Abstract
Fatigue is among the most common, debilitating, and distressing symptoms associated with chronic condition in pediatric population. The purpose of this study was to identify non-pharmacological fatigue interventions in children and adolescents with cancer. For this, we carried out an integrative review of the literature from January 2000 to December 2016. A comprehensive search of four databases was conducted: Cumulative Index to Nursing and Allied Health Literature, Psychology Information, Medline via PubMed, and Web of Science. Randomized controlled trial, quasi-experimental, case-control and cohort studies were included in this review. Thirteen relevant studies were included for analysis. Seven papers reported positive outcomes for exercise, exercise plus leisure activities, healing touch and acupressure. In another six papers using exercise, exercise plus psychological intervention and massage, no effectiveness was found. Effective management of fatigue in children and adolescents is important but research in this area is limited, so the results of this review should be interpreted cautiously. Future researchers are encouraged to test the effective interventions in homogenous cancer populations and in other groups where fatigue is a common concern.
Introduction
Most often children and adolescents with cancer, experience multiple symptoms, with the most common being fatigue, sleep disruptions, pain, nausea, decrease in appetite, and depression (Lopes-Júnior et al., 2015; Miller et al., 2001; Nunes et al., 2015; Walker et al., 2010). These symptoms are associated with a poor quality of life (Berger et al., 2015; Daniel et al., 2013; Miyauti-Silva et al., 2016). Fatigue is a subjective and diffuse experience involving physical, psychological and cognitive domains (McCabe, 2009; Mota and Pimenta, 2002). In cancer, fatigue is also among the most common, debilitating, and distressing symptoms, and is associated with both diagnosis and its treatment (Gordijn et al., 2013; Hinds et al., 2007; Jalmsell et al., 2006; Menezes and Camargo, 2006; Saligan et al., 2015; Theunissen et al., 2007; Wolfe et al., 2000). Furthermore, studies also identify fatigue as a symptom that increases in frequency and intensity after chemotherapy (Karthikeyan et al., 2012; Stasi et al., 2003). Both patient self-report and parent proxy-report indicated that fatigue changed significantly over time, especially in the first few days after the start of a cycle of chemotherapy (Yeh et al., 2008). Also, children experienced a high number of symptoms, including fatigue, at the initiation of a chemotherapy cycle, which persisted over the following two weeks (Baggot et al., 2009). Fatigue was also associated with sleep disturbance, nausea and vomiting, depressive symptoms, and behavior changes after chemotherapy (Hockenberry et al., 2010).
Nursing has an important role in controlling symptoms in children and adolescent with cancer. Improved management of symptoms such as fatigue can improve health outcomes for children and adolescents as well as their parents. It is important to recognize the effects of fatigue and provide therapeutic interventions to decrease it (Saligan et al., 2015; Yeh et al., 2008).
Aim
The aim of this review was to identify interventions used to minimize fatigue in children and adolescents with cancer. We plan to use these results to develop a nursing intervention for the effective management of fatigue in children and adolescents, and to sensitize other professionals to this symptom that is still neglected.
Methods
Design and search strategy
This study is an integrative review of the literature regarding non-pharmacological interventions to manage fatigue in children and adolescents with cancer. An integrative review is used to synthesize current evidence in a particular area when the authors of published studies used a variety of different designs to address a particular problem (Whittemore and Knalf et al., 2005).
The study was guided by Cooper (1982) and used the following stages: (1) elaborating of a guiding question; (2) selection of the descriptors, keywords, inclusion and exclusion criteria; (3) outline the search procedures; (4) assessment of papers included in the integrative review; (5) interpretation of the data; (6) presentation of the review (Baggott et al., 2009). The research question of the review was the following: ‘Which non-pharmacological interventions have been used to management of fatigue in children and adolescents with a chronic condition?’
The inclusion criteria were (a) original articles, (b) studies that aimed to intervene on fatigue in children and adolescents with cancer, (c) written in English, Portuguese or Spanish, and (d) published from January 2000 to December 2016. The exclusion criteria were (1) dissertations and thesis, as well as non-research articles, such as review and opinion papers, (2) studies that did not test a fatigue intervention, (3) studies not conducted with children or adolescents.
