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Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence
JCF-01541; No of Pages 5
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Short Communication
Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence☆,☆☆ Anna M. Georgiopoulos a,b,⁎, Deborah Friedman a,b , Elizabeth A. Porter a , Amy Krasner b,c , Sheetal P. Kakarala b,c , Breanna K. Glaeser a , Siena C. Napoleon a , Janet Wozniak a,d a
Department of Psychiatry (Child and Adolescent Psychiatry), Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA b Cystic Fibrosis Program, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA c Department of Social Service, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA d Chair, Quality and Safety, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA Received 23 May 2017; revised 11 August 2017; accepted 14 August 2017 Available online xxxx
Abstract Background: International guidelines recommend depression and anxiety screening in individuals with cystic fibrosis (CF), but Attention-Deficit Hyperactivity Disorder (ADHD) remains understudied. Methods: Adults with CF (n = 53) were screened using the Adult ADHD Self-Report Scale-v1.1 Symptom Checklist (ASRS-v1.1), Cystic Fibrosis Questionnaire-Revised (CFQ-R), and a self-report measure of treatment adherence. Results: Elevated ADHD symptoms on the ASRS-v1.1 screener were reported by 15% of participants. Self-reported adherence, Body Mass Index in kg/m2 (BMI), and Forced Expiratory Volume in 1 Second, Percent Predicted (FEV1%pred) did not differ between participants with vs. without elevated ADHD scores. Three CFQ-R scales, Physical Functioning, Role Functioning, and Respiratory Symptoms, were significantly lower in participants with elevated ADHD screens (unadjusted p b 0.05). This difference remained statistically significant for the Role Functioning and Respiratory Symptoms scales following correction for multiple comparisons. Conclusions: The highly specific screening tool ASRS-v1.1 can ascertain previously undetected ADHD symptoms in adults with CF. ADHD was substantially more prevalent than expected in this population. Elevated ASRS-v1.1 screens correlated with poorer Health-Related Quality of Life (HRQoL) in some domains, but not with BMI, FEV1%pred, or self-reported CF treatment adherence. Additional research will elucidate the impact of ADHD and its treatment on HRQoL, CF self-care and health outcomes. © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Attention-deficit hyperactivity disorder; Health-related quality of life; Adherence
Abbreviations: ADHD, Attention-Deficit Hyperactivity Disorder; ASRS-v1.1, Adult ADHD Self-Report Scale-v1.1 symptom checklist; BMI, Body Mass Index in kg/m2; CES-D, Center for Epidemiologic Studies Depression scale; CF, Cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CFTR, Cystic Fibrosis Transmembrane Conductance Regulator; FEV1%pred, Forced Expiratory Volume in 1 Second, Percent Predicted; HADS, Hospital and Anxiety Depression Scale; HRQoL, Health-Related Quality of Life; MGH, Massachusetts General Hospital; TIDES-CF, The International Depression Epidemiological Study. ☆ Funding: This work was supported by an American Academy of Child and Adolescent Psychiatry Pilot Research Award for Attention Disorders for Junior Faculty and Child and Adolescent Psychiatry Residents, Supported by the Elaine Schlosser Lewis Fund. ☆☆ Conflicts of interests: Dr. Georgiopoulos and Dr. Friedman received a Circle of Care Grant from Vertex Pharmaceuticals and research funding from Cystic Fibrosis Foundation CMHC175-15 (Fracchia PI) CMHC287-15 (Sicilian PI) MOSKOW13A0 (Moskowitz/Yonker PI) and Cystic Fibrosis Foundation Therapeutics FRIEDM17A0 (Friedman/Georgiopoulos PI) for unrelated work. Dr. Georgiopoulos also received honoraria and travel reimbursement from Cystic Fibrosis Foundation, travel reimbursement from European Cystic Fibrosis Society, and honoraria from St. Christopher's Foundation for Children and Johns Hopkins Hospital, outside the submitted work. Dr. Wozniak's spouse received the following: Speaker Honoraria, Otsuka; Royalties, UptoDate; Consultation Fees, Advance Medical, FlexPharma, Merck; Research Support, UCB Pharma, NeuroMetrix, Luitpold. None of the other authors have conflicts of interest to disclose. ⁎ Corresponding author at: Harvard Medical School, Department of Child and Adolescent Psychiatry, Massachusetts General Hospital, Yawkey 6900, 55 Fruit Street, Boston, MA 02114, USA. E-mail addresses: [email protected] (A.M. Georgiopoulos), [email protected] (D. Friedman), [email protected] (E.A. Porter), [email protected] (A. Krasner), [email protected] (S.P. Kakarala), [email protected] (B.K. Glaeser), [email protected] (S.C. Napoleon), [email protected] (J. Wozniak). http://dx.doi.org/10.1016/j.jcf.2017.08.011 1569-1993/© 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Georgiopoulos AM, et al, Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.08.011
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A.M. Georgiopoulos et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
1. Background
2.1. Measures
While international consensus statements recommend universal screening of adolescents and adults with CF for depression and anxiety [1], insufficient data exists regarding the prevalence and impact of Attention-Deficit Hyperactivity Disorder (ADHD) in CF. ADHD is a syndrome featuring hyperactivity, impulsivity, and/or inattention impairing self-regulation in multiple settings (e.g., home, school/work, social interaction) [2]. ADHD occurs in 7–9% of children and adolescents and 4–5% of adults, but is more common in some medically ill populations [2]. The prevalence of diagnosed ADHD in children and adolescents with CF is estimated at 8–10%, mirroring the general population [3–5]. For individuals with chronic illness, ADHD symptoms such as forgetfulness, task avoidance, disorganization, and difficulty attending to detailed instructions can be barriers to successfully managing treatment and navigating the health care system [2]. ADHD is associated with increased mortality [6] and adverse health markers [7], and increases risk for onset of depression, anxiety, substance abuse and disordered eating, which could magnify detrimental effects on self-care [2]. In previously reported pediatric cases, successful treatment of ADHD frequently corresponded with improved adherence to CF treatment [4]. However, no prior studies document the prevalence or correlates of ADHD in adults with CF. This study pilots systematic screening in a CF clinic for ADHD symptoms using the Adult ADHD Self-Report Scale-v1.1 Symptom Checklist (ASRS-v1.1), evaluating the prevalence of ADHD symptoms in adults with CF, and relationships with health status and self-report measures of HRQoL and treatment adherence.
