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Abstract

Introduction: Research on the benefits of physical activity (PA) for children diagnosed with sickle cell disease (SCD) remains divided. This scoping review aimed to describe PA and physical fitness assessments, detail existing PA interventions, and document adverse events related to PA interventions in children with SCD. Methods: We searched MEDLINE, Embase, Cochrane, Web of Science, and PEDro for clinical trials and observational studies on children ≤21 years old diagnosed with SCD and providing at least one assessment of PA and/or physical fitness and/or a PA intervention. Results: A total of 45 studies were included in this review. Only 28.9% of studies provided an assessment of PA, with the most common assessment being self-reported questionnaires. Most studies (ie, 88.9%) detailed using physical fitness assessments, with the most common being the 6-minute walk test. Two studies described a PA intervention, and one adverse event was reported. Conclusion: This scoping review indicated that approaches to assess PA and physical fitness in children with SCD are heterogenous and PA interventions in this population are limited. Conducting future research aiming to address these gaps is critical to allow for the formulation of PA guidelines that are specific to the needs/challenges of children with SCD.

Keywords

sickle cell disease pediatric physical activity physical fitness intervention adverse events

Introduction

It is estimated that approximately 100,000 individuals, all ages included, have sickle cell disease (SCD) in the United States.¹ SCD is an umbrella term that encompasses a group of genetically inherited hemoglobinopathies and includes variants such as sickle cell anemia (SCA/HbSS), hemoglobin SC disease (HbSC) and hemoglobin S/ß thalassemia (HbSß). SCA is the homozygosity of Hemoglobin S (HbSS), making it the most severe and frequently occurring hemoglobinopathy, affecting approximately 65% of individuals with SCD.^2,3 When oxygen levels are low, hemoglobin S (HbS) can form long polymers that are inflexible, leading to severe vaso-occlusion and chronic anemia.²

In contrast, SC hemoglobinopathy is a milder presentation of SCD because unlike HbS, HbC molecules do not readily polymerize under low oxygen tension.⁴ Individuals with HbSC disease still have aggregates of hemoglobin molecules within red blood cells which can lead to sickling, resulting in symptoms similar to SCA.² HbS-β thalassemia is a compound heterozygous condition that results from the inheritance of a β thalassemia gene from one parent and a HbS gene from the other parent. The heterogeneity of the β-Thal mutations leads to differing amounts of β-globin synthesis and consequently different amounts of Hb A. HbS-β thalassemia is usually classified in 2 types: HbS-β⁺ thalassemia and HbS-β⁰ thalassemia. In HbS-β⁰ thalassemia, the production of HbA is absent making it clinically indistinct from sickle cell anemia while in HbS-β⁺ thalassemia, the amount of HbA produced is variable.⁵

Regardless of genotype, individuals with SCD are at an increased risk for multiple comorbidities, including chronic pain, organ dysfunction, and cardiovascular complications.^6-8 Beyond these comorbidities, individuals with SCD also experience a host of physical impairments that affect multiple systems. These include impairments to the neuromuscular system (eg, pain or balance), the musculoskeletal system (eg, strength or range of motion), and the cardiopulmonary system (eg, endurance or energy expenditure).⁹ In children and adolescents specifically, research has shown that SCD is associated with changes in muscle and bone composition, impaired muscle strength, impaired cardiopulmonary function at rest, and deficits in motor performance and physical function.⁹ Importantly, children and adolescents with SCD are reported to have an increased number of physical impairments and limitations compared to their healthy peers.⁹ In an effort to better understand the possible implications of these physical impairments, Silva et al, 2023 found that children with SCD walk a significantly shorter distance during the 6-minute walk test (6MWT) than their healthy counterparts.¹⁰ Having also found that the distance covered during the 6MWT was inversely associated with reticulocyte count and the IL-6 biomarker. Silva et al, 2023 hypothesized that the shorter distance may be attributable to increased levels of inflammation (ie, increased levels of IL-6) in children with SCD, thereby impacting their physical capacity.¹⁰

Additional studies have found that time spent doing moderate and high intensity physical activity (PA) was lower in children with SCD than in their healthy peers.^11,12 Specifically, children and adolescents with SCD engage in a level and amount of PA that is 24%–58% lower than their peers, despite preliminary evidence supporting the benefits of PA in alleviating certain symptoms associated with the disease, such as pain.¹³ The potential benefits of PA in this population also extend to improvements in the cardiorespiratory system and muscle function when engaging in regular endurance exercises that include resistance training.¹³ Nevertheless, some studies have shown that acute and intense exercise can increase the risk of sickling due to dehydration and oxidative stress in individuals with SCD.¹⁴ As such, there is little consensus on the safety of high-intensity exercise for children with SCD,^15,16 which highlights the need for additional research to confirm whether specific types of PA should be encouraged to confer benefits in this population.

While research within this field remains relatively new, there is promise of potential therapeutic interventions with PA for the SCD population. While there are studies in the field of PA and SCD,¹⁷ there is limited understanding of the implications of PA specifically for children and adolescents. Health complications often occur earlier in life for individuals diagnosed with SCD. These complications can include, for example, acute splenic sequestration (prevalence ∼30% in children under 6 years old), functional asplenia (prevalence ∼80% in children with SCA under 1 years old), and acute chest syndrome (∼30% of individuals with SCD have at least 1 episode throughout their life).¹⁸ Due to the severity of these complications in childhood for individuals with SCD and the lack of understanding of the role of PA associated with acute splenic sequestration, functional asplenia and acute chest syndrome in this population, it is vital to better understand the impact PA can have on the symptomatology and management of SCD in childhood.

This scoping review aims to describe and synthesize previously reported data in the field of PA and pediatric SCD to map the current evidence in response to the following aims: (1) to provide a description of PA and physical fitness assessments, (2) to provide a description of PA interventions, (3) to document the impact of PA interventions on health-related outcomes, and (4) to document adverse events related to PA interventions.

Review Questions

The scoping review objectives translate to the following question: In children and adolescents (≤21 years of age) diagnosed with SCD, what are the assessment methodologies to measure PA levels and physical fitness and what PA interventions have been conducted in this population?

Methods

This review was conducted and is reported following the Preferred Reporting Items for Systematic Reviews and the Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) statement.¹⁹

Search Strategy

A preliminary search was performed in PROSPERO and several other journal indices and databases to ensure no scoping reviews, systematic reviews, or meta-analyses on the same topic were underway. Search structures, subject headings, and keywords were tailored to each database by a medical research librarian (KJK) specializing in systematic reviews in consultation with the senior author (MC), based on current literature.^12,20-22 Search terms included a combination of subject headings and keywords covering the population, concept, and context (Supplemental materials). Databases included: Ovid MEDLINE, Ovid Embase, Cochrane Central, Web of Science, and PEDro Physiotherapy Evidence database. No limits were applied to geographical locations or publication dates, but searches were restricted to human and English-language articles. The full search strings for all databases and other resources can be found in supplemental materials. The reference lists of included articles were manually scanned for additional articles. The last database search was performed on January 28th, 2025.

Study Eligibility Criteria

Eligibility criteria included observational studies, RCTs, NCTs and uncontrolled interventions (ie, pre- and post-tests without controls), regardless of the study objectives, published in a peer-reviewed journal. Only quantitative studies were eligible for inclusion. For inclusion, studies had to include samples comprising children, adolescents and young adults (21 years of age or younger) diagnosed with SCD. SCD is an umbrella term that represents a heterogeneous group of genetically inherited disorders, characterized by mutations in the gene encoding the hemoglobin subunit ß, including SCA, HbSC and HbSß-thalassemia. Sickle cell trait patients were not included in this review.

Furthermore, eligible studies had to include at least one assessment of PA and/or physical fitness and/or a PA intervention focusing on improving health outcomes as a primary or secondary outcome. PA assessments were defined as behavioral measures quantifying “any bodily movement produced by contracting skeletal muscles, with a concomitant increase in energy expenditure”.²³ Physical fitness assessments were defined as quantitative measures assessing 1 or more of the following indicators: cardiorespiratory fitness, muscle strength and endurance, flexibility, balance and agility.^24,25 PA interventions were defined as interventions that caused “any bodily movement produced by contracting skeletal muscles, with a concomitant increase in energy expenditure”.²³ Exercise was considered as a component of PA to reach the end goal of the PA intervention.^23,26 Examples include, but are not limited to, aerobic exercise interventions, resistance training, flexibility, balance, agility or stretching exercises.

