The 2021 Dutch Working Party on Antibiotic Policy (SWAB) guidelines for empirical antibacterial therapy of sepsis in adults.

BACKGROUND: The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults. METHODS: Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements). RESULTS: Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment. CONCLUSIONS: Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands.

Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence.

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.

A reintroduction of environmental mite allergen control strategies for asthma treatment and the debate on their effectiveness.

Asthma affects three hundred million people worldwide. The effectiveness of house dust mite allergen control for asthma treatment is debatable. One aspect that has been little discussed in existing meta-analyses is the possible role of environmental strategies. Here, we reintroduce the previously defined strategies for mite allergen control and discuss their importance to the debate on clinical effectiveness. The strategy of concurrent bedroom interventions is related to the combined use of a priori defined interventions, while the strategy of exposure-based control relates to the treatment of relevant textiles after assessing exposure. The air purification strategy aims to purify the human breathing zone of airborne allergens. In Western European patient practice, the use of these strategies differs. A post hoc study of the dominant Cochrane review by Gøtzsche and Johansen (Cochrane Database of Systematic Reviews, 2008, Art. No: CD001187) appears to indicate that a majority of the underlying trials reported on the strategy of concurrent bedroom interventions, which were mainly executed in a minimal manner. Some trials have reported on the air purification strategy and may potentially alter the debate on effectiveness. No trial has reported on the strategy of exposure-based control. We therefore hypothesize that the absence of evidence for the effectiveness of mite allergen control for asthma treatment applies to the strategy of concurrent bedroom interventions. The evidence-based effectiveness of the exposure-based control strategy appears to be undetermined. The results of our post hoc reanalysis urge that future meta-analyses of mite allergen control should a priori define the environmental strategy under study. Future trials of mite allergen control are warranted to test the exposure-based strategy as well as the sparsely tested strategy of air purification.

EAACI Guidelines on Allergen Immunotherapy: House dust mite-driven allergic asthma.

Allergen immunotherapy (AIT) has been in use for the treatment of allergic disease for more than 100 years. Asthma treatment relies mainly on corticosteroids and other controllers recommended to achieve and maintain asthma control, prevent exacerbations, and improve quality of life. AIT is underused in asthma, both in children and in adults. Notably, patients with allergic asthma not adequately controlled on pharmacotherapy (including biologics) represent an unmet health need. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence-based recommendations for the use of house dust mites (HDM) AIT as add-on treatment for HDM-driven allergic asthma. This guideline was developed by a multi-disciplinary working group using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. HDM AIT was separately evaluated by route of administration and children and adults: subcutaneous (SCIT) and sublingual AIT (SLIT), drops, and tablets. Recommendations were formulated for each. The important prerequisites for successful treatment with HDM AIT are (a) selection of patients most likely to respond to AIT and (b) use of allergen extracts and desensitization protocols of proven efficacy. To date, only AIT with HDM SLIT-tablet has demonstrated a robust effect in adults for critical end points (exacerbations, asthma control, and safety). Thus, it is recommended as an add-on to regular asthma therapy for adults with controlled or partially controlled HDM-driven allergic asthma (conditional recommendation, moderate-quality evidence). HDM SCIT is recommended for adults and children, and SLIT drops are recommended for children with controlled HDM-driven allergic asthma as the add-on to regular asthma therapy to decrease symptoms and medication needs (conditional recommendation, low-quality evidence).

Parental and child factors associated with inhalant and food allergy in a population-based prospective cohort study: the Generation R Study.

The prevalence of allergic diseases in children is markedly increasing to epidemic proportions. The aim of this study is to describe the presence and examine associated parental and child characteristics of allergic sensitization and physician-diagnosed allergy in Dutch children at age 10 years. This study among 5471 children was performed in a population-based prospective cohort from fetal life onwards. Allergic sensitization was measured by skin prick tests. Physician-diagnosed allergy and parental and child characteristics were collected by questionnaires. In children aged 10 years, inhalant and food allergic sensitization was present in 32.2% and 7.1%, and physician-diagnosed inhalant and food allergy in 12.4% and 2.3%. Maternal and paternal history of allergy, eczema or asthma was associated with increased risks of physician-diagnosed inhalant allergy (aOR (95% CI) 1.44 (1.23-1.70) and 1.59 (1.30-1.94), respectively), but not with food allergy. Asthma and eczema ever at age 10 years were associated with increased risks of physician-diagnosed inhalant allergy (4.60 (3.55-5.96) and 2.42 (1.94-3.03), respectively). Eczema ever at age 10 years was associated with an increased risk of physician-diagnosed food allergy (5.78, 3.04-9.52), with the highest risk of cashew (7.36, 3.20-16.94) and peanut (5.58, 3.08-10.10) food allergy.Conclusions: We found strong effects of parental history of allergy, eczema or asthma on the presence of physician-diagnosed inhalant allergy in children at age 10 years. Eczema ever at age 10 years was a strong risk factor for the development of physician-diagnosed inhalant and food allergy. What is Known: • The prevalence of allergic diseases in children has markedly increased. • Early-life influences are critically important in the development of allergic diseases. What is New: • Maternal and paternal history of allergy, eczema or asthma is associated with increased risks of physician-diagnosed inhalant allergy but not with food allergy. • Eczema ever at age 10 years is associated with an increased risk of physician-diagnosed food allergy, with the highest risk for cashew and peanut food allergy.

