Adiponectin Levels During Steady State and Vaso-Occlusive Crisis in Nigerian Children with Sickle Cell Anaemia

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Adiponectin, an adipokine with anti-inflammatory and insulin-sensitizing properties, is well-studied in metabolic disorders but remains underexplored in SCA. This study assessed serum adiponectin levels in Nigerian children with SCA during steady state and VOC. Methods We conducted a cross-sectional study involving 50 children with SCA (HbSS genotype) and 46 age- and sex-matched healthy controls (HbAA genotype). Adiponectin levels were measured using ELISA, and group comparisons were performed. Multivariable linear regression was used to assess associations between adiponectin and clinical variables. Results Children with SCA had significantly higher adiponectin levels (median 3.2 µg/mL, IQR 2.2–4.38) compared to healthy controls (0.4 µg/mL, IQR 0.3–0.6; p < 0.001). Among the SCA group, those in VOC had higher adiponectin concentrations than those in steady state (median 4.00 µg/mL vs. 2.27 µg/mL; p < 0.001). These differences remained significant after adjusting for age, sex, BMI, and socio-economic status. Conclusion Adiponectin levels are elevated in children with SCA, particularly during VOC, suggesting its potential role as a dynamic biomarker of disease activity. These findings contribute to understanding the inflammatory profile of paediatric SCA and support further research into adiponectin as a non-invasive marker in clinical monitoring. Sickle cell anaemia Adiponectin Inflammation Biomarker Vaso-occlusive crisis Therapeutic target Figures Figure 1 Introduction Sickle cell anaemia (SCA) is a life-threatening genetic disorder characterized by a single-point mutation in the β-globin gene that leads to abnormal sickle haemoglobin (HbS) formation. Under low oxygen tension, erythrocytes become rigid and sickle-shaped, causing microvascular occlusions, tissue ischemia, and painful vaso-occlusive crises (VOC) [ 1 , 2 ]. Chronic intravascular haemolysis and recurrent VOC events drive a persistent state of systemic inflammation, endothelial dysfunction, and oxidative stress [ 1 ]. Indeed, chronic inflammation plays a central role in SCA pathogenesis and underlies many of its complications [ 1 ]. While pro-inflammatory pathways in SCA have been extensively studied, the role of endogenous anti-inflammatory mediators in counterbalancing this inflammation remains poorly understood. Identifying such mediators could unveil new biomarkers of disease activity and novel therapeutic approaches. Adiponectin is a hormone secreted predominantly by adipose tissue that has potent anti-inflammatory, anti-atherogenic, and insulin-sensitizing properties [ 3 ]. It suppresses pro-inflammatory cytokines (e.g., tumour necrosis factor-α and interleukin-6) via inhibition of NF-κB signalling and reduces oxidative stress while enhancing nitric oxide-mediated endothelial function [ 3 ]. High circulating adiponectin levels are generally associated with improved metabolic profiles and reduced cardiovascular risk [ 3 ]. In conditions of chronic inflammation, adiponectin is thought to act as a compensatory, protective factor. However, its role in hemoglobinopathies such as SCA remains underexplored particularly in children. SCA patients often have lower body mass index and a high inflammatory burden, factors that could influence adiponectin levels [ 4 , 5 ]. Given adiponectin’s anti-inflammatory and metabolic effects, we hypothesized that adiponectin might be elevated in children with SCA as a counter-inflammatory mechanism, and that it could serve as a biomarker of disease severity or activity (particularly during VOC). This study aimed to compare serum adiponectin levels between children with SCA (HbSS genotype) and healthy controls (Hb AA genotype). By elucidating adiponectin’s profile in paediatric SCA, we seek to evaluate its viability as a biomarker of disease progression and lay groundwork for future therapeutic strategies leveraging adiponectin to mitigate inflammation in SCA. Methods Study Design and Participants We conducted a cross-sectional comparative study of paediatric SCA patients and healthy controls. Children aged 1–17 years with a confirmed diagnosis of SCA (homozygous HbSS genotype) were recruited from the paediatric haematology clinic at Nnamdi Azikiwe University Teaching Hospital (NAUTH) in Nnewi, Nigeria. SCA diagnosis was confirmed by haemoglobin electrophoresis. Both SCA patients in steady state and those experiencing an acute vaso-occlusive crisis at the time of evaluation were eligible. “Steady state” was defined as at least four weeks without acute crisis or transfusion. An age-, sex-, and socio-economic status-matched control group comprised healthy children (HbAA genotype) with no history of chronic illness. Controls were recruited from the general paediatric outpatient department and community, and confirmed HbAA by electrophoresis. Inclusion criteria: The study included children aged 1 to 17 years with a confirmed diagnosis of HbSS sickle cell anemia (SCA) in the patient group. Participants with SCA were either in a steady state or experiencing an acute vaso-occlusive crisis (VOC). A control group of healthy children with an HbAA genotype was also recruited, matched to the SCA group by age (± 2 years), sex, and socio-economic status (SES). Exclusion criteria: Children were excluded if they had any known chronic comorbidities, such as diabetes, renal disease, or liver disease, that could potentially affect adiponectin levels. Those who had received a blood transfusion within the four months preceding enrollment were also excluded to avoid transient donor influences. Additionally, children classified as obese, defined as having a body mass index (BMI) at or above the 95th percentile for age and sex, were not included due to the known impact of obesity on adiponectin levels. Lastly, any child with an acute infection or inflammatory condition at the time of sampling, except for those experiencing VOC in the SCA group, was excluded from participation. All participants were enrolled after obtaining written informed consent from parents or guardians (and assent from older children). The study protocol was approved by the NAUTH Institutional Review Board, and all procedures followed the ethical standards of the Helsinki Declaration. Data Collection and Clinical Assessment Upon enrolment, a standardized questionnaire was administered to collect demographic information (age, sex, SES) and relevant clinical history. For SCA patients, we recorded SCA-specific clinical data including frequency of VOC in the past year and current clinical status (steady state vs. VOC). Socio-economic status was classified (lower, middle, or upper) based on parental occupation and education. A focused physical examination was conducted for each child. Anthropometric measurements were obtained using standard techniques: weight was measured to the nearest 0.1 kg using a calibrated scale and height to the nearest 0.1 cm using a stadiometer. Body mass index (BMI) was calculated as weight (kg) divided by height in meters squared (kg/m²) and interpreted using age- and sex-specific percentiles. Laboratory Measurements Venous blood samples (4 mL) were collected from each participant under aseptic conditions. Half of the sample (2 mL) was anticoagulated with EDTA and used to confirm haemoglobin genotype by electrophoresis (to ensure accurate group classification). The remaining 2 mL was allowed to clot, and serum was separated by centrifugation. Sera were immediately frozen at − 80°C until batch analysis. Serum adiponectin concentration was measured for all subjects using a quantitative enzyme-linked immunosorbent assay (ELISA) kit (specific for human total adiponectin). All samples were run in duplicate, and the mean value was used for analysis. The assay’s intra- and inter-assay coefficients of variation were < 8%. Laboratory personnel were blinded to the participant’s group (SCA or control) during adiponectin measurements to reduce bias. Statistical Analysis Analyses were conducted using Python 3.12. Participant characteristics and adiponectin levels were summarized using descriptive statistics. Normality of continuous variables was assessed, with means and standard deviations (SD) reported for approximately normal distributions (e.g., age) and medians with interquartile ranges (IQR) for skewed variables (e.g., adiponectin, BMI). Categorical variables (sex, SES) were presented as frequencies and percentages. Group comparisons between SCA and controls were conducted using independent t-tests for normally distributed data and the Mann-Whitney U test for non-parametric variables. Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate. To assess independent associations of adiponectin with SCA and other covariates, multivariable linear regression was performed, with log-transformed adiponectin as the outcome variable. Predictors included disease status (SCA vs. control), age, sex, BMI, and SES. Additional models examined differences within SCA subgroups (steady state vs. control, VOC vs. steady state). β coefficients, 95% confidence intervals (CI), and p-values were reported, with statistical significance set at p < 0.05. Results Participant Characteristics A total of 96 children were studied: 50 with SCA and 46 healthy controls. Table 1 summarizes the demographic and clinical characteristics of the SCA and control groups. The mean age of participants was 8.99 ± 4.61 years (range 1–17), with no significant age difference between the SCA group (9.00 ± 4.62 years) and controls (8.98 ± 4.65 years; p = 0.982). The sex distribution was similar in both groups (approximately 58% male in each; p = 0.999). Socio-economic status categories were evenly represented in SCA vs. controls (lower, middle, upper SES proportions did not differ significantly, p = 0.869). Notably, children with SCA had lower body mass indices on average than healthy peers. The median BMI in the SCA group was 15.24 (IQR 13.73–16.30) compared to 16.22 (IQR 15.28–18.44) in controls. This difference was statistically significant ( p = 0.002). No SCA patient in the study was obese by paediatric criteria, in line with our exclusion criteria. Table 1 Baseline characteristics of the study population (SCA patients vs. healthy controls). Variable Total (n = 96) SCA (n = 50) Control (N = 46) p-value Age (years, mean ± SD) 8.99 ± 4.61 9.00 ± 4.62 8.98 ± 4.65 0.982 Gender Male, n (%) 56 (58) 29 (58) 27 (59) 0.999 Female, n (%) 40 (42) 21 (42) 19 (41) SES Lower SES, n (%) 41 (43) 21 (42) 20 (43) 0.869 Middle SES, n (%) 45 (47) 23 (46) 22 (48) Upper SES, n (%) 10 (10) 6 (12) 4 (9) BMI (kg/m², median [IQR]) 15.7 [14.37–17.31] 15.24 [13.73–16.30] 16.22 [15.28–18.44] 0.002 ** Serum Adiponectin Levels in SCA vs. Controls SCA patients demonstrated markedly higher circulating adiponectin levels compared to healthy children. The overall median adiponectin level in the SCA group was 3.20 µg/mL (IQR 2.20–4.38), whereas in the control group it was 0.4 µg/mL (IQR 0.30–0.6). This reflects an approximately eight-fold elevation of median adiponectin in SCA. The difference was highly significant ( p < 0.0001). There was also greater variability among SCA patients, with some values exceeding 6 µg/mL, while controls consistently had low levels (< 1 µg/mL). These results suggest that SCA is associated with an upregulation of adiponectin. In a subgroup analysis within the SCA cohort, adiponectin levels were further stratified by clinical status (steady state vs. VOC at time of sampling). SCA patients in VOC exhibited significantly higher adiponectin concentrations than those in steady state. The median adiponectin in the VOC subgroup was 4.00 µg/mL (IQR 3.20–5.62) µg/mL, compared to 2.27 µg/mL (IQR 1.65–2.95) in the steady-state subgroup ( p < 0.0001). Table 2 shows this comparison. Thus, not only are adiponectin levels elevated in SCA generally, but they appear to rise even more during acute vaso-occlusive episodes. Table 2 Serum Adiponectin Levels in SCA vs. Controls Group Median Adiponectin (µg/mL) Interquartile Range (IQR) Range p-value SCA (Total) 3.20 2.20–4.38 0.9–9.4 < 0.0001 ** Control 0.40 0.30–0.60 0.2–1.2 SCA (Steady State) 2.27 1.65–2.95 0.9–4.8 SCA (VOC) 4.00 3.20–5.62 2.1–9.4 < 0.0001 ** Multivariate Analysis of Factors Associated with Adiponectin To determine whether SCA status independently predicts higher adiponectin after accounting for potential confounders, we performed multivariate linear regression. In the full model comparing all SCA patients (combining steady state and VOC) against controls, SCA status was a strong independent predictor of increased adiponectin (β = 3.268, 95% CI 2.724–3.813, p < 0.001). This indicates that even after adjusting for age, sex, BMI, and SES, children with SCA had on average ~ 3.27 µg/mL higher adiponectin than controls. Figure 1 A presents a forest plot of the regression results (Model 1). Among the covariates, age showed a significant inverse association with adiponectin levels. In the model, older children tended to have lower adiponectin. Specifically, compared to the reference (children < 6 years), adolescents ≥ 16 years had significantly reduced adiponectin (β ≈ − 1.94, 95% CI − 3.06 to − 0.81, p = 0.001), and those aged 11–15 also had lower levels (β ≈ − 1.73, 95% CI − 2.56 to − 0.90, p < 0.001). This age effect is consistent with trends observed in healthy paediatric populations, where adiponectin levels naturally decline with age during adolescence. BMI was positively associated with adiponectin in the combined SCA vs. control model (β ≈ 0.20 per kg/m², p = 0.016), meaning higher BMI was linked to slightly higher adiponectin when considering all participants. Notably, SES had an effect: children from upper SES backgrounds showed higher adiponectin than those from lower SES (β ≈ 1.16, 95% CI 0.26–2.06, p = 0.012). Sex did not significantly influence adiponectin in this model (p = 0.24). We also ran two secondary regression models focusing on within-SCA comparisons. In a model comparing SCA patients in steady state to healthy controls (excluding SCA VOC cases), SCA steady-state status remained associated with elevated adiponectin (β = 1.82, 95% CI 1.48–2.16, p < 0.001), though the age effect was attenuated (age categories were not significant in this subset). Interestingly, in this steady-state model, BMI carried a negative association with adiponectin (β ≈ − 0.14, p = 0.011), suggesting that among relatively stable SCA patients, those with higher BMI tended to have slightly lower adiponectin – a pattern opposite to that seen when including the VOC cases or controls (Fig. 1 B). Finally, in a model comparing SCA VOC vs. SCA steady state (to assess factors in acute crisis), VOC status was a strong independent predictor of higher adiponectin (β = 1.963, 95% CI 1.19–2.74, p < 0.001). Within SCA, the inverse age relationship persisted (older SCA patients had significantly lower adiponectin even accounting for crisis status). Upper SES also remained associated with higher adiponectin in the SCA-only model (β ≈ 1.77, p = 0.007), and BMI again showed a positive association (β ≈ 0.22, p = 0.027). In all models, the presence of SCA (and particularly VOC) emerged as the dominant factor related to increased adiponectin levels (Fig. 1 C). These multivariate findings reinforce that the observed adiponectin elevation in SCA is robust and not solely explained by confounding differences in age, body composition, or other factors. Discussion In this study, we provide evidence that adiponectin, an anti-inflammatory adipokine, is significantly elevated in children with sickle cell anaemia compared to healthy peers. Median adiponectin levels in the SCA group were higher than in controls, and this difference remained significant after adjusting for age, sex, BMI, and socio-economic factors. Furthermore, we observed that adiponectin concentrations were especially high during acute vaso-occlusive crises, nearly double the levels seen in steady-state SCA patients. These novel findings suggest that adiponectin may play a role as an endogenous modulator of inflammation in SCA and could serve as a biomarker for disease activity or stress. The chronic inflammatory state of SCA is well established [ 1 ], yet counter-regulatory mechanisms have received less attention. The elevation of adiponectin in SCA, particularly during VOC, may represent a compensatory response to acute inflammation and vascular injury. Adiponectin exerts anti-inflammatory effects by inhibiting NF-κB signaling and reducing cytokine production. During VOC—characterized by intense inflammation, ischemia-reperfusion injury, and endothelial activation—an adiponectin surge may serve to mitigate tissue damage by attenuating inflammatory cascades and enhancing endothelial function, possibly through nitric oxide production [ 3 ]. Our finding of increased adiponectin levels in VOC supports the concept of adiponectin as a rapid-response anti-inflammatory mediator. Notably, a similar pattern is observed in other acute inflammatory states, where adiponectin rises as part of the endogenous effort to counteract