised to eliminate cashew nuts and pistachio nuts from their diet. The 'Improvement of Diagnostic mEthods for ALlergy assessment (IDEAL trial number NTR3572) study showed that cashew nut sensitised children were co-sensitised to pistachio nut in 98% of cases and to mango in 21% of cases. The aim of this follow-up study to IDEAL is to assess the clinical relevance of co-sensitisation to pistachio nut and mango in cashew nut sensitised children. METHODS: Children were recruited from the study: 'Improvement of Diagnostic mEthods for ALlergy assessment (IDEAL trial number NTR3572). Inclusion criterion for the IDEAL study was sensitization to cashew nut as demonstrated by either SPT or sIgE, and a clinical history of reactions to cashew nuts or no previous (known) exposure. Sensitized children who were tolerant to cashew nuts were excluded. Inclusion criterion for this IDEAL follow-up study was co-sensitization to pistachio nut, regardless the result of the DBPCFC with cashew nut. In this follow-up study a double-blind placebo-controlled food challenge with pistachio nut and an open food challenge with mango were performed. RESULTS: Twenty-nine children (mean age of 11.6 years, 62% male) were included. Pistachio nut sensitisation was clinically relevant in only 34% of cashew-sensitised children and only 31% of cashew challenge positive children. None of the children was challenge positive to mango. CONCLUSION: Although co-sensitisation between cashew nut and pistachio nut was observed in 98%, pistachio nut sensitisation was only clinically relevant in 34% of the children. Therefore, a challenge test with pistachio nut is recommended in children with cashew nut and pistachio nut sensitisation. Trial registration The study was registered in the Dutch trial register (registration number 3572) on 10 August 2012 (retrospectively registered).

sIgE Ana o 1, 2 and 3 accurately distinguish tolerant from allergic children sensitized to cashew nuts.

BACKGROUND: The double-blind, placebo-controlled food challenge test (DBPCFC) is the gold standard in cashew nut allergy. This test is costly, time consuming and not without side effects. Analysis of IgE reactivity to cashew nut components may reduce the need for food challenge tests. METHODS: In a prospective and multicentre study, children with suspected cashew nut allergy underwent a DBPCFC with cashew nut. Specific IgE to cashew nut and to the components Ana o 1, 2 and 3 were determined. A skin prick test (SPT) with cashew nut extract was performed. The association between the outcome of the food challenge test and specific IgE to Ana o 1, 2 and 3 was assessed with logistic regression analyses, unadjusted and adjusted for other diagnostic variables. Discriminative ability was quantified with a concordance index (c). RESULTS: A total of 173 children (103 boys, 60%) with a median age of 9 years were included. About 79% had a positive challenge test outcome. A steep rise in the risk of a positive challenge was observed for specific IgE to each individual component Ana o 1, 2 and 3 with estimated risks up to approximately 100%. Median values of Ana o 1, 2, 3 were 1.29 kU/l (range 0-100 kU/l), 4.77 kU/l (range 0-100 kU/l) and 8.33 kU/l (range 0-100 kU/l) respectively and varied significantly (p < 0.001). Specific IgE to Ana o 1, 2 and 3 was better distinguished between cashew-allergic and tolerant children (c = 0.87, 0.85 and 0.89, respectively) than specific IgE to cashew nut or SPT (c = 0.76 and 0.83, respectively). CONCLUSION: The major cashew nut allergens Ana o 1, 2 and 3 are each individually predictive for the outcome of food challenge tests in cashew-allergic children.

No difference in health-related quality of life, after a food challenge with cashew nut in children participating in a clinical trial.

