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Sense of smell and quality of life in children with diabetes mellitus
International Journal of Pediatric Otorhinolaryngology 123 (2019) 43–46
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International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Sense of smell and quality of life in children with diabetes mellitus a,b,∗
b
b
b
T
b
Yasin Yilmaz , Seyma Polat , Melek Yildiz , Sumeyye Betul Turgut , Neval Topal , Banu Aydinb, Hasan Onalb, Hakan Tekelic, Richard L. Dotyd a
Ankara University, Ankara Medical Faculty, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Ankara, Turkey Health Science University, Kanuni Sultan Suleyman Research and Training Hospital, Department of Pediatrics, Istanbul, Turkey Health Science University, Prof. Dr. Ilhan Varank Sancaktepe Research and Training Hospital, Department of Neurology, Istanbul, Turkey d University of Pennsylvania, Perelman School of Medicine, Smell and Taste Center, Philadelphia, USA b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Type 1 diabetes mellitus Olfactory dysfunction Sense of smell Pediatric smell wheel PedsQL Quality of life
Introduction: Diabetes mellitus is one of the most common chronic systemic diseases seen in children. The increasing prevalence of Type 1 diabetes mellitus (T1DM) among children is alarming. Although olfaction has been found to be altered in some adult T1DM subjects, it is unknown whether this is the case in children and, if so, whether the dysfunction adversely influences their quality of life (QOL). Methods: Using the Pediatric Smell Wheel® (PSW), we measured the olfactory function of 30 T1DM patients and 30 healthy controls [mean ages = 13.1 & 13.0, respectively]. The Turkish version of the Pediatric Quality of Life Inventory (PedsQL) was also administered. Results: The PSW scores were lower in the T1DM patients than in the controls (9.17 vs 10.37; p < 0.0001), although, in both cases, the scores fell within the normal range for individuals of their age (i.e., at or above 80%). Interestingly, such scores were lower in left-handed than in right-handed patients (8.00 vs 9.46; p = 0.001). Lower QOL indices were also found for the T1DM than for the controls for the domains of Emotional Function (p = 0.02), Social Function (p = 0.014), School Function (p = 0.011), and Psychosocial Status (p = 0.002). No significant associations were evident between PSW scores and disease duration and QOL scales. Conclusions: Our study demonstrates, for the first time, that modest decrements in smell function are evident in children with TIDM.
1. Introduction Among the most common systemic diseases seen in children is immune-associated diabetes mellitus type I (T1DM). Aside from debilitation of the disease itself, up to 10% of children suffering from this disorder have such complications as retinopathy, nephropathy, and neuropathy. Unfortunately, in recent years the frequency of T1DM in the general population has been increasing at an alarming rate [1]. The risk of T1DM-related complications markedly increases after puberty [2] and health-related quality of life (QOL) becomes more problematical at that time [3]. The sense of smell, which has been found to be altered in some adult diabetic subjects, [4–6] is critical for safety, quality of life (QOL), and the appreciation of foods and beverages. However, it is not entirely clear whether diabetes, per se, or complications of diabetes, is the determining factor of the smell dysfunction, and some studies fail to find any olfactory dysfunction in this disease at all [7,8]. Type 1 DM is insulin dependent and based on an immune associated process, unlike
∗
type 2 DM. Since type 2 DM patients carry an increased co-morbidity compared to patients with type 1 DM, co-morbidity might be responsible for the olfactory dysfunction of patients with type 2 DM. Regarding this, Naka et al. [8] found no difference in smell or taste function between 29 controls and either 29 patients with uncomplicated diabetes (type 1 and 2) or 24 patients with diabetic microangiopathy and/or macroangiopathy. However, olfactory dysfunction was found in 23 whose diabetes was accompanied by comorbidities such as hypothyroidism, hypertension, rheumatoid arthritis, or liver, kidney, or neurological disease. Similarly, while Weinstock et al. [5] found a significant segment of 111 adult diabetic patients (type 1 and 2) had decreased odor identification test scores, the test scores were related to comorbid macrovascular disease, but not to the type of diabetes, duration of disease, or presence of neuropathy, retinopathy, nephropathy, hypertension, or impotence. In this study we determined whether children with T1DM exhibit olfactory dysfunction and, if so whether the loss is confined to those with significant complications. Potential associations with handedness
Corresponding author.Ankara University, Ankara Medical Faculty, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Ankara, Turkey. E-mail address: [email protected] (Y. Yilmaz).
https://doi.org/10.1016/j.ijporl.2019.04.033 Received 13 January 2019; Received in revised form 20 April 2019; Accepted 20 April 2019 Available online 25 April 2019 0165-5876/ © 2019 Elsevier B.V. All rights reserved.
International Journal of Pediatric Otorhinolaryngology 123 (2019) 43–46
Y. Yilmaz, et al.
and scores on a QOL questionnaire were also assessed. It is noteworthy that children and adolescents with T1DM only rarely have overt diabetic neuropathy, although subclinical diabetic neuropathy may occur in ∼25% of newly diagnosed cases and in ∼50% of those whose disease has been present for five or more years [9]. To our knowledge, this is the first study to examine olfactory function in children with T1DM.
Table 1 Sociodemographic and laboratory data of participants.