Participants completed the ASRS-v1.1, a widely available 18-item measure including a 6-item screener that contains the items most predictive of ADHD. A positive ADHD screen was defined per ASRS-v1.1 instructions, in participants who checked 4 or more shaded boxes on screening items 1–6; this threshold results in sensitivity of 68.7% and specificity of 99.5% for ADHD [9]. Participants also completed the Cystic Fibrosis Questionnaire-Revised Teen/Adult v2.0 (CFQ-R), a CF-specific measure of HRQoL [10], and 2 scales selected for TIDES-CF [8], the Center for Epidemiologic Studies Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale (HADS). The adherence questionnaire was designed to assess difficulty with completing specific categories of CF treatment. For each item applicable to their treatment plan, participants completed a linear scale from 0% (missed every treatment) to 100% (completed every treatment) by decile, circling the spot closest to the percentage of time that they completed the treatment in the past month. The questionnaire was introduced with wording normalizing difficulty with adherence: “Many people with chronic illness have difficulty keeping up with treatments. In the past month, how much of the time did you actually take the following treatments?” Overall adherence was calculated by averaging the percentage of treatments completed for all reported applicable treatments. Data analysis was performed using IBM SPSS Statistics for Windows, version 22. Analysis of Variance (ANOVA) analyses were conducted to examine differences in BMI, FEV1%pred, CFQ-R, and self-reported frequency of adherence to CF care in participants with and without elevated screening scores for ADHD. An alpha level of 0.05 was used for statistical tests; to adjust for multiple comparisons, a Benjamini-Hochberg procedure was applied with a critical value for false discovery rate of 0.05.
2. Methods This study was developed to contribute data to The International Depression Epidemiological Study (TIDES-CF) [8], while expanding our single-center protocol to include aims regarding ADHD screening, reported herein. This analysis, approved by the Massachusetts General Hospital (MGH) Institutional Review Board, includes all participants ≥ 18 years old; solid organ transplant recipients were ineligible. Following written informed consent, participants completed questionnaires at a routine CF clinic outpatient well-visit. At this visit, participants completed a demographics and health history form requesting self-report of current, past or suspected clinical diagnoses of ADHD or other psychiatric conditions, CF-related and psychological treatments, as well as educational history and work status. Participants also completed established measures of depression, anxiety, ADHD and HRQoL, as well as self-reported estimates of adherence. Forced expiratory volume in one second percent predicted (FEV1%pred) and body mass index in kg/m2 (BMI) obtained on the date of questionnaire completion were extracted from medical records; in the event that FEV1%pred or BMI measurements were not made in the course of usual care at the time of the CF clinic visit during which the study questionnaires were completed, the FEV1%pred or BMI values chronologically nearest to the date of questionnaire completion were used.
3. Results 3.1. Participant characteristics, ADHD screening data, and psychiatric comorbidity Of the 152 patients ≥ 18 years old followed in the MGH CF Program during the study period, 53 (35%) participated in this study. FEV1%pred ranged from 24 to 104%. Fifteen percent scored in the elevated range on the 6-item ASRS-v1.1 screener, indicating a probable diagnosis of ADHD (Table 1). There were no statistically significant differences in age, gender, educational attainment or employment between participants with and without elevated ADHD scores. Three of the 8 (38%) participants with elevated ASRS-v1.1 screens had repeated a grade in school. All 3 reported that learning, social, or behavioral difficulties contributed to this decision; two reported that medical illness also contributed. Only 11% (5 of 45) of participants without elevated ADHD screening scores had repeated a grade. Six of the 8 participants with elevated ADHD screens reported lifetime evaluation by a psychologist/psychiatrist. None reported a current clinical diagnosis of ADHD, but 2 reported suspected ADHD, and 1 reported a past ADHD diagnosis. Only 1 participant who met criteria for probable ADHD on the ASRSv1.1 reported
Please cite this article as: Georgiopoulos AM, et al, Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.08.011
A.M. Georgiopoulos et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 1 Participant characteristics and ADHD screening data.
