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Journal of Asthma, Early Online, 1–7, 2010Copyright 2010 Informa Healthcare USA, Inc.
ISSN: 0277-0903 print / 1532-4303 onlineDOI: 10.3109/02770903.2010.528497 Behavioral Problems in Children and Adolescents with Difficult-To-Treat
MARIEKE VERKLEIJ, M.SC.,1,2,∗ ERIK-JONAS VAN DE GRIENDT, M.D.,3,4 AD A. KAPTEIN, PH.D.,5 LIESBETH VAN ESSEN-ZANDVLIET, M.D., PH.D.,2 ERIC DUIVERMAN, M.D., PH.D.,6 AND RINIE GEENEN, PH.D.7,8 1European Asthma and Allergy Center, Davos, Switzerland. 2 Asthma Center Heideheuvel, Hilversum, The Netherlands. 3Dutch Asthma Center, Davos, Switzerland. 4 Emma Children’s Hospital Academic Medical Center, Amsterdam, The Netherlands. 5 Unit of Psychology, Leiden University Medical Center, Leiden, The Netherlands. 6 Department of Paediatrics, Division of Paediatric Pulmonology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, The Netherlands. 7 Department of Clinical & Health Psychology, Utrecht University, Utrecht, the Netherlands. 8 Department of Rheumatology & Clinical Immunology, University Medical Center, Utrecht, The Netherlands. Background. The aim of this study was to quantify behavioral problems in clinically treated children and adolescents with asthma and toexamine the association of these problems and quality of life with difficult-to-treat asthma. Methods. Clinical patients with difficult-to-treatasthma (n = 31) and patients with asthma who were not classified as difficult-to-treat asthma (n = 52) completed the Pediatric Asthma Qualityof Life Questionnaire [PAQLQ(S)]. Their parents completed the Child Behavior Checklist (CBCL) to assess behavioral problems. Behavioralproblem scores were compared to norms of population reference groups and both behavioral problems and quality of life were comparedbetween children and adolescents with and without difficult-to-treat asthma. Results. Especially internalizing behavioral problems such asbeing withdrawn/depressed and somatic complaints were more severe in the asthmatic groups compared to the healthy reference groups. Thebehavioral problems ‘somatic complaints’ and ‘thought problems’ as well as a lower quality of life were more severe in children and adolescentswith difficult-to-treat asthma than in asthma patients who did not fulfill the criteria of difficult-to-treat asthma. Conclusions. Behavioral problemsand a lower quality of life are suggested to be more pronounced in clinically treated children and adolescents with difficult-to-treat asthma thanin asthma patients who are not classified as difficult-to-treat asthma. With respect to practical implications, our data suggest that health-careprofessionals should – especially in children and adolescents with difficult-to-treat asthma – assess and, if necessary, treat behavioral problems.
Keywords asthma, behavior, child, difficult-to-treat asthma, quality of life
and emotional problems such as anxiety and depres-sive symptoms (7, 8). There are multiple, complemen- Asthma, the most common chronic disease in children, is tary explanations for the association between asthma and a respiratory disease characterized by airway obstruction, behavioral problems. The burden of disease may lead to airway inflammation, and bronchial hyperresponsiveness J Asthma Downloaded from informahealthcare.com by 77.167.126.219 on 11/15/10 behavioral problems such as difficulties in separation and (1) with negative consequences for quality of life (2). In individuation from parents and associated anxiety (8), adults, some 5% of patients with asthma have difficult- and psychosocial factors may trigger the expression of to-treat asthma as defined by the European Respiratory asthma through neuroendocrine and immune mechanisms Society (3). In difficult-to-treat asthma, the clinical man- (9). Behavioral problems may underlie poor adherence, ifestations of disease are insufficiently reduced despite poor asthma management, and poor functional health sta- optimal treatment (4). Difficult-to-treat asthma has been tus (10). As such, behavioral problems play a key role in less well studied in children and adolescents than in difficult-to-treat asthma. Both the symptoms of asthma adults. It is unclear why these patients are difficult-to- and the associated emotional and behavioral problems treat, to what extent the quality of life of children and threaten the quality of life of children and adolescents adolescents with difficult-to-treat asthma is disturbed, and which specific behavioral problems most severely deviate In contrast to previous studies in children and adoles- cents with asthma, the focus of our study is on difficult- Selected children and adolescents with asthma may to-treat asthma. First, our aim was to quantify behavioral have a higher than normal risk of internalizing behavioral problems in a selected group of children and adolescentswith asthma from specialized clinics. Second, we exam-ined the association of these problems and quality of ∗Corresponding author: Marieke Verkleij, M.Sc., Asthma Center life with being or not being classified as difficult-to-treat Heideheuvel, Soestdijkerstraatweg 129, 1213 VX Hilversum, The asthma. We hypothesized that children with difficult-to- Netherlands; E-mail: mverkleij@heideheuvel.nl treat asthma have more behavioral problems and a lower quality of life than children with asthma who are not the day of arrival by one pediatrician per clinic during a classified as difficult-to-treat asthma.