Studies were excluded if they were: (1) in a language other than English, (2) conference abstracts, case reports, case studies, short communications, systematic reviews, meta-analyses, position papers, white papers/editorials, letters to the editor and protocol papers, (3) unpublished research (eg, theses/dissertations), and (4) studies with animals.

Study Selection

All studies identified from the search strategy were collated and uploaded into Covidence systematic review software. Duplicate citations were removed manually in Endnote. The first step consisted of 2 authors independently screening the titles and abstracts (MC and DPS) to identify potentially relevant studies. When the titles and abstracts were considered potentially relevant, the full text articles were obtained. The second step consisted of 2 authors independently reviewing the full text articles (MC and DPS) to confirm their eligibility. If an article did not meet the inclusion criteria, the reason for exclusion was recorded. The PRISMA flow diagram (Figure 1) shows the entire selection process from the original search results to the final selection of studies.

Figure 1.

PRISMA-ScR flowchart.

Data Extraction and Presentation

Data were extracted by the lead author (AL) and co-authors (DPS, LS, PN). To address review objectives, extracted data from eligible articles were as follows: authors, publication year, country, participant characteristics (ie, sample size(s), sex/gender [note: we did not distinguish between these terms because authors did not always make clear which one they assessed], age at enrollment, type of disease/genotypes, treatment), stated objectives, type and description of PA assessment(s), type and description of physical fitness assessment(s), type of PA intervention and description of PA intervention, reported adverse events, main results, and authors’ conclusion.

During the data extraction process, if data were incomplete or unclear in the full text, we contacted the corresponding authors by email (up to 2 times, 3 weeks apart) to obtain additional information.

Risk of Bias Assessment

In accordance with the methodological recommendations for scoping reviews,²⁷ no risk of bias assessment was performed.

Results

Search Strategy and Study Selection

The literature search yielded a total of 788 studies and 6 additional studies were identified by reviewing the references of included studies. After duplicate records were removed, a total of 553 records were screened by title and abstract. Of these 553 records, 100 underwent a full-text screening and 55 studies did not meet the inclusion criteria. A total of 45 studies were included in this review as meeting the inclusion criteria. Figure 1 illustrates the flow diagram of the search strategy in accordance with the PRISMA-ScR guidelines.

Sample Characteristics of the Included Articles

The sample characteristics of all included studies are summarized in Table 1. The conclusions and relevant results of all included studies are available in Table 2. A total of 2,013 participants (903 males, 44.9%; 845 females, 42.0%; 265 not reported, 13.1%) were included in the studies included in this review. A total of 17 studies included only participants with HbSS, 2 studies included only participants with SCA, 8 studies included either participants with HbSS or HbSβ⁰ thalassemia, 8 studies included participants with HbSS or HbSC, 1 study included participants with HbF or HbS, 1 study included participants with HbSS, HbSC or HbSβ⁰ thalassemia, 1 study included participants with HBSS, HbSC or α-thalassemia and 6 studies included participants of all genotypes. Only 1 study did not specify any inclusion criteria relative to the genotype.

Table 1.

Data Extraction, Objectives, and Physical Activity and Fitness Assessments of Included Studies (N = 45).