Table 2 Elevated ADHD symptoms and treatment adherence. Elevated ADHD screen ⁎⁎
Mean ± SD N = 53 Age FEV1% pred BMI ADHD score (18-item ASRSv1.1 total) Sex (% Male) In school Working full time Working part time Not working for health reasons Not working for other reasons Elevated ADHD screen ‡ ‡
3
34.6 ± 11.2 60.3 ± 22.4 24.0 ± 3.8 25.4 ± 10.2 N (%) 26 (49) 6 (11) 23 (43) 8 (15) 13 (24.5) 3 (5.7) 8 (15)
Elevated ADHD = Probable ADHD based on ASRS-v1.1 items 1–6.
currently taking ADHD medication. An additional 3 study participants who did not meet criteria for probable ADHD on the ASRSv1.1 reported having a current clinical diagnosis of ADHD, 1 of whom was currently treated with ADHD medication. Four of the 8 participants with elevated ADHD screens also had elevated depression screens (≥ 16 on the CES-D) and 3 additionally had elevated anxiety screens (≥ 11 on the HADS-A subscale). Participants with an elevated ADHD screen reported the following current, past or suspected clinical diagnoses: depression (3 current, 2 past—including 1 bipolar depression); anxiety (5 current, 2 suspected); obsessive-compulsive disorder (2 current, 1 suspected); post-traumatic stress disorder (1 past); substance dependence (1 current); oppositional defiant/conduct disorder (1 past). None reported diagnosed autism or eating disorders; however, 2 endorsed intense struggles regarding eating/food intake (1 current, 1 past). 3.2. Medical variables, treatment adherence, and HRQoL FEV1%pred and BMI did not differ significantly in participants with vs. without elevated ADHD screening scores. Self-reported CF treatment adherence did not differ significantly between participants with elevated vs. non-elevated ADHD screening scores (Table 2). The Physical Functioning, Role Functioning, and Respiratory Symptoms CFQ-R scales were significantly lower in participants meeting criteria for probable ADHD vs. those without ADHD using a threshold for unadjusted p-values b 0.05 (Table 3). This difference remained statistically significant following Benjamini-Hochberg correction for multiple comparisons for the Role Functioning and Respiratory Symptoms scales. 4. Conclusions The prevalence of probable ADHD (15%) found by screening adults with CF in our clinic is substantially higher than expected in the general population. In a population-based study in the United Kingdom, only 5.36% of adult respondents met the same ASRS-V1.1 screening threshold used in our study [11]. In the United States, 4.4% of participants ages 18–44 in the National Comorbidity Survey Replication met criteria for
Yes
No
Treatment adherence ⁎
Mean ± SD (N)
Mean ± SD (N)
p-value
Overall average (N = 52) Primary airway clearance (N = 44) Exercise for airway clearance (N = 45) Nasal irrigation (N = 25) Pancreatic enzymes (N = 43) Nebulizers (N = 45) Inhalers (N = 36) Diabetes medicine/insulin (N = 15) Other oral medications (N = 41)
81.1 ± 12.9 (7) 70.0 ± 28.9 (7)
77.5 ± 20.6 (45) 76.9 ± 25.6 (37)
0.7 0.5
75.0 ± 24.3 (6)
64.9 ± 27.7 (39)
0.4
64.0 ± 41.0 (5) 96.7 ± 5.2 (6)
59.0 ± 36.7 (20) 86.8 ± 24.5 (37)
0.8 0.3
88.6 ± 10.7 (7) 86.7 ± 15.1 (6) 56.7 ± 51.3 (3)
76.1 ± 29.1 (38) 77.0 ± 32.4 (30) 71.7 ± 43.7 (12)
0.3 0.5 0.6
96.0 ± 8.9 (5)
86.1 ± 27.1 (36)
0.4
⁎ Only subjects prescribed the various treatments indicated adherence percentages. Mean adherence for each treatment category refers to the mean percentage of time in the last month that those participants who were prescribed a specific type of treatment self-reported having completed that treatment. ⁎⁎ Elevated ADHD = Probable ADHD based on ASRS-v1.1 items 1–6.