structured interview with the patients and their parents,and using data from the referring clinician about compli-ance history and pulmonary function testing at the time of diagnosis. Good compliance implicated no missing doseson 6 or 7 days per week. In case of doubt or an anamnes- tic compliance less than 6 days a week, compliance was A cross-sectional study examined children and adoles- regarded as ‘poor’ and thus criteria on difficult-to-treat cents with asthma before the start of inpatient treat- asthma were not met. Intake of medication was supervised ment in the Dutch Asthma Center Davos (hosting Dutch patients) and the Hochgebirgsklinik Davos (high-altitudeclinic Davos, hosting German patients), Switzerland, two high-altitude asthma clinics with a hypoallergenic envi- Pulmonary function testing (PFT) was performed using ronment due to a lower concentration of pollen and almost the Masterscreen PFT (Jaeger Viasys, Hoechberg, complete absence of house dust mite (11).
Germany). A standardized protocol was used and atleast three technically correct maneuvers were performed.
Short- or long-acting β2-adrenergic agonists were stopped All children aged 7–17 years with a confirmed diagno- 12 hours before PFT. Lung function parameters that were sis of asthma were included. The diagnosis of asthma and obtained and evaluated were forced expiratory volume in criteria of difficult-to-treat asthma including (history of) 1 second (FEV1) and maximal expiratory flow at 50% of compliance were approved or rejected by one selected forced vital capacity (MEF50). Airway inflammation was pediatrician per clinic, on the day of arrival. From January measured using the fractional concentration of exhaled to December, 2008, the patients were invited to participate nitric oxide (FeNO) according to the ATS and ERS guide- lines (17, 18). The Niox Flex (Aerocrine, Solna, Sweden) The medical ethics committee of the Amsterdam was used according to the manufacturer’s instructions.
Medical Center (AMC), Amsterdam, the Netherlands,approved the study. The parents of all children and ado- lescents were provided written informed consent.
Parental Report: The Child Behavior Checklist. TheChild Behavior Checklist (CBCL) is a standardized ques- tionnaire for assessing emotional and behavioral problems Patients were diagnosed and treated for asthma in their of children and adolescents by parent or caregiver ratings respective countries. Two weeks before the start of clinical (19). Parents of the Dutch and German children and ado- treatment in one of the high-altitude clinics, all patients lescents filled out the Dutch 2001 version of the CBCL and parents received questionnaires at their homes. On (6–18 years) or the 1998 German version of the CBCL arrival of the patients at the clinic, medical history was taken including atopic symptoms, exercise intolerance, Results of the CBCL are expressed in a global score medication, reliever therapy, and adherence. Pulmonary and in scores for internalizing and externalizing behav- function testing was performed. History and physical ior problems. Internalizing behavior problems include J Asthma Downloaded from informahealthcare.com by 77.167.126.219 on 11/15/10 examination were performed on the day of arrival by one the syndrome domains anxious/depressed, withdrawn/ depressed, and somatic complaints. Externalizing prob-lems include rule-breaking behavior and aggressivebehavior. Three other syndrome domains are not part of the global scores: social problems, thought problems, and The diagnosis of asthma was approved or rejected on the attention problems. The raw scores of the CBCL were basis of history, examination, and confirmed bronchocon- striction with (partial) reversibility in history.