Data bases searched were Cumulative Index to Nursing and Allied Health Literature (CINAHL), Psychology Information (PsycInfo), Web of Science, and MEDLINE via PubMed (National Library of Medicine, USA). Initially, the existence of controlled descriptors or keywords (free-text words) and their synonyms was verified in each of the eight databases. The following Descriptors in Health Sciences, Medical Subject Headings terms, PsycoInfo thesaurus, CINAHL headings, and keywords in different combinations were entered into the databases, such as, ‘child’, ‘adolescent’, ‘cancer’, ‘chronic condition’, ‘fatigue’, and ‘intervention’. The primary studies were located with the help of advanced search tools, in which the search terms were crossed and combined using the Boolean operators ‘AND’ and ‘OR’ (Lefebvre et al., 2011).
Two authors conducted the search independently (MDRN and EOB). Likewise, all results were evaluated independently by those authors using an extraction template developed by the first author for the purposes of this study, with discussion used to achieve consensus in areas where the reviewers disagreed.
Hierarchy of evidence and quality assessment
Initially, the studies were read in detail and their contents were critically analyzed according to Melnyk and Fineout-Overholt (2011). The evidence level of the studies was identified based on the study design as follows, I for systematic reviews and meta-analysis of randomized controlled trials (RCTs); II for RCTs; III for non-RCT (quasi-experiment); IV for case-control or cohort studies; V for systematic reviews of qualitative or descriptive studies; VI for qualitative or descriptive studies; and VII for opinion of authorities and/or reports of expert committees. Also, this hierarchy classifies levels I and II as strong, III to V as moderate, and VI and VII as weak (Melnyk and Fineout-Overholt, 2011).
The methodological quality of the selected studies were assessed using the generic quantitative appraisal tool adapted by Machotka et al. (2009), which has 12 criteria representing key elements to assess the methodological quality of the studies. Each statement of the tool was scored as 1 or 0 and the overall score was calculated by summing the scores and converted into percentages for interpretation (Machotka et al., 2009). Scoring was performed by two reviewers. Table 1 presents the methodological assessment of the studies included in the review.
Methodological quality of studies.
Note: 1 = Study purpose reported; 2 = Relevant background literature; 3 = Sample description; 4 = Sample size justification; 5 = Reliable & valid outcomes measures; 6 = Intervention description; 7 = Contamination & co-intervention; 8 = Statistical significance; 9 = Appropriate analysis method(s); 10 = Clinical importance; 11 = Drop outs; 12 = Appropriate conclusions. N = no; NA= not applicable; NR= not reported; Y= yes.
Data extraction, synthesis, and analysis
An extraction template was developed by the first author. Extracted data were transferred to synopsis tables to synthesize relevant data. The data extracted included the following specific details of significance to the review question and objective: reference, study design, study objective or research question, host institution of the study (hospital; university; research center; community), patient population/sample, intervention (protocols, number of sessions, dosage), outcome measures, efficacy results, data analysis, safety results, limitations, conclusions, and study quality. The main outcome of interest was levels of fatigue or chronic fatigue after receiving non-pharmacological interventions.
In order to decide which articles should be included, two reviewers (MDRN and EOB) independently screened the titles and assessed study quality using the above mentioned template. Two Microsoft Excel spreadsheets were developed to summarize the extracted data. After that phase, the spreadsheets were combined to build a single spreadsheet. In case of disagreement in any of the phases, new readings took place followed by discussions between the researchers until a consensus was reached.
The findings of this review were presented descriptively after carefully considering the heterogeneity and limitations of some of the methodologies used in the included studies, as well as the inappropriateness in using their results to perform statistical analyses such as meta-analyses.
Results
Study selection and critical appraisal
Initially, 8897 records were retrieved. Among them, 39 duplicated articles were located and excluded. Then, 8858 records were preselected by reading the titles and abstracts. Afterwards, 39 studies were selected for critical appraisals based on exclusion and inclusion criteria. Finally, after reading the full version of those 39 papers, 13 records were selected for data extraction and analysis in this integrative review (Figure 1).
PRISMA’s flow diagram (Moher et al., 2009).
Characteristics of the included studies
The summary characteristics of the original studies (aim, sample, methods, results, and evidence level) can be found in Table 2.
Characteristics of the included studies.
