Factors associated with musculoskeletal injuries in children and adolescents with sickle cell disease
Authors: Jeffrey A. guy, James R. Stallworth, Lisa M. Knight, Yinding Wang, Candler G. Mathews, Jeanette M. Jerrell
Journal: American Journal of Hematology (2016)

To the Editor: Sickle cell disease (SCD) is the most common disorder identified by newborn screening among those of African-American, Middle Eastern, or Indian descent in the US, with about one in every 500 births affected 1. Erythrocytes in children with SCD become deoxygenated, dehydrated, and crescent-shaped, and tend to aggregate or stick to blood vessel walls, blocking blood flow within limbs and organs, causing painful episodes. Vaso-occlusion, tissue ischemia, and chronic hemolysis lead to damage in many organs, including the cardiovascular system, bones, and joints. Previous studies have identified aseptic bone necrosis, osteomyelitis, septic arthritis, severe low back pain, and soft tissue changes as the predominant musculoskeletal manifestations of SCD in adults, but the musculoskeletal manifestations of SCD in children remain under-studied 1. Hydroxyurea (HU), a myelosuppressive agent used off-label to treat SCD in children, has been shown to reduce episodes of vaso-occlusive pain (VOC), acute chest syndrome (ACS), and may be associated with reduced end-organ damage 2. Over recent decades, however, a decline in the daily amount of physical activity that youth engage in has also been noted and a concomitant “explosion” in the number of children diagnosed at an early age with obesity, hypertension, dyslipidemia, and diabetes, and incident traumatic or overuse musculoskeletal injuries (MSI) in youth 3, 4, which must be considered. Medical and pharmacy claims for the calendar years January 1, 1996 through December 31, 2006 were used to identify a cohort of children and adolescent patients (ages 17 and under) enrolled in and eligible for Medicaid for a minimum of 9 months in each calendar year included in this analysis, who had service encounters with a diagnosis of SCD (HbSS homozygous). Any other disease variants, including sickle-hemoglobin C disease (Hb SC) and sickle β-thalassemia, were excluded. Primary or secondary (International Classification of Disease 9th Clinical Modification) diagnosis codes for MSI, SCD severity indicators, and comorbid cardio-metabolic disorders were assessed: fracture, dislocation, sprain, concussion, thorax/abdomen/pelvis, arthropathies/connective tissue disorders; dorsospinal disorders, muscle/joint disorders, bone/cartilage disorders; VOC pain crisis visits, ACS/pneumonia visits; obesity, diabetes, dyslipidemia, essential hypertension, arrhythmia, cardiovascular disease; and a substance use disorder. Prescription of HU was coded as the number of months HU was filled/refilled from the Medicaid Pharmacy file. This study was approved by the University of South Carolina Institutional Review Board. Because MSI result from a complex interaction of multiple risk factors 5, a multivariate statistical analysis approach was used to assess the relative odds associated with having each of the diagnosed MSI categories, with individual risk factors (age, sex, ethnicity), VOC or ACS visits, comorbid cardio-metabolic conditions, and months prescribed HU as predictor variables. Each of the full regression models was then reduced through a stepwise procedure to reflect only the statistically significant variables. The measure of association reported for these results is the adjusted odds ratio (aOR) with a corresponding 95% confidence interval. All statistical analyses were performed in SAS software 9.3 (SAS Institute, Cary, North Carolina). This cohort was primarily African-American and male, initially diagnosed with SCD at 5–6 years of age, and remaining in the data set for follow-up for a mean of 7 years (Table 1). Diagnosed cardiovascular disorders (30.3%) included cardiomegaly, pulmonary hypertension, and heart failure. Supraventricular tachycardia was present in 8.5% of the cohort, substance use disorder in 4.8%, obesity in 8.4%, hypertension in 6.1%, diabetes in 2.5%, and dyslipidemia in 26.8%. HU was prescribed to 9.5% of the cohort, for a mean of 15 months. Total VOC care averaged 45.4 visits per patient experiencing these episodes, while ACS care averaged 8.4 visits. These youth were primarily diagnosed with sprains in the ankles/feet and back, and fractures in the upper limbs, with fewer concussions, dislocations, and thoracic/pelvic injuries, but with overuse injuries predominantly involving joint, back, or muscle pain, and bone/cartilage disorders, primarily aseptic bone necrosis, stress fractures, osteomyelitis, and costochondritis. We then compared the increased risk for traumatic MSI fractures, sprains, and concussions, and micro-traumatic, overuse injuries associated with frequent VOC or ACS episodes, substance use, or being prescribed HU, controlling for other chronic metabolic conditions of childhood (i.e., obesity, diabetes, dyslipidemia) or comorbid cardiac disorders (Table 2), and for individual differences in age, sex, and race/ethnicity. More VOC or ACS visits were associated with an increased risk (2–4% per visit) of incident fractures, sprains, joint, back, and muscle pain, and bone/cartilage disorders. Diagnosed arrhythmia was associated with an increased risk of fractures and concussions, whereas cardiomegaly/pulmonary hypertension/heart failure were associated with a higher risk of joint/connective tissue disorders, muscle/joint pain, and bone/cartilage disorders. Comorbid obesity and dyslipidemia were associated with an increased risk of sprains, joint pain, and neck/back pain. Diabetes and dyslipidemia were associated with a higher risk of muscle/joint pain, and bone/cartilage disorders. SCD tissue ischemia and bone marrow hyperplasia appear to underlie the most prevalent MSIs and cardiovascular complications noted herein, with comorbid metabolic diseases representing important, additional risk factors. While the cohort represents a large, heterogeneous group of children and adolescents being treated for diagnosed SCD, varying periods of exposure to the SCD medications examined, and a long-term observational study period regarding incident MSI, VOC pain or ACS episodes, clinical intervention with HU, and comorbid cardio-metabolic conditions, the data were not gathered using a prospective, controlled design and clinical research interviews were not employed to confirm any of the assigned medical conditions. However, previous studies have found that although observational (Medicaid) databases provide much less detailed information on individuals than primary data collection, the physician diagnoses coded and the utilization data correspond to clinical medical record reviews in the majority of cases 6. The cohort is also representative of pediatric patients in routine care settings in the southeastern USA states and other small states with predominantly small-city and rural populations in terms of age, sex, racial demographics, and Medicaid eligibility, but these results may not be generalizable to other patient groups. These findings update the existing literature on the musculoskeletal manifestations of SCD in youth and the knowledge base of pediatric practitioners to better anticipate their clinical care needs and to provide them more effective care. The views expressed do not necessarily represent official findings of the South Carolina, Department of Health and Human Services (Medicaid). No external support was received for dataset acquisition or data analysis. Jeffrey A. Guy1, James R. Stallworth2, Lisa M. Knight2, Yinding Wang3, Candler G. Mathews III4, Jeanette M. Jerrell5* 1Department of Orthopedics, University of South Carolina School of Medicine, Columbia, South Carolina; 2Department of Pediatrics, University of South Carolina School of Medicine, Columbia, South Carolina; 3Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health, Columbia, South Carolina; 4University of South Carolina School of Medicine, Columbia, South Carolina; 5Department of Neuropsychiatry and Behavioral Science, University of South Carolina School of Medicine, Columbia, South Carolina