Risk factors and clinical outcomes of serum Aspergillus galactomannan antigen (AGA) positivity in lung transplantation

Introduction

Background

Lung transplantation (LTx) offers a critical therapeutic option for patients with advanced pulmonary diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), cystic fibrosis, primary ciliary dyskinesia, and pulmonary arterial hypertension (PAH) (1-3). Despite technical and medical advances, long-term outcomes remain suboptimal, with 5-year survival rates of approximately 50% (4). Multiple factors contribute to this limited survival, including primary graft dysfunction (PGD), acute and chronic rejection, infections, and thromboembolic events (5-7). As a result, identifying reliable biomarkers that can aid in early risk stratification and guide post-transplant management has become increasingly important.

Rationale and knowledge gap

One such candidate biomarker is the Aspergillus galactomannan antigen (AGA). This polysaccharide antigen is released by Aspergillus spp. During active growth, it is traditionally measured to help diagnose invasive pulmonary aspergillosis (IPA) (8). IPA is a life-threatening opportunistic infection after LTx. The serum AGA assay detects a polysaccharide released during hyphal growth and is widely used as an adjunctive diagnostic test for IPA. In the context of LTx, patients are immunosuppressed and thus remain particularly susceptible to Aspergillus colonization and infection. However, the significance of serum AGA detection beyond its diagnostic role for IPA remains poorly characterized. Several studies in solid organ transplantation suggest that fungal antigenemia may sometimes indicate heightened immune or inflammatory activity rather than definitive infection alone, potentially conferring a higher risk of complications (9,10). Moreover, false positives—often due to cross-reactivity with certain drugs or dietary factors—add complexity to interpreting a positive AGA without clinical signs of infection.

Emerging evidence indicates that AGA elevations frequently coincide with systemic inflammatory responses rather than solely reflecting fungal burden. In patients with invasive aspergillosis, higher serum galactomannan indices have been correlated with increased levels of acute-phase reactants and proinflammatory cytokines such as C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), even after accounting for antifungal therapy (11,12).

Objective

Against this background, we conducted a retrospective study to examine the risk factors associated with AGA positivity in lung transplant recipients and determine how this biomarker correlates with early and long-term clinical outcomes. We hypothesized that early AGA detection would be associated with increased susceptibility to infectious and thrombotic complications and survival. By analyzing a wide range of recipient, donor, intraoperative, and postoperative factors, we sought to clarify the clinical utility of AGA monitoring and explore whether integrating routine AGA surveillance into standard post-transplant care could help improve outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1105/rc).

Methods

Study design

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Northwestern University (STU00207250 and STU00213616). The need for patient consent for data collection was waived by the institutional review board due to the retrospective nature of this study. Patient data were collected retrospectively using electronic medical records and stored in a database at the Northwestern University Medical Center in Chicago, Illinois, USA. Adult patients who underwent LTx at our institution between January 2018 and June 2023 were included. Multiorgan transplant recipients and re-transplant recipients were excluded from the study. Data on patient demographics, comorbidities, donor characteristics, preoperative laboratory values, intraoperative and postoperative outcomes were collected and compared in two groups of lung transplant patients delineated by serum detection of AGA.

Statistical analysis

Continuous data are shown as median (interquartile range) and categorical data are shown as number (%). The Mann-Whitney U test was used to compare independent continuous variables. Fisher’s exact test was used to compare categorical variables. The Kaplan-Meier method was used to estimate survival, and the log-rank test was performed to compare survival between the groups. Hazard ratios (HR) were obtained using a univariate and multivariate Cox proportional hazards analysis. Statistical significance was set at P<0.05. All statistical analyses were performed using the JMP Pro 17.0.0 software program (SAS Institute Inc.).