2. Materials and methods 2.1. Subjects The T1DM study group was comprised of 16 girls and 14 boys [mean (SD) age = 13.33 (3.13) years; range 6–18 years] from the Istanbul Kanuni Sultan Suleyman Research and Training Hospital Endocrinology Clinics. A healthy control group of 17 girls and 13 boys [mean (SD) age = 13.03 (3.11) years; range 6–18 years] who were admitted to general pediatric polyclinics for routine general examinations without any complaints was also tested. Testing occurred between July and September of 2018. The T1DM study group was screened from diabetic patients who visited the clinic during the study period. The inclusion criteria were appropriate age (6–18 years), the diagnosis of type 1 DM, and regular follow up for at least six months at the clinic. The exclusion criteria were acute infections (i.e. acute rhinitis, allergic rhinitis, upper or lower respiratory tract infection, urinary tract infection, acute gastroenteritis) or any other evidence of nasosinus disease or dentofacial surgery/intervention, as these can affect olfaction in children [28]. The mean (SD) disease duration was 4.33 (3.04) years (range 1–13.5 years) and the mean (SD) age at the time of diagnosis was 9.00 (3.95) years. The mean (SD) body mass index (BMI) of the patients was 18.91 (3.11) and 18.45 (4.43) for the healthy controls (p = 0.63) (Table 1). Only two patients had complications such as retinopathy and nephropathy; and four patients had comorbidities such as one had celiac disease and three had hypothyroidism. None reported difficulties with their sense of smell. Fifty of the 60 participants (83.3%) did not regularly exercise. Fiftythree were right-handed (88%). The mean (SD) hypoglycemia attack number was 2.53 (2.56). The mean (SD) score for dietary compliance was 6.18 (2.24) on a 10-point scale, with 0 being worst and 10 being best.
Characteristics [mean (SD)]
Diabetes group (n = 30)
Healthy group (n = 30)
p value
Gender (female) Age (years) Body Mass Index WBC (103/μl) HCT (%) ALT (U/L) AST (U/L) Urea (mg/dL) Crea (mg/dL) HbA1c (%) Disease duration (years) Age of diagnosis (years)
n = 16 (55%) 13.33 (3.13) 18.91 (3.11) 8.07 (2.15) 39.0 (2.6) 17.9 (12.1) 25.1 (38.3) 25.8 (6.5) 0.57 (0.14) 9.7 (1.9) 4.33 (3.04) 9.00 (3.95)
n = 17 (57%) 13.03 (3.11) 18.45 (4.43) 8.05 (1.8) 38.0 (3.6) 16.5 (17.0) 20.3 (9.2) 23.5 (6.6) 0.56 (0.13) – – –
p = 0.79 p = 0.71 p = 0.63 p = 0.95 p = 0.21 p = 0.70 p = 0.51 p = 0.17 p = 0.82
WBC, White Blood Cells; HCT, Hematocrit; ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; Crea, Creatinine; HbA1c, Hemoglobin A1c.
perceived or the answer is unknown, by filling in a small circle next to the alternatives (i.e., the test is forced-choice). When the test is completed and the disk completely rotated, the correct answers appear as dark dots in a series of holes in the jacket. The number of holes that have marks signify the total test score, i.e., the number of items that are correctly identified [12]. 2.3. Data analyses The olfactory, quality of life, and laboratory data were analysed using SPSS (IBM Corp.). Initially, descriptive analysis of quantitative variables was performed. The Kolmogorov-Smirnov test was used to assess the normality of sample distributions. Analyses of Covariance (ANCOVA) with group and sex as main factors and age as a covariate were performed on the olfactory test scores. The Chi-square test was performed for the evaluation of categorical variables. Pearson correlations were computed to evaluate the relationship between continuous variables. For all analyses, ps < 0.05 were considered significant. A power analysis using the Gpower computer program showed that a total sample of 44 people (patients and control) would be needed to detect large effects (d = 0.8) with 95% power using a two-tailed t-test between means with alpha at 0.05 [27].
2.2. Test procedures
3. Results
This study was approved by the Institutional Review Board (Health Science University, Istanbul Kanuni Sultan Suleyman Research and Training Hospital Clinical Research Ethics Committee (no. 2018/05). Upon acceptance into the study and following signed informed consent, each subject was administered the Pediatric Quality of Life Inventory version 4.0 (PedsQL) [10]. This 23-item questionnaire assesses four health-related quality of life domains: Physical, Emotional, Social, School Functioning. The psychosocial status is the sum of the emotional, social, and school domains. PedsQL was translated into Turkish. Validation studies of the Turkish version of this test had been performed in 2007 [11]. For each quality of life domain tested, item scores were coded 0 (always) to 100 (never) using the standard scoring algorithms and summed within each subgroup [10]. Smell function was measured using the Pediatric Smell Wheel® (PSW, Sensonics International, Haddon Hts., NJ, USA). In this test, a cardboard disk, on which microencapsulated ‘scratch and sniff’ odorant pads are positioned around its circumference, rotates within an outer jacket such that only one odorant at a time appears in a small window for sampling [12]. Eleven odorants are employed – banana, bubblegum, cherry, chocolate, cinnamon, onion, peppermint, popcorn, rose, soap, and smoke. Four multiple-choice alternatives consisting of both words and pictures are positioned under each odorant pad. The subject is required to provide an answer from these alternatives, even if no odor is
The T1DM group had, on average, lower olfactory test scores than the control group [means (SDs) = 9.17 (1.14) & 10.37 (0.96), i.e., 83% vs. 94% correct responses, respectively; p < 0.0001]. Anosmia was not evident, however, and the average decrement still falls, for individuals averaging ∼13 years of age, within the low range of test scores obtained on normal subjects using this test [12]. The PSW percent correct responses, extrapolated to the normative data of the 40-item University of Pennsylvania Smell Identification Test (UPSIT)1, fell at approximately the 33rd percentile for normal subjects of the same age and sex [26,29]. Gender and age were not significant (respective p's = 0.22 & 0.11). The mean (SD) olfactory scores of patients with complications [9.50 (0.70)] and patients with comorbidities [9.25 (1.70)] were similar to those of patients without complications [9.14 (1.17)] and patients without comorbidities [9.15 (1.08)]. Interestingly, left-handed patients (n = 6) had lower olfactory scores than right-handed patients (n = 24) (8.00 vs 9.46, p = 0.001). Lower QOL indices were found for the T1DM than for the controls 1 Such extrapolation is valid because (a) most of the PSW test items are derived from those of the UPSIT, (b) UPSIT items are well correlated, and (c) previous studies have shown that UPSIT subsets of similar size correlate strongly with one another as well as with the total UPSIT score [26,29].
