Autoimmune/Inflammatory Syndrome Induced by Adjuvants in Silicone Breast Implant Recipients: A Systematic Review and Meta-Analysis of Prevalence, Risk Factors, and Clinical Outcomes

Autoimmune/Inflammatory Syndrome Induced by Adjuvants in Silicone Breast Implant Recipients: A Systematic Review and Meta-Analysis of Prevalence, Risk Factors, and Clinical Outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Autoimmune/Inflammatory Syndrome Induced by Adjuvants in Silicone Breast Implant Recipients: A Systematic Review and Meta-Analysis of Prevalence, Risk Factors, and Clinical Outcomes Luís Jesuíno de Oliveira Andrade, Gabriela Correia Matos de Oliveira, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8451089/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Silicone breast implants remain among the most frequently performed cosmetic procedures worldwide, yet concerns persist regarding potential associations with autoimmune and inflammatory conditions. The Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA) has emerged as a framework for understanding immune-mediated responses to silicone, though evidence remains fragmented and inconsistent. Objective To systematically review and quantitatively synthesize existing literature on ASIA syndrome associated with silicone breast implants, estimating pooled prevalence and identifying potential risk factors. Methods Following PRISMA 2020 guidelines, we searched multiple databases through October 2024 for observational studies evaluating ASIA syndrome in silicone breast implant recipients. Two independent reviewers conducted study selection, data extraction, and quality assessment using the Newcastle-Ottawa Scale. Statistical analyses employed random-effects models with Freeman-Tukey double arcsine transformation. Results Eight observational cohort studies comprising approximately 1,980 patients met inclusion criteria. ASIA prevalence ranged from 50% to 100% in symptomatic referral populations. Most common manifestations included chronic fatigue (88–90%), arthralgia (65–71%), and myalgia (48–65%). Pre-existing allergies were present in 56–75% of symptomatic cohorts. Post-explantation improvement rates varied from 43% to 96%, with early removal (< 10 years) yielding superior outcomes (p = 0.007). Substantial heterogeneity precluded quantitative meta-analysis, reflecting variability in diagnostic criteria, study populations, and referral bias. Conclusions While population-level risk remains undefined, clinically meaningful symptom improvement following explantation occurs consistently in selected patients. Prospective studies with standardized diagnostic criteria and immunophenotyping are essential to clarify causality and guide clinical decision-making. Immunology Autoimmune syndrome Silicone breast implants ASIA syndrome Systematic review Meta-Analysis Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Breast augmentation with silicone implants remains one of the most frequently performed cosmetic surgical procedures worldwide, with an estimated 1.8 million procedures conducted annually. 1 While these devices have undergone substantial refinements in design and biocompatibility since their introduction in the 1960s, concerns regarding their long-term safety profile persist within the medical community. 2 Among the most contentious issues is the potential association between silicone breast implants and the development of systemic autoimmune or inflammatory conditions, particularly in predisposed individuals. 3 The concept of Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA syndrome), first proposed by Shoenfeld and Agmon-Levin in 2011, 4 has gained considerable attention as a unifying framework for understanding immune-mediated responses to various adjuvant substances, including silicone. 5 This syndrome encompasses a constellation of clinical manifestations, ranging from chronic fatigue and cognitive dysfunction to frank autoimmune disease, that emerge following exposure to materials capable of triggering persistent immune activation. 6 Silicone, despite being considered biologically inert for decades, possesses adjuvant properties that may stimulate both innate and adaptive immune responses through mechanisms including macrophage activation, cytokine dysregulation, and molecular mimicry. 7 Clinical reports and case series have documented temporal associations between breast implant placement and the subsequent development of ASIA-compatible symptoms, with some patients experiencing dramatic improvement following explantation. 8 However, the evidence base remains fragmented and inconsistent, with studies varying substantially in methodology, diagnostic criteria, and outcome assessment. Despite growing patient advocacy and increasing clinical awareness, significant knowledge gaps persist regarding the true incidence, risk factors, and pathophysiological mechanisms underlying ASIA syndrome in breast implant recipients. The lack of standardized diagnostic criteria and the heterogeneous nature of reported symptoms have hampered efforts to establish definitive causal relationships. Furthermore, no comprehensive quantitative synthesis has been performed to systematically evaluate the available evidence and provide clinicians with reliable risk estimates. 9 This meta-analysis aims to systematically review and quantitatively synthesize the existing literature on ASIA syndrome associated with silicone breast implants, estimating the pooled prevalence of this condition and identifying potential clinical and demographic risk factors that may predispose patients to its development. METHODS Protocol and Registration This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. 10 The review protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) prior to study commencement to ensure methodological transparency and minimize reporting bias. Search Strategy An extensive literature search was performed across multiple electronic databases including MEDLINE/PubMed, Embase, Web of Science, Scopus, and the Cochrane Library from their inception through October 2024. The search strategy incorporated both Medical Subject Headings (MeSH) terms and free-text keywords related to silicone breast implants, ASIA syndrome, and autoimmune manifestations. The core search string utilized for PubMed was: ("breast implants"[MeSH] OR "breast implant*" OR "mammary implant*" OR "silicone gel implant*") AND ("autoimmune diseases"[MeSH] OR "ASIA syndrome" OR "autoimmune syndrome induced by adjuvants" OR "autoimmune/inflammatory syndrome induced by adjuvants" OR "adjuvant-induced autoimmune syndrome" OR "silicone implant illness" OR "breast implant illness"). This strategy was appropriately modified for each database to accommodate their specific indexing systems and controlled vocabularies. No language restrictions were imposed, and non-English publications were translated when necessary. Additionally, reference lists of included studies and relevant systematic reviews were manually scrutinized to identify studies potentially missed by the electronic search. Eligibility Criteria Studies were considered eligible for inclusion if they met the following criteria: observational studies (cohort, case-control, or cross-sectional designs) or clinical trials evaluating patients with silicone breast implants; explicit assessment or reporting of ASIA syndrome diagnosis according to established diagnostic criteria or clinically compatible symptomatology; provision of sufficient data to calculate prevalence estimates or effect measures; and peer-reviewed publications. Studies were excluded if they: consisted solely of case reports or case series with fewer than 10 patients; included patients with non-silicone implants without separate subgroup analysis; lacked clear diagnostic criteria for ASIA syndrome; presented duplicate data from previously published cohorts; or consisted of editorials, commentaries, or review articles without original data. Study Selection Two independent reviewers (LJOA and LMO) conducted the study selection process in duplicate, initially screening titles and abstracts against the predetermined eligibility criteria. Subsequently, full-text articles of potentially relevant studies were retrieved and assessed for final inclusion. Any disagreements between reviewers were resolved through discussion, with arbitration by a third senior reviewer (AMVB) when consensus could not be achieved. The inter-rater agreement was quantified using Cohen's kappa statistic. Data Extraction Standardized data extraction forms were developed and pilot-tested prior to formal data collection. Two reviewers (GCMO, OJMS) independently extracted the following information from each included study: study characteristics (first author, publication year, country, study design, sample size, follow-up duration); population characteristics (age, indication for implantation, implant type and generation, duration of implantation); diagnostic criteria employed for ASIA syndrome; prevalence or incidence of ASIA syndrome; clinical manifestations and laboratory findings; outcomes following explantation when reported; and potential confounding variables and effect modifiers. For studies reporting multiple time points, data from the longest follow-up period were extracted. Quality Assessment The methodological quality of included studies was assessed independently by two reviewers using appropriate tools based on study design. For cohort and case-control studies, the Newcastle-Ottawa Scale (NOS) was utilized, evaluating three domains: selection of study groups, comparability of groups, and ascertainment of outcome or exposure. Studies achieving scores of 7–9, 4–6, and 0–3 were classified as high, moderate, and low quality, respectively. Cross-sectional studies were evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for analytical cross-sectional studies. Risk of bias graphs were generated to provide visual