Definition of complication

PGD

PGD was defined based on the International Society for Heart and Lung Transplantation (ISHLT) guideline (13), and graded by PaO₂/FiO₂ (arterial oxygen partial pressure/fractional inspired oxygen) ratio: grade 1, PaO₂/FiO₂ ratio >300; grade 2, PaO_2/FiO₂ ratio is 200–300; grade 3, PaO₂/FiO₂ ratio <200. The use of extracorporeal membrane oxygenation (ECMO) for bilateral pulmonary edema on chest X-ray was classified as grade 3.

Acute cellular rejection (ACR)

ACR is defined by the ISHLT working formulation as the presence of perivascular and interstitial mononuclear inflammatory infiltrates on transbronchial lung biopsy. Rejection is graded on a scale from A0 (no rejection) to A4 (severe rejection) based on the extent and character of the cellular infiltrate (14). Histopathologic diagnoses were independently confirmed by two board-certified pulmonary pathologists.

Antibody-mediated rejection (AMR)

AMR in LTx is characterized by the presence of donor-specific antibody (DSA) along with histopathologic evidence of capillaritis and complement deposition in lung tissue, combined with clinical graft dysfunction. Transbronchial biopsies were performed for routine surveillance at 1-, 3-, 6-, 9-, and 12-month post-transplant, as well as at any time clinical suspicion for rejection arose. The diagnosis of AMR requires an integrated assessment of serologic, histologic, and clinical findings after excluding other potential causes of graft dysfunction (15). Histopathologic diagnoses were independently confirmed by two board-certified pulmonary pathologists.

Chronic lung allograft dysfunction (CLAD)

CLAD is defined as a sustained (at least 3 months) decline in the forced expiratory volume in one second (FEV₁) of at least 20% from the post-transplant baseline, in the absence of other reversible causes (16).

Acute kidney injury (AKI)

AKI was staged by RIFLE (Risk, Injury, Failure, Loss, End-stage) criteria based on changes in serum creatinine or estimated glomerular filtration rate (GFR) and urine output (17).

Infection

The simultaneous presence of three criteria defined respiratory infection: (I) clinical findings—such as fever, tachypnea, and abnormal lung auscultation; (II) radiological evidence—manifested as pulmonary infiltrates or consolidation on chest imaging; and (III) microbiological confirmation—a positive culture from bronchoalveolar lavage (BAL) specimens (18). Cytomegalovirus (CMV) infection was defined as the presence of viremia, as confirmed by the detection of CMV DNA in peripheral blood samples via a quantitative polymerase chain reaction assay, using a cutoff value of 500 IU/mL. This approach is consistent with established diagnostic criteria used in immunocompromised patient populations (19). Recurrent respiratory infection was defined as the occurrence of three or more distinct respiratory infection episodes per year, with each episode persisting for more than four weeks.

Measurement and positive AGA

Serum AGA levels were measured at the discretion of the treating physician in response to clinical concerns. Defined as an index value at or above the manufacturer’s threshold (typically ≥0.5) in serum or BAL fluid, which is indicative of invasive aspergillosis. This definition is based on the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria for invasive fungal infections (20).

Immunosuppression management

Induction

• Methylprednisolone 1,000 mg via intravenous at intraoperatively.
• Basiliximab 20 mg intraoperatively and on postoperative day (POD) 4.

Maintenance immunosuppression

• Prednisone 0.5 mg/kg p.o. daily (maximum 40 mg daily) from POD 1 for 1 month, then tapered by 5 mg every 2 weeks down to 5 mg/day as a maintenance dose.
• Mycophenolate mofetil 1,000 mg b.i.d. from POD 1.
• Tacrolimus start POD 1. Goal target levels 8–12 within the first-year post-transplant; then target 8–10 thereafter.

Anti-fungal prophylactic protocol

Our antifungal prophylaxis protocol was implemented as follows:

Primary prophylaxis with posaconazole

Patients received posaconazole at a dose of 300 mg IV daily, or alternatively 300 mg delayed-release (DR) tablets administered orally or per tube daily, beginning on POD 1.