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International Journal of Pediatric Otorhinolaryngology 123 (2019) 43–46
Y. Yilmaz, et al.
in children with T1DM, although subclinical diabetic neuropathy may occur in ∼25% of newly diagnosed cases and in ∼50% of those whose disease has been present for five or more years [9]. Despite such statistics, it would appear unlikely that the smell dysfunction of young T1DM patients is due to overt neuropathies. On the other hand, very few of our patients exhibited complications. An accurate assessment of this would require comparing larger samples of young patients with and without clearly defined neuropathies. An unexpected finding of our study was that left-handed T1DM children performed more poorly on the bilaterally administered olfactory test than right-handed T1DM children. To our knowledge, our study is the first to assess olfaction and handedness in this population. In general, handedness has not been shown to influence bilateral olfactory test scores in adults [15–18]. The prevalence of left handers is known to be elevated, to some degree, in both Type I and Type II diabetes [30,31]. Moreover, while olfaction has not been previously measured in young T1DM patients, it is well known that a number of other autoimmune diseases in which the prevalence of left-handedness is elevated are also accompanied by olfactory dysfunction. Among such diseases are asthma [32,33], Crohn's disease [34,35], myasthenia gravis [36,37], and ulcerative colitis [34,35]. Such observations suggest the possiblity that immunological processes may be responsible for the olfactory loss we observe in T1DM and its association with handedness. Our finding that left-handed T1DM children scored somewhat higher than right-handed T1DM children on the social function scale of the PedsQL inventory was also unexpected. In potential accord with this finding is the observation by Atay et al. [23] that, of all of the items of the PedsQL that distinguish between T1DM patients and non-T1DM controls, the social function scale was the weakest. This potentially provides a basement score that could exacerbate differences between sinstrals and dextrals with TIDM. Interestingly, there are data that suggest that, in general, adult left handers exhibit higher social function and leadership skills than adult right handers [38]. Whether or how this would interact with T1DM is not clear but intriguing. Overall, children with T1DM typically have a lower quality of life than their non-diabetic peers [19,20], perhaps mirroring the lower quality of life reported in persons with smell dysfunction [21,22]. T1DM children generally score lower on most PedsQL items than their healthy counterparts [23]. Some elements of motor function of the dominant hand are decreased in T1DM children relative to controls (e.g., manual dexterity as measured by time required to complete a writing task), as are some such elements of the non-dominant hand (e.g., time required to turn over cards) [23]. Whether and to what degree such deficits in motor dexterity influence quality of life is not known. The possibility exists that altered smell function may adversely influence dietary habits, thereby disrupting metabolic control [8]. Body weight changes in patients with smell and taste disorders, including anosmia, can place patients at nutritional risk [24]. Decreased olfactory acuity in extremely obese patients is another key point in clarifying the nutrition and chemosensory disorders [25]. The decrement in olfactory function in diabetes can affect nutritional status and consequently might cause failure in metabolic control. However, in this study we found no meaningful correlations between the olfactory test scores and body mass index and weight. We also found no significant correlations between PSW scores and HbA1c level. This may implicate that metabolic control and weight control may not be associated with olfactory acuity in children with diabetes. The present study has both strengths and weaknesses. We tested well-documented T1DM children and compared their test results to those of non-diabetic controls of the same age. We employed a wellvalid olfactory test specifically designed to maintain the attention and interest of children. However, our sample size was relatively small, the disease durations were not long, and only a few subjects exhibited comorbidities. Such factors may explain why no associations with diseaserelated complications were observed. Moreover, our measure of
Table 2 Olfactory Test Scores and PedsQL scores for study and healthy group. Characteristics [mean (SD)]
Diabetes group
Healthy group
p value
Olfactory test scores PedsQL domains Physical function Emotional function Social function School function Psychosocial status Overall health status
9.17 (1.14)
10.37 (0.96)
p < 0.0001
85.20 75.83 92.16 77.05 81.29 82.56
90.19 86.16 97.66 86.50 90.10 90.13
p = 0.13 p = 0.02 p = 0.014 p = 0.011 p = 0.002 p = 0.004
(11.89) (16.76) (10.64) (14.31) (11.64) (10.26)
(13.65) (17.60) (4.86) (13.33) (9.18) (9.41)
Greater olfactory test scores indicate better olfaction. Higher QOL scores show better health status. p < 0.05 shows significance.