representation of quality assessment across studies. Statistical Analysis All statistical analyses were performed using R software (version 4.3.1) with the meta and metafor packages. The primary outcome measure was the pooled prevalence of ASIA syndrome among silicone breast implant recipients, calculated using a random-effects model with the DerSimonian-Laird method to account for anticipated heterogeneity across studies. Prevalence estimates were transformed using the Freeman-Tukey double arcsine transformation to stabilize variances and accommodate studies with prevalence values near the boundaries of 0 or 1. Secondary outcomes included odds ratios (OR) for categorical risk factors and standardized mean differences (SMD) for continuous variables, comparing patients who developed ASIA syndrome with those who did not. Between-study heterogeneity was quantified using Cochran's Q statistic (with statistical significance set at p < 0.10) and the I² statistic, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively. Prediction intervals were calculated to estimate the range of true effects in future studies. To explore sources of heterogeneity, prespecified subgroup analyses were conducted based on: geographic region; implant indication (cosmetic versus reconstructive); implant generation; duration of implantation (< 10 years versus ≥ 10 years); and diagnostic criteria employed. Meta-regression analyses were performed when at least 10 studies were available to examine the influence of continuous moderator variables. Publication bias was assessed through visual inspection of funnel plots and formally tested using Egger's regression asymmetry test and Begg's rank correlation test. When significant publication bias was detected (p < 0.10), the trim-and-fill method was applied to estimate the potential impact on pooled effect sizes. Sensitivity analyses were conducted by systematically excluding individual studies to evaluate the robustness of findings and identify potentially influential studies. Additional sensitivity analyses involved restricting the analysis to high-quality studies only and comparing results from fixed-effect versus random-effects models. Statistical significance was defined as a two-tailed p-value < 0.05 for all analyses except heterogeneity and publication bias tests. RESULTS Study Selection and Characteristics The systematic literature search identified 491 records published from January 2011 onwards, following the formal definition of ASIA syndrome by Shoenfeld and Agmon-Levin. 4 After removal of duplicates and application of predetermined eligibility criteria, eight observational cohort studies comprising approximately 1,980 patients with silicone breast implants were included in the final qualitative synthesis. Inter-rater agreement during study selection was substantial (Cohen's kappa: 0.82, 95% CI: 0.76–0.88). No randomized controlled trials or population-based incidence studies specifically diagnosing ASIA syndrome were identified. Following initial screening, full-text evaluation was performed for a subset of potentially eligible articles. After application of the predefined inclusion and exclusion criteria, 8 observational cohort studies met all eligibility requirements and were included in the final qualitative synthesis (Fig. 1 ). Overview of the main features of the included studies Table 1 General Characteristics of Included Studies Study Reference Sample Size (n) Diagnostic Criteria Implant Characteristics Explantation Rate Key Conclusions Serena et al. 11 (2023) 229 Clinical BII scoring Not Specified 100% Total capsulectomy significantly reduces disease severity. Metzinger et al. 12 (2022) 200 Mastodynia & capsular contracture Bilateral; Cosmetic only 100% (Implied) Explantation with capsulectomy drastically improves BII symptoms Lieffering et al. 13 (2025) 254 Longitudinal assessment of 13 symptoms Silicone (Reconstruction) 0% (Cohort) No evidence of Breast Inflammation Syndrome in reconstruction patients. Lieffering et al. 14 (2024) 688 Primary care presentation of 13 symptoms Silicone (Cosmetic) 0% (Cohort) Positive association between cosmetic implants and health symptoms Woźniak-Roszkowska et al. 15 (2020) 30 Validated ASIA (Schoenfeld) criteria Polyacrylamide hydrogel (PAAG) 26.7% PAAG triggers ASIA; surgical removal leads to complete symptom resolution. Spit et al. 16 (2022) 467 Systemic BII symptoms Silicone Breast Implants (SBI) 32.5% Early explantation (< 10 years) yields superior clinical outcomes. Maijers et al. 17 (2013) 80 ASIA criteria & unexplained symptoms Silicone Breast Implants (SBI) 65.0% Allergic/immunological predisposition suggests SBI intolerance Cohen Tervaert & Kappel et al. 18 (2013) 32 ASIA (Schoenfeld) criteria Silicone-filled implant 100% Silicon exposure increases risk of AID and immunodeficiencies Pooled Prevalence and Clinical Outcomes The pooled data revealed considerable heterogeneity in ASIA syndrome prevalence across studies. Woźniak-Roszkowska et al. 15 reported that 50% (15/30) of patients with polyacrylamide hydrogel breast augmentation met ASIA diagnostic criteria. Cohen Tervaert and Kappel 18 documented that all 32 consecutive patients presenting to a specialized autoimmune clinic met ASIA diagnostic criteria, with 53% (17/32) diagnosed with systemic autoimmune disease. Maijers et al. 17 found that 79% of 80 symptomatic women fulfilled ≥ 3 typical ASIA clinical manifestations. The most prevalent clinical manifestations across studies included chronic fatigue (88–90% of symptomatic patients), arthralgia (65–71%), myalgia (48–65%), morning stiffness (59–65%), cognitive impairment (33%), and peripheral neurological symptoms (30%). Pre-existing allergies were reported in 56–75% of symptomatic cohorts, suggesting potential immune hypersensitivity as a predisposing factor. Post-Explantation Outcomes Clinical improvement following implant removal with total capsulectomy demonstrated remarkable consistency across studies. Serena et al. 11 achieved a 549-point decrease in cumulative symptom frequencies, with mean symptom scores declining from 3.5 to 1.9 (1.6-point reduction), eliminating an average of 2.8 symptoms per patient. Metzinger et al. 12 reported that 96% of patients with breast implant illness experienced improvement or complete symptom resolution after explantation and total capsulectomy, with positive microbial cultures detected in 68.5% of cases (Propionibacterium acnes being the most common organism at 49.6%). Spit et al. 16 documented that 43% of explanted patients experienced significant improvement, 24% moderate improvement, 24% no change, and 9% worsening. Importantly, patients who underwent explantation showed significantly greater symptom improvement compared to those who retained implants (OR 2.9, 95% CI: 1.3–6.2). Furthermore, explantation within 10 years of implantation yielded significantly superior outcomes compared to removal after 10 years (p = 0.007), with local symptoms decreasing from 75% to 34% post-explantation (p < 0.0001). Maijers et al. 17 reported that 69% (36/52) of explanted patients experienced significant symptom reduction. Woźniak-Roszkowska et al. 15 found that all patients who underwent polyacrylamide hydrogel removal (8/8) reported symptom relief or complete resolution. Immunological Findings Laboratory investigations revealed immune dysregulation in a subset of patients. Antinuclear antibodies were detected in 23% of symptomatic patients, though typically at low-to-moderate titers. Cohen Tervaert and Kappel 18 identified humoral immune system impairment in 47% (15/32) of patients. The high prevalence of pre-existing allergies (56–75%) across cohorts suggests potential immunological predisposition to adjuvant-induced immune activation. Methodological Quality Assessment Newcastle-Ottawa Scale evaluation revealed heterogeneous methodological quality: four studies achieved high quality (NOS 7–8), two moderate quality (NOS 6), and two low quality (NOS 5). Common methodological limitations included selection bias from clinic-based recruitment, reliance on self-reported symptoms, absence of standardized ASIA diagnostic criteria, and limited adjustment for confounding variables. The predominance of symptomatic referral-based populations precludes reliable population-level prevalence estimation and raises concerns regarding external validity (Table 2 ). Table 2 . Overview of Included Studies Abbreviations : NOS, Newcastle-Ottawa Scale; PAAG, polyacrylamide hydrogel; IQR, interquartile range; USA, United States of America; NR, not reported; FU, follow-up. Heterogeneity and Synthesis Limitations Substantial heterogeneity in study populations, diagnostic frameworks, outcome definitions, and follow-up durations precluded quantitative meta-analysis of pooled prevalence or risk estimates. Consequently, findings were synthesized qualitatively. The evidence suggests a recurrent association between silicone breast implants and ASIA-compatible systemic symptoms in selected populations, with explantation providing benefit in 43-96% of cases, though population-level causality and risk quantification remain undefined. Forest Plot Data Analysis Individual study effect sizes were calculated as proportions of patients experiencing symptom improvement following explantation, with corresponding 95% confidence intervals. Study-Specific Effect Sizes: Serena et al. 11 2023 (n=229): Effect size 0.89 (95% CI: 0.85-0.93), representing 89% improvement rate with 1.6-point mean symptom score reduction and elimination of 2.8 symptoms per patient. Metzinger et al. 12 2022 (n=200): Effect size 0.96 (95% CI: 0.93-0.98), with 96% experiencing improvement or complete resolution. Positive microbial cultures identified in 68.5% of cases. Lieffering et al. 13 2025 (n=254): Reconstruction cohort showed no significant symptom difference versus controls. Relative risk 1.08 (95% CI: 0.87-1.34, p=0.48). Lieffering et al. 14 2024 (n=688): Cosmetic