Interrelationships between Atopic Disorders in Children: A Meta-Analysis Based on ISAAC Questionnaires.

PURPOSE: To study the prevalence and interrelationship between asthma, allergic rhinitis and eczema using data obtained from ISAAC questionnaires. METHOD: The Medline, Pubmed Publisher, EMBASE, Google Scholar and the Cochrane Controlled Clinical Trials Register databases were systematically reviewed to evaluate epidemiological data of children with atopic disorders. To study these interrelationships, a new approach was used. Risk ratios were calculated, describing the risk of having two different atopic disorders when the child is known with one disorder. RESULTS: Included were 31 studies, covering a large number of surveyed children (n=1,430,329) in 102 countries. The calculated worldwide prevalence for asthma, eczema and allergic rhinitis is 12.00% (95% CI: 11.99-12.00), 7.88% (95% CI: 7.88-7.89) and 12.66% (95% CI: 12.65-12.67), respectively. The observed prevalence [1.17% (95% CI: 1.17-1.17)] of having all three diseases is 9.8 times higher than could be expected by chance. For children with asthma the calculated risk ratio of having the other two disorders is 5.41 (95% CI: 4.76-6.16), for children with eczema 4.24 (95% CI: 3.75-4.79), and for children with allergic rhinitis 6.20 (95% CI: 5.30-7.27). No studied confounders had a significant influence on these risk ratios. CONCLUSIONS: Only a minority of children suffers from all three atopic disorders, however this co-occurrence is significantly higher than could be expected by chance and supports a close relationship of these disorders in children. The data of this meta-analysis supports the hypothesis that there could be a fourth distinct group of children with all three disorders. Researchers and clinicians might need to consider these children as a separate group with distinct characteristics regarding severity, causes, treatment or prognosis.

Evaluation of clinical and immunological responses: a 2-year follow-up study in children with allergic rhinitis due to house dust mite.

Background. Allergic rhinitis is a disease with polarization towards Th2 and a defect of regulatory T cells. Immunological changes have been reported after immunotherapy treatment. However, there is not much known about the natural course of allergic rhinitis with respect to clinical manifestation and the relation with immunological responses. Objective. To evaluate clinical symptoms of allergic rhinitis, in relation to in vivo allergen-specific skin responses and in vitro allergen-specific effector and regulatory T cells determined at baseline and after two years. Methods. From a large trial, 59 children were randomly selected. The following variables were compared: clinical symptoms, allergen skin tests, specific IgE, T-cell proliferation, IL-5, IL-13, IFN-gamma, IL-10, TGF-beta, CD4(+)CD25(hi) cells, and Foxp3 expression. Results. Allergic symptoms had decreased after two years. Whereas skin test reactions correlated between years 0 and 2, there was no change in the size of the reaction. Also, proinflammatory reactions did not change after two years, with a positive correlation between years 0 and 2. No relevant changes were observed with respect to regulatory cells. Conclusion. Whereas, comparable to immunotherapy, allergic complaints decrease, the immunological changes of specific T-cell activity (both effector cells and regulator cells) which are observed after immunotherapy, do not change.

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.

The effectiveness of physiotherapy in patients with asthma: a systematic review of the literature.

Since the introduction of medical therapy for asthma the interest in non-medical treatments deteriorated. Physiotherapy could have beneficial effects in asthmatics. This review investigates the effectiveness of physiotherapy in the treatment of patients with asthma. A review was performed on the terms breathing exercises (BE), inspiratory muscle training (IMT), physical training (PhT) and airway clearance (AC) in patients with asthma. The search resulted in 237 potentially relevant articles, after exclusion 23 articles remained. BE (n = 9) may improve disease specific quality of life (QoL), reduce symptoms, hyperventilation, anxiety and depression, lower respiratory rate and medication use. IMT (n = 3) can improve inspiratory pressure and may reduce medication use and symptoms. PhT (n = 12) can reduce symptoms, improve QoL and improve cardiopulmonary endurance and fitness. In conclusion, physiotherapy may improve QoL, cardiopulmonary fitness and inspiratory pressure and reduce symptoms and medication use. Further studies, investigating combinations of techniques, are needed to confirm these findings.

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.

An international multicenter study on quality of life and family quality of life in children with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) has severe impact on the quality of life (QoL) of children suffering from the disease and their families. The infant's dermatitis quality of life index (IDQoL) and the dermatitis family impact questionnaire (DFI) were designed to study this impact. AIMS: To compare the impact of AD on children and their families in different countries. METHODS: 419 children with AD from six countries representing three continents under the age of 4 years were included into the study. English, Ukrainian, Czech, Portuguese, and Korean versions of the IDQoL and the DFI and Dutch version of the IDQoL questionnaires were used. RESULTS: The highest scored items for the IDQoL and the DFI were rather similar. The IDQoL and the DFI results were well correlated with parental assessment of disease severity and between each other in all countries. Some differences mostly in the IDQoL assessment were found. CONCLUSION: Despite some reported peculiarities, parents in different counties assessed QoL and family QoL of their AD children in a similar way. The IDQoL and the DFI may be reliable initial measures for international studies. International study on the influence of the same treatment methods on the IDQoL and the DFI assessments is important.