ADHD [12]. Of note, 3 additional participants who did not meet screening criteria for probable ADHD on the ASRSv1.1 reported a current clinical diagnosis of ADHD. Although 1 of these was receiving pharmacotherapy, which likely minimized symptoms, given that the sensitivity of the ASRSv1.1 (68.7%) is poorer than its specificity (99.5%), these may well represent false negative screens. Counting these as ADHD “cases” would bring the probable prevalence of ADHD in adults with CF in our study higher, to 21% (11/53). The finding of lower scores on the CFQ-R Physical Functioning, Role Functioning, and Respiratory Symptoms scales in individuals with CF and elevated ADHD symptoms in this study is novel and concerning. The reduction in the CFQ-R Physical Function scale did not remain statistically significant Table 3 Elevated ADHD symptoms and health-related quality of life. Elevated ADHD screen ⁎ Yes
No
CFQ-R item
N=8
Physical functioning Role functioning Vitality Emotional functioning Social functioning Body image Eating problems Treatment burden Health perceptions Weight Respiratory symptoms Digestive symptoms
36.5 59.4 41.7 55.0 59.0 61.1 94.4 52.8 45.8 87.5 38.2 80.6
± ± ± ± ± ± ± ± ± ± ± ±
N = 45 17.2 20.6 19.9 28.0 14.2 23.8 8.4 19.5 26.2 24.8 15.3 12.9
61.8 81.1 55.2 69.9 67.0 73.1 88.6 62.5 63.0 74.1 61.0 82.2
± ± ± ± ± ± ± ± ± ± ± ±
p-value 32.6 18.2 21.0 23.5 18.9 28.9 21.4 21.6 24.4 38.2 21.8 16.8
0.04 0.004 ⁎⁎ 0.1 0.1 0.3 0.3 0.5 0.2 0.08 0.3 0.007 ⁎⁎ 0.8
⁎ Elevated ADHD = Probable ADHD based on ASRS-v1.1 items 1–6. ⁎⁎ Remains statistically significant using Benjamini-Hochberg procedure with false discovery rate of 0.05.
Please cite this article as: Georgiopoulos AM, et al, Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.08.011
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A.M. Georgiopoulos et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
following correction for multiple comparisons; these potential associations will be important to clarify in future studies using larger samples, particularly given that low scores on the Physical Functioning scale of the CFQ-R predict long-term decline and mortality in CF [13]. The lack of association between ADHD and difficulty with adherence is counterintuitive and inconsistent with our clinical experience [4]. Given that BMI and FEV1%pred did not differ between participants with vs. without elevated ADHD scores, it is possible that individuals in this study had developed compensatory skills and supports to reduce the impact of ADHD symptoms on their CF self-care [2]. However, sample size may limit our ability to detect between-group differences. Sample bias toward those patients with comorbid ADHD and CF who do attend clinic regularly and are more likely to attend to self-care must be considered given that this pilot captured only one-third of the eligible cohort. Mean adherence ratings were quite high; self-report measures tend to inflate estimates of adherence [14], and this phenomenon could be exacerbated in individuals with ADHD who may lack insight into their symptoms or over-use optimism to avoid anxiety-provoking thoughts [15]. Although the ASRSv1.1 screener is highly specific for ADHD [9], our finding of a high prevalence of ADHD symptoms in adults with CF warrants further examination. In this study, adults with elevated ADHD screening scores frequently also had elevated depression (50%) and anxiety (38%) screens. Depression and anxiety can worsen attentional symptoms, as could fatigue or sleep disturbance associated with CF itself. The questionnaire-based design did not permit further assessment to confirm whether attentional symptoms were attributable to ADHD or other factors. Nonetheless, it is plausible that ADHD is more common in adults with CF than in the general population, given several factors that could increase the phenotypic expression of ADHD. First, CF Transmembrane Conductance Regulator (CFTR) is expressed in neurons [16] and expressed differentially during the growth of fetuses with and without CF, with unknown effects on development [17]. While children with CF typically have normal global intelligence [18], studies have demonstrated neurocognitive impairment in specific domains, including memory and executive function, in individuals with CF throughout the life span [19–21]. In a disease marked by increasing loss of pulmonary function, effects of hypoxia on neurocognition would be expected to worsen with progression of disease. Additionally, adults with CF who grew up in an era before newborn screening may more likely have suffered failure to thrive and early malnutrition than children born in later cohorts. Finally, the complex daily treatment burden coupled with recurring absences from educational or occupational settings for medical treatment [18,22] may increase demands on organization, memory, task-efficiency, and executive function for individuals with ADHD who also have CF, which may outstrip compensatory capacities and increase functional impairment associated with ADHD [23]. Left untreated, ADHD interferes with self regulation in multiple domains, jeopardizing functioning in relationships, school, work, and medical self-care. For example, 38% of participants with elevated ADHD screens had repeated a grade in school. The impact of ADHD can be effectively addressed
with psychological interventions, pharmacotherapy, and adaptations of medical care delivery [2]. Although 75% of participants with elevated ASRSv1.1 screens had previous psychological/psychiatric evaluation, none was aware of a current confirmed diagnosis of ADHD, which likely indicates underdiagnosis and undertreatment. While screening tools such as the ASRS-v1.1 can be useful in the ascertainment of ADHD symptoms, the diagnosis of ADHD requires careful clinical assessment. In adults with CF, co-occurring psychiatric and physical symptoms, along with the individual impact of ADHD symptoms on medical self care and HRQoL, should be comprehensively assessed as part of a patient-centered decision-making process around ADHD treatment. This study is the first to document that symptoms of ADHD are common in adults with CF and can be readily detected by administering the short, specific, and easily accessible adult ADHD screening tool, the ASRS-v1.1, during a routine CF clinic appointment. Additional research is necessary to confirm the prevalence of ADHD in adults with CF following full diagnostic evaluation, and to further elucidate the impact of ADHD and its treatment on HRQoL, treatment adherence and health outcomes.