House dust mite allergen avoidance strategies for the treatment of allergic asthma: A hypothesis-generating meta-analysis.

Background: This study continues the review by Gøtzsche and Johansen (Cochrane Database of Systematic Reviews, 2008, Art. No: CD001187), aiming to systematically generate hypotheses on the effectiveness of (sub)strategies for house dust mite allergen avoidance in the treatment of allergic asthma. Methods: We used the trials previously analysed by Gøtzsche and Johansen and searched recently published studies. Data on asthma symptom scores (ASS), ACQ, number of improved patients, AQLQ-scores, medication use, FEV1%, PC20, and FeNO levels were analysed. The effectiveness of strategies was assessed using Metafor in R. Results: Thirty-five trials involving 2419 patients were included in the final study. The patient-reported outcome number of patients with improved condition following total bedroom control was RR = 3.39 (95% confidence interval: 1.04 to 11.04, P = 0.04). The mean differences in the ASS by nocturnal air purification was -0.7 (95% confidence interval: -1.08 to -0.32, P < 0.001). Other outcomes including partial bedroom control were non-significant or clinically not of importance. Conclusions: Total bedroom control and nocturnal air purification of the breathing zone hypothetically provides clinical benefits in patients with house dust mite-induced allergic asthma. The number of patients with improvements in their condition respectively the asthma symptom score differences showed potential in small subgroups, consisting of single studies. Partial bedroom control is not recommended. Systematic Review Registration: Prospero CRD42022323660.

The relevance of patient-reported outcomes in a grass pollen immunotherapy trial in children and adolescents with rhinoconjunctivitis.

BACKGROUND: Patient-reported outcomes (PROs) are the only instruments available to assess the efficacy of an intervention in patients with allergic rhinoconjunctivitis. As allergic rhinoconjunctivitis is a systemic disease, it is now recommended to use not only PROs focusing at classical symptoms, but also health-related quality of life (HRQL) instruments in immunotherapy trials. METHODS: A previously published immunotherapy trial in children and adolescents (6-18 yr) with hay fever provided us with data to assess the relevance of two of these additional outcome measures, the disease-specific rhinoconjunctivitis quality of life questionnaire (RQLQ) and the generic COOP/WONCA-charts (CWC). A PRO was considered relevant if it was responsive to pollen exposure and at least had a moderate correlation with the classical symptoms of allergic rhinoconjunctivitis. Furthermore, we evaluated a post-season PRO, that is, a global assessment of symptoms (GAS). This assessment is used in clinical trials as a tool for selecting participants with sufficient symptoms and in daily practice to evaluate the patient's complaints during the preceding season. We assessed the correlation of this retrospective score with the actual symptoms during the previous pollen season. RESULTS: Data from 36 children and 63 adolescents were analysed. On the basis of the total scores of the paediatric and adolescent version of the RQLQ, both questionnaires were considered relevant as they were responsive to exposure and showed a moderate to strong correlation with the rhinoconjunctivitis symptoms. However, in both children and adolescents, 40% of the RQLQ items were not relevant according to our definition. The CWC as a whole and the separate charts appear less relevant because of the weak correlations with the daily symptom score from the diary. The correlation between our post-season GAS and the in season daily symptom score was weak. CONCLUSION: The paediatric and adolescent RQLQ are relevant, but could be shortened as they contain a substantial number of irrelevant items. The CWC are not relevant in the monitoring of children and adolescents with allergic rhinoconjunctivitis caused by grass pollen. The retrospective GAS does not sufficiently reflect the actual symptoms during the preceding season.