Authors and Publication year	Participant Characteristics		Main Stated Objectives	Type and Description of PA Assessments	Type and Description of Physical Fitness Assessments
Alpert et al, 1981²⁸	Sample size	N = 47	To determine whether exercise responses are different from normal in children with SCA	Not assessed	Cycle ergometer exercise testing
	Sex/gender	Males = 28/Females = 19			• The protocol was a modification of the Bruce and Hornsten continuous format and the continuous two-stage bicycle ergometer format of G. R. Cumming (personal communication)
	Age at enrollment	10.3 ± 2.8 years old			• Three continuous three-minute workloads were performed: They were staged to produce approximate HR of 120, 150, and 170 or near maximal levels at the end of the third workload. An additional workload was performed if the participant was not exhausted at the end of the test
	Age range	5 to 18 years old			• Maximal test until exhaustion
	Type of disease/ genotypes	HbSS			• Pedal rate of 50 to 60 r/min was maintained (a metronome was used)
	Country	USA			• Participants were cajoled, tickled, and begged to keep up the pace
Alvarado et al, 2015²⁹	Sample size	N = 58	To examine heart rate recovery as an indicator of autonomic nervous system dysfunction after maximal exercise testing in children and young adults with SCA	Not assessed	Maximal cardiopulmonary exercise testing • The protocol was a standard ramp cycle protocol using the modified Godfrey protocol • Until volitional exhaustion (symptom-limited)
	Sex/gender	Males = 30/Females = 28
	Age at enrollment	15.1 ± NA years old
	Age range	8 to 21 years old
	Type of disease/genotypes	HbSS, β⁰ thalassemia
	Country	USA
Barriteau et al, 2021³⁰	Sample size	N = 17	To measure cerebral and quadriceps StO2 (tissue oxygenation) during exercise in children and young adults with SCA and healthy controls using near-infrared spectroscopy	Not assessed	Maximal cardiopulmonary exercise testing • The protocol was a continuous ramping cycle protocol using the modified Godfrey protocol • Until volitional exhaustion (symptom-limited)
	Sex/gender	Males = 9/Females = 7
	Age at enrollment	13.5 ± 3 years old
	Age range	10 to 21 years old
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia
	Country	USA
Brousse et al, 2020³¹	Sample size	N = 51	To compare the 6MWT responses between SCA children with and without exercise-related hemoglobin desaturation	Not assessed	Self-paced six-minute walk test • According to the guidelines of the American thoracic society (ATS 2002)
	Sex/gender^a	Males = 17/Females = 34
	Age at enrollment	11.9 ± 3.8 years old
	Age range	5 to 17 years old	To test the associations between EHD and several biological/physiological parameters
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia
	Country	France
Brownell et al, 2020³²	Sample size	N = 22	To compare vitamin A and nutritional status of children with HbSS to a cohort of healthy volunteers	Not assessed	Gross and fine muscle function and strength • Measured using hand grip, force plate, biodex, and tests of motor proficiency
	Sex/gender	Males = 13/Females = 9
	Age at enrollment	13.8 ± 3.3 years old
	Age range	9 to 19 years old
	Type of disease/genotypes	HbSS
	Country	USA
Buchowski et al, 2002¹¹	Sample size	N = 28	To examine the relationship between physical activity, physical activity-associated energy expenditure, and total daily energy expenditure in free-living adolescents with SCA	Body movements	24-hour protocol • Standard daily activities • Two-hour non-intensive exercise protocol (eg, walking and stepping) • Intensity = manual work and leisure activities that participants would perform in free-living conditions • Performed at the same pace and speed
	Sample size	N = 28		• Tritrac-R3D activity monitor
	Sex/gender	N/A		• 6-8 consecutive days
	Age at enrollment	15.6 ± 1.5 years old		Physical activity diary
	Age range	14 to 18 years old		Energy expenditure of physical activity
	Type of disease/genotypes	SCA		• Derived from the body movement recordings
	Country	USA		• 24-hour period
Chaudry et al, 2013³³	Sample size	N = 44	To determine subtle pulmonary vascular abnormalities in adolescents with SCD during exercise using noninvasive respiratory mass spectrometry	Not assessed	Maximal cardiopulmonary exercise testing • Ergometer exercise protocol • The exercise stages began with rest, then backpedaling at zero load, followed by forward pedaling, with an initial load of 25 W/m² increasing every 3 min by 15 W/m² • Until exhaustion
	Sex/gender	Males = 20/Females = 24
	Age at enrollment	M: 14.1 ± 2.4 years old; F: 14.2 ± 2.5 years old
	Age range	10 to 18 years old
	Type of disease/genotypes	HbSS, HbSC
	Country	England
Das et al, 2008³⁴	Sample size	N = 16	To assess the feasibility and safety of symptom-limited cardiopulmonary stress testing in children with SCD who are on long-term erythrocytapheresis	Not assessed	Maximal symptom-limited cardiopulmonary stress testing • Bruce protocol on a treadmill • According to the guidelines of the American heart association
	Sex/gender	Males = 7/Females = 9
	Age at enrollment	12.8 ± 5.25 years old
	Age range	9 to 20 years old
	Type of disease/genotypes	HbSS
	Country	USA
Da silva et al., 2022¹⁰	Sample size	N = 48	To evaluate and compare the functional capacity, pulmonary function and quality of life of children and adolescents with SCA with their healthy peers and to analyze the reproducibility of the functional capacity tests on the SCA group	Not assessed	Functional capacity • Modified shuttle test: performed twice in a 10m long corridor • Five-Repetition sit-to-stand: Performed twice
	Sex/gender	Males = 21/Females = 27
	Age at enrollment	13 ± 3 years old
	Age range	6 to 18 years old
	Type of disease/genotypes	HbSS
	Country	Brazil
Da silva et al, 2023³⁵	Sample size	N = 18	To assess exercise capacity through the 6MWT and biomarkers in children and adolescents with SCD	Not assessed	Six-minute walk test • According to the guidelines of the American thoracic society • Standardized phrases of encouragement were used every minute
	Sex/gender	Males = 11/Females = 7
	Age at enrollment	10.4 ± 2.6 years old
	Age range	6 to 14 years old
	Type of disease/genotypes	HbSS, HbSC
	Country	Brazil
Dedeken et al, 2014³⁶	Sample size	N = 46	To explore the submaximal exercise capacity and to analyze factors affecting the 6MWT and the 6MWD in the cohort of SCD children and adolescents	Not assessed	6-minute walk testing • Performed according to the guidelines of the American thoracic society
	Sex/gender^a	Males = 20/Females = 26
	Age at enrollment	NA
	Age range	6 to 20 years old
	Type of disease/genotypes	HbSS, HbSbu, HbSC and HbSb+
	Country	Belgium
Dougherty et al, 2011³⁷	Sample size	N = 35	To examine maximal muscle strength and peak power in children with SCD-SS	Not assessed	Maximal handgrip strength of both hands • Handgrip dynamometer (kilograms) Peak power • Measured during a maximal vertical squat jump
	Sex/gender	Males = 19/Females = 16
	Age at enrollment	9.0 ± 2.2 years old
	Age range	5 to 13 years old
	Type of disease/genotypes	HbSS
	Country	USA
Dougherty et al, 2018³⁸	Sample size	N = 21	To compare dominant hand maximum grip strength, peak power and plantar flexion isometric maximal voluntary contraction torque in African American children with and without SCD-SS	Not assessed	Treadmill protocol • Five minutes warm-up at a comfortable self-selected speed at 0% grade Maximal handgrip strength of both hands • Handgrip dynamometer (kilograms) • 3 maximal effort trials lasting 4 to 5 seconds interspersed with 60 seconds rests Maximal vertical squat jump • Three warm-ups • Three maximal vertical jumps (watts) Muscle torque • Plantar flexion isometric MVC torques of the left ankle were measured in triplicate at each of 4 angles (−10, 0, 10, and 20°) and the highest value in Newton meters recorded for dorsiflexion and plantar flexion at each angle
	Sex/gender	Males = 9/Females = 12
	Age at enrollment	11 ± 1 years old
	Age range	5 to 17 years old
	Type of disease/genotypes	HbSS
	Country	USA
Dougherty et al, 2020³⁹	Sample size	N = 21	To assess the impact of high-dose vitamin D supplementation over 12 weeks in African	Not assessed	Neuromuscular motor skills • Bruininks-Oseretsky test of motor proficiency • Fourteen measures that represent 8 neuromuscular motor skill domains, including strength (push-ups, sit-ups) Treadmill protocol • Five minutes warm-up at a comfortable self-selected speed at 0% grade Maximal handgrip strength of both hands • Handgrip dynamometer (kilograms) • 3 maximal effort trials lasting 4 to 5 seconds interspersed with 60 seconds rests Maximal vertical squat jump • 3 warm-ups • 3 maximal vertical jumps (watts) Muscle torque • Plantar flexion isometric MVC torques of the left ankle were measured in triplicate at each of 4 angles (−10, 0, 10, and 20°) and the highest value in Newton meters recorded for dorsiflexion and plantar flexion at each angle
	Sex/gender	Males = 9/Females = 12
	Age at enrollment	11 ± 4 years old
	Age range	5 to 20 years old	American children with and without HbSS on HRQL, physical performance and muscle strength and function
	Type of disease/genotypes	HbSS
	Country	USA
Gordeuk et al, 2011⁴⁰	Sample size	N = 160	To describe the consequences of increased hemolytic rate, elevated tricuspid regurgitation velocity, and left ventricular dysfunction among children with SCA	Not assessed	6-minute walk testing • Non-encouraged • According to the guidelines of the American thoracic society
	Sex/gender^a	Males = 79/Females = 81