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Please cite this article as: Georgiopoulos AM, et al, Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.08.011
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Short Communication
Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence☆,☆☆ Anna M. Georgiopoulos a,b,⁎, Deborah Friedman a,b , Elizabeth A. Porter a , Amy Krasner b,c , Sheetal P. Kakarala b,c , Breanna K. Glaeser a , Siena C. Napoleon a , Janet Wozniak a,d a
Department of Psychiatry (Child and Adolescent Psychiatry), Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA b Cystic Fibrosis Program, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA c Department of Social Service, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA d Chair, Quality and Safety, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA Received 23 May 2017; revised 11 August 2017; accepted 14 August 2017 Available online xxxx
Abstract Background: International guidelines recommend depression and anxiety screening in individuals with cystic fibrosis (CF), but Attention-Deficit Hyperactivity Disorder (ADHD) remains understudied. Methods: Adults with CF (n = 53) were screened using the Adult ADHD Self-Report Scale-v1.1 Symptom Checklist (ASRS-v1.1), Cystic Fibrosis Questionnaire-Revised (CFQ-R), and a self-report measure of treatment adherence. Results: Elevated ADHD symptoms on the ASRS-v1.1 screener were reported by 15% of participants. Self-reported adherence, Body Mass Index in kg/m2 (BMI), and Forced Expiratory Volume in 1 Second, Percent Predicted (FEV1%pred) did not differ between participants with vs. without elevated ADHD scores. Three CFQ-R scales, Physical Functioning, Role Functioning, and Respiratory Symptoms, were significantly lower in participants with elevated ADHD screens (unadjusted p b 0.05). This difference remained statistically significant for the Role Functioning and Respiratory Symptoms scales following correction for multiple comparisons. Conclusions: The highly specific screening tool ASRS-v1.1 can ascertain previously undetected ADHD symptoms in adults with CF. ADHD was substantially more prevalent than expected in this population. Elevated ASRS-v1.1 screens correlated with poorer Health-Related Quality of Life (HRQoL) in some domains, but not with BMI, FEV1%pred, or self-reported CF treatment adherence. Additional research will elucidate the impact of ADHD and its treatment on HRQoL, CF self-care and health outcomes. © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Attention-deficit hyperactivity disorder; Health-related quality of life; Adherence
Abbreviations: ADHD, Attention-Deficit Hyperactivity Disorder; ASRS-v1.1, Adult ADHD Self-Report Scale-v1.1 symptom checklist; BMI, Body Mass Index in kg/m2; CES-D, Center for Epidemiologic Studies Depression scale; CF, Cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CFTR, Cystic Fibrosis Transmembrane Conductance Regulator; FEV1%pred, Forced Expiratory Volume in 1 Second, Percent Predicted; HADS, Hospital and Anxiety Depression Scale; HRQoL, Health-Related Quality of Life; MGH, Massachusetts General Hospital; TIDES-CF, The International Depression Epidemiological Study. ☆ Funding: This work was supported by an American Academy of Child and Adolescent Psychiatry Pilot Research Award for Attention Disorders for Junior Faculty and Child and Adolescent Psychiatry Residents, Supported by the Elaine Schlosser Lewis Fund. ☆☆ Conflicts of interests: Dr. Georgiopoulos and Dr. Friedman received a Circle of Care Grant from Vertex Pharmaceuticals and research funding from Cystic Fibrosis Foundation CMHC175-15 (Fracchia PI) CMHC287-15 (Sicilian PI) MOSKOW13A0 (Moskowitz/Yonker PI) and Cystic Fibrosis Foundation Therapeutics FRIEDM17A0 (Friedman/Georgiopoulos PI) for unrelated work. Dr. Georgiopoulos also received honoraria and travel reimbursement from Cystic Fibrosis Foundation, travel reimbursement from European Cystic Fibrosis Society, and honoraria from St. Christopher's Foundation for Children and Johns Hopkins Hospital, outside the submitted work. Dr. Wozniak's spouse received the following: Speaker Honoraria, Otsuka; Royalties, UptoDate; Consultation Fees, Advance Medical, FlexPharma, Merck; Research Support, UCB Pharma, NeuroMetrix, Luitpold. None of the other authors have conflicts of interest to disclose. ⁎ Corresponding author at: Harvard Medical School, Department of Child and Adolescent Psychiatry, Massachusetts General Hospital, Yawkey 6900, 55 Fruit Street, Boston, MA 02114, USA. E-mail addresses: [email protected] (A.M. Georgiopoulos), [email protected] (D. Friedman), [email protected] (E.A. Porter), [email protected] (A. Krasner), [email protected] (S.P. Kakarala), [email protected] (B.K. Glaeser), [email protected] (S.C. Napoleon), [email protected] (J. Wozniak). http://dx.doi.org/10.1016/j.jcf.2017.08.011 1569-1993/© 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Georgiopoulos AM, et al, Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.08.011
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1. Background
2.1. Measures
While international consensus statements recommend universal screening of adolescents and adults with CF for depression and anxiety [1], insufficient data exists regarding the prevalence and impact of Attention-Deficit Hyperactivity Disorder (ADHD) in CF. ADHD is a syndrome featuring hyperactivity, impulsivity, and/or inattention impairing self-regulation in multiple settings (e.g., home, school/work, social interaction) [2]. ADHD occurs in 7–9% of children and adolescents and 4–5% of adults, but is more common in some medically ill populations [2]. The prevalence of diagnosed ADHD in children and adolescents with CF is estimated at 8–10%, mirroring the general population [3–5]. For individuals with chronic illness, ADHD symptoms such as forgetfulness, task avoidance, disorganization, and difficulty attending to detailed instructions can be barriers to successfully managing treatment and navigating the health care system [2]. ADHD is associated with increased mortality [6] and adverse health markers [7], and increases risk for onset of depression, anxiety, substance abuse and disordered eating, which could magnify detrimental effects on self-care [2]. In previously reported pediatric cases, successful treatment of ADHD frequently corresponded with improved adherence to CF treatment [4]. However, no prior studies document the prevalence or correlates of ADHD in adults with CF. This study pilots systematic screening in a CF clinic for ADHD symptoms using the Adult ADHD Self-Report Scale-v1.1 Symptom Checklist (ASRS-v1.1), evaluating the prevalence of ADHD symptoms in adults with CF, and relationships with health status and self-report measures of HRQoL and treatment adherence.
