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Abstract Rationale We hypothesize that corticosteroid resistance causes uncontrolled inflammation and severe asthma. The genetic and molecular mechanisms underlying steroid responsiveness in asthma remain poorly understood (PMID28493293). This study aims to characterize transcriptomic profiles distinguishing steroid responders from steroid resistant asthma. Methods Longitudinal bulk RNA-seq of SARP3 sputum samples was analyzed before and after an “induced phenotype” with 40 mg triamcinolone acetonide (TCA) injection (PMID 27967215). Participants were classified as responders or non-responders based on whether their FEV₁ change after TCA exceeded the median. Paired differential gene expression analyses were performed separately for each group using limma and voom, with participant as a factor and adjustment for sputum cell count differentials. Z-scores were calculated to compare gene expression changes after TCA injection between responders and non-responders, and pathway enrichment was assessed using the fgsea package. Results Baseline demographics and clinical characteristics of 696 SARP3 asthma participants receiving TCA are shown in Table 1. The median [IQR] FEV1 change post-TCA was 1.81% [-2.16, 7.17]. Responders had higher baseline FEV1%, FEV1/FVC ratio, blood eosinophil counts, and sputum eosinophil percentages, but lower serum CRP levels. Steroid responsiveness was associated with asthma severity (Table 1). Among 154 participants with paired sputum RNA-seq data, 70 (45%) exhibited >1.81% improvement in FEV₁ and were classified as responders. Following TCA treatment, non-responders showed no significant changes in gene expression. In responders, 18 genes were upregulated and 203 downregulated. Downregulated genes were associated with Th2 immunity (IL13, IL1RL1, CCL17, SIGLEC8), IgE signaling (FCER1A, FCER2), epithelial barrier function and mucus production (MUC2, MUC7, ALOX15, TFF3), tissue remodeling and fibrosis (MMP10, TIMP3), ciliary function (DNAH5, CFAP43, FOXJ1), and airway hyperreactivity (HRH4, RAMP1). Key genes notably downregulated in responders compared to non-responders included IL13, CCL5, PTGDR2, FCER2, and CLEC10A. Pathway analysis revealed enhanced IL-10-mediated anti-inflammatory signaling, suppression of pro-inflammatory pathways (NF-κB, IL-1, Th1/Th2, asthma, arachidonic acid metabolism, chemokine, NOTCH4), and regulation of mitochondrial oxidative phosphorylation. Conclusions Steroid resistance impairs glucocorticoid-mediated suppression of pro-inflammatory pathways, including NF-κB, IL-1, and Th1/Th2 signaling. This persistent airway inflammation limits improvements in lung function and contributes to worse clinical outcomes, including increased airflow obstruction, and symptom burden. Glucocorticoid resistance in asthma may be driven by receptor dysfunction, airway inflammation, epigenetic changes, and environmental exposures resulting in persistent airway inflammation and remodeling. Elucidating the molecular mechanisms underlying steroid resistance is critical for developing personalized targeted therapies in asthma. This abstract is funded by: NIH-NHLBI - R01 HL161674 (PI: Joe Zein)

Abstract Rationale Primary ciliary dyskinesia (PCD) pathogenic gene variants disrupt motile cilia, leading to both PCD and asthma through epithelial dysfunction. Asthma shows sex differences, and progesterone regulates ciliary beat frequency, indicating that genetic defects in ciliary proteins may exert sex-dependent effects. Therefore, we hypothesize that rare, pathogenic variants in PCD genes contribute to asthma risk in a sex-specific manner. Methods We performed a rare-variant aggregation analysis of the DNAH11 gene using UK Biobank OQFE exome dosages, with sex-stratified analyses. Within each sex, genotype dosages were coded as individual-level minor allele counts (0-2) and filtered to include variants with a minor allele