for the domains of Emotional Function [means (SD) = 75.83 (16.76) & 86.16 (17.60); p = 0.02], Social Function [means (SD) = 92.16 (10.64) & 97.66 (4.86); p = 0.014], School Function [means (SD) = 77.05 (14.31) & 86.50 (13.33); p = 0.011], and Psychosocial Status [means (SD) = 81.29 (11.64) & 90.10 (9.18); p = 0.002]. The total QOL questionnaire score was also lower in T1DM subjects than in control subjects [means (SD) = 82.56 (10.26) & 90.13 (9.41); p = 0.004] (Table 2). In addition, left-handed patients had higher scores for social function than did right-handed patients [(97.50 (2.73) vs. 90.83 (11.48), p = 0.016]. For the T1DM group, the correlation coefficients between the olfactory test scores and the disease duration, body mass index, hypoglycemia attack number, and dietary compliance scores were not significant [respective r's = 0.26 (p = 0.16), 0.02 (p = 0.83), 0.29 (p = 0.11) and −0.06 (p = 0.73)]. There were also no significant correlations between olfactory test scores and laboratory values such as white blood cell count, hematocrit level, ALT, AST, urea, creatinine, HbA1c and microalbuminuria (p's > 0.10). No significant correlations between olfactory test scores and Physical, Emotional, Social and School Function scales were evident within each study group.
4. Discussion The present study demonstrates that children with T1DM experience some deficit in their ability to smell. The decrement was present in both sexes and did not differ between those with or without diabetesrelated complications. However, the degree of deficit was not large, since the test scores still fell, on average, within the low normal range of children their age [12]. T1DM patients, relative to controls, had lower scores on the Emotional Function, Social Function, School Function, and Psychosocial Status and Overall Health items of the PedsQL inventory. Whether or to what degree this was related, even in a minor way, to the olfactory dysfuction is unknown. The possibility of some association is suggested by evidence that, in adults, the sense of smell significantly impacts safety, nutrition, and quality of life [13]. In regards to safety, one study found that about a third of their sample of patients who exhibited olfactory dysfunction had experienced at least one olfactory-related hazardous event during adulthood, such as cooking-related incidents, ingestion of spoiled food, the inability to detect a natural gas leak, and the inability to smell a fire [14]. This was in contrast to 19% of those with normal smell ability. Our finding of no differences between the smell function of children with and without diabetes-related complications contrasts with findings from a number of studies of adult diabetics. For example, several studies have found olfactory dysfunction primarily in those with neuropathies and macrovascular complications [4,5]. In one study, the olfactory dysfunction was related to disease duration [4]. Moreover, a recent study found no olfactory dysfunction in 39 adult diabetic patients without complications [6]. Whether our finding reflects a fundamental difference between young and old diabetics or other factors is not clear. As noted in the introduction, overt diabetic neuropathy is rare 45
International Journal of Pediatric Otorhinolaryngology 123 (2019) 43–46
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handedness was not based on sophisticated handedness inventory that measures of handedness or overall motor or sensory laterality. Nonetheless, our sample classification of handedness is clearly related to olfactory dysfunction in T1DM subjects. Longitudinal studies are needed to establish whether the frequency or magnitude of the olfactory dysfunction of children with TIDM evolves with the development of disease-related comorbities.
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Authorship contribution Drs. Yilmaz, Aydin and Onal analysed data and wrote the initial version of the article. Dr. Doty re-edited the article and provided guidance in terms of its focus. Drs. Polat, Yildiz, Turgut, Topal and Tekeli were responsible for collecting and analysing the data. Conflicts of interest Richard L. Doty is the President of Sensonics International, the manufacturer and distributor of the Pediatric Smell Wheel test system employed in this study. Acknowledgements We gratefully thank medical students Fatma Zehra Calikusu and Sevval Ozyildirim and polyclinic nurses Filiz Sahin and Selime Ozmen for their great help during study. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijporl.2019.04.033. References [1] D. Dabelea, J.M. Stafford, E.J. Mayer-Davis, et al., Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood, JAMA 317 (2017) 825–835. [2] S.J. Glastras, F. Mohsin, K.C. Donaghue, Complications of diabetes mellitus in childhood, Pediatr. Clin. North Am. 52 (2005) 1735–1753. [3] M. Murillo, J. Bel, J. Pérez, R. Corripio, G. Carreras, X. Herrero, J.M. Mengibar, D. Rodriguez-Arjona, U. Ravens-Sieberer, H. Raat, L. Rajmil, Health-related quality of life (HRQOL) and its associated factors in children with Type 1 Diabetes Mellitus (T1DM), BMC Pediatr. 17 (1) (2017) 16. [4] J.P. Le Floch, G. Le Liévre, M. Labroue, M. Paul, R. Peynegre, L. Perlemuter, Smell dysfunction and related factors in diabetic patients, Diabetes Care 16 (6) (1993) 934–937. [5] R.S. Weinstock, H.N. Wright, D.U. Smith, Olfactory dysfunction in diabetes mellitus, Physiol. Behav. 53 (1) (1993) 17–21. [6] A. Altundag, S.A. Ay, S. Hira, M. Salihoglu, K. Baskoy, F. Deniz, H. Tekeli, O. Kurt, A. Yonem, T. Hummel, Olfactory and gustatory functions in patients with noncomplicated type 1 diabetes mellitus, Eur. Arch. Oto-Rhino-Laryngol. 274 (6) (2017) 2621–2627. [7] D.S. Patterson, P. Turner, J.V. Smart, Smell threshold in diabetes mellitus, Nature 209 (5023) (1966) 625. [8] A. Naka, M. Riedl, A. Luger, T. Hummel, C.A. Mueller, Clinical significance of smell and taste disorders in patients with diabetes mellitus, Eur. Arch. Oto-RhinoLaryngol. 267 (4) (2010) 547–550. [9] J.K. Mah, D. Pacaud, Diabetic neuropathy in children, Handb. Clin. Neurol. 126 (2014) 123–143. [10] J.W. Varni, T.M. Burwinkle, M. Seid, D. Skarr, The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity, Ambul. Pediatr. 3 (6) (2003) 329–341.