BACKGROUND: Previous studies showed that health-related quality of life (HRQL) significantly improved after the food challenge, with greater improvements in HRQL after a negative outcome than after a positive outcome. It is currently unknown whether this also occurs in patients undergoing DBPCFCs with cashew nut in the context of a clinical trial. METHODS: Quality of life was studied in children enrolled in a cashew nut study using Food Allergy Quality of Life Questionnaires (FAQLQs). Children, teenagers and parents of the children completed the questionnaires before the challenge test and 6 months after the DBPCFC with cashew nut. The difference in the change in HRQL between the children with a positive and negative DBPCFC outcome was studied by Mann-Whitney U-test. RESULTS: In total, 112 children (67 boys, median age of 9 years) were included. The children, teenagers and parents of the children completed 143 sets of questionnaires in total. There were no significant differences in baseline total and domain scores compared to the follow-up scores in the FAQLQ-CF, FAQLQ-TF and FAQLQ-PF. In children, the delta FAIM score in the negative DBPCFC tested group was significantly better than the delta FAIM score in the positive challenged group (p = 0.026). There were no significant differences in the changes in the scores of the FAQLQ-CF and FAQLQ-PF in the children with a positive challenge outcome, compared to the children with a negative challenge result. However, there was a significant difference in the change in score between the latter groups in the domain 'accidental exposure' of the FAQLQ-TF (p = 0.049). CONCLUSION: This study showed no difference in the change in HRQL scores after a DBPCFC with cashew nut in children participating in a clinical trial. The utility of HRQL as an outcome for clinical trials in food allergy may be limited if participant baseline HRQL is relatively unimpaired.

Mono-sensitisation to peanut component Ara h 6: a case series of five children and literature review.

UNLABELLED: Here, we summarise the current clinical knowledge on Ara h 6 sensitisation and clinical relevance of this sensitisation pattern using five illustrative clinical cases. The literature search yielded a total of 166 papers, and an additional relevant article was found by 'snowballing'. A total of ten articles were considered relevant for this review. Most studies included patients with a sensitisation to Ara h 6 and cosensitisation to Ara h 2. Only three studies showed patients with a mono-sensitisation to Ara h 6. This illustrates that Ara h 6 mono-sensitisation has been neglected in literature. We present a case series of five children with sensitisation to peanut component Ara h 6. Only one of these five patients showed Ara h 8 cosensitivity. Three out of the five children had a positive double-blind placebo-controlled food challenge (DBPCFC), with moderate to strong reactions. CONCLUSION: A mono-sensitisation to peanut component Ara h 6 is uncommon but can cause severe allergic reactions. Therefore, the determination of sIgE to Ara h 6 is warranted in patients with a suspected peanut allergy, especially in the absence of sensitisation to Ara h 1, 2, 3 and 9. WHAT IS KNOWN: • Peanut allergy is common and can cause severe allergic reactions. • The diagnostics of peanut allergy has recently improved with the use of component resolved diagnosis What is new: • A mono-sensitisation to peanut component Ara h 6 is uncommon, but can cause severe allergic reactions • Determination of sIgE to Ara h 6 is warranted in patients with a suspected peanut allergy, especially in the absence of sensitisation to Ara h 1, 2, 3 and 9.

Review on immunotherapy in airway allergen sensitised patients.

Allergen immunotherapy is a more than 100-year-old treatment in particular for birch pollen, grass pollen, house dust mite and cat dander sensitised allergic patients. The mechanism of allergen-specific immunotherapy is complex. Different hypotheses have been postulated to explain the mode of action, such as a decrease of the number of tissue mast cells, eosinophils and basophils, an increase of IgG4 and IgA synthesis, a shift from Th2 to Th1 cells and an increase in the number and function of IL-10 producing T-regulatory cells (T-reg). All these immunological effects may contribute to immune tolerance and long-term changes in the immune system. The efficacy and safety of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with pollen and house dust mite have been investigated in many trials, meta-analyses and reviews. Nowadays grass pollen SLIT and SCIT, and birch pollen and house dust mite SCIT are implemented in clinical practice to treat therapy-resistant patients. However, the treatment is not effective for all patients and often not without side effects. Therefore, the development of new, safer and more effective immunotherapies is needed. These are approached along novel routes, including improved administration, combined treatment with immune response modifiers, fusion with immune response modifiers, allergen coupled to adjuvants and reconstruction of natural extracts with multiple recombinant allergens or with modified allergens. These developments are promising, but more research is required to implement them in clinical practice.

Failure of introduction of food allergens after negative oral food challenge tests in children.

