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Symptom clusters in children

Rodgers, Cheryl C.a; Hooke, Mary C.b; Hockenberry, Marilyn J.c

Current Opinion in Supportive and Palliative Care: March 2013 - Volume 7 - Issue 1 - p 67–72
doi: 10.1097/SPC.0b013e32835ad551
SYMPTOM CLUSTERS IN CANCER AND PALLIATIVE CARE: Edited by Andrea M. Barsevick and Aynur Aktas

Purpose of review Researchers have focused on identifying and describing symptom experiences among children with various diseases but symptoms can have a synergistic and/or an antecedent effect that must be evaluated. This review reports the current knowledge of symptoms among various pediatric diseases and highlights symptom cluster research.

Recent findings Symptoms of depression and anxiety are the most prevalent variables studied across pediatric disease studies followed by pain, fatigue, and quality of life. Although previous pediatric symptom research provides a foundation for understanding the complexities of these symptoms, there is limited evidence on symptom cluster research in pediatrics. Pain and fatigue are the most common symptoms analyzed for correlations, and relationships among symptoms that have been evaluated in children with juvenile idiopathic arthritis, HIV, cancer, cardiac disease requiring an implantable cardioverter defibrillator, and at end of life. Pain and fatigue have been associated with sleep disturbances, anxiety, depression, anorexia, and nausea/vomiting.

Summary Pediatric oncology researchers are leading the way with symptom cluster studies; however, this work remains in the early stages. There is great potential to advance the state of the science with cluster analysis. Future research work should focus on evaluating symptoms and their interactions.

aBaylor College of Medicine/Texas Children's Hospital, Houston, Texas, USA

bUniversity of Minnesota School of Nursing, University of Minnesota School of Nursing, Minneapolis, Minnesota, USA

cDuke University School of Nursing, Durham, North Carolina, USA

Correspondence to Cheryl C. Rodgers, PhD, RN, CPNP, CPON, Baylor College of Medicine/Texas Children's Hospital, 6621 Fannin, MC, WT 8-150, Houston, Texas 77030, USA. Tel: +1 832 824 4645; fax: +1 832 825 0872; e-mail:

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Children commonly experience symptoms with any variation in their health status. Researchers have identified symptom occurrences with various pediatric illnesses, and have focused on defining symptoms in relation to timing, intensity, distress, and quality of life (QOL) outcomes [1]. This descriptive work provides an important foundation to the understanding of symptoms; however, symptoms rarely occur alone [2]. Any symptom can cluster with another symptom, creating a synergistic effect that leads to a significant increase in intensity, or an antecedent effect that leads to the development of additional symptoms [3].

Assessing symptom clusters provides a holistic depiction of the child's experience. Understanding the symptom experience of children with chronic illness is particularly important because of the potential influence on the child's development. The cognitive, psychological, physiological, and physical components of the child's development involve reciprocal interactions within a dynamic, continual process of development [4]. Symptoms associated with the chronic disease and its treatment can include physical (i.e., increased fatigue), cognitive (i.e., neurocognitive effects), and psychosocial (i.e., depression and/or anxiety) symptoms that can greatly influence the child's development.

Research is beginning to focus on identifying and evaluating symptom clusters in children; however, this work is early in development. The concept of symptom clusters in children is currently in the stages of exploration and clarification, involving an introduction of the concept and a refinement of definitions and attributes [3]. Symptom clusters have been defined as two or more symptoms occurring together [5] and as three or more symptoms relating to each other [3]. With the aim of providing a comprehensive overview on symptom clusters in children, this article used the definition of symptom clusters consisting of two or more symptoms occurring together. This article will report current knowledge regarding symptom clusters with common childhood diseases, childhood cancer, and children at the end of life and will discuss the importance of advancing the science of pediatric symptom cluster research.