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International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Sense of smell and quality of life in children with diabetes mellitus a,b,∗
b
b
b
T
b
Yasin Yilmaz , Seyma Polat , Melek Yildiz , Sumeyye Betul Turgut , Neval Topal , Banu Aydinb, Hasan Onalb, Hakan Tekelic, Richard L. Dotyd a
Ankara University, Ankara Medical Faculty, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Ankara, Turkey Health Science University, Kanuni Sultan Suleyman Research and Training Hospital, Department of Pediatrics, Istanbul, Turkey Health Science University, Prof. Dr. Ilhan Varank Sancaktepe Research and Training Hospital, Department of Neurology, Istanbul, Turkey d University of Pennsylvania, Perelman School of Medicine, Smell and Taste Center, Philadelphia, USA b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Type 1 diabetes mellitus Olfactory dysfunction Sense of smell Pediatric smell wheel PedsQL Quality of life
Introduction: Diabetes mellitus is one of the most common chronic systemic diseases seen in children. The increasing prevalence of Type 1 diabetes mellitus (T1DM) among children is alarming. Although olfaction has been found to be altered in some adult T1DM subjects, it is unknown whether this is the case in children and, if so, whether the dysfunction adversely influences their quality of life (QOL). Methods: Using the Pediatric Smell Wheel® (PSW), we measured the olfactory function of 30 T1DM patients and 30 healthy controls [mean ages = 13.1 & 13.0, respectively]. The Turkish version of the Pediatric Quality of Life Inventory (PedsQL) was also administered. Results: The PSW scores were lower in the T1DM patients than in the controls (9.17 vs 10.37; p < 0.0001), although, in both cases, the scores fell within the normal range for individuals of their age (i.e., at or above 80%). Interestingly, such scores were lower in left-handed than in right-handed patients (8.00 vs 9.46; p = 0.001). Lower QOL indices were also found for the T1DM than for the controls for the domains of Emotional Function (p = 0.02), Social Function (p = 0.014), School Function (p = 0.011), and Psychosocial Status (p = 0.002). No significant associations were evident between PSW scores and disease duration and QOL scales. Conclusions: Our study demonstrates, for the first time, that modest decrements in smell function are evident in children with TIDM.
1. Introduction Among the most common systemic diseases seen in children is immune-associated diabetes mellitus type I (T1DM). Aside from debilitation of the disease itself, up to 10% of children suffering from this disorder have such complications as retinopathy, nephropathy, and neuropathy. Unfortunately, in recent years the frequency of T1DM in the general population has been increasing at an alarming rate [1]. The risk of T1DM-related complications markedly increases after puberty [2] and health-related quality of life (QOL) becomes more problematical at that time [3]. The sense of smell, which has been found to be altered in some adult diabetic subjects, [4–6] is critical for safety, quality of life (QOL), and the appreciation of foods and beverages. However, it is not entirely clear whether diabetes, per se, or complications of diabetes, is the determining factor of the smell dysfunction, and some studies fail to find any olfactory dysfunction in this disease at all [7,8]. Type 1 DM is insulin dependent and based on an immune associated process, unlike
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type 2 DM. Since type 2 DM patients carry an increased co-morbidity compared to patients with type 1 DM, co-morbidity might be responsible for the olfactory dysfunction of patients with type 2 DM. Regarding this, Naka et al. [8] found no difference in smell or taste function between 29 controls and either 29 patients with uncomplicated diabetes (type 1 and 2) or 24 patients with diabetic microangiopathy and/or macroangiopathy. However, olfactory dysfunction was found in 23 whose diabetes was accompanied by comorbidities such as hypothyroidism, hypertension, rheumatoid arthritis, or liver, kidney, or neurological disease. Similarly, while Weinstock et al. [5] found a significant segment of 111 adult diabetic patients (type 1 and 2) had decreased odor identification test scores, the test scores were related to comorbid macrovascular disease, but not to the type of diabetes, duration of disease, or presence of neuropathy, retinopathy, nephropathy, hypertension, or impotence. In this study we determined whether children with T1DM exhibit olfactory dysfunction and, if so whether the loss is confined to those with significant complications. Potential associations with handedness
Corresponding author.Ankara University, Ankara Medical Faculty, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Ankara, Turkey. E-mail address: [email protected] (Y. Yilmaz).
https://doi.org/10.1016/j.ijporl.2019.04.033 Received 13 January 2019; Received in revised form 20 April 2019; Accepted 20 April 2019 Available online 25 April 2019 0165-5876/ © 2019 Elsevier B.V. All rights reserved.
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and scores on a QOL questionnaire were also assessed. It is noteworthy that children and adolescents with T1DM only rarely have overt diabetic neuropathy, although subclinical diabetic neuropathy may occur in ∼25% of newly diagnosed cases and in ∼50% of those whose disease has been present for five or more years [9]. To our knowledge, this is the first study to examine olfactory function in children with T1DM.
Table 1 Sociodemographic and laboratory data of participants.