inflammation [ 6 ]. Further investigation is warranted to determine whether specific adiponectin isoforms (e.g., high-molecular-weight vs. low-molecular-weight) are preferentially upregulated during VOC and how they correlate with inflammatory markers. We found an inverse relationship between age and adiponectin levels in SCA, mirroring patterns in the general paediatric population where adiponectin tends to be highest in early childhood and declines through adolescence [ 3 , 5 ]. Younger children with SCA had the highest adiponectin levels, which might confer some protective advantage and could potentially contribute to the observation that disease severity often increases with age. As SCA patients get older, cumulative organ damage and more frequent complications occur; a decline in beneficial adiponectin could be one contributing factor to this worsening. This raises an interesting question: might interventions to maintain higher adiponectin levels as patients age improve clinical outcomes? While purely speculative at this stage, our data open the door to considering adiponectin-targeted therapies in SCA. For instance, recombinant adiponectin or adiponectin receptor agonists (such as AdipoRon) have shown anti-inflammatory effects in experimental models [ 6 ]. If safely applicable, these could be explored in SCA to augment the patient’s anti-inflammatory defences, particularly in older children or adults with severe disease. From a clinical perspective, adiponectin shows promise as a biomarker in SCA. Monitoring adiponectin levels could potentially help identify patients at higher risk of complications or incipient VOC. For example, an acute rise in adiponectin might precede or coincide with a VOC episode, serving as a biochemical indicator of ongoing vascular inflammation. Regular adiponectin measurements could complement existing laboratory markers (like C-reactive protein) to provide a more nuanced picture of a patient’s inflammatory status. Moreover, inter-individual differences in baseline adiponectin might correlate with disease severity – an area that could be investigated by correlating adiponectin with frequency of VOC, organ damage, or other clinical indices in a larger study. If adiponectin proves to be a reliable marker of disease activity, it could aid in patient stratification and personalized management. High-adiponectin patients might have different supportive care needs than low-adiponectin patients, for instance. In terms of therapeutic implications, our findings encourage further exploration of adiponectin or its pathways as therapeutic targets. One could envision adjunct therapies that boost adiponectin levels or mimic its actions to reduce inflammation in SCA. An interesting possibility is the synergistic use of adiponectin-modulating strategies with existing SCA treatments. Hydroxyurea remains the cornerstone of SCA therapy, primarily increasing foetal haemoglobin and reducing haemolysis and VOC frequency. Hydroxyurea also has some anti-inflammatory effects, though indirect. It is conceivable that combining hydroxyurea with an adiponectin-elevating agent could yield additive benefits: hydroxyurea ameliorating the hematologic cause of VOC and adiponectin mitigating the inflammatory consequences. Preclinical studies could test this synergy. Additionally, lifestyle interventions that raise adiponectin – such as exercise or certain dietary components – might be advised as supportive care. For example, weight management is relevant: we observed a complex relationship between BMI and adiponectin in SCA (with higher BMI correlating with higher adiponectin overall, but lower adiponectin in stable SCA). Regardless, given that SCA patients are often underweight or lean, nutritional interventions to ensure adequate adipose function (hence adiponectin production) could be beneficial. The elevation of adiponectin in SCA may have significant metabolic implications. Despite the chronic inflammatory state, which typically predisposes individuals to insulin resistance, SCA patients have historically exhibited a lower incidence of type 2 diabetes compared to the general population [ 7 – 11 ]. One proposed explanation is that persistently high adiponectin levels enhance insulin sensitivity, counteracting the pro-diabetic effects of inflammation[ 12 – 16 ]. Adiponectin facilitates glucose uptake, promotes fatty acid oxidation, and suppresses hepatic gluconeogenesis, thereby supporting metabolic homeostasis. However, recent evidence suggests that as SCA patients age, their diabetes risk converges with that of the general population [ 17 ]. This pattern aligns with the progressive decline in adiponectin levels over time, suggesting that the protective metabolic effects of adiponectin diminish with age, unmasking an underlying diabetes risk [ 5 ]. This raises an intriguing possibility: Could adiponectin itself serve as a therapeutic target for diabetes, beyond its relevance to SCA? Given its dual role in insulin sensitivity and inflammation regulation, adiponectin-based interventions could offer metabolic benefits to both SCA patients and individuals at risk for diabetes. Future studies should explore whether strategies aimed at sustaining adiponectin levels—such as adiponectin-mimetic therapies—can delay or mitigate diabetes onset, particularly in aging SCA patients and other high-risk populations. Our findings highlight the need for further research into adiponectin’s role as both a biomarker and a potential therapeutic target for metabolic regulation in SCA and beyond[ 18 ]. The paradox of low diabetes rates in younger SCA patients, despite chronic inflammation, followed by an increasing prevalence with age, underscores adiponectin’s critical role in metabolic homeostasis and its broader implications for haematology, endocrinology, and metabolic disease research. It is important to note the limitations of our study. First, as a cross-sectional study with a modest sample size, we cannot establish causality or temporal dynamics. Our single time-point measurements provide a snapshot; a longitudinal approach would be needed to see how adiponectin fluctuates during and after VOC in the same individual, and whether low baseline adiponectin predicts future complications. Second, we focused on total adiponectin level but did not measure specific multimers (high- vs. low-molecular-weight adiponectin), which may have differing bioactivity. Including multimer analysis could yield deeper insight. Third, we did not directly measure inflammatory markers (such as IL-6, TNF-α, or high-sensitivity CRP) alongside adiponectin in this study. Thus, we infer anti-inflammatory effects of adiponectin based on known biology, but correlating adiponectin with inflammatory marker levels in SCA patients would strengthen the evidence for its immunomodulatory role [ 3 , 6 ]. Finally, this study was conducted in a single centre and predominantly in an African paediatric population, which is appropriate given the high SCA burden in this setting, but the findings should be generalized with caution. Genetic, nutritional, or environmental factors could influence adiponectin levels; thus, replication in other populations is recommended. Despite these limitations, our study provides a crucial first look at adiponectin in paediatric SCA and yields several clinically relevant insights. We have identified adiponectin as a potential biomarker of interest in SCA, given its significant elevation and variation with disease state. The results lay groundwork for larger studies to validate adiponectin’s prognostic value. Moreover, by highlighting adiponectin’s possible protective role, we open discussion on novel anti-inflammatory therapeutic avenues in SCA care. If future trials (for instance, with adiponectin analogues or drugs that upregulate adiponectin) demonstrate improved outcomes, it could herald a new adjunct therapy aimed at the inflammatory aspect of SCA – an angle not directly addressed by current treatments aside from hydroxyurea. In conclusion, this study demonstrates that children with sickle cell anaemia have significantly elevated serum adiponectin levels compared to healthy peers, with the highest levels observed during vaso-occlusive crises. These findings suggest that adiponectin is responsive to the inflammatory and vaso-occlusive stress of SCA, supporting its potential as a biomarker of disease activity. The anti-inflammatory and metabolic effects of adiponectin make it an attractive candidate for further research as a therapeutic target. Enhancing adiponectin activity in SCA patients could conceivably