Note: RCT: randomized controlled trial; PBSCT: peripheral blood stem cell transplantation; ALL: acute lymphoblastic leukemia; PedsQL: pediatric quality of life inventory; HT: healing touch; MT: massage therapy; QT: quiet-time; HrQoL: health-related quality of life; FSC: Fatigue Scale-Child; FSP: Fatigue Scale-Parent; MFS: multidimensional fatigue scale; VAS: visual analog scale; HSCT: hematopoietic stem cell transplantation; EPA: enhanced physical activity; AML: acute myeloid leukemia ; STAI: State–Trait Anxiety Inventory; PPS: play performance scale; POMS: Profile of Mood States; CIS: checklist individual strength; ASWS: Adolescent Sleep-Wake Scale; BASES: Behavioral, Affective and Somatic Experiences Scale.
Some study characteristics were collected. The year of publication, ranged from 2007 to 2016, one in 2007 (Hinds et al., 2007), one in 2008 (Ekti and Conk, 2008), two in 2009 (Post-White et al., 2009; Takken et al., 2009), two in 2011 (Rosenhagen et al., 2011; Yeh et al., 2011), one in 2013 (Wong et al., 2013), two in 2015 (Bastani et al., 2015; Diorio et al., 2015) and four in 2016 (van Dijk-Lokkart et al., 2016; Hooke et al, 2016a; Hooke et al., 2016b; Jacobs et al., 2016), indicating a growing interest in recent years. Sample size ranged between 9 and 120 participants. Regarding the country of origin, six were from the United States (Hinds et al., 2007; Hooke et al., 2016a; Hooke et al., 2016b; Jacobs et al., 2016; Post-White et al., 2009; Wong et al., 2013), two were from Netherlands, (van Dijk-Lokkart et al., 2016; Takken et al., 2009) one each from Taiwan (Yeh et al., 2011), Germany (Rosenhagen et al., 2011), Turkey (Ekti and Conk, 2008), Canada (Diorio et al., 2015), and from Iran and Canada (Bastani et al., 2015). The assessment instruments used to assess fatigue were Pediatric quality of life inventory (PedsQL) Multidimensional fatigue scale (MFS) (Diorio et al., 2015; van Dijk-Lokkart et al., 2016; Hooke et al., 2016b; Rosenhagen et al., 2011; Yeh et al., 2011), Fatigue Child Scale (Diorio et al., 2015; Ekti and Conk, 2008; Hinds et al, 2007; Hooke et al., 2016a; Post-White et al., 2009), Fatigue Adolescent Scale (Diorio et al., 2015; Hinds et al., 2007; Hooke et al., 2016a; Jacobs et al., 2016), Fatigue Parent Scale (Ekti and Conk, 2008; Hinds et al., 2007; Jacobs et al., 2016), Checklist Individual Strength (CIS)-20 (Takken et al., 2009), Visual Analog Scale (Bastani et al, 2015) and My Fatigue meter (Wong et al., 2013).
The study designs were RCT (Bastani et al., 2015; van Dijk-Lokkart et al. 2016; Ekti and Conk, 2008; Hinds et al., 2007; Jacobs et al., 2016; Post-White et al., 2009; Wong et al., 2013), a nonrandomized pilot trial (Diorio et al., 2015), Nonrandomized cohort design (Hooke et al., 2016b); quasi-experimental (Hooke et al., 2016a; Takken et al., 2009; Yeh et al., 2011) and case-control (Rosenhagen et al., 2011).
The interventions used were exercises (Diorio et al., 2015; Hooke et al., 2016a; Hooke et al., 2016b; Hinds et al., 2007; Rosenhagen et al., 2011; Takken et al., 2009; Yeh et al., 2011), exercise plus leisure activities (Ekti and Conk, 2008), exercise plus psychosocial training (van Dijk-Lokkart et al. 2016), massage therapy (Jacobs et al., 2016; Post-White et al., 2009), healing touch (Wong et al., 2013) and acupressure (Bastani et al., 2015).
Quality assessment
Evidence level was classified according to Melnyk & Fineout-Overholt (2011), considering levels I and II as strong, III to V as moderate, and VI and VII as weak. Evidence level in the studies ranged between II and IV. All of the identified studies were classified as strong (levels II) or moderate (level III or IV). The quality of most studies was moderate to strong based on the critical appraisal checklists Machotka et al. (2009). Thirteen studies were deemed of sufficient quality to be included in the review (Table 1).