2. Materials and methods 2.1. Subjects The T1DM study group was comprised of 16 girls and 14 boys [mean (SD) age = 13.33 (3.13) years; range 6–18 years] from the Istanbul Kanuni Sultan Suleyman Research and Training Hospital Endocrinology Clinics. A healthy control group of 17 girls and 13 boys [mean (SD) age = 13.03 (3.11) years; range 6–18 years] who were admitted to general pediatric polyclinics for routine general examinations without any complaints was also tested. Testing occurred between July and September of 2018. The T1DM study group was screened from diabetic patients who visited the clinic during the study period. The inclusion criteria were appropriate age (6–18 years), the diagnosis of type 1 DM, and regular follow up for at least six months at the clinic. The exclusion criteria were acute infections (i.e. acute rhinitis, allergic rhinitis, upper or lower respiratory tract infection, urinary tract infection, acute gastroenteritis) or any other evidence of nasosinus disease or dentofacial surgery/intervention, as these can affect olfaction in children [28]. The mean (SD) disease duration was 4.33 (3.04) years (range 1–13.5 years) and the mean (SD) age at the time of diagnosis was 9.00 (3.95) years. The mean (SD) body mass index (BMI) of the patients was 18.91 (3.11) and 18.45 (4.43) for the healthy controls (p = 0.63) (Table 1). Only two patients had complications such as retinopathy and nephropathy; and four patients had comorbidities such as one had celiac disease and three had hypothyroidism. None reported difficulties with their sense of smell. Fifty of the 60 participants (83.3%) did not regularly exercise. Fiftythree were right-handed (88%). The mean (SD) hypoglycemia attack number was 2.53 (2.56). The mean (SD) score for dietary compliance was 6.18 (2.24) on a 10-point scale, with 0 being worst and 10 being best.
Characteristics [mean (SD)]
Diabetes group (n = 30)
Healthy group (n = 30)
p value
Gender (female) Age (years) Body Mass Index WBC (103/μl) HCT (%) ALT (U/L) AST (U/L) Urea (mg/dL) Crea (mg/dL) HbA1c (%) Disease duration (years) Age of diagnosis (years)
n = 16 (55%) 13.33 (3.13) 18.91 (3.11) 8.07 (2.15) 39.0 (2.6) 17.9 (12.1) 25.1 (38.3) 25.8 (6.5) 0.57 (0.14) 9.7 (1.9) 4.33 (3.04) 9.00 (3.95)
n = 17 (57%) 13.03 (3.11) 18.45 (4.43) 8.05 (1.8) 38.0 (3.6) 16.5 (17.0) 20.3 (9.2) 23.5 (6.6) 0.56 (0.13) – – –
p = 0.79 p = 0.71 p = 0.63 p = 0.95 p = 0.21 p = 0.70 p = 0.51 p = 0.17 p = 0.82
WBC, White Blood Cells; HCT, Hematocrit; ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; Crea, Creatinine; HbA1c, Hemoglobin A1c.
perceived or the answer is unknown, by filling in a small circle next to the alternatives (i.e., the test is forced-choice). When the test is completed and the disk completely rotated, the correct answers appear as dark dots in a series of holes in the jacket. The number of holes that have marks signify the total test score, i.e., the number of items that are correctly identified [12]. 2.3. Data analyses The olfactory, quality of life, and laboratory data were analysed using SPSS (IBM Corp.). Initially, descriptive analysis of quantitative variables was performed. The Kolmogorov-Smirnov test was used to assess the normality of sample distributions. Analyses of Covariance (ANCOVA) with group and sex as main factors and age as a covariate were performed on the olfactory test scores. The Chi-square test was performed for the evaluation of categorical variables. Pearson correlations were computed to evaluate the relationship between continuous variables. For all analyses, ps < 0.05 were considered significant. A power analysis using the Gpower computer program showed that a total sample of 44 people (patients and control) would be needed to detect large effects (d = 0.8) with 95% power using a two-tailed t-test between means with alpha at 0.05 [27].
2.2. Test procedures
3. Results
This study was approved by the Institutional Review Board (Health Science University, Istanbul Kanuni Sultan Suleyman Research and Training Hospital Clinical Research Ethics Committee (no. 2018/05). Upon acceptance into the study and following signed informed consent, each subject was administered the Pediatric Quality of Life Inventory version 4.0 (PedsQL) [10]. This 23-item questionnaire assesses four health-related quality of life domains: Physical, Emotional, Social, School Functioning. The psychosocial status is the sum of the emotional, social, and school domains. PedsQL was translated into Turkish. Validation studies of the Turkish version of this test had been performed in 2007 [11]. For each quality of life domain tested, item scores were coded 0 (always) to 100 (never) using the standard scoring algorithms and summed within each subgroup [10]. Smell function was measured using the Pediatric Smell Wheel® (PSW, Sensonics International, Haddon Hts., NJ, USA). In this test, a cardboard disk, on which microencapsulated ‘scratch and sniff’ odorant pads are positioned around its circumference, rotates within an outer jacket such that only one odorant at a time appears in a small window for sampling [12]. Eleven odorants are employed – banana, bubblegum, cherry, chocolate, cinnamon, onion, peppermint, popcorn, rose, soap, and smoke. Four multiple-choice alternatives consisting of both words and pictures are positioned under each odorant pad. The subject is required to provide an answer from these alternatives, even if no odor is
The T1DM group had, on average, lower olfactory test scores than the control group [means (SDs) = 9.17 (1.14) & 10.37 (0.96), i.e., 83% vs. 94% correct responses, respectively; p < 0.0001]. Anosmia was not evident, however, and the average decrement still falls, for individuals averaging ∼13 years of age, within the low range of test scores obtained on normal subjects using this test [12]. The PSW percent correct responses, extrapolated to the normative data of the 40-item University of Pennsylvania Smell Identification Test (UPSIT)1, fell at approximately the 33rd percentile for normal subjects of the same age and sex [26,29]. Gender and age were not significant (respective p's = 0.22 & 0.11). The mean (SD) olfactory scores of patients with complications [9.50 (0.70)] and patients with comorbidities [9.25 (1.70)] were similar to those of patients without complications [9.14 (1.17)] and patients without comorbidities [9.15 (1.08)]. Interestingly, left-handed patients (n = 6) had lower olfactory scores than right-handed patients (n = 24) (8.00 vs 9.46, p = 0.001). Lower QOL indices were found for the T1DM than for the controls 1 Such extrapolation is valid because (a) most of the PSW test items are derived from those of the UPSIT, (b) UPSIT items are well correlated, and (c) previous studies have shown that UPSIT subsets of similar size correlate strongly with one another as well as with the total UPSIT score [26,29].