ameliorate inflammation, reduce vaso-occlusive damage, and improve metabolic health, thereby addressing two critical dimensions of SCA pathophysiology. Future longitudinal studies and clinical trials will be crucial to determine whether harnessing adiponectin can translate into tangible benefits for patients with SCA. This study’s insights contribute to a growing recognition that SCA management may be improved by not only targeting the sickling process itself but also by augmenting the body’s endogenous protective factors like adiponectin. Declarations Data Sharing Statement Data supporting this study are available from the corresponding author upon reasonable request, subject to ethical and regulatory guidelines. Clinical trial number: Not applicable. Authorship Contributions A.E.U. and C.A.N conceptualized the study. A.E.U and C.A.N contributed to study design, patient recruitment, and data collection. C.A.N supervised data analysis, interpreted findings, and critically revised the manuscript. I.O. performed laboratory analyses, including adiponectin quantification, and contributed to data interpretation. A.I. provided clinical oversight, assisted in patient evaluation, and reviewed the manuscript. T.U. contributed to statistical analysis, manuscript writing, and final approval of the work. All authors reviewed and approved the final manuscript for submission. Ethical Approval Our study involved human participants, and ethical approval was obtained from the Ethical Committee Board of Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria . Written informed consent was obtained from parents or legal guardians of all participants, and assent was obtained from children where applicable, in accordance with institutional and ethical guidelines. The study was conducted in compliance with the Helsinki Declaration on Ethical Principles for Medical Research Involving Human Subjects . Conflict of Interest Statement The authors declare that there are no conflicts of interest regarding the publication of this paper. Funding Statement This research was fully funded by the authors without external financial support. No grants or institutional funding were received, and all study-related expenses were covered personally by the authors. 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Similar burden of type 2 diabetes among adult patients with sickle cell disease relative to African Americans in the U.S. population: a six-year population-based cohort analysis. Br J Haematol [Internet] 2019 [cited 2025 Feb 27];185:116–27. Available from: https://chatgpt.com. Adaobi Nri-Ezedi C, Chima Okpara H, Nchekwube Okeke K, Ifeyinwa Nwaneli E, Stephen Edokwe E, Tochukwu Echendu S et al. Exploring the Relationship between Adiponectin and Blood Pressure in Nigerian Children Open Access. Open J Endocr Metab Dis [Internet] 2017 [cited 2023 Jul 15];12:9–19. Available from: http://creativecommons.org/licenses/by/4.0/ Additional Declarations No competing interests reported. Supplementary Files working2.csv Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6319157","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":512874587,"identity":"6204bccb-a47f-43e5-95f0-63a3b407593f","order_by":0,"name":"Arinze Ejike Ulasi","email":"","orcid":"","institution":"Nnamdi Azikiwe University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Arinze","middleName":"Ejike","lastName":"Ulasi","suffix":""},{"id":512874588,"identity":"e89dc5a7-6db6-4e22-be0f-ed97ed74bc82","order_by":1,"name":"Chisom Adaobi Nri-Ezedi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIie3QMUvEMBTA8RcCueVJ1xzI5SukOMgh4leJCLoodCpuVyiky8GtHf0K4hfI8aDTcbd2cKgITg4db1C0OR1bvVEw/yHNkB8vKUAo9GfTX6trARC46PZiT7Is9yffkOPu+wuJCieebxOYqCK/p1P7eKgKYaBNCY6ju14iV2YUrzQcsXmV0I19QZYLx8o1wbRsBl5hxDjTH+e5vNYdIeR8lPEDS6Br10+ixhOYWfWqadoR4cn7T0TupoBBiZpYR5ALx5knm6z/LfWT9SQu8TJZzteEkgvTba5Q1wN/bHFRjbM3UKqgh3ab0plaVHGzTU8metN/MQDWM96fRZBmgAwXDU0JhUKhf9Ynrw1W2tGS3qUAAAAASUVORK5CYII=","orcid":"","institution":"Nnamdi Azikiwe University","correspondingAuthor":true,"prefix":"","firstName":"Chisom","middleName":"Adaobi","lastName":"Nri-Ezedi","suffix":""},{"id":512874589,"identity":"8d13c989-565d-49b4-ba1d-2b1b1f357e32","order_by":2,"name":"Ifeanyi Okpara","email":"","orcid":"","institution":"Nnamdi Azikiwe University","correspondingAuthor":false,"prefix":"","firstName":"Ifeanyi","middleName":"","lastName":"Okpara","suffix":""},{"id":512874590,"identity":"43ae46c4-9c4b-454d-acc2-dcc7bf44263f","order_by":3,"name":"Anthony Ikefuna","email":"","orcid":"","institution":"University of Nigeria","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"Ikefuna","suffix":""},{"id":512874591,"identity":"12bd9f08-110c-4751-be88-d2d02c3c5af9","order_by":4,"name":"Thomas Obiajulu Ulasi","email":"","orcid":"","institution":"Nnamdi Azikiwe University","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"Obiajulu","lastName":"Ulasi","suffix":""}],"badges":[],"createdAt":"2025-03-27 09:38:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6319157/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6319157/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91103876,"identity":"03cbcf47-94f8-4900-93ec-1bc2266f1972","added_by":"auto","created_at":"2025-09-11 15:10:43","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":265783,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of multivariate regression coefficients for factors associated with adiponectin.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6319157/v1/e510d37ffd101f14dc3a91f8.jpeg"},{"id":91105792,"identity":"f9b423fa-7691-4e17-905e-9c73dc1a99f9","added_by":"auto","created_at":"2025-09-11 15:34:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1047274,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6319157/v1/2e431e7c-693b-42d9-a760-26655ada235d.pdf"},{"id":91103874,"identity":"d03841c4-5825-409f-a38a-90dc1e364539","added_by":"auto","created_at":"2025-09-11 15:10:43","extension":"csv","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":4678,"visible":true,"origin":"","legend":"","description":"","filename":"working2.csv","url":"https://assets-eu.researchsquare.com/files/rs-6319157/v1/a73a28e0e2ef3d2d791aef05.csv"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adiponectin Levels During Steady State and Vaso-Occlusive Crisis in Nigerian Children with Sickle Cell Anaemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSickle cell anaemia (SCA) is a life-threatening genetic disorder characterized by a single-point mutation in the β-globin gene that leads to abnormal sickle haemoglobin (HbS) formation. Under low oxygen tension, erythrocytes become rigid and sickle-shaped, causing microvascular occlusions, tissue ischemia, and painful vaso-occlusive crises (VOC) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Chronic intravascular haemolysis and recurrent VOC events drive a persistent state of systemic inflammation, endothelial dysfunction, and oxidative stress [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Indeed, chronic inflammation plays a central role in SCA pathogenesis and underlies many of its complications [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. While pro-inflammatory pathways in SCA have been extensively studied, the role of endogenous anti-inflammatory mediators in counterbalancing this inflammation remains poorly understood. Identifying such mediators could unveil new biomarkers of disease activity and novel therapeutic approaches.\u003c/p\u003e \u003cp\u003eAdiponectin is a hormone secreted predominantly by adipose tissue that has potent anti-inflammatory, anti-atherogenic, and insulin-sensitizing properties [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It suppresses pro-inflammatory cytokines (e.g., tumour necrosis factor-α and interleukin-6) via inhibition of NF-κB signalling and reduces oxidative stress while enhancing nitric oxide-mediated endothelial function [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. High circulating adiponectin levels are generally associated with improved metabolic profiles and reduced cardiovascular risk [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In conditions of chronic inflammation, adiponectin is thought to act as a compensatory, protective factor. However, its role in hemoglobinopathies such as SCA remains underexplored particularly in children. SCA patients often have lower body mass index and a high inflammatory burden, factors that could influence adiponectin levels [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven adiponectin\u0026rsquo;s anti-inflammatory and metabolic effects, we hypothesized that adiponectin might be elevated in children with SCA as a counter-inflammatory mechanism, and that it could serve as a biomarker of disease severity or activity (particularly during VOC). This study aimed to compare serum adiponectin levels between children with SCA (HbSS genotype) and healthy controls (Hb AA genotype). By elucidating adiponectin\u0026rsquo;s profile in paediatric SCA, we seek to evaluate its viability as a biomarker of disease progression and lay groundwork for future therapeutic strategies leveraging adiponectin to mitigate inflammation in SCA.