	Age at enrollment	NA
	Age range	3 to 20 years old
	Type of disease/genotypes	HbSS
	Country	USA
Grau et al, 2019⁴¹	Sample size	N = 8	To investigate whether exercise might affect red blood cell deformability and nitric oxide bioavailability in SCA	Not assessed	Progressive submaximal bout of exercise • Cycle ergometer • Initial workload was 20 watts, and workload increased every 2 min by 20 watts • A cadence of 60 revolutions per • minute was maintained • Until subject reached the first ventilatory threshold
	Sex/gender^a	Males = 4/Females = 4
	Age at enrollment	17.4 ± 3.6 years old
	Age range	NA
	Type of disease/genotypes	HbF, HbS
	Country	Germany
Halphen et al, 2014⁴²	Sample size	N = 39	To assess the prevalence of hypoxia in children with SCD	Not assessed	6-minute walk testing • Non-encouraged • According to the guidelines of the American thoracic society • Performed on a 20-m straight track
	Sex/gender^a	Males = 14/Females = 25
	Age at enrollment	NA
	Age range	5.7 to 17 years old	To identify risk factors for daytime, nocturnal, and postexercise hypoxia and to identify correlations linking hypoxia to vasoocclusive crises, ACS, and TRV.
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia
	Country	France
Hariman et al, 1991⁴³	Sample size	N = 14	To evaluate retrospectively the functional status of children with SCD	Not assessed	Motoric functions • Evaluated using a modified motor assessment scale Activity of daily living • Assessed using the Barthel index
	Sex/gender	Males = 5/Females = 9
	Age at enrollment	11.6 ± 4.3 years old
	Age range	5 to 18 years old
	Type of disease/genotypes	HbSS, HbSC, HbSβ⁰ thalassemia
	Country	USA
Ho et al, 2023⁴⁴	Sample size	N = 9	To characterize diaphragm function and ventilation during the 6MWT in children with SCS	Not assessed	6-minute walk testing • Instructed to walk as fast as possible without running • Performed ion a 15.24 m track
	Sex/gender	Males = 5/Females = 4
	Age at enrollment	9.89 ± 2.93 years old
	Age range	6 to 17 years old	To investigate potential contributors to exercise intolerance
	Type of disease/genotypes	HbSS, HbSC, HbSβ⁺, HbSβ⁻
	Country	USA
Hostyn et al, 2013⁴⁵	Sample size	N = 46	To evaluate lung functional capacity for physical exercise in children and adolescents with SCD through the 6MWT	Not assessed	6-minute walk testing • Performed in a 10-meter long corridor • Two tests (with a 30-minute interval between them) • Administered by 2 trained physical therapists
	Sex/gender^a	NA
	Age at enrollment	9.15 ± 3.06 years old
	Age range	6 to 18 years old
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia, HbSC, and HbSβ⁺-thalassemia
	Country	Brazil
Karlson et al, 2017¹³	Sample size	N = 30	To examine the temporal and potentially bidirectional relationships between daily physical activity measured by actigraphy, self-reported fluid intake, and self-reported pain in children with SCD who experience frequent pain in the home setting	Physical activity	Not assessed
	Sex/gender^a	Males = 14/Females = 16		Physical activity
	Age at enrollment	13.9 ± 2.9 years old		• Actiwatch 2
	Age range	8 to 18 years old		• Actiwatch 2
	Type of disease/genotypes	HbSS, HbSC, HbSβ⁺ thalassemia, HbSβ⁰ thalassemia		• 14-day study period
	Country	USA		• 14-day study period
Karlson, et al, 2020⁴⁶	Sample size	N = 206	To characterize pain, pain interference, and physical activity	Physical activity	Not assessed
	Sex/gender^a	Males = 93/Females = 113		• Child physical activity
	Age at enrollment	11.73 ± 4.42 years old		• Self-report questionnaire to assess frequency of physical activity
	Age range	8 to 18 years old	To examine the relationships between these variables and psychological distress in youth with SCD
	Type of disease/genotypes	HbSS, HbSC		• The original 60-minute physical activity cutoff was modified to 30 minutes
	Country	USA
Kienzle, et al, 2022¹⁵	Sample size	N = 20	To characterize the relationship between heart rate variability and high-intensity exercise during maximal cardiopulmonary exercise testing in children and adolescents with SCA	Not assessed	Maximal symptom-limited cardiopulmonary stress testing • Incremental cycle ergometer protocol • Workload was increased every minute (standardized by height (8 watts for <120 cm, 10 watts for 120-150 cm, and 15 watts for >150 cm) • Until volitional exhaustion
	Sex/gender	Males = 10/Females = 10
	Age at enrollment	NA
	Age range	10 to 21 years old
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia
	Country	USA
Knight-Madden, et al, 2005⁴⁷	Sample size	N = 80	To characterize asthma and bronchial hyperreactivity in children with SCD	Not assessed	Exercise test • Standing on a treadmill • The speed was increased to approximately 2 mph and the inclination increased to 15° within 1 minute • The speed was adjusted to keep the subject’s heart rate within 10 beats/ minute of (and not exceeding) the target heart rate • Test lasted at least 6 minutes
	Sex/gender	Males = 40/Females = 40
	Age at enrollment	7.1 ± 1.1 years old
	Age range	5 to 10 years old
	Type of disease/genotypes	HbSS
	Country	Jamaica
Laurent-Lacroix et al, 2024⁴⁸	Sample size	N = 24	To evaluate aerobic capacity in children and adolescents with SCD in comparison with healthy matched controls	Self-reported physical activity	Maximal cardiopulmonary exercise testing • Pediatric cycle ergometer standardized protocol • Homogeneous incremental overall duration between 10 and 12 minutes • One-min rest; 3-min warm-up (10-20 watts) in increments of 10, 15, or 20 watts each minute • Pedaling rate of 60-80 revolutions per minute • Three-min active recovery (20 watts); 2-min rest • Until exhaustion
	Sex/gender	NA
	Age at enrollment	NA
	Age range	6 to 17 years old		• Measured using the Ricci and Gagnon questionnaire
	Type of disease/genotypes	HbSS, HbSC, α-thalassemia
	Country	France
Liem, et al, 2015a⁴⁹	Sample size	N = 60	To characterize the acute phase response to exercise of soluble vascular cell adhesion molecule and other biomarkers, including total WBC, IL6, CRP, and D-dimer, among children and young adults with SCA undergoing maximal cardiopulmonary exercise testing	Not assessed	Maximal cardiopulmonary exercise testing • The protocol was a standard ramp cycle protocol using the modified Godfrey protocol • Initial workload and workload increments were based on subject height • Workload increments occurred by continuous ramping at 1-min intervals • Until volitional exhaustion (symptom-limited)
	Sex/gender	Males = 30/Females = 30
	Age at enrollment	15.1 ± NA years old
	Age range	NA
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia
	Country	USA
Liem, et al, 2015b⁵⁰	Sample size	N = 60	To characterize the cardiopulmonary response to maximal exercise and to evaluate potential contributors to reduced exercise capacity among children and young adults with SCA	Not assessed	Maximal cardiopulmonary exercise testing • The protocol was a standard ramp cycle protocol using the modified Godfrey protocol • Initial workload and workload increments were based on subject height • Workload increments occurred by continuous ramping at 1-min intervals • Until volitional exhaustion (symptom-limited)
	Sex/gender	Males = NA/Females = NA
	Age at enrollment	15.1 ± 3.4 years old
	Age range	8 to 21 years old
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia
	Country	USA
Liem et al, 2017²⁰	Sample size	N = 10	To study a single-arm feasibility trial of home-based, aerobic exercise training in children with SCA	Physical activity	Maximal cardiopulmonary exercise testing • Cycle ergometer
	Sex/gender	Males = 5/Females = 5
	Age at enrollment	15.1 ± 2.8 years old
	Age range	13 to 21 years old		• Wearable HR monitor (polar)
	Type of disease/genotypes	HbSS
	Country	USA
Melo et al, 2017⁵¹	Sample size	N = 57	To establish determinants of maximum walking distance in the 6-minute walk test of children and adolescents with SCA	Physical activity	6-minute walk testing • According to the guidelines of the American thoracic society • Performed along a flat and straight corridor of 30m • Standard verbal encouragement
	Sex/gender^a	Males = 33/Females = 24		Physical activity
	Age at enrollment	11.9 ± 3.5 years old		• Physical activity questionnaire for older children and adolescents
	Age range	6 to 18 years old	To compare the performance in this test with physical activity level between patients and healthy controls
	Type of disease/genotypes	HbSS		• Brazilian version
	Country	Brazil		• Brazilian version
Melo et al, 2018¹²	Sample size	N = 50	To evaluate objectively and subjectively the level of physical activity and sedentary behavior of children and adolescents with SCA compared to healthy individuals	Physical activity	Not assessed
	Sex/gender	Males = 30/Females = 20		• Physical activity questionnaire for older children and adolescents
	Age at enrollment	12.0 ± 3.6 years old		• Brazilian version
	Age range	6 to 18 years old		Physical activity
	Type of disease/genotypes	HbSS		• ActiGraph GT3X
	Country	Brazil		• Time spent in physical activity and sedentary behavior
	Country	Brazil		• 7 consecutive days
Millis et al, 1994⁵²	Sample size	N = 15	To evaluate differences between children with SCA and matched control group of children having normal adult hemoglobin in performance of activities that are encountered during routine physical educational experiences in schools and summer camps	Not assessed	Physical performance • Hundred-Yard potato race: • Twenty-Yard and 40-yard freestyle swimming tests
	Sex/gender	Males = 0/Females = 15
	Age at enrollment	NA
	Age range	10 years old