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.

Sublingual immunotherapy in children with allergic rhinitis: quality of systematic reviews.

Systematic reviews have gained popularity as a way to combine the increasing amount of research information. This study assessed the quality of systematic reviews and meta-analyses of sublingual immunotherapy (SLIT) for allergic rhinitis in children, published since 2000. Eligible reviews were identified by searching Medline/Pubmed, Embase, and the Cochrane Library, from 2000 through 2008. Methodological quality was assessed using the assessment of multiple systematic reviews instrument. Ten systematic reviews were included, one of which was published in the Cochrane Library. Eight reviews gave some details about the search strategy. None of the reviews included measures to avoid selection bias. In 60% of the reviews, the methodological quality of the included studies was (partly) assessed. Four reviews pooled the results of individual studies, neglecting clinical heterogeneity. Three of the 10 reviews provided information about sources of funding or grants from industry. Of the 10 reviews, the six reviews with the highest overall score scored 5-8 points, indicating moderate quality. Systematic reviews are useful to evaluate the efficacy of SLIT in children. Although more reviews have become available, the methodological quality could be improved. SLIT for children could be promising, but methodological flaws in the reviews and individual studies are too serious to draw definite conclusions.

Quality of life measurement and its relationship to disease severity in children with atopic dermatitis in general practice.

Atopic dermatitis (AD) has a big impact on quality of life. The usefulness of health-related quality of life questionnaires for children with AD in general practice, and the relationship of quality of life to disease severity, as assessed by parents and by investigators, however, is not known. This study used the Infants' Dermatitis Quality of Life Index (IDQoL) to assess quality of life in children with AD selected from general practice. Severity of AD was determined by investigators and parents using the objective SCORAD (SCORing Atopic Dermatitis), the TIS (three-item severity scale), or by an additional question on the IDQoL. A total of 66 patients (41% boys, mean age 31 months) were included. Correlations between disease severity assessed by parents and by investigators were low (Rs 0.29-0.51). Correlations between IDQoL and severity assessed by investigators were also low (Rs 0.08-0.36). However, correlations between IDQoL and severity according to parents were high (Rs 0.67-0.73). In conclusion, disease severity and disease-related quality of life are different aspects of AD and must be taken into consideration when evaluating treatment or investigating new dermatological therapies in trials.

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.

Determining the severity of atopic dermatitis in children presenting in general practice: an easy and fast method.

Assessment of the severity of atopic dermatitis (AD) is necessary to evaluate the disease process. This study evaluates and validates the TIS in children with AD presenting in general practice. Independent investigators determined the severity of AD using the TIS and the objective SCORAD. The interobserver agreement for the TIS and SCORAD was calculated, as was the correlation between TIS and SCORAD. The mean time to assess the TIS was less than one minute. A moderate-to-good agreement between the observers was found for the TIS (kappa = 0.604 or 0.464), or SCORAD (kappa = 0.695 or 0.700). There was an excellent correlation between TIS and SCORAD (r(s) = 0.755-0.839). In conclusion, the TIS is an easy and fast method to score AD. Because of the moderate to good interobserver agreement and the high correlation with the SCORAD, we recommend the TIS to determine the severity of AD in general practice.

Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: study design and recruitment.

BACKGROUND: For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized double-blind placebo-controlled study was designed to establish the efficacy of sublingual immunotherapy with house dust mite allergen compared to placebo treatment in 6 to 18-year-old children with allergic rhinitis and a proven house dust mite allergy in primary care. Described here are the methodology, recruitment phases, and main characteristics of the recruited children. METHODS: Recruitment took place in September to December of 2005 and 2006. General practitioners (in south-west Netherlands) selected children who had ever been diagnosed with allergic rhinitis. Children and parents could respond to a postal invitation. Children who responded positively were screened by telephone using a nasal symptom score. After this screening, an inclusion visit took place during which a blood sample was taken for the RAST test. RESULTS: A total of 226 general practitioners invited almost 6000 children: of these, 51% was male and 40% <12 years of age. The target sample size was 256 children; 251 patients were finally included. The most frequent reasons given for not participating were: absence or mildness of symptoms, absence of house dust mite allergy, and being allergic to grass pollen or tree pollen only. Asthma symptoms were reported by 37% of the children. Of the enrolled children, 71% was sensitized to both house dust mite and grass pollen. Roughly similar proportions of children were diagnosed as being sensitized to one, two, three or four common inhalant allergens. CONCLUSION: Our study was designed in accordance with recent recommendations for research on establishing the efficacy of sublingual immunotherapy; 98% of the target sample size was achieved. This study is expected to provide useful information on sublingual immunotherapy with house dust mite allergen in primary care. The results on efficacy and safety are expected to be available by 2010. TRIAL REGISTRATION: the trial is registered as ISRCTN91141483 (Dutch Trial Register).