• Posaconazole prophylaxis was continued for 6 months post-transplant.
• A posaconazole trough level was measured approximately 7 days after initiating the PO or per-tube regimen to ensure therapeutic levels.

Alternative prophylaxis

In patients for whom posaconazole was not appropriate, voriconazole was administered at a dose of 200 mg every 12 hours, with or without an initial loading dose. This could be given intravenously, as a solution, or in tablet form.

Adjunctive nebulized amphotericin therapy

Amphotericin liposomal nebulizers were administered at a dose of 25 mg every Monday, Wednesday, and Friday (QMWF), beginning once the patient was transferred to the floor or 1–2 days prior to discharge. This nebulized regimen was continued for 30 days post-discharge only if posaconazole levels were found to be subtherapeutic at the time of discharge.

Results

Patient demographics

A total of 293 lung transplant recipients were analyzed, with 71 patients having an elevated AGA level in the follow-up period. Recipient demographic and clinical characteristics were largely comparable between the two groups (Table 1). Median recipient age was 62 years in both groups (P=0.12), and the proportion of female recipients was slightly lower in the AGA-positive group (33.8%) compared to the AGA-negative group (44.6%) but did not reach statistical significance (P=0.13). Body mass index (BMI) and body surface area (BSA) were similar between groups (P=0.36 and P=0.10, respectively). Prevalence of comorbidities, such as hypertension, diabetes, and chronic kidney disease (CKD), did not significantly differ; however, CKD was more frequently present in the AGA-positive group (12.7% vs. 5.4%, P=0.06).

Donor characteristics were also assessed. Notably, donors for the AGA-positive group were slightly younger (median age: 31.0 vs. 32.0 years, P=0.59), and the proportion of female donors was significantly lower (19.7% vs. 35.1%, P=0.02).

Intra- and postoperative outcomes after LTx

Intraoperative outcomes, including operative time, intraoperative blood transfusion rates, and ischemic time, were comparable between the two groups (all P>0.40) (Table 2). Use of veno-arterial (VA)-ECMO during surgery was slightly less frequent in the positive AGA group (56.3% vs. 64.0%, P=0.26), with no significant difference in VA-ECMO duration (median: 3.1 vs. 2.9 hours, P=0.06).

Postoperative outcomes revealed notable differences. The incidence of respiratory infections and recurrent respiratory infections was significantly higher in the AGA-positive group. Additionally, pulmonary embolism (PE) occurred more frequently in the AGA-positive group (23.9% vs. 12.6%, P=0.04). Intensive care unit (ICU) stay and post-transplant ventilator duration were comparable between groups (P=0.45 and P=0.26, respectively), but hospital length of stay was significantly longer in the AGA-positive group (median: 24.0 vs. 16.0 days, P=0.03). One-year survival trended lower in the AGA-positive group (83.1% vs. 90.5%, P=0.09). While no difference was observed in ACR or CLAD.

Figure 1 illustrates the timing of AGA detection following LTx. A majority of AGA-positive cases were identified within the first 100 days post-transplant, with nearly 50% diagnosed within 50 days after transplantation. The frequency of AGA-positive cases declined progressively after the first 100 days, with sporadic cases observed up to 400 days post-transplant.

Figure 1 Timing of first serum AGA positivity in lung transplant recipients. AGA, Aspergillus galactomannan antigen; LTx, lung transplantation.

Respiratory infection outcomes and AGA positivity

Results of the univariate and multivariate Cox proportional hazard analyses for predictors of post-transplant respiratory infection are summarized in Table 3. On univariate analysis, positive AGA was associated with a markedly elevated risk of respiratory infection [HR: 2.76, 95% confidence interval (CI) 2.01–3.79, P<0.001] and remained significant in the multivariate model (HR: 2.47, 95% CI: 1.68–3.65, P<0.001). Hospital stays emerged as another independent risk factor (HR: 5.79, 95% CI: 1.33–25.26, P=0.02) for respiratory infection on multivariate analysis.

