Health-related quality of life in children and adolescents with sickle cell disease

To assess the health-related quality of life of children and adolescents with sickle cell disease (SCD). This is a cross-sectional study carried out with 97 male and female patients aged 5 to 18 years with clinical and laboratory diagnosis of SCD, seen at the Hematology and Hemotherapy Hospital of Pernambuco. The Pediatric Quality of Life Inventory questionnaires, version 4.0 – child/adolescent report – were applied. Most patients were female (76.3%), had sickle cell anemia (89.7%) and mixed race (59.8%). There was a significant association in the psychosocial domain between age groups 5 to 7 (72.10) and 8 to Research, Society and Development, v. 9, n. 9, e998998120, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i9.8120 2 12 years (p≤0.05), the latter of which had the worst quality of life score (65.36). There were significant differences between sexes only in patients aged 13 to 18 years for physical functioning and for the overall mean of the domains. The means in both cases were higher in female patients than in male ones (70.89 x 56.88 for physical functioning and 71.72 x 59.77 for the overall mean of the domains). Poor quality of life was observed among children and adolescents with SCD, with negative impacts according to age and sex.


Introduction
Sickle cell disease (SCD) is one of the most common inherited hemoglobinopathies worldwide. It is caused by a single nucleotide substitution, converting a glutamic acid codon to a valine codon at position 6 of the β-globin subunit. This amino acid substitution causes some changes in the physical properties of the globin chain, leading to hemoglobin S (Hb S) polymerization during physiological stress (especially hypoxia), causing erythrocytes to take on a sickle shape. This intracellular event also induces the expression of several cell adhesion molecules that facilitate the physical interaction of sickle-shaped erythrocytes with leukocytes and endothelium, leading to vaso-occlusive events and hemolytic anemia, which play a central role in the clinical complications associated with SCD (Raghunathan et al., 2018).
This disease comprises a generic term that encompasses a group of inherited hemolytic anemias (Felix et al., 2010). Notwithstanding the markedly distinct features of sickle cell diseases, their clinical and hematologic manifestations are similar (Brasil, 2014).
Sickle cell anemia (SCA) is the genetic disorder with the most severe clinical and hematologic presentation and also the one with the highest prevalence (Naoum, 2000). In Brazil, SCA is highly prevalent and considered a public health problem (De Sousa & Silva, 2017).
As far as the physiology of this disease is concerned, red blood cells containing polymerized Hb S are rigid and non-deformable, contributing to microvascular occlusion, which eventually leads to tissue ischemia and organ dysfunction (Madigan & Malik, 2006;Vekilov, 2007). Interestingly, SCD is characterized by many acute and chronic complications, including anemia, serious infections, hemolytic and vaso-occlusive crises, bouts of recurrent pain, stroke, acute chest syndrome, pulmonary hypertension, and chronic organ damage (Steinberg, 2009;Therrel et al., 2015). In addition to systemic symptoms, clinical oral signs Development, v. 9, n. 9, e998998120, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i9.8120 4 commonly described in the literature include mucosal pallor, delayed tooth eruption, enamel and dentin demineralization, hypercementosis, dental pulp calcifications, changes in the superficial cells of the tongue epithelium, and bone alterations, causing maxillary protrusion and formation of a dense trabecular pattern (Pithon, 2011).
As patients with SCD are at a greater risk for severe comorbidities associated with vascular occlusion, hemolysis, and infection, in addition to oral disorders, their quality of life could be compromised (Fernandes et al., 2016). Hemoglobinopathies are often severe, present difficult management, and have a remarkable psychosocial impact on patients and on their families (Dahmani et al., 2017).
Therefore, the aim of the present study was to assess the health-related quality of life of children and adolescents with SCD.