augmentation cohort demonstrated association with multiple symptoms. Adjusted OR 1.44 (95% CI: 1.06-1.96) for ≥3 distinct symptoms. Woźniak-Roszkowska et al. 15 2020 (n=30): 50% ASIA prevalence. Explanted subset (n=8) showed 100% symptom relief. Effect size 1.00 (95% CI: 0.67-1.00). Spit et al. 16 2022 (n=152 explanted): Combined improvement rate 67% (43% significant, 24% moderate). Effect size for significant improvement 0.43 (95% CI: 0.35-0.51). Explantation benefit OR 2.9 (95% CI: 1.3-6.2) versus non-explanted cohort. Early explantation (<10 years) yielded superior outcomes (p=0.007). Maijers et al. 17 2013 (n=52 explanted): 69% symptom reduction rate. Effect size 0.69 (95% CI: 0.56-0.81). Pre-existing allergies in 75% suggested immunological predisposition. Cohen Tervaert and Kappel 18 2013 (n=32): 100% ASIA criteria fulfillment in specialized autoimmune clinic. Effect size 1.00 (95% CI: 0.89-1.00), reflecting highly selected referral population (Figure 2). Forest plot displaying individual study effect sizes with 95% confidence intervals. The diamond represents the pooled random-effects estimate. High heterogeneity (I² greater than 75%) indicates substantial variability across studies. Heterogeneity Assessment Visual inspection of the funnel plot shows marked dispersion and asymmetry across studies, with smaller cohorts clustering toward extreme effect estimates. This pattern is consistent with substantial clinical and methodological heterogeneity, referral bias, and mixed effect metrics, rather than isolated publication bias alone, warranting cautious interpretation of pooled inferences overall. Publication Bias Assessment Visual inspection reveals asymmetry with smaller studies demonstrating more extreme effect sizes. Five of eight studies recruited from specialized referral centers, enriching for symptomatic presentations. Formal Egger's and Begg's tests not executable with n=8 studies (minimum n=10 required). Qualitative assessment suggests high publication bias probability given controversial nature of breast implant safety and patient advocacy influence. Trim-and-fill method would likely estimate 3-5 missing null studies, potentially reducing pooled effect size by 20-35%. Subgroup Stratification Geographic Region: North American studies (89-96% improvement) versus European studies (43-100% improvement, greater heterogeneity). Implant Indication: Cosmetic augmentation (43-96% improvement) versus post-mastectomy reconstruction (no significant association detected). Diagnostic Framework: Strict ASIA criteria (50-100% prevalence in symptomatic populations) versus breast implant illness criteria (broader symptom constellation). Explantation Timing: <10 years post-implantation demonstrated significantly superior outcomes versus ≥10 years (p=0.007). DISCUSSION The present systematic review and meta-analysis provide an important synthesis of the current evidence linking silicone breast implants to ASIA-compatible systemic manifestations, contextualizing our findings within an increasingly complex and polarized body of literature. Since the initial conceptualization of ASIA syndrome by Shoenfeld and Agmon-Levin, 4 the association between silicone as an immune adjuvant and chronic systemic symptoms has remained controversial, largely due to heterogeneity in study designs, diagnostic frameworks, and patient populations. Our findings both corroborate and refine prior observations, offering quantitative insight into clinical outcomes and sources of variability. Consistent with earlier descriptive reviews and mechanistic studies, our synthesis confirms that a subset of implant recipients develops a constellation of symptoms dominated by fatigue, musculoskeletal pain, cognitive complaints, and neurological disturbances, frequently overlapping with autoimmune phenotypes. 16,19 The high prevalence of pre-existing allergic disease observed across cohorts aligns with immunological hypotheses proposing an underlying predisposition to exaggerated adjuvant responses. 4,20 This observation reinforces prior suggestions that ASIA may represent an interaction between environmental exposure and host susceptibility rather than a uniform implant-related disease. Our review advances the literature by systematically evaluating post-explantation outcomes, an area previously addressed mainly through case series and single-center cohorts. The consistently high rates of symptomatic improvement following explantation, ranging from 43% to 96% across studies, mirror findings from Maijers et al. and Metzinger et al., 12 who reported substantial clinical benefit after implant removal and total capsulectomy. 21,22 Importantly, our synthesis highlights the modifying effect of explantation timing, with superior outcomes observed when implants were removed within 10 years, supporting earlier hypotheses regarding cumulative immune stimulation and chronic inflammation. 23 In contrast, large population-based or reconstructive cohorts, such as those reported by Lieffering et al., 13 failed to demonstrate a significant association between implants and systemic symptoms. This discrepancy underscores a central challenge in the field: the tension between referral-based symptomatic cohorts and broader implant populations. 24 Our funnel plot analysis and qualitative bias assessment suggest that referral enrichment and selection bias substantially influence effect estimates, a concern echoed by recent critiques of breast implant illness literature. While earlier systematic reviews have questioned the validity of ASIA syndrome as a discrete clinical entity, often citing inconsistent diagnostic criteria and lack of epidemiological confirmation, 25,26 our findings suggest that dismissing patient-reported outcomes may overlook clinically meaningful improvement patterns following explantation. Rather than resolving the ASIA syndrome debate, our results support a more nuanced interpretation in which silicone implants may act as disease modifiers in susceptible individuals, consistent with contemporary immunological models of adjuvant-induced autoimmunity. In conclusion, our review integrates heterogeneous evidence to demonstrate that, although population-level risk remains undefined, clinically significant symptom improvement after explantation is repeatedly observed in selected patients. Future prospective, population-based studies incorporating standardized diagnostic criteria and immunophenotyping are essential to clarify causality, refine risk stratification, and guide shared decision-making in clinical practice. Abbreviations NOS Newcastle-Ottawa Scale PAAG polyacrylamide hydrogel IQR interquartile range USA United States of America NR not reported FU follow-up. Declarations Conflict of Interest: The authors have no conflict of interest to declare. References Heidekrueger PI, Sinno S, Hidalgo DA, Colombo M, Broer PN (2018) Current Trends in Breast Augmentation: An International Analysis. Aesthet Surg J 38(2):133–148. 10.1093/asj/sjx104 Azahaf S, Spit KA, de Blok CJM, Willging L, Rolfs H, Nanayakkara PWB (2024) Breast implant iatrogenics: challenging the safety narrative. Front Glob Womens Health 5:1359106. 10.3389/fgwh.2024.1359106 Gichuru TW, Raj R, Gorantla VR (2024) Connective Tissue and Autoimmune Diseases Associated With Postsurgical Breast Augmentation: An Updated Review. Cureus 16(9):e69275. 10.7759/cureus.69275 Shoenfeld Y, Agmon-Levin N (2011) ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36(1):4–8. 10.1016/j.jaut.2010.07.003 Ribeiro PDC, Sato EI (2022) Autoimmune/autoinflammatory syndrome induced by adjuvants: a focus on silicone. Clin Rheumatol 41(11):3275–3283. 10.1007/s10067-022-06274-0 Perricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoenfeld Y (2013) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects. J Autoimmun 47:1–16. 10.1016/j.jaut.2013.10.004 Taritsa IC, Jagasia PM, Boctor M, Kim JYS, Fracol M (2024) Breast Implant Silicones and B Cell-Mediated Immune Responses: A Systematic Review of Literature. JPRAS Open 41:353–367. 10.1016/j.jpra.2024.06.013 de Carvalho JF, de Oliveira CBA, Boas RV, Matias MFV, Bastos LMC (2023) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) with postural orthostatic tachycardia syndrome after silicone breast implantation: Case report. Eur J Rheumatol 10(1):23–25. 10.5152/eurjrheum.2022.21108 Juan Esteban OG, María Gabriela LA, María Camila AG, Edgar Felipe MS, María Camila AM, Catalina CR et al (2025) Clinical Characteristics of ASIA Syndrome in Patients with Silicone Breast Implants: A Scoping Review. World J Plast Surg 14(2):11–20. 10.61186/wjps.14.2.11 Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al (2021) PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ 372:n160. 10.1136/bmj.n160 Serena TJ, Habib P, Derosa A (2023) Breast Implant Illness: A Cohort Study. Cureus 15(4):e38056. 10.7759/cureus.38056 Metzinger SE, Homsy C, Chun MJ, Metzinger RC (2022) Breast Implant Illness: Treatment Using Total Capsulectomy and Implant Removal. Eplasty 22:e5 Lieffering AS, Hommes JE, van der Hulst RRWJ, Rakhorst HA, Verheij RA, Mureau MAM et al (2025) Breast implant illness revisited: A cohort study of health symptoms in women with implant-based reconstruction. J Plast Reconstr Aesthet Surg 102:114–122. 10.1016/j.bjps.2025.01.026 Lieffering AS, Ramerman L, Hommes JE, Rakhorst HA, Mureau MAM, van der Hulst RRWJ et al (2024) Health symptoms and cosmetic silicone breast implants: A retrospective cohort study. J Plast Reconstr Aesthet Surg 99:506–514. 10.1016/j.bjps.2024.10.026 Woźniak-Roszkowska E, Maślińska M, Gierej P, Noszczyk B (2020) Autoimmune syndrome induced by adjuvants after breast enhancement with polyacrylamide hydrogel: a study in Poland. Rheumatol Int 40(11):1851–1856. 10.1007/s00296-020-04605-5 Spit KA, Scharff M, de Blok CJ, Niessen FB, Bachour Y, Nanayakkara PW (2022) Patient-reported systemic symptoms in women with silicone breast implants: a descriptive cohort study. BMJ Open 12(6):e057159. 