Difficult-to-treat asthma was defined using criteria of Children’s Self-Report: Quality of Life. The Pediatric the Dutch Pediatric Respiratory Society (12), which are Asthma Quality of Life Questionnaire [PAQLQ(S)] is based on the task forces of the American Thoracic Society a widely used disease-specific health-related quality-of- and European Respiratory Society, and ENFUMOSA life self-report measure for children and adolescents aged study (Table 1) (13–16). A positive score on difficult-to- 7–17 years (22). The Dutch PAQLQ(S) has adequate psy- treat asthma denotes persistent or severe asthma and lack chometric properties and excellent responsiveness, which of adequate control of asthma symptoms (such as exercise supports longitudinal and cross-sectional construct valid- intolerance, two or more times per week in need of extra ity (23). It has three domains: symptoms (10 items), activ- reliever therapy, symptoms at night) despite high dose of ity limitations (5 items), and emotional function (8 items).
maintenance therapy, adequate use of spacers and devices, The item range 1–7 is reported per domain and for the confirmed diagnosis, and good compliance. Difficult-to- whole instrument. Higher scores indicate better quality of treat asthma according to these criteria was established on BEHAVIORAL PROBLEMS IN DIFFICULT-TO-TREAT ASTHMA TABLE 1.—Criteria of difficult-to-treat asthma (12).
1. Age ≥6 years.
2. ≥6 months treatment on the following treatment regime (doses are adapted to the Dutch situation): daily use of ≥800 μg budesonide/beclometasone dipropionate or equivalent (≥500 μg fluticasone of ≥400 μg beclometasone dipropionate extra-fine or ≥320 μg ciclesonide), and long-acting β2-agonist,and a (history of) treatment on a leukotriene receptor antagonist.
3. With respect to the medication mentioned above, at least one of the following criteria should apply: decreased exercise tolerance and/or symptoms at night and/or, use of reliever therapy ≥2 times weekly, frequent exacerbations with need for oral prednisolone (≥2 per year),exacerbation(s) requiring ICU treatment in history,persistent airway obstruction (FEV < 4. At least 6 months treatment in pediatric practice.
5. History of good compliance.
6. Checked inhalation technique.
7. Asthma diagnosis, confirmed at that time by pulmonary function testing, defined as obstructive flow volume curve with (partial) reversibility of forced expiratory volume in 1 second (FEV1) on β2-agonists.
8. Medication as mentioned above may be prescribed temporarily and built down because of lack of effect.
FEV1 score in the difficult-to-treat asthma group was The score distributions were checked for outliers and significantly better. The scores of both groups were in the normality. Outliers (z > 3.29) were detected for the fol- lowing CBCL scales: total problem score (1 outlier); the broadband scales internalizing (1 outlier) and exter-nalizing problems (2 outliers); and the domain scales Table 3 shows the quality of life scores [PAQLQ(S)] of anxious/depressed (2), withdrawn/depressed (1), thought children and adolescents with and without difficult-to- problems (1), attention problems (1), rule-breaking behav- treat asthma. Patients with difficult-to-treat asthma experi- ior (2), and aggressive behavior (2). These outlying vari- enced a poorer overall quality of life than patients without ables were assigned a score that was one unit larger than difficult-to-treat asthma (large effect size, d > 0.8). They the next most extreme score of the score distribution (24).
reported more symptoms (large effect size, d = 0.8) and Statistical analyses were done with SPSS 16.0. The val- were more hampered in their activities (large effect size, ues of α < 0.05 (two-sided) were considered statistically d = 0.8) than patients without difficult-to-treat asthma.
significant. Differences between groups were examined The group difference in emotional problems was just not with independent samples t-tests and with a nonparamet- significant (small effect size, d = 0.4).
ric test for lung function (Mann–Whitney U test). Cohen’s effect size estimates (d) were calculated: 0.2 ≤ d < 0.5indicates a small effect, 0.5 ≤ d < 0.8 a medium effect Table 4 shows the parental ratings of behavioral problems and d ≥ 0.8 a large effect (25).
as measured by the CBCL in children with difficult-to-treat asthma and those who did not fulfill the criteria ofdifficult-to-treat asthma. The scores (d) reflect deviations in standard deviation units from healthy norm groups, and J Asthma Downloaded from informahealthcare.com by 77.167.126.219 on 11/15/10 The deviation from healthy norm groups on parents’ Thirty-three of 38 (87%) Dutch clinical patients were reported behavioral problems of patients with difficult- included; 2 patients did not provide informed consent, the to-treat asthma was significant on the total problem parents of 2 patients did not complete the CBCL, and in score (medium effect size) and internalizing problems 1 patient the diagnosis of asthma was withdrawn. Out of (large effect size), and on the domains anxious/depressed 63 German clinical patients, 50 were included (79%); 3 (medium effect size), withdrawn/depressed (large effect patients did not provide informed consent, 8 did not com- size), somatic complaints (large effect size), and thought plete the CBCL questionnaire, and in 2 the diagnosis of problems (large effect size). Within this group of patients with difficult-to-treat asthma, 7 (22%) patients scored in Table 2 shows the characteristics of 83 patients with a the clinical range with respect to the total problem score complete data set and a certified diagnosis of asthma. The (CBCL T-score ≥ 63; 90th percentile).