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eWe conducted a cross-sectional comparative study of paediatric SCA patients and healthy controls. Children aged 1\u0026ndash;17 years with a confirmed diagnosis of SCA (homozygous HbSS genotype) were recruited from the paediatric haematology clinic at Nnamdi Azikiwe University Teaching Hospital (NAUTH) in Nnewi, Nigeria. SCA diagnosis was confirmed by haemoglobin electrophoresis. Both SCA patients in steady state and those experiencing an acute vaso-occlusive crisis at the time of evaluation were eligible. \u0026ldquo;Steady state\u0026rdquo; was defined as at least four weeks without acute crisis or transfusion. An age-, sex-, and socio-economic status-matched control group comprised healthy children (HbAA genotype) with no history of chronic illness. Controls were recruited from the general paediatric outpatient department and community, and confirmed HbAA by electrophoresis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInclusion criteria:\u003c/h3\u003e\n\u003cp\u003eThe study included children aged 1 to 17 years with a confirmed diagnosis of HbSS sickle cell anemia (SCA) in the patient group. Participants with SCA were either in a steady state or experiencing an acute vaso-occlusive crisis (VOC). A control group of healthy children with an HbAA genotype was also recruited, matched to the SCA group by age (\u0026plusmn;\u0026thinsp;2 years), sex, and socio-economic status (SES).\u003c/p\u003e\n\u003ch3\u003eExclusion criteria:\u003c/h3\u003e\n\u003cp\u003eChildren were excluded if they had any known chronic comorbidities, such as diabetes, renal disease, or liver disease, that could potentially affect adiponectin levels. Those who had received a blood transfusion within the four months preceding enrollment were also excluded to avoid transient donor influences. Additionally, children classified as obese, defined as having a body mass index (BMI) at or above the 95th percentile for age and sex, were not included due to the known impact of obesity on adiponectin levels. Lastly, any child with an acute infection or inflammatory condition at the time of sampling, except for those experiencing VOC in the SCA group, was excluded from participation.\u003c/p\u003e \u003cp\u003e All participants were enrolled after obtaining written informed consent from parents or guardians (and assent from older children). The study protocol was approved by the NAUTH Institutional Review Board, and all procedures followed the ethical standards of the Helsinki Declaration.\u003c/p\u003e\n\u003ch3\u003eData Collection and Clinical Assessment\u003c/h3\u003e\n\u003cp\u003eUpon enrolment, a standardized questionnaire was administered to collect demographic information (age, sex, SES) and relevant clinical history. For SCA patients, we recorded SCA-specific clinical data including frequency of VOC in the past year and current clinical status (steady state vs. VOC). Socio-economic status was classified (lower, middle, or upper) based on parental occupation and education. A focused physical examination was conducted for each child. Anthropometric measurements were obtained using standard techniques: weight was measured to the nearest 0.1 kg using a calibrated scale and height to the nearest 0.1 cm using a stadiometer. Body mass index (BMI) was calculated as weight (kg) divided by height in meters squared (kg/m\u0026sup2;) and interpreted using age- and sex-specific percentiles.\u003c/p\u003e\n\u003ch3\u003eLaboratory Measurements\u003c/h3\u003e\n\u003cp\u003eVenous blood samples (4 mL) were collected from each participant under aseptic conditions. Half of the sample (2 mL) was anticoagulated with EDTA and used to confirm haemoglobin genotype by electrophoresis (to ensure accurate group classification). The remaining 2 mL was allowed to clot, and serum was separated by centrifugation. Sera were immediately frozen at \u0026minus;\u0026thinsp;80\u0026deg;C until batch analysis. Serum adiponectin concentration was measured for all subjects using a quantitative enzyme-linked immunosorbent assay (ELISA) kit (specific for human total adiponectin). All samples were run in duplicate, and the mean value was used for analysis. The assay\u0026rsquo;s intra- and inter-assay coefficients of variation were \u0026lt;\u0026thinsp;8%. Laboratory personnel were blinded to the participant\u0026rsquo;s group (SCA or control) during adiponectin measurements to reduce bias.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAnalyses were conducted using Python 3.12. Participant characteristics and adiponectin levels were summarized using descriptive statistics. Normality of continuous variables was assessed, with means and standard deviations (SD) reported for approximately normal distributions (e.g., age) and medians with interquartile ranges (IQR) for skewed variables (e.g., adiponectin, BMI). Categorical variables (sex, SES) were presented as frequencies and percentages.\u003c/p\u003e \u003cp\u003eGroup comparisons between SCA and controls were conducted using independent t-tests for normally distributed data and the Mann-Whitney U test for non-parametric variables. Categorical variables were compared using the chi-square test or Fisher\u0026rsquo;s exact test as appropriate.\u003c/p\u003e \u003cp\u003eTo assess independent associations of adiponectin with SCA and other covariates, multivariable linear regression was performed, with log-transformed adiponectin as the outcome variable. Predictors included disease status (SCA vs. control), age, sex, BMI, and SES. Additional models examined differences within SCA subgroups (steady state vs. control, VOC vs. steady state). β coefficients, 95% confidence intervals (CI), and p-values were reported, with statistical significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eParticipant Characteristics\u003c/h2\u003e \u003cp\u003eA total of 96 children were studied: 50 with SCA and 46 healthy controls. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the demographic and clinical characteristics of the SCA and control groups. The mean age of participants was 8.99\u0026thinsp;\u0026plusmn;\u0026thinsp;4.61 years (range 1\u0026ndash;17), with no significant age difference between the SCA group (9.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.62 years) and controls (8.98\u0026thinsp;\u0026plusmn;\u0026thinsp;4.65 years; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.982). The sex distribution was similar in both groups (approximately 58% male in each; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.999). Socio-economic status categories were evenly represented in SCA vs. controls (lower, middle, upper SES proportions did not differ significantly, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.869). Notably, children with SCA had lower body mass indices on average than healthy peers. The median BMI in the SCA group was 15.24 (IQR 13.73\u0026ndash;16.30) compared to 16.22 (IQR 15.28\u0026ndash;18.44) in controls. This difference was statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). No SCA patient in the study was obese by paediatric criteria, in line with our exclusion criteria.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eBaseline characteristics of the study population (SCA patients vs. healthy controls).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSCA (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl (N\u0026thinsp;=\u0026thinsp;46)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.99\u0026thinsp;\u0026plusmn;\u0026thinsp;4.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.98\u0026thinsp;\u0026plusmn;\u0026thinsp;4.