Interventions
The studies tested six different types of interventions for reducing fatigue in children and adolescents with cancer (exercise, exercise plus leisure activities, exercise plus psychological training, massage, healing touch, and acupressure). The synthesis of the knowledge produced in this study is shown in Table 2.
Exercise
A total of eight studies tested exercise intervention.
Four papers found that those who received an exercise intervention reported less fatigue (Diorio et al., 2015; Hooke et al., 2016a; Rosenhagen et al., 2011; Yet et al., 2011)
Yet and colleagues (2011) implemented a six-week home-based aerobic exercise intervention in 22 children with cancer under 18 years old. The exercise was practice three days a week, 30 minutes each session (5 minutes warm up, 25 minutes aerobic exercise). The authors found that children who received the exercise intervention reported significantly lower general fatigue scores than those did in the control group. This study shown that home-based aerobic exercise intervention is feasible for children with cancer to practice at home (Yeh et al., 2011). Another research group provided an exercise intervention for 23 patients with cancer (mean age, 13 years old) during the isolation phase after peripheral blood stem cell transplantation (PBSCT). Participants exercise three times a week on stationary bicycle ergometers and used a variety of sports equipment. This study showed the feasibility of supportive sports therapy in PBSCT (Rosenhagen et al., 2011). In another study, 11 patients aged 7–18 years diagnosed with cancer participated in yoga sessions 4 to 5 times a week. Both children and their parents reported the benefits of Yoga, such as increased energy levels, decreased nausea, anxiety and agitation, and a reduced need for pain medication. Children reported that feeling more relaxed and also more adapted to the hospital environment (Dioro et al., 2015). In the last effective exercise intervention study, 16 participants (6–18 years old) with acute lymphoblastic leukemia (ALL) participated in a physical activity in 17, 14, and 7 days before the next corticosteroid pulse. The child was invited to wear the FitBitR the next three days. The physical therapist recommended a weekly step goal tailored to the patient’s baseline and this goal was discussed with the patient and family. From the baseline measurement to the week 2 (14 days), the median number of steps per day evidenced little change, and higher numbers of steps were also correlated with lower fatigue (Hooke et al., 2016a).
Another three studies did not find any change in fatigue in the group that received exercise intervention (Hinds et al., 2007; Hooke et al, 2016b; Takken et al., 2009).
The first study tested a physical activity intervention with 29 children (7–18 years old) with cancer, which consisted of cycling a stationary bicycle-style exerciser for 30 minutes. The results suggested that this type of exercise did not result in a significant decline in fatigue (Hinds et al., 2007). The second study with nine children 6–14 years old who were in remission from ALL, patients received instructions to attend 45 minutes of exercises twice a week, to increase muscular strength, aerobic fitness, and resistance range (Takken et al., 2009). The intervention did not result in a significant improvement in muscle strength, exercise capacity, functional mobility, or a significant reduction for score when pre- and post-training were compared (Takken et al., 2009). Furthermore, in the third study, 13 cancer survivors (10–18 years old) realized a 6-week yoga intervention of 45 minutes. The yoga intervention evidenced a decrease in 6–12-year-old children’s anxiety/wellness scores, but did not improve significantly the fatigue and balance scores (Hooke et al., 2016b).
Exercise plus leisure activities
One research group reported positive results for a nursing intervention based on exercises and leisure activities administered to 60 children with cancer (7–12 years old) (Ekti and Conk, 2008). The intervention included 10 to 15 minutes of physical exercise and 45 to 50 minutes of leisure activities as drawing, reading, listening music, or keeping busy. This intervention started 7 to 10 days after the chemotherapy treatment and was used every day for seven days. The control group received routine nursing care. A statistically significant difference was found between mean scores of the experimental and the control group in children self-report and parent report (Ekti and Conk, 2008).
Exercise plus psychosocial intervention
One study used as intervention exercise plus a psychosocial intervention (van Dijk-Lokkart et al., 2016). Thirty children and adolescents with cancer (8–18 years old) received the physical exercise training that consisted two sessions per week (45 minutes each) for 12 weeks and the psychosocial training (psychoeducation and cognitive-behavioral techniques) session for 60 minutes every 2 weeks for 12 weeks in the treating hospital, and 38 received usual care. The intervention did not improve psychosocial functioning, health-related quality of life (HrQoL) and fatigue between the experimental group and the control group (van Dijk-Lokkart et al., 2016).