Methods
This was a quantitative cross-sectional study (Pereira et al., 2018). The census sample was compound of 97 male and female patients aged 5 to 18 years with clinical and laboratory diagnosis of SCD, seen between March and July 2019 at the Hematology and Hemotherapy Hospital of Pernambuco (HEMOPE), a referral center for the treatment of these patients. As a result of the specificity of the study population and the difficulty associated with random selection of patients with SCD, we used a nonprobability (convenience) sample.
Those children and adolescents whose parents and/or legal guardians signed the free informed consent form were included in the study. An assent form was signed by adolescents aged 10 to 18 years. Patients with other systemic diseases, psychiatric disorders, neurologic disorders, and other special needs, and whose general health status did not allow the application of the questionnaire were excluded from the study.
The Pediatric Quality of Life Inventory TM (PedsQL TM )child/adolescent report version 4 was used (Varni et al., 1999). This questionnaire evaluates the quality of life of healthy children and adolescents and of those with chronic diseases (Menezes et al., 2013).
The questionnaire was validated and translated into Portuguese (Klatchoian et al., 2008). It should be underscored that the questionnaires were applied by conducting interviews targeted at children and adolescents, in the presence of the research team only.
The instruments comprise 23 items involving the following dimensions: physical (8 items), emotional (5 items), social (5 items) and scholar (5 items), and were developed through focus groups, cognitive interviews, pre-testing and field testing measurements (Varni Research, Society and Development, v. 9, n. 9, e998998120, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10. 33448/rsd-v9i9.8120 et al., 2001). The assessment includes the following age groups: five to seven, eight to 12 and 13 to 18. The items for each of the questionnaires are similar, differing in developmentally appropriate language and the use of first or third person tense (Klatchoian et al., 2008).
Approximately 5 minutes are necessary to complete the application (Varni et al., 2001).
The questions investigated how much of a problem each item was for the children and adolescents in the past month, with three answer options for children aged 5 to 7 years (0never; 2 -sometimes; 4-almost always) and five answer options for those aged 8 years and older (0never; 1almost never; 2sometimes; 3often; 4almost always). Even though PedsQL TM was designed to be applied to children and adolescents aged 8 to 18 years as a selfadministered questionnaire, it can be administered by the interviewer. Negative questions are reversed scored on a 0-100 scale (0-100; 1-75; 2-50; 3-25; 4-0); hence, higher scores indicate better quality of life. The domain scores can be computed as the sum of the items divided by the number of answered items, but if more than 50% of the items are missing, the domain score is not computed (Klatchoian et al., 2008). The summary score for physical health (eight items) is the same as that used for the physical domain. To create a summary score for psychosocial health (15 items), the mean is computed as the sum of the answered items on the scales for emotional, social, and school functioning divided by the number of items (Klatchoian et al., 2008) Mean, median, and standard deviation of the numerical variables were estimated. One of the following tests was used for comparison of numerical variable categories: Student's t test with equal variances, Student's t test with unequal variances in case of two categories, or the F test (ANOVA) in case of more than two categories. If the F test (ANOVA) showed significant difference between the categories, the least significant difference method was used as multiple comparison test. Student's t and F (ANOVA) tests were chosen for comparisons in which data were normally distributed (in each category). The normality of data was checked by the Shapiro-Wilk test and equal variance was determined by Levene's F test.
The significance level was set at 5% for all statistical tests. The data were entered into an EXCEL spreadsheet and the statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS), version 23. Research, Society and Development, v. 9, n. 9, e998998120, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i9.8120 6

Results
The sample analyzed in this study consisted of 97 patients. Table 1 shows that most children and adolescents were female (76.3%), were in the age range of 8 to 12 years (47.4%), had SCA (89.7%), and were of mixed race (59.8%).  Table 2 shows that the only significant difference between the age groups was observed in psychosocial functioning (p < 0.05). Note that this variable had the highest mean for children aged 5 to 7 years (72.10) and the lowest mean for those aged 8 to 12 years (65.36). The remaining domains were not statistically significant in terms of age.