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.982\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLower SES, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.869\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiddle SES, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper SES, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u0026sup2;, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.7 [14.37\u0026ndash;17.31]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.24 [13.73\u0026ndash;16.30]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.22 [15.28\u0026ndash;18.44]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSerum Adiponectin Levels in SCA vs. Controls\u003c/h2\u003e \u003cp\u003eSCA patients demonstrated markedly higher circulating adiponectin levels compared to healthy children. The overall median adiponectin level in the SCA group was 3.20 \u0026micro;g/mL (IQR 2.20\u0026ndash;4.38), whereas in the control group it was 0.4 \u0026micro;g/mL (IQR 0.30\u0026ndash;0.6). This reflects an approximately eight-fold elevation of median adiponectin in SCA. The difference was highly significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). There was also greater variability among SCA patients, with some values exceeding 6 \u0026micro;g/mL, while controls consistently had low levels (\u0026lt;\u0026thinsp;1 \u0026micro;g/mL). These results suggest that SCA is associated with an upregulation of adiponectin.\u003c/p\u003e \u003cp\u003eIn a subgroup analysis within the SCA cohort, adiponectin levels were further stratified by clinical status (steady state vs. VOC at time of sampling). SCA patients in VOC exhibited significantly higher adiponectin concentrations than those in steady state. The median adiponectin in the VOC subgroup was 4.00 \u0026micro;g/mL (IQR 3.20\u0026ndash;5.62) \u0026micro;g/mL, compared to 2.27 \u0026micro;g/mL (IQR 1.65\u0026ndash;2.95) in the steady-state subgroup (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows this comparison. Thus, not only are adiponectin levels elevated in SCA generally, but they appear to rise even more during acute vaso-occlusive episodes.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerum Adiponectin Levels in SCA vs. Controls\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian Adiponectin (\u0026micro;g/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInterquartile Range (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCA (Total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.20\u0026ndash;4.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9\u0026ndash;9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.30\u0026ndash;0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.2\u0026ndash;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCA (Steady State)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.65\u0026ndash;2.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9\u0026ndash;4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCA (VOC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.20\u0026ndash;5.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.1\u0026ndash;9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMultivariate Analysis of Factors Associated with Adiponectin\u003c/h2\u003e \u003cp\u003eTo determine whether SCA status independently predicts higher adiponectin after accounting for potential confounders, we performed multivariate linear regression. In the full model comparing all SCA patients (combining steady state and VOC) against controls, SCA status was a strong independent predictor of increased adiponectin (β\u0026thinsp;=\u0026thinsp;3.268, 95% CI 2.724\u0026ndash;3.813, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This indicates that even after adjusting for age, sex, BMI, and SES, children with SCA had on average\u0026thinsp;~\u0026thinsp;3.27 \u0026micro;g/mL higher adiponectin than controls. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA presents a forest plot of the regression results (Model 1).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the covariates, age showed a significant inverse association with adiponectin levels. In the model, older children tended to have lower adiponectin. Specifically, compared to the reference (children\u0026thinsp;\u0026lt;\u0026thinsp;6 years), adolescents\u0026thinsp;\u0026ge;\u0026thinsp;16 years had significantly reduced adiponectin (β \u0026asymp; \u0026minus;\u0026thinsp;1.94, 95% CI \u0026minus;\u0026thinsp;3.06 to \u0026minus;\u0026thinsp;0.81, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and those aged 11\u0026ndash;15 also had lower levels (β \u0026asymp; \u0026minus;\u0026thinsp;1.73, 95% CI \u0026minus;\u0026thinsp;2.56 to \u0026minus;\u0026thinsp;0.90, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This age effect is consistent with trends observed in healthy paediatric populations, where adiponectin levels naturally decline with age during adolescence. BMI was positively associated with adiponectin in the combined SCA vs. control model (β\u0026thinsp;\u0026asymp;\u0026thinsp;0.20 per kg/m\u0026sup2;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016), meaning higher BMI was linked to slightly higher adiponectin when considering all participants. Notably, SES had an effect: children from upper SES backgrounds showed higher adiponectin than those from lower SES (β\u0026thinsp;\u0026asymp;\u0026thinsp;1.16, 95% CI 0.26\u0026ndash;2.06, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012). Sex did not significantly influence adiponectin in this model (p\u0026thinsp;=\u0026thinsp;0.24).\u003c/p\u003e \u003cp\u003eWe also ran two secondary regression models focusing on within-SCA comparisons. In a model comparing SCA patients in steady state to healthy controls (excluding SCA VOC cases), SCA steady-state status remained associated with elevated adiponectin (β\u0026thinsp;=\u0026thinsp;1.82, 95% CI 1.48\u0026ndash;2.16, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), though the age effect was attenuated (age categories were not significant in this subset). Interestingly, in this steady-state model, BMI carried a negative association with adiponectin (β \u0026asymp; \u0026minus;\u0026thinsp;0.14, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011), suggesting that among relatively stable SCA patients, those with higher BMI tended to have slightly lower adiponectin \u0026ndash; a pattern opposite to that seen when including the VOC cases or controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eFinally, in a model comparing SCA VOC vs. SCA steady state (to assess factors in acute crisis), VOC status was a strong independent predictor of higher adiponectin (β\u0026thinsp;=\u0026thinsp;1.963, 95% CI 1.19\u0026ndash;2.74, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Within SCA, the inverse age relationship persisted (older SCA patients had significantly lower adiponectin even accounting for crisis status). Upper SES also remained associated with higher adiponectin in the SCA-only model (β\u0026thinsp;\u0026asymp;\u0026thinsp;1.77, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), and BMI again showed a positive association (β\u0026thinsp;\u0026asymp;\u0026thinsp;0.22, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027). In all models, the presence of SCA (and particularly VOC) emerged as the dominant factor related to increased adiponectin levels (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). These multivariate findings reinforce that the observed adiponectin elevation in SCA is robust and not solely explained by confounding differences in age, body composition, or other factors.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we provide evidence that adiponectin, an anti-inflammatory adipokine, is significantly elevated in children with sickle cell anaemia compared to healthy peers. Median adiponectin levels in the SCA group were higher than in controls, and this difference remained significant after adjusting for age, sex, BMI, and socio-economic factors. Furthermore, we observed that adiponectin concentrations were especially high during acute vaso-occlusive crises, nearly double the levels seen in steady-state SCA patients. These novel findings suggest that adiponectin may play a role as an endogenous modulator of inflammation in SCA and could serve as a biomarker for disease activity or stress.