Healing touch
One study with nine children and adolescents with cancer showed positive results using healing touch (HT) as an intervention (Wong et al., 2013). The experimental group of children and adolescents (n = 6) with cancer received the HT from a trained HT practitioner for 30 minutes once a day, while the control group (n = 3) did reading or age appropriate story/play activity for 30 minutes once a day in the presence of a caring hospital volunteer who was not an HT practitioner. The participants, their parents, and their nurses all reported a significant decreases in the scores for pain, stress, and fatigue (p = 0.0001) (Wong et al., 2013).
Massage
Two studies tested massage without finding significant changes in fatigue (Jacobs et al., 2016; Post-White et al., 2009).
In one study the intervention was tested with 17 children/parent who had cancer (Post-White et al., 2009). Participants received massage therapy (MT) or quiet-time (QT) weekly for four weeks, with a cross-over design. The MT intervention was more effective than just QT at reducing heart rate in children, anxiety in children less than 14 years old, and parent anxiety. However, there were no significant changes in blood pressure, cortisol, pain, nausea, or fatigue (Post-White et al., 2009).
In the other study 34 adolescents with cancer received massage sessions lasting between 20 minutes and 30 minutes in length for two or three nights. The intervention was feasible, well received, and could potentially improve patients’ sleep; however, there was no significant changes in anxiety, mood, or fatigue from pre- to post-intervention (Jacobs et al., 2016).
Acupressure
One of the included studies reported the effects of acupressure on reducing fatigue among children with ALL. Patients in the experimental group (n = 60) received finger acupressure on point ST36, a point traditionally used for ‘energy’, whereas patients in the control group (n = 60) received pressure on another point (LI12). Acupressure caused greater reduction in fatigue in the experimental group. However, long-term effects were not proved, as its positive effects were observed only immediately after intervention (Bastani et al., 2015).
Discussion
Thirteen studies tested different interventions in children and adolescents with cancer. The effective interventions were some exercise (stationary bicycle ergometers and sports equipment; home-based aerobic exercise; yoga 4 to 5 times a week, physical activity tracked by FitBit), exercise plus leisure activities, healing touch and acupressure. The interventions that were not able to reduce fatigue were other exercises, exercise plus physiological intervention, and massage.
Results regarding the exercise in studies included in this review were not consistent. Within the eight studies using exercises as an intervention, four reported a reduction in fatigue (Diorio et al., 2015; Hooke et al., 2016a; Rosenhagen et al., 2011; Yet et al., 2011) while another tree reported that exercise was not effective in reducing fatigue (Hinds et al., 2007; Hooke et al, 2016b; Takken et al., 2009). Recent literature includes successful intervention to reduce fatigue in adults with cancer undergoing chemotherapy (Adamsen et al., 2009) and also a Chinese exercise (Qigong) in adults with chronic fatigue syndrome (Chan et al., 2013). A recent systematic review summarized the evidence of physical activity in pediatric oncology (Baumann et al., 2013). The results of this study showed a positive effect of clinical exercise interventions on disease and treatment-related side effects, especially with ALL patients and during medical treatment. Clinical exercise interventions are feasible, safe and no adverse effects have been reported. Positive effects were found on fatigue, strength, and quality of life. Single studies presented positive effects on the immune system, body composition, sleep, activity levels, and various aspects of physical functioning.
There is also one study showing the benefit of HT in adults with acute leukemia (Danhauer et al., 2008). The authors of the HT study in our review also found a benefit associated with HT in children. Therapeutic touch also was used to diminished stress in premature (Im et al., 2009), but future research using this modality is warranted in children and adolescents with cancer.
Although the massage therapy intervention included in this review was not effective for children with cancer, there is a recent study in adult cancer patients receiving chemotherapy with excellent results (Karagozoglu and Kahve E, 2013). We also identified studies in which massage was used to manage unpleasant symptoms such as nausea and vomiting (Mazlum et al., 2013). Furthermore, although there were no significant changes in study endpoints, the authors reported that the participants felt better physically, mentally, and emotionally, and that the results lasted from several hours to the end of the day (Post-White et al., 2009). Further study with larger sample sizes to better determine the effectiveness of massage in children and/or adolescents with cancer is important, specially once several studies have shown the effectiveness of this intervention in the management of symptoms in adults (Batalha and Mota, 2013; Post-White et al., 2009).