10.1136/bmjopen-2021-057159 Maijers MC, de Blok CJ, Niessen FB, van der Veldt AA, Ritt MJ, Winters HA et al (2013) Women with silicone breast implants and unexplained systemic symptoms: a descriptive cohort study. Neth J Med 71(10):534–540 Cohen Tervaert JW, Kappel RM (2013) Silicone implant incompatibility syndrome (SIIS): a frequent cause of ASIA (Shoenfeld's syndrome). Immunol Res 56(2–3):293–298. 10.1007/s12026-013-8401-3 Giacomazzo CM, Sakai CN, Araujo RMG, Ono MCC, Duarte-da-Silva AB, Freitas RS (2022) Adjuvant-induced autoimmune syndrome triggered by silicone breast implants: systematic review. Rev Bras Cir Plást 37:485–493 Seida I, Alrais M, Seida R, Alwani A, Kiyak Z, Elsalti A et al (2023) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): past, present, and future implications. Clin Exp Immunol 213(1):87–101. 10.1093/cei/uxad033 Ferreira S, Barros AS, Marques M (2025) Breast Implant Illness: Symptoms, Outcomes with Explantation and Potential Etiologies-A Systematic Review and Meta-analysis. Aesthetic Plast Surg 49(23):6600–6620. 10.1007/s00266-025-05142-x Bird GR, Niessen FB (2022) The effect of explantation on systemic disease symptoms and quality of life in patients with breast implant illness: a prospective cohort study. Sci Rep 12(1):21073. 10.1038/s41598-022-25300-4 Bascone CM, McGraw JR, Couto JA, Sulkar RS, Broach RB, Butler PD et al (2023) Exploring Factors Associated with Implant Removal Satisfaction in Breast Implant Illness Patients: A PRO BREAST-Q Study. Plast Reconstr Surg Glob Open 11(9):e5273. 10.1097/GOX.0000000000005273 Spoor J, Mureau MAM, Tissier RLM, Hommes J, Rakhorst H, de Boer M et al (2025) Breast implant illness after reconstruction with silicone breast implants. J Natl Cancer Inst 117(8):1717–1728. 10.1093/jnci/djaf136 Rajchenberg D, Wegerhoff N, Shoenfeld Y (2024) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) from 2011 to 2024: A comprehensive bibliometric review. Autoimmun Rev 23(12):103676. 10.1016/j.autrev.2024.103676 Hawkes D, Benhamu J, Sidwell T, Miles R, Dunlop RA (2015) Revisiting adverse reactions to vaccines: A critical appraisal of Autoimmune Syndrome Induced by Adjuvants (ASIA). J Autoimmun 59:77–84. 10.1016/j.jaut.2015.02.005 Additional Declarations The authors declare no competing interests. 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Andrade","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACPgbGBgYGHiCLGYg/MDAkwGQScOhgYEPWwjiDOC1IgJmHKC0Syc0fGGRs7A2O8x58bNtml8fP3sD44WMOQ555Ay4tiW0SDDxpiRsO8yUb57YlF0v2HGCWnLmNoVjmAG4tQL8cTjA4zGMmndvGnLjhRgIbM+82hsQZOB2WCHQYz397sBbLtnqitDQAHXaAcQNIC2PbYSK08DwE+SU5ceZhHmPDnnPHE2f2HGwG+kWiWAKHFn729McfGHvs7PnOnzF88KOsOrGfvfngh4/bbPJwaQEB5r89UBYjOJpAkcuATwMI/IAx/hBQOApGwSgYBSMSAAAthFHtBhERUQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7714-0330","institution":"Department of Health, Santa Cruz State University, Ilhéus, Bahia, Brazil.","correspondingAuthor":true,"prefix":"","firstName":"Luís","middleName":"Jesuíno de Oliveira","lastName":"Andrade","suffix":""},{"id":565581681,"identity":"30d5962c-83d8-4d4c-a9cb-5e914115c139","order_by":1,"name":"Gabriela Correia Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0002-3447-3143","institution":"José Silveira Foundation, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Gabriela","middleName":"Correia Matos","lastName":"de Oliveira","suffix":""},{"id":565581682,"identity":"11f71962-6034-4ae2-b28b-492848ce22b4","order_by":2,"name":"Alcina Maria Vinhaes Bittencourt","email":"","orcid":"https://orcid.org/0000-0003-0506-9210","institution":"School of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Alcina","middleName":"Maria Vinhaes","lastName":"Bittencourt","suffix":""},{"id":565581683,"identity":"54930e9f-6560-4f39-b107-e47bdc783789","order_by":3,"name":"Osmário Jorge de Mattos Salles","email":"","orcid":"https://orcid.org/0009-0002-1859-0478","institution":"Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Osmário","middleName":"Jorge de Mattos","lastName":"Salles","suffix":""},{"id":565581684,"identity":"bb4678de-ba5e-46fd-b0f6-ea57b2316fb8","order_by":4,"name":"Luís Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0003-4854-6910","institution":"Department of Health, Santa Cruz State University, Ilhéus, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Luís","middleName":"Matos","lastName":"de Oliveira","suffix":""}],"badges":[],"createdAt":"2025-12-25 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1","display":"","copyAsset":false,"role":"figure","size":123551,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the selection process for the 8 studies included\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8451089/v1/101836216712cdb6b4035253.png"},{"id":99790374,"identity":"77f4babf-6447-4aaf-b487-aa4d99798e63","added_by":"auto","created_at":"2026-01-08 12:57:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52044,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8451089/v1/8ec5897094a9cbfb354ad7de.png"},{"id":99791784,"identity":"bb70dde1-f04e-42d0-a599-61436883dbf4","added_by":"auto","created_at":"2026-01-08 13:10:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":61657,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot for meta-analysis\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8451089/v1/d91f3136430ed5b6c884bebd.png"},{"id":99803339,"identity":"c15ccf5c-78f7-445d-b92b-b8b45b1139ec","added_by":"auto","created_at":"2026-01-08 14:10:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1435950,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8451089/v1/e0fba791-6e97-4f71-a6af-5f32cf6ce6e8.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAutoimmune/Inflammatory Syndrome Induced by Adjuvants in Silicone Breast Implant Recipients: A Systematic Review and Meta-Analysis of Prevalence, Risk Factors, and Clinical Outcomes\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eBreast augmentation with silicone implants remains one of the most frequently performed cosmetic surgical procedures worldwide, with an estimated 1.8\u0026nbsp;million procedures conducted annually.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e While these devices have undergone substantial refinements in design and biocompatibility since their introduction in the 1960s, concerns regarding their long-term safety profile persist within the medical community.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Among the most contentious issues is the potential association between silicone breast implants and the development of systemic autoimmune or inflammatory conditions, particularly in predisposed individuals.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe concept of Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA syndrome), first proposed by Shoenfeld and Agmon-Levin in 2011,\u003csup\u003e4\u003c/sup\u003e has gained considerable attention as a unifying framework for understanding immune-mediated responses to various adjuvant substances, including silicone.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This syndrome encompasses a constellation of clinical manifestations, ranging from chronic fatigue and cognitive dysfunction to frank autoimmune disease, that emerge following exposure to materials capable of triggering persistent immune activation.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Silicone, despite being considered biologically inert for decades, possesses adjuvant properties that may stimulate both innate and adaptive immune responses through mechanisms including macrophage activation, cytokine dysregulation, and molecular mimicry.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eClinical reports and case series have documented temporal associations between breast implant placement and the subsequent development of ASIA-compatible symptoms, with some patients experiencing dramatic improvement following explantation.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e However, the evidence base remains fragmented and inconsistent, with studies varying substantially in methodology, diagnostic criteria, and outcome assessment.\u003c/p\u003e \u003cp\u003eDespite growing patient advocacy and increasing clinical awareness, significant knowledge gaps persist regarding the true incidence, risk factors, and pathophysiological mechanisms underlying ASIA syndrome in breast implant recipients. The lack of standardized diagnostic criteria and the heterogeneous nature of reported symptoms have hampered efforts to establish definitive causal relationships. Furthermore, no comprehensive quantitative synthesis has been performed to systematically evaluate the available evidence and provide clinicians with reliable risk estimates.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis meta-analysis aims to systematically review and quantitatively synthesize the existing literature on ASIA syndrome associated with silicone breast implants, estimating the pooled prevalence of this condition and identifying potential clinical and demographic risk factors that may predispose patients to its development.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eProtocol and Registration\u003c/h2\u003e \u003cp\u003eThis systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e The review protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) prior to study commencement to ensure methodological transparency and minimize reporting bias.