Participants completed the ASRS-v1.1, a widely available 18-item measure including a 6-item screener that contains the items most predictive of ADHD. A positive ADHD screen was defined per ASRS-v1.1 instructions, in participants who checked 4 or more shaded boxes on screening items 1–6; this threshold results in sensitivity of 68.7% and specificity of 99.5% for ADHD [9]. Participants also completed the Cystic Fibrosis Questionnaire-Revised Teen/Adult v2.0 (CFQ-R), a CF-specific measure of HRQoL [10], and 2 scales selected for TIDES-CF [8], the Center for Epidemiologic Studies Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale (HADS). The adherence questionnaire was designed to assess difficulty with completing specific categories of CF treatment. For each item applicable to their treatment plan, participants completed a linear scale from 0% (missed every treatment) to 100% (completed every treatment) by decile, circling the spot closest to the percentage of time that they completed the treatment in the past month. The questionnaire was introduced with wording normalizing difficulty with adherence: “Many people with chronic illness have difficulty keeping up with treatments. In the past month, how much of the time did you actually take the following treatments?” Overall adherence was calculated by averaging the percentage of treatments completed for all reported applicable treatments. Data analysis was performed using IBM SPSS Statistics for Windows, version 22. Analysis of Variance (ANOVA) analyses were conducted to examine differences in BMI, FEV1%pred, CFQ-R, and self-reported frequency of adherence to CF care in participants with and without elevated screening scores for ADHD. An alpha level of 0.05 was used for statistical tests; to adjust for multiple comparisons, a Benjamini-Hochberg procedure was applied with a critical value for false discovery rate of 0.05.
2. Methods This study was developed to contribute data to The International Depression Epidemiological Study (TIDES-CF) [8], while expanding our single-center protocol to include aims regarding ADHD screening, reported herein. This analysis, approved by the Massachusetts General Hospital (MGH) Institutional Review Board, includes all participants ≥ 18 years old; solid organ transplant recipients were ineligible. Following written informed consent, participants completed questionnaires at a routine CF clinic outpatient well-visit. At this visit, participants completed a demographics and health history form requesting self-report of current, past or suspected clinical diagnoses of ADHD or other psychiatric conditions, CF-related and psychological treatments, as well as educational history and work status. Participants also completed established measures of depression, anxiety, ADHD and HRQoL, as well as self-reported estimates of adherence. Forced expiratory volume in one second percent predicted (FEV1%pred) and body mass index in kg/m2 (BMI) obtained on the date of questionnaire completion were extracted from medical records; in the event that FEV1%pred or BMI measurements were not made in the course of usual care at the time of the CF clinic visit during which the study questionnaires were completed, the FEV1%pred or BMI values chronologically nearest to the date of questionnaire completion were used.
3. Results 3.1. Participant characteristics, ADHD screening data, and psychiatric comorbidity Of the 152 patients ≥ 18 years old followed in the MGH CF Program during the study period, 53 (35%) participated in this study. FEV1%pred ranged from 24 to 104%. Fifteen percent scored in the elevated range on the 6-item ASRS-v1.1 screener, indicating a probable diagnosis of ADHD (Table 1). There were no statistically significant differences in age, gender, educational attainment or employment between participants with and without elevated ADHD scores. Three of the 8 (38%) participants with elevated ASRS-v1.1 screens had repeated a grade in school. All 3 reported that learning, social, or behavioral difficulties contributed to this decision; two reported that medical illness also contributed. Only 11% (5 of 45) of participants without elevated ADHD screening scores had repeated a grade. Six of the 8 participants with elevated ADHD screens reported lifetime evaluation by a psychologist/psychiatrist. None reported a current clinical diagnosis of ADHD, but 2 reported suspected ADHD, and 1 reported a past ADHD diagnosis. Only 1 participant who met criteria for probable ADHD on the ASRSv1.1 reported
Please cite this article as: Georgiopoulos AM, et al, Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.08.011
A.M. Georgiopoulos et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 1 Participant characteristics and ADHD screening data.