UNLABELLED: One of the purposes to perform an oral food challenge (FC) test is to avoid unnecessary elimination of food allergens. In case of a negative FC test result, the food can be introduced. It is, however, unknown if patients act according to the outcome of the test. This study evaluates the rate of introduction of peanut, hazelnut, cow's milk or hen's egg allergens after a negative FC test. We investigated the introduction rate of children (0-18 years) with a negative FC test visiting the Department of Allergology, Erasmus Medical Centre Rotterdam from 2008 till 2013 and the factors that influence the rate of introduction. Patients were asked to complete a comprehensive questionnaire about their FC test. In total, 157 (38% girls, mean age during challenge 6.9 years) participated in the study. Of these FC tests, 104 (56%) were followed by a successful introduction, 30 (16%) by a partly introduction (traces or processed foods) and 52 (28%) by a failed introduction. Peanut and hazelnut showed a statistically significant lower successful introduction rate. Age, gender, symptoms during FC test, dietary advice and time period to introduction significantly influenced the rate of introduction. One fourth of the children with failure of introducing foods experienced symptoms during the introduction. CONCLUSION: More than one quarter of all children with a negative FC test result did not introduce the food. The FC test in its current form does not achieve its objective for this group of children.

Measurement and interpretation of skin prick test results.

BACKGROUND: There are several methods to read skin prick test results in type-I allergy testing. A commonly used method is to characterize the wheal size by its 'average diameter'. A more accurate method is to scan the area of the wheal to calculate the actual size. In both methods, skin prick test (SPT) results can be corrected for histamine-sensitivity of the skin by dividing the results of the allergic reaction by the histamine control. The objectives of this study are to compare different techniques of quantifying SPT results, to determine a cut-off value for a positive SPT for histamine equivalent prick -index (HEP) area, and to study the accuracy of predicting cashew nut reactions in double-blind placebo-controlled food challenge (DBPCFC) tests with the different SPT methods. METHODS: Data of 172 children with cashew nut sensitisation were used for the analysis. All patients underwent a DBPCFC with cashew nut. Per patient, the average diameter and scanned area of the wheal size were recorded. In addition, the same data for the histamine-induced wheal were collected for each patient. The accuracy in predicting the outcome of the DBPCFC using four different SPT readings (i.e. average diameter, area, HEP-index diameter, HEP-index area) were compared in a Receiver-Operating Characteristic (ROC) plot. RESULTS: Characterizing the wheal size by the average diameter method is inaccurate compared to scanning method. A wheal average diameter of 3 mm is generally considered as a positive SPT cut-off value and an equivalent HEP-index area cut-off value of 0.4 was calculated. The four SPT methods yielded a comparable area under the curve (AUC) of 0.84, 0.85, 0.83 and 0.83, respectively. The four methods showed comparable accuracy in predicting cashew nut reactions in a DBPCFC. CONCLUSIONS: The 'scanned area method' is theoretically more accurate in determining the wheal area than the 'average diameter method' and is recommended in academic research. A HEP-index area of 0.4 is determined as cut-off value for a positive SPT. However, in clinical practice, the 'average diameter method' is also useful, because this method provides similar accuracy in predicting cashew nut allergic reactions in the DBPCFC. TRIAL REGISTRATION: Trial number NTR3572.

Systematic review on cashew nut allergy.

Recent studies on cashew nut allergy suggest that the prevalence of cashew nut allergy is increasing. Cashew nut consumption by allergic patients can cause severe reactions, including anaphylaxis. This review summarizes current knowledge on cashew nut allergy to facilitate timely clinical recognition and to promote awareness of this emerging food allergy amongst clinicians. The goal of this study is to present a systematic review focused on the clinical aspects of allergy to cashew nut including the characteristics of cashew nut, the prevalence, allergenic components, cross-reactivity, diagnosis and management of cashew nut allergy. The literature search yielded 255 articles of which 40 met our selection criteria and were considered to be relevant for this review. The 40 articles included one prospective study, six retrospective studies and seven case reports. The remaining 26 papers were not directly related to cashew nut allergy. The literature suggests that the prevalence of cashew nut allergy is increasing, although the level of evidence for this is low. A minimal amount of cashew nut allergen may cause a severe allergic reaction, suggesting high potency comparable with other tree nuts and peanuts. Cashew allergy is clearly an underestimated important healthcare problem, especially in children.

Acute adrenal insufficiency due to bilateral adrenal hemorrhage.

We report a rare case of bilateral hemorrhage of adrenal glands diagnosed in a 61-year-old female. The case presented with classic clinical findings and typical imaging features.

Optimization of chemically defined cell culture media--replacing fetal bovine serum in mammalian in vitro methods.