frequency (MAF) ≤1% and a minor allele count (MAC) ≥5 across the cohort. Asthma phenotypes were defined from a curated dataset (N = 452,927), excluding COPD and other lung diseases. For each sex, logistic null models adjusted for age were fitted, and gene-level associations for binary outcomes were tested using SKAT, Burden, and SKAT-O. To assess variant-specific influences, we performed leave-one-out (LOO) analyses, sequentially omitting each variant and recalculating p-values. The effect size across the cohort was calculated by fitting a Firth logistic regression comparing carriers to non-carriers, adjusted for age by sex. Finally, sex modification was tested using a Firth model including carrier-by-sex interaction term. Results After filtering, DNAH11 included two rare variants; 7:21564185-G>T and 7:21591370-G>A in each sex (MAF≈1-2x10-5). Among females (N = 245,718; 28,649 with asthma), 16 carriers were observed (MAC≈16). Gene-based tests showed a significant association with asthma (Burden_p=0.004; SKAT-O_p=0.005; SKAT_p=0.013). Firth carrier model OR was 4.58 (95% CI 1.62-11.98, p = 0.0055) (Figure 1A). LOO analyses (Figure 1B) showed both variants contributed to the signal; removing 7:21591370-G>A increased SKAT-O p to 0.075 (Δ-log10p≈+1.15), while removing 7:21564185-G>T increased p to 0.014 (Δ-log10p≈+0.41, with the association remaining significant after removing the latter. Among males (N = 207,209; 20,777 with asthma), 10 carriers were observed (MAC≈10) with no significant association (Burden_p=0.926; SKAT-O_p=0.797; SKAT_p=0.668; Firth_p=0.781). The carrier-by-sex interaction term in the combined Firth model was not significant (p = 0.190), suggesting the female-specific signal could not be detected in the males due to limited power. Conclusions This analysis provides primary evidence that these rare, pathogenic variants in the DNAH11 PCD gene may contribute to asthma susceptibility in a sex-specific manner, with a significant association observed only in females. The signal was predominantly driven by 7:21591370-G>A. This suggests that genetic disruption of ciliary function may interact with female-specific hormonal factors (i.e., progesterone) to influence asthma risk. This abstract is funded by: NIH

Abstract Rationale Asthma, a chronic inflammatory airway disease, can be influenced by hormonal fluctuations that affect immune function and airway responsiveness. During in-vitro fertilization (IVF), women undergo sequential hormonal treatments—including gonadotropin administration to stimulate follicle development and induce ovulation, and progesterone and estrogen to support implantation and early pregnancy. These precisely timed hormonal changes may affect asthma symptoms and increase the risk of exacerbations. This study evaluates the hypothesis that undergoing IVF increases the risk of asthma exacerbations prior to, but not during or after pregnancy. Methods Data were extracted from the Mayo Clinic electronic health records. Women were included if their pregnancy was recorded in the Mayo Clinic obstetric delivery dataset. Asthma was defined as the presence of an ICD code J45.xx in combination with a prescription for any asthma medication. For women with multiple pregnancies, only the first pregnancy was analyzed. An asthma exacerbation was defined as a course of oral corticosteroids lasting ≤28 days or a corticosteroid injection. Multivariable logistic regression was used to assess exacerbation risk, adjusting for age, body mass index (BMI), and prior history of diabetes mellitus. Results Among 3,623 pregnant women, 112 underwent IVF treatment. Compared with non-IVF patients, women undergoing IVF were older (mean ± SD: 34.16 ± 5.24 vs. 29.11 ± 5.55, p < 0.001), had lower parity (1.44 ± 0.79 vs. 1.83 ± 1.20, p = 0.001), and fewer full-term deliveries (1.31 ± 0.79 vs. 1.68 ± 1.11, p = 0.001) (Table 1). There were no differences in pre-pregnancy BMI, racial distribution, ethnicity, or