\u003c/p\u003e \u003cp\u003eThe chronic inflammatory state of SCA is well established [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], yet counter-regulatory mechanisms have received less attention. The elevation of adiponectin in SCA, particularly during VOC, may represent a compensatory response to acute inflammation and vascular injury. Adiponectin exerts anti-inflammatory effects by inhibiting NF-κB signaling and reducing cytokine production. During VOC\u0026mdash;characterized by intense inflammation, ischemia-reperfusion injury, and endothelial activation\u0026mdash;an adiponectin surge may serve to mitigate tissue damage by attenuating inflammatory cascades and enhancing endothelial function, possibly through nitric oxide production [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Our finding of increased adiponectin levels in VOC supports the concept of adiponectin as a rapid-response anti-inflammatory mediator. Notably, a similar pattern is observed in other acute inflammatory states, where adiponectin rises as part of the endogenous effort to counteract inflammation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Further investigation is warranted to determine whether specific adiponectin isoforms (e.g., high-molecular-weight vs. low-molecular-weight) are preferentially upregulated during VOC and how they correlate with inflammatory markers.\u003c/p\u003e \u003cp\u003eWe found an inverse relationship between age and adiponectin levels in SCA, mirroring patterns in the general paediatric population where adiponectin tends to be highest in early childhood and declines through adolescence [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Younger children with SCA had the highest adiponectin levels, which might confer some protective advantage and could potentially contribute to the observation that disease severity often increases with age. As SCA patients get older, cumulative organ damage and more frequent complications occur; a decline in beneficial adiponectin could be one contributing factor to this worsening. This raises an interesting question: might interventions to maintain higher adiponectin levels as patients age improve clinical outcomes? While purely speculative at this stage, our data open the door to considering adiponectin-targeted therapies in SCA. For instance, recombinant adiponectin or adiponectin receptor agonists (such as AdipoRon) have shown anti-inflammatory effects in experimental models [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. If safely applicable, these could be explored in SCA to augment the patient\u0026rsquo;s anti-inflammatory defences, particularly in older children or adults with severe disease.\u003c/p\u003e \u003cp\u003eFrom a clinical perspective, adiponectin shows promise as a biomarker in SCA. Monitoring adiponectin levels could potentially help identify patients at higher risk of complications or incipient VOC. For example, an acute rise in adiponectin might precede or coincide with a VOC episode, serving as a biochemical indicator of ongoing vascular inflammation. Regular adiponectin measurements could complement existing laboratory markers (like C-reactive protein) to provide a more nuanced picture of a patient\u0026rsquo;s inflammatory status. Moreover, inter-individual differences in baseline adiponectin might correlate with disease severity \u0026ndash; an area that could be investigated by correlating adiponectin with frequency of VOC, organ damage, or other clinical indices in a larger study. If adiponectin proves to be a reliable marker of disease activity, it could aid in patient stratification and personalized management. High-adiponectin patients might have different supportive care needs than low-adiponectin patients, for instance.\u003c/p\u003e \u003cp\u003eIn terms of therapeutic implications, our findings encourage further exploration of adiponectin or its pathways as therapeutic targets. One could envision adjunct therapies that boost adiponectin levels or mimic its actions to reduce inflammation in SCA. An interesting possibility is the synergistic use of adiponectin-modulating strategies with existing SCA treatments. Hydroxyurea remains the cornerstone of SCA therapy, primarily increasing foetal haemoglobin and reducing haemolysis and VOC frequency. Hydroxyurea also has some anti-inflammatory effects, though indirect. It is conceivable that combining hydroxyurea with an adiponectin-elevating agent could yield additive benefits: hydroxyurea ameliorating the hematologic cause of VOC and adiponectin mitigating the inflammatory consequences. Preclinical studies could test this synergy. Additionally, lifestyle interventions that raise adiponectin \u0026ndash; such as exercise or certain dietary components \u0026ndash; might be advised as supportive care. For example, weight management is relevant: we observed a complex relationship between BMI and adiponectin in SCA (with higher BMI correlating with higher adiponectin overall, but lower adiponectin in stable SCA). Regardless, given that SCA patients are often underweight or lean, nutritional interventions to ensure adequate adipose function (hence adiponectin production) could be beneficial.\u003c/p\u003e \u003cp\u003eThe elevation of adiponectin in SCA may have significant metabolic implications. Despite the chronic inflammatory state, which typically predisposes individuals to insulin resistance, SCA patients have historically exhibited a lower incidence of type 2 diabetes compared to the general population [\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. One proposed explanation is that persistently high adiponectin levels enhance insulin sensitivity, counteracting the pro-diabetic effects of inflammation[\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Adiponectin facilitates glucose uptake, promotes fatty acid oxidation, and suppresses hepatic gluconeogenesis, thereby supporting metabolic homeostasis. However, recent evidence suggests that as SCA patients age, their diabetes risk converges with that of the general population [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This pattern aligns with the progressive decline in adiponectin levels over time, suggesting that the protective metabolic effects of adiponectin diminish with age, unmasking an underlying diabetes risk [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis raises an intriguing possibility: Could adiponectin itself serve as a therapeutic target for diabetes, beyond its relevance to SCA? Given its dual role in insulin sensitivity and inflammation regulation, adiponectin-based interventions could offer metabolic benefits to both SCA patients and individuals at risk for diabetes. Future studies should explore whether strategies aimed at sustaining adiponectin levels\u0026mdash;such as adiponectin-mimetic therapies\u0026mdash;can delay or mitigate diabetes onset, particularly in aging SCA patients and other high-risk populations. Our findings highlight the need for further research into adiponectin\u0026rsquo;s role as both a biomarker and a potential therapeutic target for metabolic regulation in SCA and beyond[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The paradox of low diabetes rates in younger SCA patients, despite chronic inflammation, followed by an increasing prevalence with age, underscores adiponectin\u0026rsquo;s critical role in metabolic homeostasis and its broader implications for haematology, endocrinology, and metabolic disease research.\u003c/p\u003e \u003cp\u003eIt is important to note the limitations of our study. First, as a cross-sectional study with a modest sample size, we cannot establish causality or temporal dynamics. Our single time-point measurements provide a snapshot; a longitudinal approach would be needed to see how adiponectin fluctuates during and after VOC in the same individual, and whether low baseline adiponectin predicts future complications. Second, we focused on total adiponectin level but did not measure specific multimers (high- vs. low-molecular-weight adiponectin), which may have differing bioactivity. Including multimer analysis could yield deeper insight. Third, we did not directly measure inflammatory markers (such as IL-6, TNF-α, or high-sensitivity CRP) alongside adiponectin in this study. Thus, we infer anti-inflammatory effects of adiponectin based on known biology, but correlating adiponectin with inflammatory marker levels in SCA patients would strengthen the evidence for its immunomodulatory role [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Finally, this study was conducted in a single centre and predominantly in an African paediatric population, which is appropriate given the high SCA burden in this setting, but the findings should be generalized with caution. Genetic, nutritional, or environmental factors could influence adiponectin levels; thus, replication in other populations is recommended.