Quality assurance is becoming increasingly important. Good laboratory practice (GLP) and good manufacturing practice (GMP) are now established standards. The biomedical field aims at an increasing reliance on the use of in vitro methods. Cell and tissue culture methods are generally fast, cheap, reproducible and reduce the use of experimental animals. Good cell culture practice (GCCP) is an attempt to develop a common standard for in vitro methods. The implementation of the use of chemically defined media is part of the GCCP. This will decrease the dependence on animal serum, a supplement with an undefined and variable composition. Defined media supplements are commercially available for some cell types. However, information on the formulation by the companies is often limited and such supplements can therefore not be regarded as completely defined. The development of defined media is difficult and often takes place in isolation. A workshop was organised in 2009 in Copenhagen to discuss strategies to improve the development and use of serum-free defined media. In this report, the results from the meeting are discussed and the formulation of a basic serum-free medium is suggested. Furthermore, recommendations are provided to improve information exchange on newly developed serum-free media.

The humane collection of fetal bovine serum and possibilities for serum-free cell and tissue culture.

Fetal bovine serum (FBS) is a common supplement to in vitro culture media. A workshop was organized to discuss whether or not fetuses might suffer when blood is withdrawn, and to discuss serum replacement methods. When bovine fetuses are exposed after slaughter of the dam, they can suffer only if they inflate their lungs with air and increase their blood oxygen to levels compatible with awareness. Preventing fetuses from breathing air or killing them by an efficient method, according to clearly defined safeguards, ensures that fetal blood collection is humane. Since serum is a supplement of unknown composition, which could be contaminated with unwanted factors, there are scientific and safety reasons for omitting FBS from culture media. Several media have been developed in which minimal or no animal derived components are present. Also, different cell types have been adapted to serum-free media. As yet, no standard serum free media are present, and each cell type requires its own medium composition. Among other recommendations, the establishment of a public database with information on cell types and their serum-free medium composition is proposed.

Using shared and unique parental views to study the etiology of 7-year-old twins' internalizing and externalizing problems.

In a sample of 1,940 Dutch 7-year-old twin pairs we studied the etiology of individual differences in Internalizing and Externalizing behavioral problems. For the majority of twins in the sample, both maternal and paternal ratings of behavioral problems were obtained from the Child Behavior Checklist. This made it possible to take into account processes underlying agreement and disagreement between maternal and paternal ratings. For both problem behaviors, a Psychometric model fitted the data better than a Rater Bias model, implying that parents, in addition to the behaviors they similarly observed, also assessed unique aspects of their children's behaviors. Relatively large genetic influences were found for Externalizing problems, explaining over 50% of the variance in both boys and girls. For internalizing problems, the heritability was over 30% in both sexes. Shared environmental factors were nearly as important as genetic influences in explaining the variation in behavioral problems. For both Externalizing and Internalizing problems, around 30% of the variance was accounted for by the shared environmental factors.

Using parental ratings to study the etiology of 3-year-old twins' problem behaviors: different views or rater bias?

Child Behavior Checklist questionnaires (Achenbach, 1992), filled in separately by mothers and fathers, were collected for an effective sample of 3,501 Dutch 3-year-old twin pairs. To disentangle the child's phenotype from that of the rater, two contrasting models were fitted to the data. One model, called a Rater Bias model, is based on the assumption that both parents assess exactly the same behaviors in the child. A weaker alternative of this model, called a Psychometric model, assumes that apart from these common behavioral views, each parent also assesses a unique aspect of the child's behavior. A Psychometric model fitted the data of both Internalizing and Externalizing scales significantly better than a Rater Bias model. This implied that each parent provided unique information from his or her own perspective, apart from the common behavioral view. Using this best fitting model, the etiology of both the Internalizing and Externalizing scales was studied. Common factors (influencing behaviors similarly assessed by both parents) were more important than unique factors (influencing behaviors uniquely assessed by one parent). Common genetic factors explained about 50% of the variance of both scales, indicating a possible inborn vulnerability to childhood psychopathology. Common environmental factors not shared between twins (free of unreliability and error) explained around 14% of both scales, suggesting the importance of pure idiosyncratic experiences even for children as young as 3 years. Common environmental factors shared between twins (unconfounded by rater bias) were only found for the Externalizing scale, explaining 18% of the variance. Rater bias and unreliability, if present in the data, were included in the estimates of the unique factors. Unique genetic, shared, and nonshared environmental factors each explained around 8% of the variance for both scales. These small effects could be detected because of the large sample of twin pairs used.