prior history of diabetes mellitus. Adjusted analysis indicated that IVF was associated with an increased risk of asthma exacerbation in the year before pregnancy (adjusted OR [95% CI]: 1.097 [1.025-1.173]), but not during (adjusted OR [95% CI]: 1.044 [0.973-1.121]) or after pregnancy (adjusted OR [95% CI]: 1.026 [0.963-1.094]). Conclusion These findings suggest that the preconception hormonal changes associated with IVF may temporarily worsen asthma control. Further studies are warranted to replicate these results, clarify the underlying mechanisms, and guide asthma management in women undergoing fertility treatment. This abstract is funded by: NIH

Abstract Rationale Asthma is a chronic inflammatory airway disorder influenced by pulmonary and systemic factors. Epidemiologic and experimental data suggest associations between asthma, anemia, and reduced iron stores. Sex may modify this relationship: females, with lower baseline iron reserves, menstrual blood loss, and hormone-mediated immune effects, may exhibit greater susceptibility, whereas males, with higher iron stores and androgen-related anti-inflammatory influences, appear less affected. This study tested the hypothesis that diminished iron stores, rather than anemia itself, are associated with asthma, and that this relationship differs by sex. Methods Data were analyzed from nine consecutive NHANES 2-year cycles (1999-2018), a nationally representative U.S. dataset. Lifetime asthma was defined as a prior physician diagnosis and active asthma as “Do you still have asthma?”. Anemia was defined by WHO criteria (hemoglobin <12 g/dL in females and <13 g/dL in males), and iron deficiency as ferritin <30 ng/mL. Accordingly, iron status was categorized as normal, iron deficiency anemia (IDA), iron deficiency without anemia (IDWA), and anemia without iron deficiency (AWID). Analyses followed NHANES guidelines and were conducted with the SURVEY package in R. Results Female participants were older and had lower eosinophil counts, ferritin, and hemoglobin levels, with a higher prevalence of anemia, lifetime asthma, and current asthma. Similar trends were observed among participants with available ferritin data (Table 1). In unadjusted analyses, ferritin levels were inversely associated with lifetime (β = -0.19; p <0.001) and active asthma (β = -0.35; p <0.001), but these associations were not significant after adjustment for sex, age, BMI, race, and log10-transformed eosinophil count (lifetime: β = 0.03; p = 0.61; active: β = -0.08; p = 0.40). In contrast, anemia was associated with increased odds of lifetime (adjusted OR [95% CI], 1.52 [1.21-1.92]) and active (1.50 [1.13-1.99]) asthma in males, but not in females (0.98 [0.86-1.12] and 0.98 [0.83-1.15], respectively). Among males, AWID was associated with active asthma (2.07 [1.08-3.96]), whereas IDA and IDWA were not. No associations were observed among females. Conclusion The relationship between anemia and asthma may be primarily driven by inflammation related to asthma rather than true iron deficiency. After adjustment, ferritin was not independently associated with asthma, whereas anemia—particularly AWID—remained associated among males. These findings suggest that asthma-associated systemic inflammation contributes to anemia of chronic disease, underscoring the need to distinguish inflammatory anemia from nutritional iron deficiency in research and clinical management. This abstract is funded by: NIH