Sensitisation patterns and association with age, gender, and clinical symptoms in children with allergic rhinitis in primary care: a cross-sectional study.

BACKGROUND: Polysensitisation is a frequent phenomenon in patients with allergic rhinitis. However, few studies have investigated the characteristics of polysensitised children, especially in primary care. OBJECTIVES: This analysis describes the patterns of sensitisation to common allergens and the association with age, gender, and clinical symptoms in children in primary care diagnosed with allergic rhinitis. METHODS: Cross-sectional data from two randomised double-blind placebo-controlled studies were used to select children aged 6-18 years (n=784) with a doctor's diagnosis of allergic rhinitis or use of relevant medication for allergic rhinitis in primary care. They were assessed for age, gender, specific IgE (type and number of sensitisations), nasal and eye symptom scores. RESULTS: In 699 of the 784 children (89%) with a doctor's diagnosis or relevant medication use, a positive IgE test for one or more allergens was found. Polysensitisation (>2 sensitisations) was found in 69% of all children. Sensitisation was more common in children aged 9-13 than in younger children aged 5-8 years (p=0.03). Monosensitisation and polysensitisation were not significantly different in girls and boys. The severity of clinical symptoms did not differ between polysensitised and monosensitised children, but symptoms were significantly lower in non-sensitised children. CONCLUSIONS: Polysensitisation to multiple allergens occurs frequently in children with allergic rhinitis in general practice. Overall, clinical symptoms are equally severe in polysensitised and monosensitised children. Treatment decisions for allergic rhinitis should be made on the basis of a clinical history and allergy testing.

Exhaled nitric oxide measures allergy not symptoms in children with allergic rhinitis in primary care: a prospective cross-sectional and longitudinal cohort study.

BACKGROUND: Allergic rhinitis (AR) and asthma are both inflammatory diseases and are often associated. Relationships between fractional exhaled nitric oxide (FeNO) and asthma, atopy, and quality of life have been shown. AIMS: This study aimed to determine whether FeNO in children with AR (n=158) or combined AR and asthma (n=93) was associated with clinical symptoms, house dust mite (HDM)-specific IgE, and rhinitis-specific quality of life, both cross-sectionally and longitudinally. METHODS: Children with AR aged 6-18 years (n=251) in primary care were assessed for FeNO, nasal symptom scores, asthma symptom scores, quality of life, and HDM-specific IgE at baseline and 2 years later. RESULTS: We found similarly elevated FeNO in children with only AR and in those with combined AR and asthma. No correlations were found between FeNO and nasal or asthma symptoms and rhinitis-related quality of life. Longitudinal correlations were strongest for HDM-specific IgE (r=0.91, p<0.0001). CONCLUSIONS: FeNO was similar in a selected group of children with AR with and without asthma in primary care and was unrelated to symptoms or quality of life in both groups. FeNO is unlikely to be a useful biomarker of the clinical severity of upper or lower airway disease in primary care.

Quantile regression for the statistical analysis of immunological data with many non-detects.

BACKGROUND: Immunological parameters are hard to measure. A well-known problem is the occurrence of values below the detection limit, the non-detects. Non-detects are a nuisance, because classical statistical analyses, like ANOVA and regression, cannot be applied. The more advanced statistical techniques currently available for the analysis of datasets with non-detects can only be used if a small percentage of the data are non-detects. METHODS AND RESULTS: Quantile regression, a generalization of percentiles to regression models, models the median or higher percentiles and tolerates very high numbers of non-detects. We present a non-technical introduction and illustrate it with an implementation to real data from a clinical trial. We show that by using quantile regression, groups can be compared and that meaningful linear trends can be computed, even if more than half of the data consists of non-detects. CONCLUSION: Quantile regression is a valuable addition to the statistical methods that can be used for the analysis of immunological datasets with non-detects.

Sublingual immunotherapy not effective in house dust mite-allergic children in primary care.