	Type of disease/genotypes	HbSS
	Country	USA
Mockesch et al, 2017⁵³	Sample size	N = 66	To determine and compare micro- and macrovascular functions between children/adolescents with SS, SC disease, and healthy children/adolescents	Physical activity	6-minute walk testing • According to the guidelines of the American thoracic society • Instructed to walk as fast as possible without running
	Sex/gender	Males = 23/Females = 23
	Age at enrollment	HbSS: 15 ± 2.4 years old
	Age at enrollment	HbSC: 15.1 ± 2.6 years old
	Age range	10 to 16 years old		• International physical activity questionnaire adapted for adolescents
	Type of disease/genotypes	HbSS, HbSC
	Country	France
Moheeb et al, 2007⁵⁴	Sample size	N = 50	To determine selected anthropometrical variables and exercise performance in Oman children with SCT and SCA in comparison with normal healthy children	Not assessed	Physical fitness indices • Vertical jump apparatus: To determine the explosive power of the leg muscles • Grip strength dynamometer: To measure grip strength • Back strength dynamometer: To measure back strength • Leg strength dynamometer: To measure leg strength • Flexibility • Whole body reaction time Treadmill exercise test • Continuous treadmill running exercise test • Five minutes at a speed corresponding to 5 km/h and a horizontal inclination
	Sex/gender	Males = 50/Females = 0
	Age at enrollment	10.263 ± 0.157 years old
	Age range	9 to 12 years old
	Type of disease/genotypes	HbSS
	Country	Oman
Noordstar et al, 2023⁵⁵	Sample size	N = 8	To examine the safety of a 10-week organized sports program for children with SCD.	Moderate-to-vigorous physical activity	Motor performance • Canadian agility and movement skill assessment (CAMSA): Participants were instructed to complete a circuit of movement exercises as fast and good as possible performance of the skills Maximal cardiopulmonary exercise testing • Cycle ergometer using the Godfrey protocol
	Sex/gender	Males = 5/Females = 3		• Actigraph GT9X link accelerometer
	Age at enrollment			Physical activity
	Age range	7 to 12 years old		• National institute for public health and the environment (RIVM) questionnaire: Completed by the parents
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia, HbSC, and HbSβ⁺-thalassemia		Self-perceived moderate-to-vigorous physical activity
	Country	Netherlands		• Assessed by asking children how many days during the past week they were physically active for at least 60 minutes a day, whereby their heart rate and breathing increased
Omwanghe et al, 2017⁵⁶	Sample size	N = 100	To determine the physical activity and exercise patterns of children with SCD related to time spent in physical activity compared to that described for a national sample of children, participation in school-based physical education and school or community-based organized sports, and sociodemographic and personal beliefs that influence physical activity and exercise patterns	Physical activity	Not assessed
	Sex/gender	Males = 50/Females = 50
	Age at enrollment	NA
	Age range	11 to 18 years old		• Combination of the 2009-2010 National health and Nutrition examination survey (NHANES) physical activity questionnaire (PAQ) AND supplemental questions on: (1) sociodemographic data, including self-reported disease severity and impact on physical activity and exercise; (2) participation in school-based physical education and school or community-based organized sports; and (3) personal and parental perceptions regarding physical activity and exercise AND questions focused on 7-day recall of physical functioning, adapted from the PROMIS pediatric item bank on physical function mobility
	Type of disease/genotypes	SCD all genotypes included
	Country	USA
Pianosi et al, 1991a⁵⁷	Sample size	N = 30	To investigate how children with SCA maintain O₂ delivery in the face of the increased demand of exercise	Not assessed	Exercise test protocol • On cycle ergometer • Jones stage I progressive exercise test: to determine Wmax • One hour rest period • Jones stage III: Subjects pedaled at 50% of their Wmax at a frequency of 50-70 r/min for 5 to 7 minutes
	Sex/gender	Males = 15/Females = 15
	Age at enrollment	13.0 ± 3.8 years old
	Age range	NA
	Type of disease/genotypes	HbSS, HbSC
	Country	Canada
Pianosi et al, 2012⁵⁸	Sample size	N = 34	To measure the ventilatory response to exercise and to assess the roles of increased physiologic dead space, anaerobic metabolism, and hypoxemia in determining this response in a group of children with SCA	Not assessed	Exercise test protocol • On cycle ergometer • Jones stage I progressive exercise test: to determine Wmax • One hour rest period • Jones stage III: Subjects pedaled at 50% of their Wmax at a frequency of 50-70 r/min for 5 to 7 minutes
	Sex/gender	Males = 17/Females = 17
	Age at enrollment	13.0 ± 3.8 years old
	Age range	6 to 19 years old
	Type of disease/genotypes	HbSS, HbSC
	Country	Canada
Rock et al, 2023⁵⁹	Sample size	14	To comprehensively explore quadriceps skeletal muscle strength, muscle size, neuromuscular activation, gross motor performance, and QoL in children with SCD compared with controls	Not assessed	Knee extension joint force at the distal tibia • Two familiarization trials of submaximal effort • Three maximal voluntary isometric contraction trials of 5 seconds each with at least a 30-second but no more than a 2-minute rest break between trialsNeuromuscular motor skills • Bruininks-Oseretsky test of motor proficiency6-minute walk testing • Standard procedures over a 30-m walkwayTimed up and down stairsTimed up and go
	Sex/gender	Males = 7/Females = 7
	Age at enrollment	11.6 ± NA years old
	Age range	6 to 17 years old
	Type of disease/genotypes	HbSS, HbSC
	Country	USA
Singhai et al, 1997⁶⁰	Sample size	N = 16	To investigate resting metabolic rate and total daily energy expenditure between post pubertal boys with SCD and control subjects	Total daily energy expenditure	Not assessed
	Sex/gender	Males = 16/Females = 0		Total daily energy expenditure
	Age at enrollment	18.0 ± 1.1 years old		• Derived from the body movement recordings
	Age range	16.1 to 20.1 years old		• Derived from the body movement recordings
	Type of disease/genotypes	NA		24-hour period
	Country	Jamaica		24-hour period
Sylvester et al, 2007⁶¹	Sample size	N = 42	To determine the occurrence and magnitude of airway hyperresponsiveness in children with SCA who had or had not had acute chest syndrome episodes	Not assessed	Exercise challenge testing • Maximum of 6 minutes on a treadmill • During the first 2 minutes, the speed and elevation of the treadmill were increased so that the subject’s heart rate during exercise was 85% of the predicted maximum • Maximum heart rate was maintained for 4min
	Sex/gender	Males = 22/Females = 20
	Age at enrollment	NA
	Age range	6.1 to 16.8 years old
	Type of disease/genotypes	HbSS
	Country	UK
Vieira et al, 2016⁶²	Sample size	N = 70	To assess abnormalities in pulmonary function and functional capacity in children and adolescents with SCD	Not assessed	Six-minute walk testing • According to the guidelines of the American thoracic society • Instructed to walk as fast as possible • Tests were performed twice within 30 minutes
	Sex/gender^a	Males = 31/Females = 39
	Age at enrollment	11 ± 2.3 years old
	Age range	8 to 15 years old
	Type of disease/genotypes	HbSS, HbSβ⁰ thalassemia
	Country	Brazil
Wali & Moheeb, 2011⁶³	Sample size	N = 41	To study the effects of the use of hydroxyurea on physical fitness parameters and exercise performance in children with SCA	Not assessed	Physical fitness indices • Vertical jump apparatus: To determine the explosive power of the leg muscles • Grip strength dynamometer: To measure grip strength • Back strength dynamometer: To measure back strength • Leg strength dynamometer: To measure leg strength • Flexibility • Whole body reaction timeTreadmill exercise test • Continuous treadmill running exercise test • Minimum of 6 minutes at a speed corresponding to 5 km/h and a horizontal inclination
	Sex/gender	Males = 41/Females = 0
	Age at enrollment	12.81 ± 0.136 years old
	Age range	10.4 to 14.6 years old
	Type of disease/genotypes	SCA
	Country	Oman
Waltz et al, 2013a⁶⁴	Sample size	N = 42	To test the associations between hemorheological/hematological abnormalities and the performance during the 6MWT in children with SCA	Not assessed	Six-minute walk testing • According to the guidelines of the American thoracic society
	Sex/gender	Males = 22/Females = 20
	Age at enrollment	11.7 ± 2.4 years old
	Age range	8 to 17 years old
	Type of disease/genotypes	HbSS
	Country	France
Waltz et al, 2013b⁶⁵	Sample size	N = 107	To determine the factors associated with resting and exercise-induced hemoglobin oxygen desaturation	Not assessed	Self-paced 6-minute walk testing • According to the guidelines of the American thoracic society
	Sex/gender	Males = NA/Females = NA
	Age at enrollment	NA
	Age range	8 to 16 years old
	Type of disease/genotypes	HbSS, HbSC
	Country	France
Watson et al, 2015⁶⁶	Sample size	N = 33	To compare longitudinal trajectories of maximal aerobic capacity in children with SCA and matched healthy controls	Not assessed	Modified treadmill exercise testing protocol • Two-minute stages of walking or running with increasing treadmill speed without incline • Starting at 2 mph and increasing by 1 mph with each stage • Until volitional fatigue
	Sex/gender	Males = 19/Females = 14
	Age at enrollment	11.4 ± 1.4 years old
	Age range	10 to 13 years old
	Type of disease/genotypes	HbSS
	Country	USA