Abstract Rationale Asthma contributes substantially to healthcare burden and morbidity through frequent exacerbations. Emerging evidence suggests that genetic factors play a crucial role in modulating susceptibility to asthma exacerbations. To better understand the genetic architecture of exacerbations, we conducted a genome-wide association study (GWAS) in the Tapestry cohort. Methods The Tapestry Study, a large-scale, decentralized and clinical grade genomic sequencing study, conducted Exome+® sequencing at Helix, Inc. on 98,075 Mayo Clinic participants. After excluding patients with ≥10 pack-years of smoking and/or emphysema, we performed a GWAS of asthma exacerbations in 3,960 adults with asthma based on ICD codes. Cases (n = 1,059) were defined as individuals who experienced at least two exacerbations between 2020 and 2025; the remaining 2,901 individuals served as controls. Asthma exacerbations were defined by oral or systemic corticosteroid prescriptions with durations ranging from 3 days up to 28 days. Logistic regression models adjusted for age, sex, BMI, and the first six principal components of ancestry. Replication was performed in 1,273 asthma patients (439 African Americans and 834 non-Hispanic Whites) from the NHLBI-sponsored Severe Asthma Research Program (SARP 1-3), with adjustments for age, sex, BMI, and the first 10 principal components of ancestry. Results Based on a minor allele frequency (MAF) threshold of > 0.05, we analyzed 5,256,135 genome-wide variants. Genome-wide significant associations for asthma exacerbations (p < 5.0 × 10⁻8) included loci at a pseudogene in SMPD4P1 (rs680548, MAF = 0.39, OR = 1.37, p = 9.10 × 10⁻9). Additional variants showing suggestive associations included loci within ENDOD1 (rs638776, OR = 0.69, p = 1.20 × 10⁻6), PCSK2 (rs2206454, OR = 1.32, p = 3.53 × 10⁻6), RBFOX1 (rs17667084, OR = 0.60, p = 5.11 × 10⁻6), and CDC42EP3 (rs721660, OR = 1.29, p = 5.68 × 10⁻6). Subthreshold associations in Tapestry including loci at CDC42EP3 (rs4670213, OR = 1.27, p = 1.41x10-5, MAF = 0.36), and SDR39U1 (rs12587663,OR = 0.83, p = 5.86x10-4, MAF = 0.46) were replicated in the SARP longitudinal visit 5 with p-values of 8.523x10-3 (rs4670213, OR = 1.78), and 2.88x10-4 (rs12587663,OR=0.43), respectively. Conclusion Our GWAS for asthma exacerbations in the Tapestry cohort identified variant loci relevant to mitophagy mechanisms (CDC42EP3, PMID: 40783597), immune signaling and RNA splicing regulation (RBFOX1, PMID: 31301374), and neuromodulatory pathways (PCSK2, PMID: 32794589), all previously implicated in asthma pathophysiology. Collectively, these findings highlight potential novel genetic contributors to asthma exacerbations and provide a foundation for improving risk stratification and therapeutic targeting in asthma management. This abstract is funded by: This abstract is funded by: Mayo Clinic Funding: X01 from the NHLBI for TOPMed whole-genome sequencing and NIH grants R01 HL142992, HL69116, HL69167, HL69170, HL69174, U10 HL109164, U10 HL109257, U10 HL109146, U10 HL109172, U10 HL109250, U10 HL109250, U10 HL109250, U10 HL109168, U10 HL109152, U10 HL109086, U10 HL109046.

Abstract Rationale Higher African genetic ancestry has been associated with lower lung function, among individuals from specific racial-ethnic groups. The influence and interactions of genetic variation and ancestry in lung function is poorly understood. This study investigates ancestry-associated loci influencing lung function via admixture mapping and fine-scale allelic association. Methods 512 African American patients with asthma (≥12 years) from the Severe Asthma Research Program and Collaborative Study on the Genetics of Asthma (SARP/CSGA) cohorts were genotyped on the OmniExpress and HumanHap1M arrays or had whole-genome sequencing (WGS). For admixture mapping, global ancestry was inferred using ADMIXTURE and local ancestry estimated using RFMix v1.5.4 with CEU (N = 99) and YRI (N = 108) references across 15,095 local ancestry segments. Peak regions and contiguous segments (p < 10-3) were fine mapped in SARP using local ancestry estimated from WGS with MAF ≥0.03. The Local Ancestry Adjusted Allelic Association (LAAA) model was used to fine map local genetic effect, local ancestry effect, and the interaction between the two, adjusted for age, sex, height, BMI, cohort, and percentage global African ancestry. SNPs with local genetic or interaction p < 10⁻³ were tested