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in children with T1DM, although subclinical diabetic neuropathy may occur in ∼25% of newly diagnosed cases and in ∼50% of those whose disease has been present for five or more years [9]. Despite such statistics, it would appear unlikely that the smell dysfunction of young T1DM patients is due to overt neuropathies. On the other hand, very few of our patients exhibited complications. An accurate assessment of this would require comparing larger samples of young patients with and without clearly defined neuropathies. An unexpected finding of our study was that left-handed T1DM children performed more poorly on the bilaterally administered olfactory test than right-handed T1DM children. To our knowledge, our study is the first to assess olfaction and handedness in this population. In general, handedness has not been shown to influence bilateral olfactory test scores in adults [15–18]. The prevalence of left handers is known to be elevated, to some degree, in both Type I and Type II diabetes [30,31]. Moreover, while olfaction has not been previously measured in young T1DM patients, it is well known that a number of other autoimmune diseases in which the prevalence of left-handedness is elevated are also accompanied by olfactory dysfunction. Among such diseases are asthma [32,33], Crohn's disease [34,35], myasthenia gravis [36,37], and ulcerative colitis [34,35]. Such observations suggest the possiblity that immunological processes may be responsible for the olfactory loss we observe in T1DM and its association with handedness. Our finding that left-handed T1DM children scored somewhat higher than right-handed T1DM children on the social function scale of the PedsQL inventory was also unexpected. In potential accord with this finding is the observation by Atay et al. [23] that, of all of the items of the PedsQL that distinguish between T1DM patients and non-T1DM controls, the social function scale was the weakest. This potentially provides a basement score that could exacerbate differences between sinstrals and dextrals with TIDM. Interestingly, there are data that suggest that, in general, adult left handers exhibit higher social function and leadership skills than adult right handers [38]. Whether or how this would interact with T1DM is not clear but intriguing. Overall, children with T1DM typically have a lower quality of life than their non-diabetic peers [19,20], perhaps mirroring the lower quality of life reported in persons with smell dysfunction [21,22]. T1DM children generally score lower on most PedsQL items than their healthy counterparts [23]. Some elements of motor function of the dominant hand are decreased in T1DM children relative to controls (e.g., manual dexterity as measured by time required to complete a writing task), as are some such elements of the non-dominant hand (e.g., time required to turn over cards) [23]. Whether and to what degree such deficits in motor dexterity influence quality of life is not known. The possibility exists that altered smell function may adversely influence dietary habits, thereby disrupting metabolic control [8]. Body weight changes in patients with smell and taste disorders, including anosmia, can place patients at nutritional risk [24]. Decreased olfactory acuity in extremely obese patients is another key point in clarifying the nutrition and chemosensory disorders [25]. The decrement in olfactory function in diabetes can affect nutritional status and consequently might cause failure in metabolic control. However, in this study we found no meaningful correlations between the olfactory test scores and body mass index and weight. We also found no significant correlations between PSW scores and HbA1c level. This may implicate that metabolic control and weight control may not be associated with olfactory acuity in children with diabetes. The present study has both strengths and weaknesses. We tested well-documented T1DM children and compared their test results to those of non-diabetic controls of the same age. We employed a wellvalid olfactory test specifically designed to maintain the attention and interest of children. However, our sample size was relatively small, the disease durations were not long, and only a few subjects exhibited comorbidities. Such factors may explain why no associations with diseaserelated complications were observed. Moreover, our measure of
Table 2 Olfactory Test Scores and PedsQL scores for study and healthy group. Characteristics [mean (SD)]
Diabetes group
Healthy group
p value
Olfactory test scores PedsQL domains Physical function Emotional function Social function School function Psychosocial status Overall health status
9.17 (1.14)
10.37 (0.96)
p < 0.0001
85.20 75.83 92.16 77.05 81.29 82.56
90.19 86.16 97.66 86.50 90.10 90.13
p = 0.13 p = 0.02 p = 0.014 p = 0.011 p = 0.002 p = 0.004
(11.89) (16.76) (10.64) (14.31) (11.64) (10.26)
(13.65) (17.60) (4.86) (13.33) (9.18) (9.41)
Greater olfactory test scores indicate better olfaction. Higher QOL scores show better health status. p < 0.05 shows significance.
for the domains of Emotional Function [means (SD) = 75.83 (16.76) & 86.16 (17.60); p = 0.02], Social Function [means (SD) = 92.16 (10.64) & 97.66 (4.86); p = 0.014], School Function [means (SD) = 77.05 (14.31) & 86.50 (13.33); p = 0.011], and Psychosocial Status [means (SD) = 81.29 (11.64) & 90.10 (9.18); p = 0.002]. The total QOL questionnaire score was also lower in T1DM subjects than in control subjects [means (SD) = 82.56 (10.26) & 90.13 (9.41); p = 0.004] (Table 2). In addition, left-handed patients had higher scores for social function than did right-handed patients [(97.50 (2.73) vs. 90.83 (11.48), p = 0.016]. For the T1DM group, the correlation coefficients between the olfactory test scores and the disease duration, body mass index, hypoglycemia attack number, and dietary compliance scores were not significant [respective r's = 0.26 (p = 0.16), 0.02 (p = 0.83), 0.29 (p = 0.11) and −0.06 (p = 0.73)]. There were also no significant correlations between olfactory test scores and laboratory values such as white blood cell count, hematocrit level, ALT, AST, urea, creatinine, HbA1c and microalbuminuria (p's > 0.10). No significant correlations between olfactory test scores and Physical, Emotional, Social and School Function scales were evident within each study group.