^aWhen participants were referred to as gender, not sex in the included paper; Age at enrollment refers to the mean age of participants.

Table 2.

Authors’ Conclusions and Relevant Results.

Authors and Publication year	Conclusions and Relevant Results
Alpert et al, 1981²⁸	“Resting heart rate in the three groups of patients with SCA was higher than control values.”
Alpert et al, 1981²⁸	“All patients with SCA had decreased blood pressure responses and maximum working capacity when compared with control subjects”
Alvarado et al, 2015²⁹	“Children with SCA demonstrate impaired heart rate recovery after maximal exercise.”
Alvarado et al, 2015²⁹	“Reduced postexercise heart rate recovery in SCA suggests impaired parasympathetic function, which may become progressively worse with age, in this population”
Barriteau et al, 2021³⁰	“Compared to controls, patients with SCA have lower cerebral StO₂ at all stages of exercise and demonstrate significantly greater decreases in cerebral StO₂ during later stages of exercise.”
	“ Quadriceps StO₂ increased during initial stages of exercise in a similar fashion in patients with SCA and controls, but subsequent decreases from warm-up are greater during later stages of exercise in patients with SCA.”
	“At similar work loads, cerebral and quadriceps StO₂ were both lower in patients with SCA compared to controls.”
Brousse et al, 2020³¹	“SCA children with hemoglobin desaturation during a 6MWT have a higher rate of perceived exertion than non-hemoglobin desaturation children, despite the fact that the heart rate responses and the normalized 6MWT distance are not different between the two groups”
Brownell et al, 2020³²	“Minor improvements in exploratory nutritional, hematologic, and muscle outcomes were noted with supplementation”
Buchowski et al, 2002¹¹	“Adolescents with SCA and control participants expend similar amounts of total daily energy despite significantly higher resting energy expenditure in SCA.”
Chaudry et al, 2013³³	“Children with SCD have a greater than normal effective pulmonary blood flow at rest, on exercise, and during recovery, achieved by raising both stroke volume and heart rate, presumably to compensate for chronic anemia”
Das et al, 2008³⁴	“Symptom-limited CPST can be performed safely in a subgroup of children with SCD and can yield valuable clinical information, which may be used in the fitness evaluation in children with SCD”
	“We found marked abnormalities consistent with decreased aerobic capacity in 75% of children with SCD”
	“No patient demonstrated evidence of myocardial ischemia.”
Da Silva et al, 2022¹⁰	“Children and adolescents with SCA showed reduced functional capacity, quality of life and pulmonary function when compared to their healthy peers”
Da Silva et al, 2023³⁵	“Children and adolescents with SCD were found to have lower than expected exercise capacity as determined by the 6MWT”
Da Silva et al, 2023³⁵	“These findings suggest that increased baseline levels of biomarkers of hemolysis and inflammation impact on 6MWT performance and, consequently, on daily activities requiring some physical effort, such as walking short distances.”
Dedeken et al, 2014³⁶	“The only independent factor predicting an abnormal 6MWT in our population was silent infarct”
Dedeken et al, 2014³⁶	“The lower exercise capacity of children with silent stroke may reflect some subclinical neurological impairment”
Dougherty et al, 2011³⁷	“Maximal muscle strength and peak power are attenuated in children with SCD-SS compared to controls beyond expectation for growth and body composition deficits suggesting additional factors contribute to the attenuation in anaerobic performance”
Dougherty et al, 2018³⁸	“African-American children with SCD-SS compared with healthy African-American children of similar age and pubertal status had performance decrements in dominant hand maximum handgrip strength, peak power and plantar flexion isometric maximal voluntary contraction torques.”
Dougherty et al, 2020³⁹	“Daily high-dose vitamin D supplementation for African American children with and without HbSS improved health-related quality of life and physical performance”
Gordeuk et al, 2011⁴⁰	“Our results indicate that elevated tricuspid regurgitation velocity may be a biomarker in children with sickle cell anemia that is associated with a decline in exercise capacity and that increases in prevalence with age, especially in the presence of high hemolytic rate or increased left ventricular filling pressure”
Grau et al, 2019⁴¹	“Our results demonstrate that a short and acute submaximal exercise bout has no deleterious effects on red blood cell deformability or oxidative stress markers in SCA”
Grau et al, 2019⁴¹	“Physical fitness was reduced in the tested SCA adolescents compared to the healthy control group”
Halphen et al, 2014⁴²	“The prevalence of severe episodes of oxygen desaturation is high among children and adolescents with SCD”
Halphen et al, 2014⁴²	“Many patients have a limited 6MWT distance.”
Hariman et al, 1991⁴³	“In children with SCD and previous stroke(s), residual psychosocial deficits outweigh physical disabilities”
Ho et al, 2023⁴⁴	“Our results showed that these children have inefficient respiratory muscles compared to age‐ and sex‐matched healthy controls”
Ho et al, 2023⁴⁴	“We provide evidence that diaphragm function is related to exercise performance in children with SCD”
Hostyn et al, 2013⁴⁵	“ Patients showed a lower lung functional capacity for exercise than that predicted for the age range in the literature”
Hostyn et al, 2013⁴⁵	“Patients diagnosed with HbSS/Sβ⁰-thalassemia had a lower performance in the test than those with HbSC/S β⁺-thalassemia regarding total distance walked, respiratory rate, and SpO₂ after the 6MWT.”
Karlson et al, 2017¹³	“Results indicated that lower levels of physical activity were associated with more pain”
	“We found that lower peak physical activity was associated with longer pain duration and more intense pain within the same day”
	“Current results suggest a complex bidirectional relationship between pain and physical activity levels in children with SCD”
Karlson et al, 2020⁴⁶	“Children involved in low levels of physical activity experienced more frequent pain and more pain interference than their counterparts who engaged in at least a moderate amount of physical activity in a given week”
Karlson et al, 2020⁴⁶	“Self-reported physical activity declines with age, similar to patterns observed, in general, in the child and adolescent population”
Kienzle et al, 2022¹⁵	“We found that compared to controls, SCA subjects had lower heart rate variability at the end of exercise as well as impaired heart rate variability recovery, especially those with higher baseline heart rate variability”
Knight-Madden et al, 2005⁴⁷	“Asthma and bronchial hyperreactivity are more common in children with SCD than in ethnically matched controls of a similar age, and that atopic asthma is associated with recurrent acute chest syndrome in children with SCD”
Laurent-Lacroix et al, 2024⁴⁸	“Aerobic capacity was seriously impaired in children and adolescents with SCD, in comparison with healthy matched controls and despite the absence of any pattern of heart failure.”
Laurent-Lacroix et al, 2024⁴⁸	“The decrease in aerobic capacity was associated with the level of anemia, the existence of a homozygote HbS/S mutation, lung function, and HRQoL.”
Liem, et al, 2015a⁴⁹	“We found that lower cardiopulmonary fitness, defined by peak VO₂, was independently associated with greater acute increases in soluble vascular cell adhesion molecule level in response to exercise”
Liem, et al, 2015a⁴⁹	“Given the absence of any adverse events associated with maximal CPET in our study, our results also provide preliminary biomarker evidence for the safety of brief, high intensity physical exertion in children and young adults with SCA”
Liem, et al, 2015b⁵⁰	“CPET at maximal exertion is safe and did not directly cause vasoocclusive pain either during or after testing”
	“Maximal CPET is safe in children and young adults with SCA, suggesting that acute exercise challenge is well tolerated in this population even at high levels of exercise intensity and physical exertion”
	“Exercise capacity, defined by peak VO2, is significantly lower in children and young adults with SCA when compared with that measured in matched controls without SCA or sickle cell trait”
	“Reduced exercise capacity was also associated with numerous derangements in the cardiopulmonary response to exercise challenge in our subjects, including reduced efficiency in oxygen uptake and delivery as well as ventilation”
	“Among subjects with SCA, age, sex, BMI, and baseline hemoglobin were independent predictors of weight-adjusted peak VO₂”
Liem et al, 2017²⁰	“Future trials are warranted to further evaluate training benefits associated with regular exercise in children with SCA”
Melo et al, 2017⁵¹	“The variables independently associated with the 6MWD in the 6MWT of children and adolescents with SCA were age (positively) and BMI (inversely).”
Melo et al, 2017⁵¹	“There was no difference in the 6-minutewalk test but patients with sickle cell anemia had a lower physical activity level compared to healthy controls”
Melo et al, 2018¹²	“Children and adolescents with SCA presented lower levels of physical activity than healthy children and adolescents, either when evaluated by physical activity questionnaires or by accelerometer”
Millis et al, 1994⁵²	“Results showed significant performance decrements in HbSS compared with HbAA children”
Mockesch et al, 2017⁵³	“Physical activity and fitness levels were markedly lower in sickle cell patients compared to healthy controls but no association was observed with vascular function”
Moheeb et al, 2007⁵⁴	“Although all groups tolerated well the treadmill exercise protocol, the SCD group exhibited higher mean values of heart rate during exercise than those observed in the SCT and normal control children”
	“SCD children showed higher serum lactate values before and after treadmill exercise compared to the other groups”
	“Children with SCD exhibit high level of adiposity; low level of fitness and their exercise performance appears to be physiologically more stressful as indicated by heart rate and blood lactate concentration responses”
Noordstar et al, 2023⁵⁵	“Children with SCD can participate safely in moderate-intensity organized sports activities when personalized medical background and practical training information is shared with the trainer”
Noordstar et al, 2023⁵⁵	“Children continued their sports participation after the study period.”
Omwanghe et al, 2017⁵⁶	“Children and adolescents with SCD engage in physical activity at levels comparable to that observed in a matched national comparison group, but mostly at moderate to vigorous intensity for shorter durations”
	“They participate in physical education and organized sports despite assumptions and concerns about their inclusion in these activities”
	“Negative personal beliefs about disease impact and perceptions of poor physical functioning were associated with decreased physical activity and participation in organized sports”
Pianosi et al, 1991a⁵⁷	“Children with SCA compensate for their lack of oxygen-carrying capacity by both an elevation of cardiac output and increased extraction of the available O₂, resulting in marked venous desaturation”
Pianosi et al, 2012⁵⁸	“Children with SCA have an exaggerated ventilatory response to exercise because of a combination of factors, most important of which are increased physiologic dead space and low hemoglobin level”
Rock et al, 2023⁵⁹	“Children with SCD present with decreased strength, neuromuscular activation, gross motor performance, and quality of life”
Singhai et al, 1997⁶⁰	“Reducing physical activity is a compensatory mechanism in children with an energy deficiency and a similar adaptive response may occur in SCD”
Sylvester et al, 2007⁶¹	“Similar proportions of children responded to the cold air and exercise challenge and the magnitude of response to the 2 tests was similar”
Vieira et al, 2016⁶²	“In children and adolescents with SCD, there was a significant prevalence of abnormal pulmonary function”
Wali & Moheeb, 2011⁶³	“Hydroxyurea treatment improved the exercise tolerance and most of the physical fitness parameters in children with SCA”
Waltz et al, 2013a⁶⁴	“We showed that a low level of red blood cell deformability, a high level of anemia and a low fetal hemoglobin level were independent predictors of a reduced 6MWT performance (ie, low percentage of predicted 6-min walk distance) in SCA children”
Waltz et al, 2013b⁶⁵	“Physiological strain during exercise and red blood cell aggregation properties are likely risk factors in the occurrence of exercise-induced hemoglobin oxygen desaturation in SS children”
Watson et al, 2015⁶⁶	“Children with SCA demonstrated lower VO2peak compared to sex, gender, race, tanner stage, and FFM matched healthy controls”
Watson et al, 2015⁶⁶	“During a 2-year follow-up period, VO2peak in children with SCA remained unchanged but it significantly increased in healthy controls”