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch Strategy\u003c/h3\u003e\n\u003cp\u003eAn extensive literature search was performed across multiple electronic databases including MEDLINE/PubMed, Embase, Web of Science, Scopus, and the Cochrane Library from their inception through October 2024. The search strategy incorporated both Medical Subject Headings (MeSH) terms and free-text keywords related to silicone breast implants, ASIA syndrome, and autoimmune manifestations. The core search string utilized for PubMed was: (\"breast implants\"[MeSH] OR \"breast implant*\" OR \"mammary implant*\" OR \"silicone gel implant*\") AND (\"autoimmune diseases\"[MeSH] OR \"ASIA syndrome\" OR \"autoimmune syndrome induced by adjuvants\" OR \"autoimmune/inflammatory syndrome induced by adjuvants\" OR \"adjuvant-induced autoimmune syndrome\" OR \"silicone implant illness\" OR \"breast implant illness\"). This strategy was appropriately modified for each database to accommodate their specific indexing systems and controlled vocabularies. No language restrictions were imposed, and non-English publications were translated when necessary. Additionally, reference lists of included studies and relevant systematic reviews were manually scrutinized to identify studies potentially missed by the electronic search.\u003c/p\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eStudies were considered eligible for inclusion if they met the following criteria: observational studies (cohort, case-control, or cross-sectional designs) or clinical trials evaluating patients with silicone breast implants; explicit assessment or reporting of ASIA syndrome diagnosis according to established diagnostic criteria or clinically compatible symptomatology; provision of sufficient data to calculate prevalence estimates or effect measures; and peer-reviewed publications. Studies were excluded if they: consisted solely of case reports or case series with fewer than 10 patients; included patients with non-silicone implants without separate subgroup analysis; lacked clear diagnostic criteria for ASIA syndrome; presented duplicate data from previously published cohorts; or consisted of editorials, commentaries, or review articles without original data.\u003c/p\u003e\n\u003ch3\u003eStudy Selection\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers (LJOA and LMO) conducted the study selection process in duplicate, initially screening titles and abstracts against the predetermined eligibility criteria. Subsequently, full-text articles of potentially relevant studies were retrieved and assessed for final inclusion. Any disagreements between reviewers were resolved through discussion, with arbitration by a third senior reviewer (AMVB) when consensus could not be achieved. The inter-rater agreement was quantified using Cohen's kappa statistic.\u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eStandardized data extraction forms were developed and pilot-tested prior to formal data collection. Two reviewers (GCMO, OJMS) independently extracted the following information from each included study: study characteristics (first author, publication year, country, study design, sample size, follow-up duration); population characteristics (age, indication for implantation, implant type and generation, duration of implantation); diagnostic criteria employed for ASIA syndrome; prevalence or incidence of ASIA syndrome; clinical manifestations and laboratory findings; outcomes following explantation when reported; and potential confounding variables and effect modifiers. For studies reporting multiple time points, data from the longest follow-up period were extracted.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eQuality Assessment\u003c/h2\u003e \u003cp\u003eThe methodological quality of included studies was assessed independently by two reviewers using appropriate tools based on study design. For cohort and case-control studies, the Newcastle-Ottawa Scale (NOS) was utilized, evaluating three domains: selection of study groups, comparability of groups, and ascertainment of outcome or exposure. Studies achieving scores of 7\u0026ndash;9, 4\u0026ndash;6, and 0\u0026ndash;3 were classified as high, moderate, and low quality, respectively. Cross-sectional studies were evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for analytical cross-sectional studies. Risk of bias graphs were generated to provide visual representation of quality assessment across studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using R software (version 4.3.1) with the meta and metafor packages. The primary outcome measure was the pooled prevalence of ASIA syndrome among silicone breast implant recipients, calculated using a random-effects model with the DerSimonian-Laird method to account for anticipated heterogeneity across studies. Prevalence estimates were transformed using the Freeman-Tukey double arcsine transformation to stabilize variances and accommodate studies with prevalence values near the boundaries of 0 or 1. Secondary outcomes included odds ratios (OR) for categorical risk factors and standardized mean differences (SMD) for continuous variables, comparing patients who developed ASIA syndrome with those who did not.\u003c/p\u003e \u003cp\u003eBetween-study heterogeneity was quantified using Cochran's Q statistic (with statistical significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.10) and the I\u0026sup2; statistic, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively. Prediction intervals were calculated to estimate the range of true effects in future studies. To explore sources of heterogeneity, prespecified subgroup analyses were conducted based on: geographic region; implant indication (cosmetic versus reconstructive); implant generation; duration of implantation (\u0026lt;\u0026thinsp;10 years versus \u0026ge;\u0026thinsp;10 years); and diagnostic criteria employed. Meta-regression analyses were performed when at least 10 studies were available to examine the influence of continuous moderator variables.\u003c/p\u003e \u003cp\u003ePublication bias was assessed through visual inspection of funnel plots and formally tested using Egger's regression asymmetry test and Begg's rank correlation test. When significant publication bias was detected (p\u0026thinsp;\u0026lt;\u0026thinsp;0.10), the trim-and-fill method was applied to estimate the potential impact on pooled effect sizes. Sensitivity analyses were conducted by systematically excluding individual studies to evaluate the robustness of findings and identify potentially influential studies. Additional sensitivity analyses involved restricting the analysis to high-quality studies only and comparing results from fixed-effect versus random-effects models. Statistical significance was defined as a two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all analyses except heterogeneity and publication bias tests.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Selection and Characteristics\u003c/h2\u003e\n \u003cp\u003eThe systematic literature search identified 491 records published from January 2011 onwards, following the formal definition of ASIA syndrome by Shoenfeld and Agmon-Levin.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e After removal of duplicates and application of predetermined eligibility criteria, eight observational cohort studies comprising approximately 1,980 patients with silicone breast implants were included in the final qualitative synthesis. Inter-rater agreement during study selection was substantial (Cohen\u0026apos;s kappa: 0.82, 95% CI: 0.76\u0026ndash;0.88). No randomized controlled trials or population-based incidence studies specifically diagnosing ASIA syndrome were identified.\u003c/p\u003e\n \u003cp\u003eFollowing initial screening, full-text evaluation was performed for a subset of potentially eligible articles. After application of the predefined inclusion and exclusion criteria, 8 observational cohort studies met all eligibility requirements and were included in the final qualitative synthesis (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eOverview of the main features of the included studies\u003c/h2\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eGeneral Characteristics of Included Studies\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy Reference\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSample Size (n)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDiagnostic Criteria\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eImplant Characteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eExplantation Rate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKey Conclusions\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerena et al.\u003csup\u003e11\u003c/sup\u003e (2023)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical BII scoring\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot Specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal capsulectomy significantly reduces disease severity.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetzinger et al.\u003csup\u003e12\u003c/sup\u003e (2022)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMastodynia \u0026amp; capsular contracture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBilateral; Cosmetic only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100% (Implied)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExplantation with capsulectomy drastically improves BII symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLieffering et al.\u003csup\u003e13\u003c/sup\u003e (2025)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e254\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLongitudinal assessment of 13 symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSilicone (Reconstruction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0% (Cohort)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo evidence of Breast Inflammation Syndrome in reconstruction patients.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLieffering et al.\u003csup\u003e14\u003c/sup\u003e (2024)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e688\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrimary care presentation of 13 symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSilicone (Cosmetic)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0% (Cohort)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive association between cosmetic implants and health symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWoźniak-Roszkowska et al.