Table 2 Elevated ADHD symptoms and treatment adherence. Elevated ADHD screen ⁎⁎
Mean ± SD N = 53 Age FEV1% pred BMI ADHD score (18-item ASRSv1.1 total) Sex (% Male) In school Working full time Working part time Not working for health reasons Not working for other reasons Elevated ADHD screen ‡ ‡
3
34.6 ± 11.2 60.3 ± 22.4 24.0 ± 3.8 25.4 ± 10.2 N (%) 26 (49) 6 (11) 23 (43) 8 (15) 13 (24.5) 3 (5.7) 8 (15)
Elevated ADHD = Probable ADHD based on ASRS-v1.1 items 1–6.
currently taking ADHD medication. An additional 3 study participants who did not meet criteria for probable ADHD on the ASRSv1.1 reported having a current clinical diagnosis of ADHD, 1 of whom was currently treated with ADHD medication. Four of the 8 participants with elevated ADHD screens also had elevated depression screens (≥ 16 on the CES-D) and 3 additionally had elevated anxiety screens (≥ 11 on the HADS-A subscale). Participants with an elevated ADHD screen reported the following current, past or suspected clinical diagnoses: depression (3 current, 2 past—including 1 bipolar depression); anxiety (5 current, 2 suspected); obsessive-compulsive disorder (2 current, 1 suspected); post-traumatic stress disorder (1 past); substance dependence (1 current); oppositional defiant/conduct disorder (1 past). None reported diagnosed autism or eating disorders; however, 2 endorsed intense struggles regarding eating/food intake (1 current, 1 past). 3.2. Medical variables, treatment adherence, and HRQoL FEV1%pred and BMI did not differ significantly in participants with vs. without elevated ADHD screening scores. Self-reported CF treatment adherence did not differ significantly between participants with elevated vs. non-elevated ADHD screening scores (Table 2). The Physical Functioning, Role Functioning, and Respiratory Symptoms CFQ-R scales were significantly lower in participants meeting criteria for probable ADHD vs. those without ADHD using a threshold for unadjusted p-values b 0.05 (Table 3). This difference remained statistically significant following Benjamini-Hochberg correction for multiple comparisons for the Role Functioning and Respiratory Symptoms scales. 4. Conclusions The prevalence of probable ADHD (15%) found by screening adults with CF in our clinic is substantially higher than expected in the general population. In a population-based study in the United Kingdom, only 5.36% of adult respondents met the same ASRS-V1.1 screening threshold used in our study [11]. In the United States, 4.4% of participants ages 18–44 in the National Comorbidity Survey Replication met criteria for
Yes
No
Treatment adherence ⁎
Mean ± SD (N)
Mean ± SD (N)
p-value
Overall average (N = 52) Primary airway clearance (N = 44) Exercise for airway clearance (N = 45) Nasal irrigation (N = 25) Pancreatic enzymes (N = 43) Nebulizers (N = 45) Inhalers (N = 36) Diabetes medicine/insulin (N = 15) Other oral medications (N = 41)
81.1 ± 12.9 (7) 70.0 ± 28.9 (7)
77.5 ± 20.6 (45) 76.9 ± 25.6 (37)
0.7 0.5
75.0 ± 24.3 (6)
64.9 ± 27.7 (39)
0.4
64.0 ± 41.0 (5) 96.7 ± 5.2 (6)
59.0 ± 36.7 (20) 86.8 ± 24.5 (37)
0.8 0.3
88.6 ± 10.7 (7) 86.7 ± 15.1 (6) 56.7 ± 51.3 (3)
76.1 ± 29.1 (38) 77.0 ± 32.4 (30) 71.7 ± 43.7 (12)
0.3 0.5 0.6
96.0 ± 8.9 (5)
86.1 ± 27.1 (36)
0.4
⁎ Only subjects prescribed the various treatments indicated adherence percentages. Mean adherence for each treatment category refers to the mean percentage of time in the last month that those participants who were prescribed a specific type of treatment self-reported having completed that treatment. ⁎⁎ Elevated ADHD = Probable ADHD based on ASRS-v1.1 items 1–6.