Box 1

Box 1

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A literature search of symptoms in children was conducted using PubMed, CINAHL, and Cochrane Databases, and hand searching articles. In order to ascertain a complete concept exploration, no time limit was placed on the searches; however, the majority of articles were published within the past decade. Keyword searches included the term of pediatric in combination with symptom, symptom clusters, or specific symptoms such as pain, fatigue, nausea, vomiting, anorexia, xerostomia, drowsy, inattention, numbness, insomnia, vertigo, dysuria, dyspnea, diarrhea, constipation, depression, alopecia, diaphoresis, worry, pruritus, dysphagia, irritability, or anxiety. Articles were reviewed if they contained any information regarding two or more symptoms in children. Articles listing symptoms as diagnostic criteria were excluded. These articles included diseases such as autism, attention deficit hyperactivity disorder, Kawasaki disease, and demyelinating disorders. The search yielded 48 articles that primarily consisted of nonexperimental, descriptive research studies.

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Symptom research in childhood disease populations excluding cancer has focused on the following chronic illnesses: juvenile idiopathic arthritis, HIV, chronic fatigue syndrome (CFS), migraines, cardiac disease requiring an implantable cardioverter defibrillator (ICD), asthma, and epilepsy. Table 1 summarizes the symptom focus of each pediatric disease. Overall the research demonstrates the presence of multiple symptoms across disease sites with depression and anxiety cited most frequently.

Table 1

Table 1

Several studies examined symptoms in children with rheumatoid arthritis. A moderate relationship between functional ability and depression was noted in a group of 52 children and adolescents with juvenile idiopathic arthritis living in Turkey, whereas relationships between physical activity, anxiety, and pain had poor agreement [6▪]. Sleep disturbance as reported by patient and parents in relationship to pain, functional assessment, and disease activity were evaluated among 26 school-age children with juvenile rheumatoid arthritis [7]. Child sleep reports correlated with pain scores while other correlations were not significant. Aviel et al.[8▪] explored relationships among sleep disturbance, fatigue, disease activity, pain, and health-related quality of life (HRQOL) in 115 children and adolescents with juvenile idiopathic arthritis and juvenile dermatomyositis. Measures of self-report supported significant bivariate relationships between poor sleep and fatigue, fatigue and poor HRQOL, and pain and sleep disturbance. Pain was also a significant predictor of other symptoms in children infected with HIV perinatally. In a cohort of 320 children, higher pain scores were associated with higher scores for general anxiety, depression, and dysthymic disorder [9].

Children and adolescents with CFS (n = 97) or migraines (n = 179) were compared with healthy controls (n = 32) on self-report measures of anxiety, depression, somatization, functional disability, and illness attribution [10]. Those with migraines had significantly higher anxiety than other cohorts and had higher depression scores than healthy controls. Children with CFS had higher functional disability scores than those with migraines or healthy controls. Factors influencing the duration of CFS were evaluated in 53 children and found no relationship between symptoms, sex, age, or duration [11▪]. High BMI was associated with greater duration of CFS but it was not clear whether the higher BMI was related to inactivity.

Psychological symptoms have been evaluated in children and adolescents with an ICD. Among 20 children and teens with ICDs, depression scores between those who received shocks and those who did not were not different, but adolescents with ICDs overall had higher depression scores than healthy adolescents [12]. Patients with ICDs had higher worry scores but anxiety scores were not higher than healthy youth. Later studies revealed different results. In a study of 10 children and adolescents evaluating the psychosocial impact of ICDs, general depression, or higher anxiety was found in the majority of patients who received a shock in the past 6 months [13]. More recently, psychological functioning and disease-related QOL were evaluated in 30 children and adolescents with an ICD [14▪]. Teens with ICD have had more anxiety, depression, and sleeping problems than healthy norms and patients who received shocks had more depression and worries [14▪]. These studies demonstrate how interventions, in addition to the illness itself, may influence the symptom experience.

Two studies examined the relationship between asthma symptoms and anxiety and depression. In a study of 767 youth ages 11–17 years, a higher incidence of asthma symptom days was significantly associated with anxiety or depression [15]. In a comparison of 82 children ages 8–15 years with asthma matched to 82 healthy controls, children with asthma had higher levels of anxiety but depression and self-esteem levels were comparable to their healthy peers [16]. Anxiety and depression were studied in a different chronic illness population, childhood absence epilepsy (CAE). In a sample of 45 children, researchers found that anxiety scores were higher in children with CAE than their healthy controls [17▪]. Additionally, children with well controlled seizures did not differ in depression and anxiety scores from children with active seizures.