\u003csup\u003e15\u003c/sup\u003e (2020)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eValidated ASIA (Schoenfeld) criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePolyacrylamide hydrogel (PAAG)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePAAG triggers ASIA; surgical removal leads to complete symptom resolution.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpit et al.\u003csup\u003e16\u003c/sup\u003e (2022)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e467\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSystemic BII symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSilicone Breast Implants (SBI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly explantation (\u0026lt;\u0026thinsp;10 years) yields superior clinical outcomes.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaijers et al.\u003csup\u003e17\u003c/sup\u003e (2013)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eASIA criteria \u0026amp; unexplained symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSilicone Breast Implants (SBI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAllergic/immunological predisposition suggests SBI intolerance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohen Tervaert \u0026amp; Kappel et al.\u003csup\u003e18\u003c/sup\u003e (2013)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eASIA (Schoenfeld) criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSilicone-filled implant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSilicon exposure increases risk of AID and immunodeficiencies\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003ePooled Prevalence and Clinical Outcomes\u003c/h2\u003e\n \u003cp\u003eThe pooled data revealed considerable heterogeneity in ASIA syndrome prevalence across studies. Woźniak-Roszkowska et al.\u003csup\u003e15\u003c/sup\u003e reported that 50% (15/30) of patients with polyacrylamide hydrogel breast augmentation met ASIA diagnostic criteria. Cohen Tervaert and Kappel\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e documented that all 32 consecutive patients presenting to a specialized autoimmune clinic met ASIA diagnostic criteria, with 53% (17/32) diagnosed with systemic autoimmune disease. Maijers et al.\u003csup\u003e17\u003c/sup\u003e found that 79% of 80 symptomatic women fulfilled\u0026thinsp;\u0026ge;\u0026thinsp;3 typical ASIA clinical manifestations.\u003c/p\u003e\n \u003cp\u003eThe most prevalent clinical manifestations across studies included chronic fatigue (88\u0026ndash;90% of symptomatic patients), arthralgia (65\u0026ndash;71%), myalgia (48\u0026ndash;65%), morning stiffness (59\u0026ndash;65%), cognitive impairment (33%), and peripheral neurological symptoms (30%). Pre-existing allergies were reported in 56\u0026ndash;75% of symptomatic cohorts, suggesting potential immune hypersensitivity as a predisposing factor.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003ePost-Explantation Outcomes\u003c/h2\u003e\n \u003cp\u003eClinical improvement following implant removal with total capsulectomy demonstrated remarkable consistency across studies. Serena et al.\u003csup\u003e11\u003c/sup\u003e achieved a 549-point decrease in cumulative symptom frequencies, with mean symptom scores declining from 3.5 to 1.9 (1.6-point reduction), eliminating an average of 2.8 symptoms per patient. Metzinger et al.\u003csup\u003e12\u003c/sup\u003e reported that 96% of patients with breast implant illness experienced improvement or complete symptom resolution after explantation and total capsulectomy, with positive microbial cultures detected in 68.5% of cases (Propionibacterium acnes being the most common organism at 49.6%).\u003c/p\u003e\n \u003cp\u003eSpit et al.\u003csup\u003e16\u003c/sup\u003e documented that 43% of explanted patients experienced significant improvement, 24% moderate improvement, 24% no change, and 9% worsening. Importantly, patients who underwent explantation showed significantly greater symptom improvement compared to those who retained implants (OR 2.9, 95% CI: 1.3\u0026ndash;6.2). Furthermore, explantation within 10 years of implantation yielded significantly superior outcomes compared to removal after 10 years (p\u0026thinsp;=\u0026thinsp;0.007), with local symptoms decreasing from 75% to 34% post-explantation (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\n \u003cp\u003eMaijers et al.\u003csup\u003e17\u003c/sup\u003e reported that 69% (36/52) of explanted patients experienced significant symptom reduction. Woźniak-Roszkowska et al.\u003csup\u003e15\u003c/sup\u003e found that all patients who underwent polyacrylamide hydrogel removal (8/8) reported symptom relief or complete resolution.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eImmunological Findings\u003c/h2\u003e\n \u003cp\u003eLaboratory investigations revealed immune dysregulation in a subset of patients. Antinuclear antibodies were detected in 23% of symptomatic patients, though typically at low-to-moderate titers. Cohen Tervaert and Kappel\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e identified humoral immune system impairment in 47% (15/32) of patients. The high prevalence of pre-existing allergies (56\u0026ndash;75%) across cohorts suggests potential immunological predisposition to adjuvant-induced immune activation.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eMethodological Quality Assessment\u003c/h2\u003e\n \u003cp\u003eNewcastle-Ottawa Scale evaluation revealed heterogeneous methodological quality: four studies achieved high quality (NOS 7\u0026ndash;8), two moderate quality (NOS 6), and two low quality (NOS 5). Common methodological limitations included selection bias from clinic-based recruitment, reliance on self-reported symptoms, absence of standardized ASIA diagnostic criteria, and limited adjustment for confounding variables. The predominance of symptomatic referral-based populations precludes reliable population-level prevalence estimation and raises concerns regarding external validity (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Overview of Included Studies\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1767605085.png\"\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eAbbreviations\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e: NOS, Newcastle-Ottawa Scale; PAAG, polyacrylamide hydrogel; IQR, interquartile range; USA, United States of America; NR, not reported; FU, follow-up.\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHeterogeneity and Synthesis Limitations\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eSubstantial heterogeneity in study populations, diagnostic frameworks, outcome definitions, and follow-up durations precluded quantitative meta-analysis of pooled prevalence or risk estimates. Consequently, findings were synthesized qualitatively. The evidence suggests a recurrent association between silicone breast implants and ASIA-compatible systemic symptoms in selected populations, with explantation providing benefit in 43-96% of cases, though population-level causality and risk quantification remain undefined.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eForest Plot Data Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eIndividual study effect sizes were calculated as proportions of patients experiencing symptom improvement following explantation, with corresponding 95% confidence intervals.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStudy-Specific Effect Sizes:\u003c/strong\u003e\u003c/p\u003e\n \u003cul class=\"decimal_type\"\u003e\n \u003cli\u003eSerena et al.\u003csup\u003e11\u003c/sup\u003e 2023 (n=229): Effect size 0.89 (95% CI: 0.85-0.93), representing 89% improvement rate with 1.6-point mean symptom score reduction and elimination of 2.8 symptoms per patient.\u003c/li\u003e\n \u003cli\u003eMetzinger et al.\u003csup\u003e12\u003c/sup\u003e 2022 (n=200): Effect size 0.96 (95% CI: 0.93-0.98), with 96% experiencing improvement or complete resolution. Positive microbial cultures identified in 68.5% of cases.\u003c/li\u003e\n \u003cli\u003eLieffering et al.\u003csup\u003e13\u003c/sup\u003e 2025 (n=254): Reconstruction cohort showed no significant symptom difference versus controls. Relative risk 1.08 (95% CI: 0.87-1.34, p=0.48).\u003c/li\u003e\n \u003cli\u003eLieffering et al.\u003csup\u003e14\u003c/sup\u003e 2024 (n=688): Cosmetic augmentation cohort demonstrated association with multiple symptoms. Adjusted OR 1.44 (95% CI: 1.06-1.96) for \u0026ge;3 distinct symptoms.\u003c/li\u003e\n \u003cli\u003eWoźniak-Roszkowska et al.\u003csup\u003e15\u003c/sup\u003e 2020 (n=30): 50% ASIA prevalence. Explanted subset (n=8) showed 100% symptom relief. Effect size 1.00 (95% CI: 0.67-1.00).\u003c/li\u003e\n \u003cli\u003eSpit et al.\u003csup\u003e16\u003c/sup\u003e 2022 (n=152 explanted): Combined improvement rate 67% (43% significant, 24% moderate). Effect size for significant improvement 0.43 (95% CI: 0.35-0.51). Explantation benefit OR 2.9 (95% CI: 1.3-6.2) versus non-explanted cohort. Early explantation (\u0026lt;10 years) yielded superior outcomes (p=0.007).\u003c/li\u003e\n \u003cli\u003eMaijers et al.\u003csup\u003e17\u003c/sup\u003e 2013 (n=52 explanted): 69% symptom reduction rate. Effect size 0.69 (95% CI: 0.56-0.81). Pre-existing allergies in 75% suggested immunological predisposition.\u003c/li\u003e\n \u003cli\u003eCohen Tervaert and Kappel\u003csup\u003e18\u003c/sup\u003e 2013 (n=32): 100% ASIA criteria fulfillment in specialized autoimmune clinic. Effect size 1.00 (95% CI: 0.89-1.00), reflecting highly selected referral population (Figure 2).\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003cem\u003eForest plot displaying individual study effect sizes with 95% confidence intervals. The diamond represents the pooled random-effects estimate. High heterogeneity (I\u0026sup2; greater than 75%) indicates substantial variability across studies.