4. Discussion The present study demonstrates that children with T1DM experience some deficit in their ability to smell. The decrement was present in both sexes and did not differ between those with or without diabetesrelated complications. However, the degree of deficit was not large, since the test scores still fell, on average, within the low normal range of children their age [12]. T1DM patients, relative to controls, had lower scores on the Emotional Function, Social Function, School Function, and Psychosocial Status and Overall Health items of the PedsQL inventory. Whether or to what degree this was related, even in a minor way, to the olfactory dysfuction is unknown. The possibility of some association is suggested by evidence that, in adults, the sense of smell significantly impacts safety, nutrition, and quality of life [13]. In regards to safety, one study found that about a third of their sample of patients who exhibited olfactory dysfunction had experienced at least one olfactory-related hazardous event during adulthood, such as cooking-related incidents, ingestion of spoiled food, the inability to detect a natural gas leak, and the inability to smell a fire [14]. This was in contrast to 19% of those with normal smell ability. Our finding of no differences between the smell function of children with and without diabetes-related complications contrasts with findings from a number of studies of adult diabetics. For example, several studies have found olfactory dysfunction primarily in those with neuropathies and macrovascular complications [4,5]. In one study, the olfactory dysfunction was related to disease duration [4]. Moreover, a recent study found no olfactory dysfunction in 39 adult diabetic patients without complications [6]. Whether our finding reflects a fundamental difference between young and old diabetics or other factors is not clear. As noted in the introduction, overt diabetic neuropathy is rare 45
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handedness was not based on sophisticated handedness inventory that measures of handedness or overall motor or sensory laterality. Nonetheless, our sample classification of handedness is clearly related to olfactory dysfunction in T1DM subjects. Longitudinal studies are needed to establish whether the frequency or magnitude of the olfactory dysfunction of children with TIDM evolves with the development of disease-related comorbities.
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Authorship contribution Drs. Yilmaz, Aydin and Onal analysed data and wrote the initial version of the article. Dr. Doty re-edited the article and provided guidance in terms of its focus. Drs. Polat, Yildiz, Turgut, Topal and Tekeli were responsible for collecting and analysing the data. Conflicts of interest Richard L. Doty is the President of Sensonics International, the manufacturer and distributor of the Pediatric Smell Wheel test system employed in this study. Acknowledgements We gratefully thank medical students Fatma Zehra Calikusu and Sevval Ozyildirim and polyclinic nurses Filiz Sahin and Selime Ozmen for their great help during study. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijporl.2019.04.033. References [1] D. Dabelea, J.M. Stafford, E.J. Mayer-Davis, et al., Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood, JAMA 317 (2017) 825–835. [2] S.J. Glastras, F. Mohsin, K.C. Donaghue, Complications of diabetes mellitus in childhood, Pediatr. Clin. North Am. 52 (2005) 1735–1753. [3] M. Murillo, J. Bel, J. Pérez, R. Corripio, G. Carreras, X. Herrero, J.M. Mengibar, D. Rodriguez-Arjona, U. Ravens-Sieberer, H. Raat, L. Rajmil, Health-related quality of life (HRQOL) and its associated factors in children with Type 1 Diabetes Mellitus (T1DM), BMC Pediatr. 17 (1) (2017) 16. [4] J.P. Le Floch, G. Le Liévre, M. Labroue, M. Paul, R. Peynegre, L. Perlemuter, Smell dysfunction and related factors in diabetic patients, Diabetes Care 16 (6) (1993) 934–937. [5] R.S. Weinstock, H.N. Wright, D.U. Smith, Olfactory dysfunction in diabetes mellitus, Physiol. Behav. 53 (1) (1993) 17–21. [6] A. Altundag, S.A. Ay, S. Hira, M. Salihoglu, K. Baskoy, F. Deniz, H. Tekeli, O. Kurt, A. Yonem, T. Hummel, Olfactory and gustatory functions in patients with noncomplicated type 1 diabetes mellitus, Eur. Arch. Oto-Rhino-Laryngol. 274 (6) (2017) 2621–2627. [7] D.S. Patterson, P. Turner, J.V. Smart, Smell threshold in diabetes mellitus, Nature 209 (5023) (1966) 625. [8] A. Naka, M. Riedl, A. Luger, T. Hummel, C.A. Mueller, Clinical significance of smell and taste disorders in patients with diabetes mellitus, Eur. Arch. Oto-RhinoLaryngol. 267 (4) (2010) 547–550. [9] J.K. Mah, D. Pacaud, Diabetic neuropathy in children, Handb. Clin. Neurol. 126 (2014) 123–143. [10] J.W. Varni, T.M. Burwinkle, M. Seid, D. Skarr, The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity, Ambul. Pediatr. 3 (6) (2003) 329–341.
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