PA Assessments

Few studies (13/45, 28.9%) reported assessing participants’ PA level, with 11/13 (84.6%) of these studies using more than 1 type of assessment. Laurent-Lacroix et al, 2024 and Liem et al., 2017 were the only studies that reported using only 1 type of PA assessment, namely they respectively used the Ricci and Gagnon questionnaire to assess self-reported PA levels⁴⁸ and a wearable heart rate monitor.²⁰ Seven other PA questionnaires were used to assess PA levels. One self-reported questionnaire for children was used to assess participants’ PA frequency.⁴⁶ The Brazilian version of the Physical Activity Questionnaire for Older Children and Adolescents was used in 2 studies.^12,51 The International Physical Activity Questionnaire adapted for adolescents was used in 1 study,⁵³ the National Institute for Public Health and the Environment (RIVM) questionnaire was also used in 1 study,⁵⁵ and Omwanghe et al., 2017 used a combination of the National Health and Nutrition Examination Survey (NHANES), the Physical Activity Questionnaire (PAQ), and questions focused on a 7-day recall of physical functioning, adapted from the PROMIS Pediatric Item Bank on Physical Function Mobility.⁵⁶ Three studies assessed PA by using an Actigraph device,⁵⁵ with Karlson et al, 2016 using measurements from the 14-day study period¹³ and Melo et al., 2018 using measurements from recordings over 7 consecutive days.¹² Two studies also used body movement recordings to measure total energy expenditure from PA over a 24-hour period.^11,60 One study used a self-reported diary to assess PA¹¹ and 1 study used self-perceived moderate-to-vigorous physical activity.⁵⁵

Physical Fitness Assessments

Most studies (40/45, 88.9%) reported assessing participants’ physical fitness level. The most common type of assessment was the 6MWT, which was used as an assessment of physical fitness in 13 studies.^{31,35,36,40,42,44,45,51,53,59,62,64,65} These studies generally reported following the American Thoracic Society Guidelines and either provided participants with verbal encouragement or not. Eight studies assessed physical fitness with maximal cardiopulmonary exercise testing using a ramp cycle protocol^20,33,48,49 and the modified Godfrey protocol.^29,30,50,55 Seven studies used ad hoc treadmill protocols to assess physical fitness.^{38,39,47,54,61,63,66} Four studies used cycle ergometer exercise testing, with 2 studies using a protocol that required a progressive increase in workload,^15,41 1 study using a modification of the Bruce and Hornsten format,²⁸ and 1 study using Jones stages I and III.⁵⁸ Maximal handgrip strength using a handgrip dynamometer,^37-39 maximal vertical squat jump (3 warm-ups followed by 3 maximal squat jumps)^37-39 were both used in 3 studies. Maximum symptom-limited cardiopulmonary exercise testing (Bruce protocol conducted according to the guidelines of the American Heart Association³⁴ and incremental cycle ergometer protocol¹⁵), muscle torque (plantar flexion isometric MVC torques),^38,39 neuromuscular motor skills (Bruininks-Oseretsky Test of Motor Proficiency),^39,59 and physical fitness indices (ie, vertical jump apparatus, grip strength dynamometer, back strength dynamometer, leg strength dynamometer, flexibility, whole body reaction time)^54,63 were each used as a measure of physical fitness in 2 studies. The following measures of physical fitness were each used in 1 study: 24-hour protocol (measurement of standard daily activities),¹¹ functional capacity (modified shuttle test),¹⁰ motoric functions questionnaires (assessed using the modified Motor Assessment Scale),⁴³ activity of daily living questionnaire (assessed using the Barthel Index),⁴³ physical performance (100-yard potato race and 20- and 40-yard freestyle swimming test),⁵² Timed Up and Down Stairs assessment,⁵⁹ Timed Up and Go assessment,⁵⁹ muscle function and strength,³² and Canadian Agility and Movement Skill Assessment (CAMSA).⁵⁵

Physical Activity Interventions

Two studies (2/45, 4.4%) piloted a physical activity intervention in children and adolescents with SCD.

Liem et al, 2017²⁰ prescribed a progressive 12-week individualized home exercise training program comprised of 3 sessions per week of cycling on stationary bicycles. Heart rate and total exercise time were used to monitor participants’ progress. During weeks 1 to 6, prescribed exercise duration ranged from 10 to 30 minutes and targeted heart rate ranged from 50 to 100% of the heart rate at ventilatory threshold. During weeks 7 to 12, prescribed exercise duration was maintained at 30 minutes and targeted heart rate was maintained at 100% of the heart rate at ventilatory threshold. No adverse events were reported.²⁰ Liem et al reported that mean peakVO₂ (baseline: 28.5 ± 5.6 mL/kg/min and 6-week: 30.8 ± 5.6 mL/kg/min, P = 0.01) and peak workload (baseline: 103 ± 20 watts and 6-week: 111 ± 26 watts, P = 0.03) significantly improved after 6 weeks of individualized home exercise training.²⁰ No significant improvement in exercise parameters, including VO₂ peak and peak workload were reported at the end of the program. There was also no significant improvements in total white blood cell count, absolute neutrophil count, absolute monocyte count, Hemoglobin, platelet count, and D-dimer.²⁰

Noordstar et al, 2023⁵⁵ conducted a 10-week moderate to vigorous intensity organized sports program. Participants’ medical background and practical training information were shared with the certified trainer before the start of the first training session. Training sessions were soccer-related activities (dribbling, shooting, and passing), practiced individually, in pairs, or with the whole group for a total duration of 90 minutes. Children participated in a soccer match at the end of each training. Noordstar et al. reported that no intensity restrictions were imposed. All sessions were supervised by the medical team. One adverse event (vaso-occlusive episode) that required hospital admission and treatment with opiates was reported by the study team.⁵⁵ At baseline, Noordstar et al reported that children spent between 4.2% and 13.2% of their time engaging in moderate-to-vigorous physical activity and they were physically active for at least 60 minutes per day for 2 to 7 days. At the end of the program, children spent between 4.5% and 9.7% of their time engaging in moderate-to-vigorous physical activity and they were physically active for at least 60 minutes per day for 3 to 7 days.

Discussion

Our scoping review provides a description of the current methods used to assess PA and physical fitness in children and adolescents (≤21 years) diagnosed with SCD. Accurately measuring PA and physical fitness is essential to effectively evaluate associations with health-related outcomes, study PA intervention efficacy, and monitor changes over time. Our review highlights substantial heterogeneity in the assessment methods across the included studies, limiting generalizability. Moreover, we identified only 2 PA interventions for SCD patients that met our inclusion criteria, emphasizing a critical gap in the literature. These findings emphasize the need for the development of safe PA interventions tailored to this understudied population. This review serves as a foundation for future research aiming to improve PA outcomes in children and adolescents with SCD.