children and adolescents in the difficult-to-treat asthma The patients who did not meet the criteria of difficult- (n = 31) and not-difficult-to-treat asthma (n = 52) groups to-treat asthma showed deviations from healthy norm did not differ with respect to percentage girls and mean groups on the CBCL domains internalizing problems age. Most of the children and adolescents with difficult- (medium effect size), anxious/depressed (small effect to-treat asthma were Dutch. There was no relevant dif- size), withdrawn/depressed (medium effect size), and ference in lung function between the two groups. The somatic complaints (large effect size).
TABLE 2.—Characteristics of the 83 asthma patients who did and did not fulfill the criteria of difficult-to-treat asthma.
Note. FEV1 (forced expiratory volume in 1 second) and MEF50 (maximal expiratory flow at 50% of forced vital capacity) are expressed as percent of predicted. Values are geometric (FeNO; fractional concentration of exhalednitric oxide) or arithmetic means (FEV1 and MEF50).
a Chi2 test for gender and country; bIndependent samples t-test; c% pred, percentage predicted; dMann–Whitney Utest; eppb, parts per billion.
TABLE 3.—Quality of life of patients with difficult-to-treat asthma (n = 31) versus not-difficult-to-treat asthma(n = 52).
a A higher score on the quality of life scales reflects a better quality of life.
TABLE 4.—Behavioral problems of patients with difficult-to-treat asthma and not-difficult-to-treat asthma. The meanscores reflect deviations from healthy CBCL norms.
J Asthma Downloaded from informahealthcare.com by 77.167.126.219 on 11/15/10 a Mean scores, standard deviations (SD), and t-test (and p-values) examining whether the scores deviate from the norm (healthy CBCLgroups) as well as t- and p-values of the comparison between the two asthma groups.
The mean scores reflect the magnitude of deviations from the normative population in standard deviation units (d-scores). A positive scoreindicates that the children with asthma are judged to have more problems than the healthy norm group. The d-values have the followingcommon effect sizes: a value smaller than 0.2 reflects no deviation from the norm, whereas values between 0.2 and 0.5, between 0.5 and0.8, and greater than 0.8 reflects small, medium, and large deviations, respectively.
One sample t-tests examined whether norm deviation scores deviated from zero (the norm) and independent sample t-tests examinedwhether the scores of the two groups were different.
BEHAVIORAL PROBLEMS IN DIFFICULT-TO-TREAT ASTHMA Patients with difficult-to-treat asthma showed signifi- Difficult-to-treat asthma denotes lack of adequate con- cantly higher scores than patients who did not fulfill the trol of asthma symptoms. We did not find relevant dif- criteria of difficult-to-treat asthma on the domains somatic ferences in pulmonary function testing between children complaints (t = 3.1, p = .003) and thought problems with and without difficult-to-treat asthma. Pulmonary function testing even indicated a better FEV1 score in thedifficult-to-treat asthma group, which suggests that themore pronounced behavioral problems and lower qual-ity of life of the children with difficult-to-treat asthma as compared to the children without difficult-to-treat asthma The behavioral problems of the clinically treated are unlikely to be explained by current differences in children and adolescents with asthma in our study lung function. Poor disease control has been observed to were more severe compared to the healthy reference be associated with a poor quality of life (29). Although groups, especially internalizing problems such as being asthma severity appears as a risk factor for a poorer qual- withdrawn/depressed and somatic complaints. The main ity of life and a better control of asthma symptoms may analysis in our study showed that the behavioral prob- probably improve quality of life, the association between lems ‘somatic complaints’ and ‘thought problems’ as well asthma severity and quality of life is far from a one-to- as a lower quality of life were more pronounced in chil- one correlation (6, 30). To the extent that disease control dren and adolescents with difficult-to-treat asthma than is difficult, to improve quality of life, treatment should in asthma patients who did not fulfill the criteria of be aimed at improving the coping with symptoms and emotions, and at increasing activities.