Discussion
SCD is one of the most prevalent inherited hematologic diseases worldwide, affecting a remarkable share of the Brazilian population and being recognized as a public health problem (Franco et al., 2007). SCD has several complications, including vaso-occlusive crisis, acute chest syndrome, stroke, and several other conditions that may significantly affect the patient's health-related quality of life (Oliveira et al., 2019).
This study assessed the quality of life of 97 patients with SCD, among whom 89.7% had SCA. Likewise, in another study, of 100 children diagnosed with SCD, 69% had SCA (Lim et al., 2012). SCA was the most common type of hemoglobinopathy detected (63.8%) in the study carried out by Felix et al. (2010).
SCD arose in Brazil with the forced displacement of African black peoples taken as slaves from 1550 to 1850. This disease is now widely spread around the world, with a predominance among black and mixed-race individuals (Brasil, 2009). This is in line with our study, in which mixed-race individuals accounted for 59.8%, followed by black (29.9%) and white (10.3%) people.
Significant difference was observed in this study for psychosocial functioning in the age ranges of 5 to 7 years and 8 to 12 years, exhibiting the lowest mean (65.36). By contrast, another study did not find any significant association between age groups for any domain (Menezes et al., 2013). According to Menezes et al. (2013), all domains had lower quality of life scores, which is in line with the findings of the present study. The literature reports a mean of 60.7 for the quality of life of children with SCD aged 8 to 12 years (Oliveira et al., 2019). This reveals that SCD is associated with limitations on different aspects of healthrelated quality of life, especially on physical, emotional, and school functioning (Menezes et al., 2013).
Another study that also applied PedsQL TM Generic Core version 4.0 compared the quality of life of children and adolescents with a chronic disease with that of healthy children and adolescents. The mean for the functioning scores in patients with a chronic disease ranged from 71.87 to 75.99, compared to 89.31 to 95.94 in healthy patients (Lim et al., 2012).
A study of 963 young individuals revealed that the mean quality of life score, in the absence of an acute or chronic condition, ranged from 78.63 to 87.42 (Varni et al., 2001). In the present study, the mean scores of patients with SCD according to age ranged from 64.85 to 69.23, demonstrating that these patients had a worse quality of life than did healthy individuals.
The negative impact, mainly on physical functioning, is associated with pain caused by SCD and with the healthcare demands from children and adolescents with this disease (Mcgrath & Finley, 2000). The scientific literature has shown generalized deterioration of quality of life, especially in those younger than 15 years, and pointed out pain as the major complication (Vilela et al., 2012).
Pain crises, hospital admissions, blood transfusions, and other morbidities associated with SCD had a strong impact on the quality of life of these patients (Pereira et al., 2013).
Therefore, appropriate pain management in SCD is a current concern and a parameter that should be used to assess quality of life (Cordeiro et al., 2015).
There was significant difference in physical functioning between sexes in the present study among patients aged 13 to 18 years, with a higher mean among female patients than among male ones (70.89 x 56.88). On the other hand, Dampier et al. (2016) demonstrated that female patients reported significantly sharper pain, fatigue, depressive symptoms, and worse scores for physical functioning than did male patients. Similarly, in another study, patients with chronic pain had worse physical functioning of upper limbs, anxiety and depression, whereas female patients had a worse quality of life score, with an increase in the demand for healthcare (Badawy et al., 2018). Conversely, the scientific literature has also revealed that male patients present with musculoskeletal disorders and impaired locomotion activity more frequently than do female patients (Cordeiro et al., 2015).
Studies on the quality of life of patients with chronic diseases are of utmost importance, as quality of life should be viewed as a determining health factor for the development of policies and measures targeted at the specific characteristics and social context of the disease, and implementation of interventions that could improve vitality, manage pain, and preserve mental health. This could help patients with SCD maintain a high quality of life (Vilela et al., 2012;Pereira et al., 2013). Given this context, it is suggested further research to be carried out in order to assess the health-related quality of life in patients with SCD compared to healthy patients. In addition, access to multidisciplinary treatment with updated medications is Development, v. 9, n. 9, e998998120, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i9.8120 10 increasingly feasible and this may reflect in healthy-related quality of life improvements in patients with SCD, showing thus the importance of developing more research in this area.

Conclusion
SCD is an inherited hemoglobinopathy that negatively affects the quality of life of children and adolescents. Male patients and those aged 8 to 12 years tend to have a worse quality of life. The most frequently affected domains are psychosocial and physical functioning. Thus, these patients should be given special attention and be followed up early on by a multidisciplinary team for implementation of preventive measures and efficient treatment options that can improve the quality of life of these patients.