The potential benefits of PA for children diagnosed with SCD have been considered in previous studies.¹³ Given that children and adolescents with SCD are prone to engage in lower levels of PA compared to their healthy peers,^11,12 understanding the role that PA can play for this population is crucial. Buchowski et al.¹¹ have reported that adolescents with SCD exhibit PA levels up to 10.8% lower than their healthy counterparts (SCD: 1.32 ± 0.10 vs controls: 1.48 ± 0.12, P < 0.001). Karlson et al.⁴⁶ have observed that 23.1% of children with SCD engage in at least 30 minutes of PA only one to 2 days per week, 43.5% participate in 30 minutes of PA 3 to 5 days per week, and 22.4% maintain this level of PA 5 to 7 days per week. While no specific PA guidelines have been developed for children and adolescents with SCD, the general Physical Activity Guidelines for healthy children and adolescents recommend at least 60 minutes of moderate-to-vigorous intensity physical activity per day each week.⁶⁷ Omwanghe et al.⁵⁶ analyzed data from NHANES using self-reported questionnaires and found that children with SCD and their healthy peers engage in a similar proportion of PA. Specifically, 66% of children with SCD and 65% of healthy children reported engaging in at least 10 minutes of vigorous PA per week (P = 0.91).⁵⁶ The study also found that a significantly higher proportion of children with SCD (67%) reported engaging in at least 10 minutes of moderate-to-vigorous PA compared to 42% of healthy children (P < 0.01)⁵⁶

To assess PA levels, both objective and subjective methods were used in the included studies. Five studies used self-reported questionnaires,^{12,46,51,53,56} while 2 used accelerometers.^12,13 A key limitation is that the majority of the included studies did not provide a comprehensive description of their PA assessment methods, likely because PA was not the primary outcome. This lack of detail reduces the reproducibility and comparability of findings across studies. To enhance transparency and facilitate reproducibility, we recommend that future studies provide thorough descriptions of their PA assessment methods. While self-reported questionnaires are widely used for their accessibility and cost effectiveness, they are often criticized due to their recall bias leading to over- or underestimation PA levels.⁶⁸ Incorporating objective measures can help mitigate these limitations by providing more precise and continuous data on PA. However, the higher cost and logistical challenges associated with accelerometers must be acknowledged, particularly in studies with limited resources. Future studies should be conducted to explore this topic further.

Selecting the appropriate method to assess PA is crucial given the lack of consensus on the optimal PA intensity for children and adolescents with SCD. Notably, only 2 studies included in this review focused on PA interventions in these patients. Liem et al, 2017 prescribed a progressive 12-week individualized home exercise training program,²⁰ while Noordstar et al., 2023 conducted a 10-week moderate to vigorous intensity organized sports program.⁵⁵ Both studies reported the feasibility and safety of their PA interventions.^20,55 However, Liem et al. did not report significant training effects on exercise parameters (eg, peak VO₂), total white blood cell count, platelet count, C-reactive protein and D-dimer.²⁰ The current literature therefore emphasizes the need for additional research to determine whether specific types or intensities of PA provide health benefits for children with SCD. Karlson et al., 2017¹³ found that the majority of children with SCD (97.7%) engage primarily in light-intensity PA, while 43.4% engage in vigorous-intensity PA. Their findings reinforced that children with SCD are generally less physically active than their healthy peers.¹³ However, there is little consensus regarding the safety of high-intensity PA for children and adolescents with SCD.¹⁵ Some studies suggest that high-intensity PA can increase vaso-occlusive pain, while other studies suggest that acute and intense PA can increase the risk of sickling due to dehydration and oxidative stress.¹⁴ Noordstar et al. reported 1 vaso-occlusive episode in 1 participant 6 days following the start of the moderate to vigorous training sessions.⁵⁵ However, the authors reported that this episode may not have been directly related to the PA intervention.⁵⁵ Further investigations are therefore necessary to establish evidence-based PA recommendations that find a balance between yielding potential benefits and taking into consideration safety concerns in children and adolescents with SCD.

The benefits that PA can confer for these patients can also extend to improvements in physical fitness outcomes. Most of the included studies assessed physical fitness, highlighting its relevance in this population. The 6MWT was the most commonly used assessment in 13 studies,^{31,35,36,40,42,44,45,51,53,59,62,64,65} while 10 studies evaluated physical fitness using a cardiopulmonary exercise test.^{15,20,29,30,33,34,48-50,55} Significant heterogeneity in assessment methods across studies limits direct comparisons and interpretations. Despite this variability, it is important to acknowledge the efforts made by researchers to measure physical fitness in children with SCD. Encouragingly, none of the included studies reported adverse events related to physical fitness assessments. Das et al, 2008³⁴ demonstrated the feasibility and safety of symptom-limited cardiopulmonary stress testing in children with SCD. Liem et al.^20,49,50 reported that SCD patients were able to complete cardiopulmonary exercise tests without any major adverse events. These findings suggest that well-monitored physical fitness assessments can be conducted safely in children with SCD. Additionally, using physical fitness assessments that are close to patients’ daily activities may provide a more comprehensive understanding of their physical fitness status. Notably, 1 study introduced an innovative approach by incorporating an unconventional physical performance test, which included a 100-yard potato race and 20- and 40-yard freestyle swimming tests.⁵²

Children and adolescents living with SCD can have a variety of complications, and it is unclear if PA is associated with an improvement in those complications. SCD results in increased energy expenditure, which could be related to the lower levels of PA observed in SCD.⁶⁹ High intensity activity could lead to sickle cell-related complications, but light-to-moderate activity could confer benefits for individuals with SCD. It can be challenging to know that exact amount of PA that is both safe and has the potential to improve clinical outcomes in SCD. Merlet et al⁷⁰ demonstrated that moderate activity resulted in improvements in capillary networks, and improved indexes of PA. Clinically, it is still unclear if this results in reduced complications such as VOCs/painful events. Other clinically significant outcomes that may improve with PA in SCD include cardiovascular capacity and pulmonary function. Further investigation studying the impact of PA on SCD symptoms and complications continues to be needed.

To conclude, it is essential to recognize the impact of SCD on PA behavior and the substantial work that remains to be done to develop and implement safe and accessible PA interventions for this understudied population. This scoping review evidenced that there is significant heterogeneity in the methods used to assess PA and physical fitness in children with SCD and that evidence-based PA interventions in this population are limited. There is also a critical need to determine the optimal PA intensity for children and adolescents with SCD, as no guidelines currently exist to define what is both safe and effective. Conducting future research aiming to address these gaps is critical to allow for the formulation of evidence-based PA recommendations that are specific to the needs and challenges of children with SCD.

Supplemental Material

Supplemental Material - Physical Activity and Physical Fitness in Children and Adolescents Diagnosed With Sickle Cell Disease: A Scoping Review

Supplemental Material for Physical Activity and Physical Fitness in Children and Adolescents Diagnosed With Sickle Cell Disease: A Scoping Review by Ariane Levesque, Deepika Pugalenthi Saravanan, Peri Newman, Lauryn E. Six, Yevgeniya Bamme, Smita Dandekar, Kate J. Krause, Maria Chang Swartz, Gayle M. Smink, and Maxime Caru in American Journal of Lifestyle Medicine

Footnotes

Acknowledgments

We acknowledge Julia McAlexander for her valuable assistance during this review.

Author Contributions

AL, DPS, GS and MC conceived the study and participated in the design and the coordination. KJK and MC performed the literature search. AL, DPS, PN, LES, and MC performed the study selection. AL, DPS, PN and LES performed data extraction from included articles. AL, DPS, PN, LES, YB, SD, KJK, MCS, GMS and MC made substantial contributions to the interpretation of the data. AL, DPS, PN, LES, YB, SD, KJK, MCS, GMS and MC critically drafted or revised the manuscript for important intellectual content. AL, DPS, PN, LES, YB, SD, KJK, MCS, GMS and MC provided final approval of the version to be published and agreed to be held accountable for all aspects of the review in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Maxime Caru, PhD, PhD is supported by the Four Diamonds Research Funds, Department of Pediatrics, Division of Hematology and Oncology, Pennsylvania State Health Children’s Hospital, Hershey, PA, USA. Ariane Levesque, PhD is supported by the Four Diamonds Research Funds, Department of Pediatrics, Division of Hematology and Oncology, Pennsylvania State Health Children’s Hospital, Hershey, PA, USA.

ORCID iD

Maxime Caru

Supplemental Material

Supplemental material for this article is available online.

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