\u003c/p\u003e \u003cp\u003eDespite these limitations, our study provides a crucial first look at adiponectin in paediatric SCA and yields several clinically relevant insights. We have identified adiponectin as a potential biomarker of interest in SCA, given its significant elevation and variation with disease state. The results lay groundwork for larger studies to validate adiponectin\u0026rsquo;s prognostic value. Moreover, by highlighting adiponectin\u0026rsquo;s possible protective role, we open discussion on novel anti-inflammatory therapeutic avenues in SCA care. If future trials (for instance, with adiponectin analogues or drugs that upregulate adiponectin) demonstrate improved outcomes, it could herald a new adjunct therapy aimed at the inflammatory aspect of SCA \u0026ndash; an angle not directly addressed by current treatments aside from hydroxyurea.\u003c/p\u003e \u003cp\u003eIn conclusion, this study demonstrates that children with sickle cell anaemia have significantly elevated serum adiponectin levels compared to healthy peers, with the highest levels observed during vaso-occlusive crises. These findings suggest that adiponectin is responsive to the inflammatory and vaso-occlusive stress of SCA, supporting its potential as a biomarker of disease activity. The anti-inflammatory and metabolic effects of adiponectin make it an attractive candidate for further research as a therapeutic target. Enhancing adiponectin activity in SCA patients could conceivably ameliorate inflammation, reduce vaso-occlusive damage, and improve metabolic health, thereby addressing two critical dimensions of SCA pathophysiology. Future longitudinal studies and clinical trials will be crucial to determine whether harnessing adiponectin can translate into tangible benefits for patients with SCA. This study\u0026rsquo;s insights contribute to a growing recognition that SCA management may be improved by not only targeting the sickling process itself but also by augmenting the body\u0026rsquo;s endogenous protective factors like adiponectin.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Sharing Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData supporting this study are available from the corresponding author upon reasonable request, subject to ethical and regulatory guidelines.\u003c/p\u003e\n\u003ch3\u003eClinical trial number:\u0026nbsp;Not applicable.\u003c/h3\u003e\n\u003ch3\u003e\u003cstrong\u003eAuthorship Contributions\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eA.E.U. and C.A.N conceptualized the study. A.E.U and C.A.N contributed to study design, patient recruitment, and data collection. C.A.N supervised data analysis, interpreted findings, and critically revised the manuscript. I.O. performed laboratory analyses, including adiponectin quantification, and contributed to data interpretation. A.I. provided clinical oversight, assisted in patient evaluation, and reviewed the manuscript. T.U. contributed to statistical analysis, manuscript writing, and final approval of the work. All authors reviewed and approved the final manuscript for submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study involved human participants, and ethical approval was obtained from the \u003cstrong\u003eEthical Committee Board of Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e Written informed consent was obtained from parents or legal guardians of all participants, and assent was obtained from children where applicable, in accordance with institutional and ethical guidelines. The study was conducted in compliance with the \u003cstrong\u003eHelsinki Declaration on Ethical Principles for Medical Research Involving Human Subjects\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no conflicts of interest regarding the publication of this paper.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThis research was fully funded by the authors without external financial support. No grants or institutional funding were received, and all study-related expenses were covered personally by the authors. The funding source had no influence on the study design, data collection, analysis, or interpretation of the results.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDorneles J, Mayer A, de Chies M. 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In: Am J Clin Nutr. 2010. page S258\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med [Internet] 2001 [cited 2015 Jan 7];7:941\u0026ndash;6. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/pubmed/11479627\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/pubmed/11479627\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWannamethee SG, Tchernova J, Whincup P, Lowe GD, Rumley A, Brown K et al. Associations of adiponectin with metabolic and vascular risk parameters in the British Regional Heart Study reveal stronger links to insulin resistance-related than to coronory heart disease risk-related parameters. Int J Obes (Lond) [Internet] 2007 [cited 2016 Mar 3];31:1089\u0026ndash;98. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1038/sj.ijo.0803544\u003c/span\u003e\u003cspan address=\"10.1038/sj.ijo.0803544\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou J, Han J, Nutescu EA, Galanter WL, Walton SM, Gordeuk VR et al. Similar burden of type 2 diabetes among adult patients with sickle cell disease relative to African Americans in the U.S. population: a six-year population-based cohort analysis. Br J Haematol [Internet] 2019 [cited 2025 Feb 27];185:116\u0026ndash;27. Available from: https://chatgpt.com.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdaobi Nri-Ezedi C, Chima Okpara H, Nchekwube Okeke K, Ifeyinwa Nwaneli E, Stephen Edokwe E, Tochukwu Echendu S et al. Exploring the Relationship between Adiponectin and Blood Pressure in Nigerian Children Open Access. Open J Endocr Metab Dis [Internet] 2017 [cited 2023 Jul 15];12:9\u0026ndash;19. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://creativecommons.org/licenses/by/4.0/\u003c/span\u003e\u003cspan address=\"http://creativecommons.org/licenses/by/4.0/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sickle cell anaemia, Adiponectin, Inflammation, Biomarker, Vaso-occlusive crisis, Therapeutic target","lastPublishedDoi":"10.21203/rs.3.rs-6319157/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6319157/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSickle cell anaemia (SCA) is a chronic inflammatory hemoglobinopathy marked by recurrent vaso-occlusive crises (VOC) and end-organ damage. Adiponectin, an adipokine with anti-inflammatory and insulin-sensitizing properties, is well-studied in metabolic disorders but remains underexplored in SCA. This study assessed serum adiponectin levels in Nigerian children with SCA during steady state and VOC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a cross-sectional study involving 50 children with SCA (HbSS genotype) and 46 age- and sex-matched healthy controls (HbAA genotype). Adiponectin levels were measured using ELISA, and group comparisons were performed. Multivariable linear regression was used to assess associations between adiponectin and clinical variables.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eChildren with SCA had significantly higher adiponectin levels (median 3.2 \u0026micro;g/mL, IQR 2.2\u0026ndash;4.38) compared to healthy controls (0.4 \u0026micro;g/mL, IQR 0.3\u0026ndash;0.6; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Among the SCA group, those in VOC had higher adiponectin concentrations than those in steady state (median 4.00 \u0026micro;g/mL vs. 2.27 \u0026micro;g/mL; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These differences remained significant after adjusting for age, sex, BMI, and socio-economic status.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAdiponectin levels are elevated in children with SCA, particularly during VOC, suggesting its potential role as a dynamic biomarker of disease activity. These findings contribute to understanding the inflammatory profile of paediatric SCA and support further research into adiponectin as a non-invasive marker in clinical monitoring.\u003c/p\u003e","manuscriptTitle":"Adiponectin Levels During Steady State and Vaso-Occlusive Crisis in Nigerian Children with Sickle Cell Anaemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-11 15:10:39","doi":"10.21203/rs.3.rs-6319157/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7d16ea72-958a-41a5-8c24-ff6137bbb96d","owner":[],"postedDate":"September 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-11T15:10:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-11 15:10:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6319157","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6319157","identity":"rs-6319157","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}