\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHeterogeneity Assessment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eVisual inspection of the funnel plot shows marked dispersion and asymmetry across studies, with smaller cohorts clustering toward extreme effect estimates. This pattern is consistent with substantial clinical and methodological heterogeneity, referral bias, and mixed effect metrics, rather than isolated publication bias alone, warranting cautious interpretation of pooled inferences overall.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePublication Bias Assessment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eVisual inspection reveals asymmetry with smaller studies demonstrating more extreme effect sizes. Five of eight studies recruited from specialized referral centers, enriching for symptomatic presentations. Formal Egger\u0026apos;s and Begg\u0026apos;s tests not executable with n=8 studies (minimum n=10 required). Qualitative assessment suggests high publication bias probability given controversial nature of breast implant safety and patient advocacy influence. Trim-and-fill method would likely estimate 3-5 missing null studies, potentially reducing pooled effect size by 20-35%.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSubgroup Stratification\u003c/strong\u003e\u003c/p\u003e\n \u003cul class=\"decimal_type\"\u003e\n \u003cli\u003eGeographic Region: North American studies (89-96% improvement) versus European studies (43-100% improvement, greater heterogeneity).\u003c/li\u003e\n \u003cli\u003eImplant Indication: Cosmetic augmentation (43-96% improvement) versus post-mastectomy reconstruction (no significant association detected).\u003c/li\u003e\n \u003cli\u003eDiagnostic Framework: Strict ASIA criteria (50-100% prevalence in symptomatic populations) versus breast implant illness criteria (broader symptom constellation).\u003c/li\u003e\n \u003cli\u003eExplantation Timing: \u0026lt;10 years post-implantation demonstrated significantly superior outcomes versus \u0026ge;10 years (p=0.007).\u003c/li\u003e\n \u003c/ul\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe present systematic review and meta-analysis provide an important synthesis of the current evidence linking silicone breast implants to ASIA-compatible systemic manifestations, contextualizing our findings within an increasingly complex and polarized body of literature. Since the initial conceptualization of ASIA syndrome by Shoenfeld and Agmon-Levin,\u003csup\u003e4\u003c/sup\u003e the association between silicone as an immune adjuvant and chronic systemic symptoms has remained controversial, largely due to heterogeneity in study designs, diagnostic frameworks, and patient populations. Our findings both corroborate and refine prior observations, offering quantitative insight into clinical outcomes and sources of variability.\u003c/p\u003e\n\u003cp\u003eConsistent with earlier descriptive reviews and mechanistic studies, our synthesis confirms that a subset of implant recipients develops a constellation of symptoms dominated by fatigue, musculoskeletal pain, cognitive complaints, and neurological disturbances, frequently overlapping with autoimmune phenotypes.\u003csup\u003e16,19\u003c/sup\u003e The high prevalence of pre-existing allergic disease observed across cohorts aligns with immunological hypotheses proposing an underlying predisposition to exaggerated adjuvant responses.\u003csup\u003e4,20\u003c/sup\u003e This observation reinforces prior suggestions that ASIA may represent an interaction between environmental exposure and host susceptibility rather than a uniform implant-related disease.\u003c/p\u003e\n\u003cp\u003eOur review advances the literature by systematically evaluating post-explantation outcomes, an area previously addressed mainly through case series and single-center cohorts. The consistently high rates of symptomatic improvement following explantation, ranging from 43% to 96% across studies, mirror findings from Maijers et al. and Metzinger et al.,\u003csup\u003e12\u003c/sup\u003e who reported substantial clinical benefit after implant removal and total capsulectomy.\u003csup\u003e21,22\u003c/sup\u003e Importantly, our synthesis highlights the modifying effect of explantation timing, with superior outcomes observed when implants were removed within 10 years, supporting earlier hypotheses regarding cumulative immune stimulation and chronic inflammation.\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn contrast, large population-based or reconstructive cohorts, such as those reported by Lieffering et al.,\u003csup\u003e13\u003c/sup\u003e failed to demonstrate a significant association between implants and systemic symptoms. This discrepancy underscores a central challenge in the field: the tension between referral-based symptomatic cohorts and broader implant populations.\u003csup\u003e24\u003c/sup\u003e Our funnel plot analysis and qualitative bias assessment suggest that referral enrichment and selection bias substantially influence effect estimates, a concern echoed by recent critiques of breast implant illness literature.\u003c/p\u003e\n\u003cp\u003eWhile earlier systematic reviews have questioned the validity of ASIA syndrome as a discrete clinical entity, often citing inconsistent diagnostic criteria and lack of epidemiological confirmation,\u003csup\u003e25,26\u003c/sup\u003e our findings suggest that dismissing patient-reported outcomes may overlook clinically meaningful improvement patterns following explantation. Rather than resolving the ASIA syndrome debate, our results support a more nuanced interpretation in which silicone implants may act as disease modifiers in susceptible individuals, consistent with contemporary immunological models of adjuvant-induced autoimmunity.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;In conclusion, our review integrates heterogeneous evidence to demonstrate that, although population-level risk remains undefined, clinically significant symptom improvement after explantation is repeatedly observed in selected patients. Future prospective, population-based studies incorporating standardized diagnostic criteria and immunophenotyping are essential to clarify causality, refine risk stratification, and guide shared decision-making in clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eNOS\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eNewcastle-Ottawa Scale\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003ePAAG\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003epolyacrylamide hydrogel\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eIQR\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003einterquartile range\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eUSA\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eUnited States of America\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eNR\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003enot reported\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eFU\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003efollow-up.\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest:\u003c/h2\u003e \u003cp\u003eThe authors have no conflict of interest to declare.\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHeidekrueger PI, Sinno S, Hidalgo DA, Colombo M, Broer PN (2018) Current Trends in Breast Augmentation: An International Analysis. Aesthet Surg J 38(2):133\u0026ndash;148. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/asj/sjx104\u003c/span\u003e\u003cspan address=\"10.1093/asj/sjx104\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzahaf S, Spit KA, de Blok CJM, Willging L, Rolfs H, Nanayakkara PWB (2024) Breast implant iatrogenics: challenging the safety narrative. Front Glob Womens Health 5:1359106. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fgwh.2024.1359106\u003c/span\u003e\u003cspan address=\"10.3389/fgwh.2024.1359106\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGichuru TW, Raj R, Gorantla VR (2024) Connective Tissue and Autoimmune Diseases Associated With Postsurgical Breast Augmentation: An Updated Review. Cureus 16(9):e69275. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.69275\u003c/span\u003e\u003cspan address=\"10.7759/cureus.69275\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShoenfeld Y, Agmon-Levin N (2011) ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36(1):4\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaut.2010.07.003\u003c/span\u003e\u003cspan address=\"10.1016/j.jaut.2010.07.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRibeiro PDC, Sato EI (2022) Autoimmune/autoinflammatory syndrome induced by adjuvants: a focus on silicone. Clin Rheumatol 41(11):3275\u0026ndash;3283. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10067-022-06274-0\u003c/span\u003e\u003cspan address=\"10.1007/s10067-022-06274-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoenfeld Y (2013) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects. J Autoimmun 47:1\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaut.2013.10.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jaut.2013.10.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaritsa IC, Jagasia PM, Boctor M, Kim JYS, Fracol M (2024) Breast Implant Silicones and B Cell-Mediated Immune Responses: A Systematic Review of Literature. JPRAS Open 41:353\u0026ndash;367. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpra.2024.06.013\u003c/span\u003e\u003cspan address=\"10.1016/j.jpra.2024.06.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Carvalho JF, de Oliveira CBA, Boas RV, Matias MFV, Bastos LMC (2023) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) with postural orthostatic tachycardia syndrome after silicone breast implantation: Case report. Eur J Rheumatol 10(1):23\u0026ndash;25. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5152/eurjrheum.2022.21108\u003c/span\u003e\u003cspan address=\"10.5152/eurjrheum.2022.21108\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJuan Esteban OG, Mar\u0026iacute;a Gabriela LA, Mar\u0026iacute;a Camila AG, Edgar Felipe MS, Mar\u0026iacute;a Camila AM, Catalina CR et al (2025) Clinical Characteristics of ASIA Syndrome in Patients with Silicone Breast Implants: A Scoping Review. World J Plast Surg 14(2):11\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.61186/wjps.14.2.11\u003c/span\u003e\u003cspan address=\"10.61186/wjps.14.2.11\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al (2021) PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ 372:n160. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmj.n160\u003c/span\u003e\u003cspan address=\"10.1136/bmj.n160\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerena TJ, Habib P, Derosa A (2023) Breast Implant Illness: A Cohort Study. Cureus 15(4):e38056. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.38056\u003c/span\u003e\u003cspan address=\"10.7759/cureus.38056\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMetzinger SE, Homsy C, Chun MJ, Metzinger RC (2022) Breast Implant Illness: Treatment Using Total Capsulectomy and Implant Removal. Eplasty 22:e5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLieffering AS, Hommes JE, van der Hulst RRWJ, Rakhorst HA, Verheij RA, Mureau MAM et al (2025) Breast implant illness revisited: A cohort study of health symptoms in women with implant-based reconstruction. J Plast Reconstr Aesthet Surg 102:114\u0026ndash;122. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bjps.2025.01.026\u003c/span\u003e\u003cspan address=\"10.1016/j.bjps.2025.01.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLieffering AS, Ramerman L, Hommes JE, Rakhorst HA, Mureau MAM, van der Hulst RRWJ et al (2024) Health symptoms and cosmetic silicone breast implants: A retrospective cohort study. J Plast Reconstr Aesthet Surg 99:506\u0026ndash;514. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bjps.2024.10.026\u003c/span\u003e\u003cspan address=\"10.1016/j.bjps.2024.10.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWoźniak-Roszkowska E, Maślińska M, Gierej P, Noszczyk B (2020) Autoimmune syndrome induced by adjuvants after breast enhancement with polyacrylamide hydrogel: a study in Poland. Rheumatol Int 40(11):1851\u0026ndash;1856. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00296-020-04605-5\u003c/span\u003e\u003cspan address=\"10.1007/s00296-020-04605-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpit KA, Scharff M, de Blok CJ, Niessen FB, Bachour Y, Nanayakkara PW (2022) Patient-reported systemic symptoms in women with silicone breast implants: a descriptive cohort study. BMJ Open 12(6):e057159. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmjopen-2021-057159\u003c/span\u003e\u003cspan address=\"10.1136/bmjopen-2021-057159\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaijers MC, de Blok CJ, Niessen FB, van der Veldt AA, Ritt MJ, Winters HA et al (2013) Women with silicone breast implants and unexplained systemic symptoms: a descriptive cohort study. Neth J Med 71(10):534\u0026ndash;540\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen Tervaert JW, Kappel RM (2013) Silicone implant incompatibility syndrome (SIIS): a frequent cause of ASIA (Shoenfeld's syndrome). Immunol Res 56(2\u0026ndash;3):293\u0026ndash;298. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12026-013-8401-3\u003c/span\u003e\u003cspan address=\"10.1007/s12026-013-8401-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiacomazzo CM, Sakai CN, Araujo RMG, Ono MCC, Duarte-da-Silva AB, Freitas RS (2022) Adjuvant-induced autoimmune syndrome triggered by silicone breast implants: systematic review. Rev Bras Cir Pl\u0026aacute;st 37:485\u0026ndash;493\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeida I, Alrais M, Seida R, Alwani A, Kiyak Z, Elsalti A et al (2023) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): past, present, and future implications. Clin Exp Immunol 213(1):87\u0026ndash;101. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cei/uxad033\u003c/span\u003e\u003cspan address=\"10.1093/cei/uxad033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreira S, Barros AS, Marques M (2025) Breast Implant Illness: Symptoms, Outcomes with Explantation and Potential Etiologies-A Systematic Review and Meta-analysis. Aesthetic Plast Surg 49(23):6600\u0026ndash;6620. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00266-025-05142-x\u003c/span\u003e\u003cspan address=\"10.1007/s00266-025-05142-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBird GR, Niessen FB (2022) The effect of explantation on systemic disease symptoms and quality of life in patients with breast implant illness: a prospective cohort study. Sci Rep 12(1):21073. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-022-25300-4\u003c/span\u003e\u003cspan address=\"10.1038/s41598-022-25300-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBascone CM, McGraw JR, Couto JA, Sulkar RS, Broach RB, Butler PD et al (2023) Exploring Factors Associated with Implant Removal Satisfaction in Breast Implant Illness Patients: A PRO BREAST-Q Study. Plast Reconstr Surg Glob Open 11(9):e5273. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/GOX.0000000000005273\u003c/span\u003e\u003cspan address=\"10.1097/GOX.0000000000005273\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpoor J, Mureau MAM, Tissier RLM, Hommes J, Rakhorst H, de Boer M et al (2025) Breast implant illness after reconstruction with silicone breast implants. J Natl Cancer Inst 117(8):1717\u0026ndash;1728. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jnci/djaf136\u003c/span\u003e\u003cspan address=\"10.1093/jnci/djaf136\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajchenberg D, Wegerhoff N, Shoenfeld Y (2024) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) from 2011 to 2024: A comprehensive bibliometric review. Autoimmun Rev 23(12):103676. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.autrev.2024.103676\u003c/span\u003e\u003cspan address=\"10.1016/j.autrev.2024.103676\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHawkes D, Benhamu J, Sidwell T, Miles R, Dunlop RA (2015) Revisiting adverse reactions to vaccines: A critical appraisal of Autoimmune Syndrome Induced by Adjuvants (ASIA). J Autoimmun 59:77\u0026ndash;84. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaut.2015.02.005\u003c/span\u003e\u003cspan address=\"10.1016/j.jaut.2015.02.005\" targettype=\"DOI\" 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":"Autoimmune syndrome, Silicone breast implants, ASIA syndrome, Systematic review, Meta-Analysis","lastPublishedDoi":"10.21203/rs.3.rs-8451089/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8451089/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSilicone breast implants remain among the most frequently performed cosmetic procedures worldwide, yet concerns persist regarding potential associations with autoimmune and inflammatory conditions. The Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA) has emerged as a framework for understanding immune-mediated responses to silicone, though evidence remains fragmented and inconsistent.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo systematically review and quantitatively synthesize existing literature on ASIA syndrome associated with silicone breast implants, estimating pooled prevalence and identifying potential risk factors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFollowing PRISMA 2020 guidelines, we searched multiple databases through October 2024 for observational studies evaluating ASIA syndrome in silicone breast implant recipients. Two independent reviewers conducted study selection, data extraction, and quality assessment using the Newcastle-Ottawa Scale. Statistical analyses employed random-effects models with Freeman-Tukey double arcsine transformation.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eEight observational cohort studies comprising approximately 1,980 patients met inclusion criteria. ASIA prevalence ranged from 50% to 100% in symptomatic referral populations. Most common manifestations included chronic fatigue (88\u0026ndash;90%), arthralgia (65\u0026ndash;71%), and myalgia (48\u0026ndash;65%). Pre-existing allergies were present in 56\u0026ndash;75% of symptomatic cohorts. Post-explantation improvement rates varied from 43% to 96%, with early removal (\u0026lt;\u0026thinsp;10 years) yielding superior outcomes (p\u0026thinsp;=\u0026thinsp;0.007). Substantial heterogeneity precluded quantitative meta-analysis, reflecting variability in diagnostic criteria, study populations, and referral bias.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWhile population-level risk remains undefined, clinically meaningful symptom improvement following explantation occurs consistently in selected patients. Prospective studies with standardized diagnostic criteria and immunophenotyping are essential to clarify causality and guide clinical decision-making.\u003c/p\u003e","manuscriptTitle":"Autoimmune/Inflammatory Syndrome Induced by Adjuvants in Silicone Breast Implant Recipients: A Systematic Review and Meta-Analysis of Prevalence, Risk Factors, and Clinical Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-05 09:34:16","doi":"10.21203/rs.3.rs-8451089/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":"ab6e42e9-7d0a-4b1a-b6b5-00f76d505028","owner":[],"postedDate":"January 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60215985,"name":"Immunology"}],"tags":[],"updatedAt":"2026-01-05T09:34:17+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-05 09:34:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8451089","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8451089","identity":"rs-8451089","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}