for replication in 282 adolescent/adult participants from the Best African Response to Asthma Drugs (BARD) cohort genotyped with the MEGA array imputed to TOPMed (MAF ≥0.03). Results Mean African genetic ancestry was 81.3% in SARP and 80.1% in BARD. In SARP, African genetic ancestry was inversely associated with lung function (FEV₁:β = −7.9, p = 0.005; FVC:β = −9.0, p = 0.004), with stronger effects in females (FEV₁: β = −9.3, p = 0.003; FVC: β = −11.4, p = 0.001) than males (FEV₁:β = −6.4, p = 0.237; FVC:β = −5.7, p = 0.340). Similar total and sex-specific associations were identified in BARD. Admixture mapping in SARP/CSGA identified significant peaks for maximum FVC (p < 1.87 × 10⁻4) on chromosomes 8 and 17 near RP1 and RBFOX3, and near-significant peaks on chromosome 5 near IQGAP2, SNRPCP2, SV2C and for the maximum FEV₁/FVC ratio on chromosome 10 near PCDH15. Fine mapping identified the top SNP on chromosome 8 (rs73587686; p-allele-dose=9.0x10-5; RGS20; q11.23), with 62 additional SNPs overlapping RGS20. SNP rs7825816 was also identified in SARP (β = 2.35, p-allele-dose =1.03 × 10⁻4) and replicated in BARD (β = 1.15, p-allele-dose =0.03). In BARD, LAAA also identified eight additional SNPs (p ≤ 0.05) in the same LD block (chr8:53914976-53918297) overlapping with RGS20, ATP6V1H, and TCEA1. Conclusions We identified multiple chromosomal regions associated with lung function in asthma patients of predominantly African genetic ancestry. Lung function associations were strongest at genetic variation near a key that was replicated in an independent asthma cohort. This abstract is funded by: R01 K08 HL118128, R01 HL142992, R01 NR013700, R01 HL69167, R01 HL161674, HL69116, HL69167, HL69170, HL69174, U10 HL109164, U10 HL109257, U10 HL109146, U10 HL109172, U10 HL109250, U10 HL109250, U10 HL109250, U10 HL109168, U10 HL109152, U10 HL109086-04, U10 HL098115, HL098102, HL098096, HL098075, HL098090, HL098177, HL098098, HL098107, HL098112, HL098103, and K12 HL89992

Abstract Background The number of arthroplasty procedures and infection-related complications, including prosthetic joint infections (PJIs) and surgical site infections (SSIs), continues to rise. Although current guidelines recommend cefazolin or cefuroxime as the first-line perioperative prophylactic antibiotic, substitutions with non-cephalosporins remain common, especially among patients with reported β-lactam allergies. These substitutions may increase infection risk and healthcare costs. Evidence comparing outcomes across antibiotic classes remains variable. Methods We conducted a systematic review and meta-analysis of studies comparing single-agent cephalosporin versus single-agent non-cephalosporin prophylaxis in adults undergoing primary arthroplasty. Cochrane, Embase, Medline, Scopus, and Web of Science were searched from database inception through January 2025. Random-effect or fixed-effect models were used to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). Subgroup analyses stratified results by cephalosporin type, study era, and risk of bias. Results Twenty-three studies (7 randomized controlled trials and 16 observational studies) were included, encompassing 191 527 arthroplasties in the cephalosporin arm and 20 058 in the non-cephalosporin arm. The odds of PJI were lower with cephalosporins (OR 0.59; 95% CI, .46–.75). No overall difference was observed for SSI (OR 0.70; 95% CI, .36–1.36), though post-2013 studies and the cefazolin subgroup demonstrated a significant protective effect. Randomized trial estimates were limited and heterogeneous and did not reach statistical significance. Certainty of evidence was graded as moderate. Conclusions Cephalosporins, particularly cefazolin or cefuroxime, remain the preferred prophylactic agents for primary arthroplasty. This quantitative synthesis reinforces their protective association against prosthetic joint infection and supports adherence to guideline-endorsed prophylaxis.