ADHD [12]. Of note, 3 additional participants who did not meet screening criteria for probable ADHD on the ASRSv1.1 reported a current clinical diagnosis of ADHD. Although 1 of these was receiving pharmacotherapy, which likely minimized symptoms, given that the sensitivity of the ASRSv1.1 (68.7%) is poorer than its specificity (99.5%), these may well represent false negative screens. Counting these as ADHD “cases” would bring the probable prevalence of ADHD in adults with CF in our study higher, to 21% (11/53). The finding of lower scores on the CFQ-R Physical Functioning, Role Functioning, and Respiratory Symptoms scales in individuals with CF and elevated ADHD symptoms in this study is novel and concerning. The reduction in the CFQ-R Physical Function scale did not remain statistically significant Table 3 Elevated ADHD symptoms and health-related quality of life. Elevated ADHD screen ⁎ Yes
No
CFQ-R item
N=8
Physical functioning Role functioning Vitality Emotional functioning Social functioning Body image Eating problems Treatment burden Health perceptions Weight Respiratory symptoms Digestive symptoms
36.5 59.4 41.7 55.0 59.0 61.1 94.4 52.8 45.8 87.5 38.2 80.6
± ± ± ± ± ± ± ± ± ± ± ±
N = 45 17.2 20.6 19.9 28.0 14.2 23.8 8.4 19.5 26.2 24.8 15.3 12.9
61.8 81.1 55.2 69.9 67.0 73.1 88.6 62.5 63.0 74.1 61.0 82.2
± ± ± ± ± ± ± ± ± ± ± ±
p-value 32.6 18.2 21.0 23.5 18.9 28.9 21.4 21.6 24.4 38.2 21.8 16.8
0.04 0.004 ⁎⁎ 0.1 0.1 0.3 0.3 0.5 0.2 0.08 0.3 0.007 ⁎⁎ 0.8
⁎ Elevated ADHD = Probable ADHD based on ASRS-v1.1 items 1–6. ⁎⁎ Remains statistically significant using Benjamini-Hochberg procedure with false discovery rate of 0.05.
Please cite this article as: Georgiopoulos AM, et al, Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.08.011
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following correction for multiple comparisons; these potential associations will be important to clarify in future studies using larger samples, particularly given that low scores on the Physical Functioning scale of the CFQ-R predict long-term decline and mortality in CF [13]. The lack of association between ADHD and difficulty with adherence is counterintuitive and inconsistent with our clinical experience [4]. Given that BMI and FEV1%pred did not differ between participants with vs. without elevated ADHD scores, it is possible that individuals in this study had developed compensatory skills and supports to reduce the impact of ADHD symptoms on their CF self-care [2]. However, sample size may limit our ability to detect between-group differences. Sample bias toward those patients with comorbid ADHD and CF who do attend clinic regularly and are more likely to attend to self-care must be considered given that this pilot captured only one-third of the eligible cohort. Mean adherence ratings were quite high; self-report measures tend to inflate estimates of adherence [14], and this phenomenon could be exacerbated in individuals with ADHD who may lack insight into their symptoms or over-use optimism to avoid anxiety-provoking thoughts [15]. Although the ASRSv1.1 screener is highly specific for ADHD [9], our finding of a high prevalence of ADHD symptoms in adults with CF warrants further examination. In this study, adults with elevated ADHD screening scores frequently also had elevated depression (50%) and anxiety (38%) screens. Depression and anxiety can worsen attentional symptoms, as could fatigue or sleep disturbance associated with CF itself. The questionnaire-based design did not permit further assessment to confirm whether attentional symptoms were attributable to ADHD or other factors. Nonetheless, it is plausible that ADHD is more common in adults with CF than in the general population, given several factors that could increase the phenotypic expression of ADHD. First, CF Transmembrane Conductance Regulator (CFTR) is expressed in neurons [16] and expressed differentially during the growth of fetuses with and without CF, with unknown effects on development [17]. While children with CF typically have normal global intelligence [18], studies have demonstrated neurocognitive impairment in specific domains, including memory and executive function, in individuals with CF throughout the life span [19–21]. In a disease marked by increasing loss of pulmonary function, effects of hypoxia on neurocognition would be expected to worsen with progression of disease. Additionally, adults with CF who grew up in an era before newborn screening may more likely have suffered failure to thrive and early malnutrition than children born in later cohorts. Finally, the complex daily treatment burden coupled with recurring absences from educational or occupational settings for medical treatment [18,22] may increase demands on organization, memory, task-efficiency, and executive function for individuals with ADHD who also have CF, which may outstrip compensatory capacities and increase functional impairment associated with ADHD [23]. Left untreated, ADHD interferes with self regulation in multiple domains, jeopardizing functioning in relationships, school, work, and medical self-care. For example, 38% of participants with elevated ADHD screens had repeated a grade in school. The impact of ADHD can be effectively addressed
with psychological interventions, pharmacotherapy, and adaptations of medical care delivery [2]. Although 75% of participants with elevated ASRSv1.1 screens had previous psychological/psychiatric evaluation, none was aware of a current confirmed diagnosis of ADHD, which likely indicates underdiagnosis and undertreatment. While screening tools such as the ASRS-v1.1 can be useful in the ascertainment of ADHD symptoms, the diagnosis of ADHD requires careful clinical assessment. In adults with CF, co-occurring psychiatric and physical symptoms, along with the individual impact of ADHD symptoms on medical self care and HRQoL, should be comprehensively assessed as part of a patient-centered decision-making process around ADHD treatment. This study is the first to document that symptoms of ADHD are common in adults with CF and can be readily detected by administering the short, specific, and easily accessible adult ADHD screening tool, the ASRS-v1.1, during a routine CF clinic appointment. Additional research is necessary to confirm the prevalence of ADHD in adults with CF following full diagnostic evaluation, and to further elucidate the impact of ADHD and its treatment on HRQoL, treatment adherence and health outcomes.
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Please cite this article as: Georgiopoulos AM, et al, Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.08.011