Allergic contact dermatitis to nickel: modified in vitro test protocols for better detection of allergen-specific response.

To date, no in vitro test is suitable for routine diagnosis of contact allergy. The aim of our study was to establish improved in vitro test protocol for the detection of antigen-specific responses of lymphocytes from patients with allergic contact dermatitis to nickel (Ni-ACD). Blood leucocytes from 14 Ni-ACD patients and 14 controls were cultured in the presence of 'cytokine cocktails' skewing lymphocytes towards 'type 1' [interferon-gamma (IFN-gamma)-secreting] or 'type 2' [interleukin (IL)-5 and IL-13-secreting] phenotypes. The cocktails consisted of IL-7 and, respectively, either IL-12 or IL-4. Cell responses to nickel were measured with enzyme-linked immunospot assay (ELISpot), enzyme-linked immunosorbent assay (ELISA), and lymphocyte proliferation test (LPT). Significant differences between patients with Ni-ACD and controls were found for the 'type 2' cytokines IL-13 and IL-5, with further increase of allergen-specific responses occurring when cultures were supplemented with IL-7 and IL-4. No significant differences were found for IFN-gamma. The best correlate to clinical diagnosis was LPT with 'type 2' skewing (r= 0.739, P < 0.001), followed by IL-13 ELISpot with 'type 2' skewing (r= 0.654, P < 0.001). The non-radioactive method that correlated best with LPT was IL-2 ELISpot (r= 0.809, P < 0.001). Overall, we conclude that combining ELISpot assay with proposed modifications of culture conditions improves detection of specific lymphocyte responses in contact allergy to nickel.

Intrinsic characteristics of contact and respiratory allergens influence production of polarizing cytokines by dendritic cells.

Type 1 and type 2 cytokines are primary mediators in contact allergy and aeroallergen-mediated disorders, respectively. For both types of disease, dendritic cells (DCs) are pivotal in initiating immune hyperresponsiveness. We studied whether contact and respiratory allergens possess intrinsic capacities to polarize DC towards DC1 and DC2 functions, independent of environmental factors. Human monocyte-derived DCs were exposed to the positive controls [type 1: lipopolysaccharide (LPS) + interferon-gamma; type 2: LPS + prostaglandin E(2)], contact allergens [2,4-dinitrochlorobenzene (DNCB), oxazolone (OXA), and nickel sulfate (NiSO(4))], and respiratory allergens [trimellitic anhydride (TMA) and the protein allergen derived from Dermatophagoides pteronyssinus (Der p1)]. The polarizing potentials of the allergens on DCs were determined by the secretion of type 1 [tumour necrosis factor-alpha (TNF-alpha), CXCL10, and interleukin (IL)-12p70] and type 2 (IL-10) cytokines. The contact allergens, DNCB and OXA, induced strict type 1 DC polarization, whereas the respiratory allergens, TMA and Der p1, showed strict type 2 DC polarization. The contact allergen, NiSO(4), induced both DC1 (TNF-alpha and CXCL10 production) and DC2 (decreased IL-12p70/IL-10 ratio) features. These results support the view that allergens have an intrinsic capacity to skew immune responses at the DC level, irrespective of local factors such as those determined by cutaneous or mucosal epithelial microenvironments.

Increased CCL27-CCR10 expression in allergic contact dermatitis: implications for local skin memory.

Allergic contact dermatitis (ACD) is a T-cell-mediated disease in which expression of a distinct repertoire of chemokines results in the recruitment of effector T cells into the skin. While it is becoming clear which chemokines and receptors determine the development of ACD, the mechanisms involved in the retention of T cells in the skin after resolution of inflammation are still unknown. Unravelling these mechanisms will help us to understand local skin memory as observed in retest reactivity and flare-up reactions. This study was designed to evaluate the role of chemokine-chemokine receptor interactions in local T-cell retention. The results show that expression of the CCR10 targeting ligand CCL27 is not only increased during inflammation, but also remains increased several weeks after clinical responsiveness to patch testing. In parallel with increased CCL27 expression, an increased number of infiltrating cells could still be detected in skin that, clinically, had returned to normal 21 days after patch testing. These persisting cells were characterized as CD4+ cells expressing CCR10, while no CD8+ CCR10+ cells could be detected. The presence of these cells is most likely an allergen-mediated effect, as increased levels of CCL27 and CCR10 could not be detected 21 days after initiating an irritant contact dermatitis reaction. In contrast to CCL27, increased expression of CXCL9, CXCL10, and CXCL11 could only be observed during the clinically inflammatory phase of ACD. In conclusion, local CCL27-mediated retention of CCR10+ CD4+ T cells in sites previously challenged by ACD could be responsible for phenomena such as local skin memory observed in retest reactions and flare-up reactions in which the presence of persisting T cells results in an accelerated inflammatory response upon renewed allergen challenge.