BACKGROUND: Sublingual immunotherapy (SLIT) as a therapy for the treatment of allergic rhinitis in children might be acceptable as an alternative for subcutaneous immunotherapy. However, the efficacy of SLIT with house dust mite extract is not well established. OBJECTIVE: To investigate whether SLIT in house dust mite-allergic children recruited in primary care is effective and safe. METHODS: Children aged 6-18 years (n = 251) recruited in primary care with a house dust mite-induced allergic rhinitis received either SLIT or placebo for 2 years. Symptoms and medication use were assessed throughout the study. Primary outcome parameter was the mean total nose symptom score (scales 0-12) during the autumn of the second treatment year. Safety was assessed by recording any adverse event. RESULTS: Overall, the mean nose symptom score ± s.d. after 2 years of treatment showed no significant effect of SLIT (symptom score intervention group 2.26 ± 1.84 vs. placebo group, 2.02 ± 1.67; p = 0.08). There were no significant differences in secondary outcomes, nor in subgroup analyses. The number of patients reporting adverse events was comparable between both groups. CONCLUSIONS: Sublingual immunotherapy with house dust mite allergen was not better than placebo in reducing rhinitis symptoms in house dust mite-allergic children in primary care. SLIT as administered in this study can be considered safe.

[Idiopathic mast cell activation syndrome]. / Het idiopathisch mestcelactivatiesyndroom.

BACKGROUND: Idiopathic mast cell activation syndrome (MCAS) is one of the causes for recurrent complaints. The diagnosis is sometimes delayed but also often made incorrectly. CASE: Our patient presented with recurrent attacks of itching, redness of the skin, diarrhea and near collapse. During an attack his serum tryptase level rose significantly. We could not identify an underlying trigger. A diagnosis of idiopathic mast cell activation syndrome was made. He was successfully treated with a combination of H1 and H2 blockade. CONCLUSION: MCAS is characterized by recurrent complaints. To make the diagnosis a significant rise in mast cell mediators is required. Given the diversity of symptoms many patients with somatically unexplained symptoms wrongfully believe to be suffering from MCAS.

Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision.

BACKGROUND: Allergic rhinitis represents a global health problem affecting 10% to 20% of the population. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines have been widely used to treat the approximately 500 million affected patients globally. OBJECTIVE: To develop explicit, unambiguous, and transparent clinical recommendations systematically for treatment of allergic rhinitis on the basis of current best evidence. METHODS: The authors updated ARIA clinical recommendations in collaboration with Global Allergy and Asthma European Network following the approach suggested by the Grading of Recommendations Assessment, Development and Evaluation working group. RESULTS: This article presents recommendations about the prevention of allergic diseases, the use of oral and topical medications, allergen specific immunotherapy, and complementary treatments in patients with allergic rhinitis as well as patients with both allergic rhinitis and asthma. The guideline panel developed evidence profiles for each recommendation and considered health benefits and harms, burden, patient preferences, and resource use, when appropriate, to formulate recommendations for patients, clinicians, and other health care professionals. CONCLUSION: These are the most recent and currently the most systematically and transparently developed recommendations about the treatment of allergic rhinitis in adults and children. Patients, clinicians, and policy makers are encouraged to use these recommendations in their daily practice and to support their decisions.

EAACI position paper on occupational rhinitis.

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.

Allergic rhinitis in children: incidence and treatment in Dutch general practice in 1987 and 2001.

Allergic rhinitis is a common chronic disorder in children, mostly diagnosed in primary health care. This study investigated the national incidence and treatment of allergic rhinitis among children aged 0-17 yr in Dutch general practice in 1987 and 2001 to establish whether changes have occurred. A comparison was made with data from the first (1987) and second (2001) Dutch national surveys of general practice on children aged 0-17 yr. Incidence rates were compared by age, sex, level of urbanization and season. The management of the general practitioner was assessed regarding drug prescriptions and referrals to medical specialists, and compared with the clinical guideline issued in 1996. The incidence rate of allergic rhinitis increased from 6.6 (1987) to 9.2 (2001) per 1000 person-years. We found a male predominance with a switch in adolescence to a female predominance at both time points. The increase in incidence was the highest in rural (<30,000 inhabitants) and suburban areas (30,000-50,000 inhabitants). Compared to 1987, there was a significant increase in incidence in the central part of the Netherlands in 2001. In both years, the incidence was higher in spring compared with the other seasons. In 2001, children of natives and western immigrants visited the general practitioner more often with complaints of allergic rhinitis compared to 1987. In 1987, prescribed medication consisted mainly of nasal corticosteroids (36%) and in 2001 of oral antihistamines (45%). Although a clinical guideline was not issued until 1996, overall, the treatment of allergic rhinitis by general practitioners was in both years in accordance with the current clinical guideline, but with a stronger adherence in 2001. The results show an increased incidence in the past decades of allergic rhinitis in children in Dutch general practice. The shift to a smaller spectrum of prescriptions in 2001 may be a result of the 1996 clinical guideline.