About acupressure, studies on adults with cancer have been demonstrating efficacy. Yeh and colleagues (2015) studied auricular acupressure to reduce pain, fatigue, and disturbed sleep in women with breast cancer and found clinically significant reductions (≥30%). In the study of Zick and colleagues (2016), they also found that patients that received relaxing acupressure or stimulating acupressure had significantly less fatigue than patients that received usual care.
Other recent interventions successfully used in adults to reduce fatigue were, acupuncture (Ng and Yiu, 2013) and Qigong (Chan et al., 2013) in adults with chronic fatigue syndrome and guided imagery compact disc (CD) in patients with cancer in Korea (Lee et al., 2013).
One important aspect to consider is if the intervention are appropriated or not for children. Exercise, HT, massage, acupressure seems to be adequate, but in case of acupuncture, despite finding evidence of some efficacy and low risk associated, needle pain can be a side effect (Tobias et al., 2006) and concerns about safety of the procedure is highlighted, once acupuncture’s mechanism is not known. A review also indicated that it is advisable to apply few needles or delay treatment to the children who have overeaten, are overfatigued, or are very weak (Jindal et al., 2008).
The ineffectiveness of some interventions could be attributed to several factors. One possibility is that some studies used scales to assess fatigue that were developed and validated in adult populations. Other studies cited the use of the scales that had acceptable scores for internal reliability in children but they may not have been sufficiently sensitive or specific to detect differences. Another possibility is that some studies may not have had enough participants to detect a change if one occurred; four of six ineffective studies had less than 30 subjects. Most studies also were with hospitalized children or children receiving chemotherapy, which may have added additional confounding variables in these studies. Interventions in children need scientific rigor, such as standardization of the intervention, and have to be balanced with their health status, their well-being on any given day, and the families’ already overwhelming schedules (Post-White et al., 2009). Another possible reason for failure to find significant results is that younger children sometimes perceived the intervention as boring, resulting in a decrease in motivation. In one study, adaptations made in the exercise-training program and non-availability of equipment caused a decrease in training intensity, another possible reason for the exercise intervention failure (Takken et al., 2009).
Limitation and Strengths
The primary limitation of our review is related to quality of the evidence; some of the interventional studies were not RCTs. Also, the methodological quality of the majority of the studies was only moderate. Furthermore, assessments of risk of bias of all studies were relatively high due to design and reporting, sample size, and lack of use of a control group.
This limits our ability to draw conclusions regarding effectiveness.
Conclusions
We found that some interventions used to reduce fatigue were successful. The authors of seven studies reported significant reductions in fatigue in children and adolescent. Effective interventions included exercise, exercise plus leisure activities, healing touch, and acupressure. It is important to consider that the studies had heterogeneous interventions, with different number of subjects, outcome measures, and intervention protocols. Ineffectiveness of the intervention may be related to research processes or inappropriate choice of interventions.
Sample size and instruments used to assess fatigue are another important factor to consider; 9 of 13 studies had a sample size smaller than 30. And some studies used adapted adult scales in pediatric population, even though there are already validated and reliable fatigue scales for pediatric population. These two factors could be a threat to internal validity and should be considered in future studies. It is also known that age and gender are significant factors that affect fatigue. Future studies are needed to further examine the effects of these variables on fatigue, as well as on differential effects they may have on interventions to alleviate fatigue.
Despite a systematic search of the literature, only a small number of studies testing interventions for fatigue in children and adolescents with cancer were found. These studies presented a significant heterogeneity indicating that our results should be interpreted with caution and reasons for the heterogeneity should be considered for interpretation.
Footnotes
Authorship declaration
Conception and design of the work: MDRN, LCN.
Acquisition, analysis, and interpretation of data: MDRN, EOB, KO, LCLJ, FMSR, RAGL, LCN.
Manuscript writing and revising it critically: MDRN, EOB, KO, LCLJ, FMSR, RAGL, LCN.
Final approval of the version to be published: MDRN, EOB, KO, LCLJ, FMSR, RAGL, LCN.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Michelle Darezzo Rodrigues Nunes was funded by the São Paulo Research Foundation – FAPESP (Process #: 2010/20055-6) and Lucila Castanheira Nascimento has been funded by the National Council for Scientific and Technological Development (Process #: 486239/2013-6).