Our finding of more severe internalizing problems in Our study design has strengths and limitations.
children and adolescents with asthma is in agreement with Children have the tendency to be more positive about their previous studies (6–8). In our study, one out of every five functioning. They notice fewer problems than parents or children (22%) with difficult-to-treat asthma scored in the teachers (31). Strength of our choice to use parental rat- clinical range of the total behavioral problem score of the ings to assess behavioral problems is that parents are more CBCL. This high frequency was mainly due to somatic objective observers, but a limitation is that parental wor- and thought problems. ‘Somatic complaints’ include ries about the behavioral functioning of their children may items such as ‘nightmares,’ ‘dizzy,’ ‘tired,’ ‘(head)aches,’ still color the ratings. We chose to compare the behavioral ‘nausea,’ and ‘stomach problems.’ ‘Thought problems’ problem ratings to established norms (i.e., normality).
comprise items such as ‘hears things,’ ‘sleep problems,’ However, because the norm group excluded children who and ‘strange behavior.’ Thus, the severity of behavioral received professional help for mental health problems or problems—especially in children with difficult-to-treat who attended special education (20), our analysis may asthma—mainly included somatic and thought problems have overestimated the actual behavioral dysfunctioning.
that are not exemplary asthma manifestations.
The children and adolescents of our study represent a pop- The higher severity of behavioral problems in chil- ulation that was referred to a specialized asthma clinic, dren and adolescents with asthma can theoretically be due which limits the generalizability of our results to a gen- to the disease, to medication related to the asthma, or eral asthma population. The observed differences between to psychosocial effects such as being treated differently difficult-to-treat asthma and not-difficult-to-treat asthma due to the disease by parents. Adverse effects of asthma in the two clinical centers may be due to possible dif- medications are rare (26). Adverse effects of inhaled cor- ferences between selection criteria and treatment in these J Asthma Downloaded from informahealthcare.com by 77.167.126.219 on 11/15/10 ticosteroids (ICS) are mild and sporadic (27) and ICS centers. From the moment of arrival, the administration of should not be avoided for that reason (28). More severe medication was supervised on a twice daily basis. Before internal behavioral problems may intensify the severity of arrival in the clinic, compliance was taken into account as asthma through poor adherence or neuroendocrine mecha- reported by the patients and their parents. We did not use nisms (9, 10). The higher prevalence of somatic problems electronic devices (like a Smartinhaler®) to detect irreg- in our sample of children with difficult-to-treat asthma ularities in compliance. However, using the data of the may also suggest that more severe asthma is a risk fac- referring clinician and adding a structured interview on tor for more internalizing problems instead of the other the day of arrival with the patients and their parents, we way around. Correlation is necessary to verify an asso- made the best consideration clinically possible. Still, this ciation, but it does not prove the causal direction of might implicate that compliance on the moment of arrival the association. Our data also confirmed the hypothe- was lower than assumed and therefore overestimates the sis that difficult-to-treat asthma coincides with a lower number of patients in the difficult-to-treat asthma group.
quality of life. Mostly large differences in physical and The inclusion of both Dutch and German patients mental aspects of quality of life were observed between will not have influenced the behavioral problem scores patients with difficult-to-treat asthma and patients with to a large extent. In a cross-cultural comparison of not-difficult-to-treat asthma. At a descriptive level, our parental CBCL ratings of healthy children and adoles- study clearly indicates that especially the children and cents in Germany (21), in the Netherlands, and in the adolescents with difficult-to-treat asthma have behavioral United States, relatively minor differences were observed between the three groups (32). The discriminant validity of the German version of the CBCL is comparable to 2. Hayden ML, Dolan CM, Johnson C, Morris SM, Bleecker ER. High the English 2001 version (33). Studies employing the level health care utilization in severe and difficult-to-treat asthma. J 2001 version of the CBCL demonstrated a somewhat Allergy Clin Immunol 2002; 109:292–293.
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Triamterene Kidney Stones FaDI I. Jabr, mD A64-year-old woman with a history of recur-rent kidney stones presented with severe left flank pain radiating to the left lower quadrant of 4 days’ duration. She brought that she had passed in urine. Her medications included hydrochlorothiazide, 25 mg/triamterene, 37.5 mg. An abdominal radiograph ( A ) and a CT scan of the kidneys, ureter

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Introduction The family Chlamydiaceae , obligate intracellular bacteria, is comprised of four species: C. trachomatis, C. pneumoniae, C. psittaci and C. pecorum , which cause many types of diseases. Species are divided according to host range, biochemical, biologic, and molecular properties1. C. trachomatis has 15 serovars which are divided into the trachoma serotypes A-C, the occul

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