Abstract Background Native joint septic arthritis (NJSA) is a serious musculoskeletal infection requiring timely surgical intervention to prevent long-term morbidity. Although current guidelines recommend early surgical debridement, supporting data, particularly on long-term outcomes, remain scarce. Given this, we evaluated the association between surgical timing and 1-year clinical outcomes using the Desirability of Outcome Ranking (DOOR) framework, applied for the first time in NJSA.Table 1.Desirability of Outcome Ranking (DOOR) ordinal scaleTable 2.Baseline demographic, clinical characteristics, and treatment outcomes Methods We conducted a retrospective multicenter cohort study of adults (≥18 years) with NJSA who underwent surgery across Mayo Clinic campuses between 2012 and 2021. Clinical outcomes at one year were assessed using a 9-level DOOR scale, incorporating survival, treatment failure (relapse, reinfection, readmission, or significant surgical events), and joint recovery (full vs qualified) (Table 1). Time to surgery from hospital admission was analyzed both as a continuous variable and as categories: < 1, 1–2, or ≥3 days.Table 3.Associations between duration and outcomesFigure 1.Association Between Time to Surgery and DOOR Scores in Native Joint Septic Arthritis.A) Distribution of Modified DOOR Scores by Surgical Timing. B) Modeled Probability of DOOR Scores by Time to Surgery. Results Among 268 patients (median age 62 years, 61% male), 30% underwent surgery < 1 day from admission, 47% within 1–2 days, and 24% at ≥3 days. At 1 year, 57% achieved full recovery without unfavorable events (DOOR score 1), while treatment failure occurred in 34% (Table 2). In unadjusted analyses, longer surgical delay was significantly associated with higher DOOR scores (per IQR increase [from 0 to 2 days], OR: 1.5; 95% CI: 1.0–2.1; p = 0.026) and with increased 1-year mortality (HR: 1.7; 95% CI: 1.1–2.6; p = 0.019) and treatment failure (HR: 1.5; 95% CI: 1.1–2.0; p = 0.007). Similar results were obtained when delay was used as a categorical 3-level variable, with the highest risk observed in patients undergoing surgery after ≥3 days. After adjusting for age and Charlson index, only the association between surgical delay and treatment failure remained statistically significant (HR: 1.5; 95% CI, 1.1–2.0; p=0.016) (Table 3, Figure 1). Conclusion Delayed surgical intervention for management of NJSA was independently associated with higher risk of treatment failure at 1 year. These findings reinforce current guideline recommendations for timely operative management and further underscore the potential of the DOOR framework to capture clinically meaningful, multidimensional outcomes in NJSA. Disclosures All Authors: No reported disclosures

Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained. Aim To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity. Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing). Results EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate <0.05). Four of those modules were enriched for forced expiratory volume in 1 s/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with MUC5B, including important pathway genes: B3GNT6 , DGKI and ITGA8 . CpGs in an independent COPD-associated module showed the most correlations with Rothia , with directionality suggestive of negative associations with moderate-severe COPD. Conclusions Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.

Aims Native vertebral osteomyelitis (NVO) and infective endocarditis (IE) are increasingly seen as interconnected conditions, sharing similar risk factors — such as advanced age and immunosuppression — and overlapping microbial profiles, notably Staphylococcus aureus and streptococci. When these infections occur together, they present distinct challenges in diagnosis and treatment, which can obscure clear outcomes and mortality estimates. Therefore, we aimed to systematically assess the combined mortality associated with concurrent NVO and IE and to detail the clinical characteristics of affected patients. Methods We conducted a systematic review following the PRISMA framework, searching MEDLINE, Embase, the Cochrane Library, and Scopus for relevant studies published between 1970 and October 2023. Studies included were those reporting mortality outcomes for at least ten adult patients with both NVO and IE. Two independent reviewers screened the literature, extracted data, and evaluated study quality using a modified Newcastle-Ottawa Scale. We then performed a random-effects meta-analysis to pool in-hospital, 1-month, 1-year, and 3-year mortality rates. Results A total of 16 studies (12 retrospective, 3 prospective, and 1 mixed design) involving 641 patients (mean age 67.1 years) with concomitant NVO and IE were included. The pooled in-hospital mortality rate was 10.0% (95% CI: 5.2–14.7%), with mortality rates of 5.6% (95% CI: 2.2–9.0%) at 1 month, 12.1% (95% CI: 5.3–18.8%) at 1 year, and 14.5% (95% CI: 4.3–24.8%) at 3 years. There was significant heterogeneity among studies (I² ranging from 46% to 86%). Common comorbidities included diabetes (24.6%), renal failure (17.3%), and immunosuppression (11.1%). The predominant pathogens identified were streptococci (31.3%), S. aureus (27.3%), and enterococci (13.7%). Approximately 40.6% of patients underwent surgical intervention, though its effect on mortality remains inconclusive. Overall, the certainty of the estimates was limited by imprecision and impossibility of perform subgroup analysis. Conclusion The coexistence of NVO and IE is associated with significant mortality, emphasizing the need for earlier diagnosis, coordinated multidisciplinary management, and standardized treatment protocols. Future prospective, high-quality studies are crucial to determine optimal diagnostic and surgical strategies for managing this complex clinical scenario.