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The focus on cure for childhood cancer over the last three decades has resulted in increased survival rates of more than 80% [18]. However, efforts to manage cancer treatment symptoms have not kept pace with new therapies for childhood cancer [19]. Four systematic reviews have been published on the complexity of symptoms experienced by children with cancer and confirm that symptoms are numerous and vary in the level of distress across treatment phases [20,21▪,22,23].

Fatigue is the most prevalent symptoms experienced during childhood cancer treatment and provides a foundation for exploring symptom associations and interactions [24–26]. In a survey of parents of cancer patients and healthcare professionals concerning cancer-related fatigue, 57% in each group reported fatigue as a frequent symptom [27]. Fatigue is associated with pain and sleep disturbances affecting not only the child but the entire family's QOL [28]. The most common symptoms in a group of 121 children with cancer were treatment-related pain, nausea, and fatigue [29]. Collins et al.[30] described the most common physical symptoms (prevalence >35%) in a group of 160 children with cancer as lack of energy, pain, drowsiness, nausea, cough, and lack of appetite. Young children experience multiple physical and psychological symptoms with a high level of symptom distress [31]. Children and adolescents reported frequent depression, decreased desire to communicate with others, and wanting to be left alone; patients were acutely aware of emotional changes during treatment [24–26].

Increased prevalence of physical and psychosocial distress including fatigue, pain, nausea, and changes in appetite are common symptoms experienced during hospitalization for chemotherapy [32▪,33]. Although there is limited understanding of symptom pattern changes over time, Miller et al.[32▪] found the prevalence of pain and fatigue decreased over time but nausea remained the same throughout hospitalization for a group of children 10–17 years of age. In a study of HRQOL in 61 children receiving myelosuppressive chemotherapy, children experienced on average 10.6 symptoms, and those with poorer functional status and higher symptom burden had significant decreases in HRQOL [22]. Expectations and beliefs about childhood cancer symptoms were evaluated in a group of 39 children and their family members and found that these individuals expected to experience suffering as part of the cancer treatment [34]. Symptom experiences during childhood cancer treatment greatly influence the child's and family's QOL and reflect transition periods that emphasize the dynamic nature of the cancer experience [35,36]. In a study of 39 children receiving cancer treatment, children experienced symptoms as feeling states; symptom meanings were unique to each child and family [37].

Although there is limited evidence on specific treatment factors that influence symptom clusters during childhood cancer treatment, the effect of steroids has been explored. Early studies of short-term, high-dose steroid therapy on behavior, depression, and sleep in pediatric oncology patients indicated significant negative changes in these symptoms between periods on and off treatment [38,39]. Dexamethasone treatment during maintenance therapy for childhood leukemia significantly influences sleep and fatigue [40]. In addition to treatment-related factors, the hospital environment plays a role in symptom experiences; in a study of 29 hospitalized children with cancer frequent nocturnal awakenings significantly altered sleep resulting in more fatigue [41].

Although previous studies increase awareness of common symptom causes, they provide limited understanding of interaction and synergy when multiple symptoms exist. Limited studies were found evaluating specific symptom clusters in children with cancer. In a study of 144 older pediatric oncology patients treated in Taiwan, five symptom clusters were established: sensory discomfort and body image; circulatory and respiratory problems; fatigue, sleep, and depression; body image and eating difficulties; and gastrointestinal irritation and pain [42]. A study of 131 children receiving myelosuppressive chemotherapy found three clusters classified as a chemotherapy sequela that included physical side effects, mood disturbance, and neuropsychological discomfort [43▪]. In a study of 67 children and adolescents receiving chemotherapy with cisplatin, doxorubicin or ifosfamide, adolescents with the cluster of fatigue and sleep disturbances experienced more depressive symptoms and behavior changes, whereas younger children with higher levels of fatigue had more depressive symptoms [44▪]. These symptoms clustered in ways similar to observed patterns in individuals experiencing sickness behavior symptoms; both emotional and physical symptoms were observed [45]. A recent longitudinal study in Turkey of 54 children and adolescents reported four to five symptom clusters in each of the first 3 months following a cancer diagnosis and illustrated a wide range of physical and emotional symptoms [46▪].

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Although there have been significant improvements in the treatment of many pediatric diseases and life-threatening conditions, for some children, there is no possibility for a cure. Care at the end of life focuses on optimizing the QOL through effective communication and symptom management [47]. However, symptom strategies can only be implemented when there is an adequate understanding of the symptom experience. Table 1 reports symptoms studied in children at the end of life. There has been little attention on identifying symptom clusters in children during the dying process [48].

The majority of pediatric end of life research focuses on symptom occurrences in children with cancer. This research frequently uses a retrospective design wherein parents complete a symptom questionnaire based on memory, after their child's death, to report the child's symptoms at the end of life. Pain and fatigue are the most frequently reported symptoms during the last 6 months of life [49▪,50–52]. Other commonly reported physical symptoms included dyspnea, nausea, vomiting, anorexia, drowsiness, and constipation, whereas common psychological symptoms included anxiety, sadness, and fear [50–53]. A study of hospitalized children dying from a variety of diseases found similar physical symptom reports with fatigue, pain, drowsiness, and anorexia occurring commonly in the last week of life, and fatigue, drowsiness, and dry mouth occurring during the last day of life [48].

Despite the occurrence of multiple symptoms in children at the end of life, few studies have evaluated symptoms in clusters. A retrospective study of 103 parents of children who died of cancer found that 51% of the children had three or more symptoms during their last month of life [52]. Another study used parent reports to identify factors associated with fatigue among 141 children who died of cancer [54]. Fatigue was associated with physical symptoms of pain, dyspnea, anorexia, and nausea and vomiting, and with psychological symptoms of anxiety, sadness, and fear. Children who suffered highly from fatigue had significantly more symptoms (6.2 symptoms) compared with children who did not suffer highly from fatigue (5.3 symptoms).

Symptom management is an important component of caring for children at the end of life. In order to provide effective care for dying children, caregivers must have an understanding of the synergistic effects of multiple symptoms.

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Symptom research in children has primarily evaluated bivariate relationships between individual symptoms or differences in symptoms between chronically ill children and healthy controls. As seen in Table 1, the psychological symptoms of depression and/or anxiety were the most prevalent variables studied with eight out of nine pediatric disease groups focusing on these symptoms. Pain, fatigue, and QOL were the next most prevalent variables studied; however, less than half of the nine pediatric disease groups evaluated these variables. Although research on childhood symptom prevalence provides a foundation for understanding the complexities of symptoms, there is limited evidence and concept development on symptom clusters in children. Pediatric oncology researchers are leading the way with symptom cluster studies, as they begin to move beyond identifying bivariate relationships and use symptom cluster analysis methods in their work. These findings will provide valuable information to advance the concept and refine the definition of symptom clusters. Identifying attributes associated with symptom clusters will further clarify the concept and advance the state of science. Researchers are now exploring attributes such as biologic pathways of symptoms in adult cancer patients [55▪] but work is just beginning with biologic mechanisms of symptoms in children.

Symptom research in children has primarily focused on school-age children through adolescents. Our review was consistent with a 2008 review of developmental diversity in symptom research, which noted that researchers have given limited attention to the variation of the symptom experience across developmental stages [56]. Furthermore, there is a lack of symptom research with longitudinal designs that incorporate developmental, long-term outcomes [23]. When designing longitudinal studies, science must consider that symptom measurements must not only be developmentally appropriate but must also accommodate developmental advances that occur over time [57].

There is great potential to advance the science by evaluating symptoms and their interactions as well as developmental changes in symptom severity over time. Even more critical to understanding symptom experiences during childhood illness is the need for exploration of ‘why’ symptom differences occur; this will allow us to identify who may be most susceptible to disease and treatment.

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Conflicts of interest

The authors have no conflict of interest to disclose.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 122).

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This descriptive study found higher anxiety scores in 45 children with absence epilepsy when compared with 41 healthy controls. However, depression and anxiety scores did not differ in children with active seizures when compared with children with well controlled seizures. This article highlights the importance of evaluating depression and anxiety in children with seizures.

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pediatric; symptom; symptom clusters

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