Figure 2 illustrates a comparison of respiratory infection-free survival (Figure 2A) and Aspergillus-related respiratory infection-free survival (Figure 2B) between AGA-negative and AGA-positive groups. In Figure 2A, patients with positive AGA demonstrated significantly lower respiratory infection-free survival than those with negative AGA (P<0.001). Similarly, in Figure 2B, Aspergillus-related respiratory infection-free survival was significantly worse among AGA-positive recipients (P<0.001). Table S1 provides a detailed breakdown of the pathogens isolated during respiratory infections in each group.

Figure 2 Kaplan-Meier survival curves illustrating respiratory infection-free survival and Aspergillus-related respiratory infection-free survival in lung transplant recipients based on AGA positivity. (A) Respiratory infection-free survival; (B) Aspergillus-related respiratory infection-free survival. AGA, Aspergillus galactomannan antigen; LTx, lung transplantation.

Overall survival and predictors of mortality

Figure 3 presents the Kaplan-Meier curves comparing overall survival between patients with positive AGA and those with negative AGA. Although the survival curve for the AGA-positive group trended lower, the difference did not reach statistical significance (P=0.07).

Figure 3 Kaplan-Meier survival curve comparing overall survival between lung transplant recipients with positive and negative AGA. AGA, Aspergillus galactomannan antigen; LTx, lung transplantation.

Table 4 summarizes the univariate and multivariate Cox proportional hazard analyses for overall survival. Although positive AGA had a borderline association with mortality in the univariate model (HR: 1.53, 95% CI: 0.97–2.41, P=0.07), it lost significance after adjustment in the multivariate analysis (P=0.33).

In the final multivariate model, several variables remained independently predictive of worse survival, including BMI (HR: 1.06, 95% CI: 1.00–1.12, P=0.03), diabetes (HR: 1.82, 95% CI: 1.08–3.06, P=0.02), bilateral transplantation as a protective factor (HR: 0.46, 95% CI: 0.25–0.85, P=0.01), COPD (HR: 2.51, 95% CI: 1.36–4.65, P=0.003), aspartate aminotransferase (AST) (HR: 1.01, 95% CI: 1.00–1.02, P=0.02), post-veno-venous (VV)-ECMO use (HR: 2.79, 95% CI: 1.10–7.07, P=0.03), cerebrovascular accident (CVA) (HR: 4.48, 95% CI: 1.34–14.98, P=0.02), digital ischemia (HR: 5.53, 95% CI: 1.85–16.52, P=0.002), and respiratory infection (HR: 2.17, 95% CI: 1.21–3.88, P=0.009). In addition, prolonged ICU stay was associated with reduced survival (HR: 1.03, 95% CI: 1.01–1.05, P=0.009).

AGA risk factors

Univariate and multivariate analyses identified key predictors of AGA positivity in lung transplant recipients (Table 5). Among recipient characteristics, older age (HR: 1.02, 95% CI: 1.00–1.05, P=0.04) and CKD (HR: 2.39, 95% CI: 1.14–5.01, P=0.02) were independent predictors of AGA positivity. Additionally, in the multivariate analysis, prolonged ischemic time (HR: 1.15, 95% CI: 1.02–1.27, P=0.01) was significantly associated with an increased likelihood of AGA detection. Conversely, donor-related factors also played a role, with female donor status (HR: 0.52, 95% CI: 0.89–0.95, P=0.03) appearing to be protective against AGA positivity; however, the estimate is imprecise and should be interpreted cautiously.

Although pH and PaCO₂ showed statistical significance in the univariate analysis, they did not retain significance in the multivariate model. Other clinical and intraoperative variables, such as bilateral LTx, diabetes, smoking history, and intraoperative blood transfusion, were not significantly associated with AGA positivity.

Discussion

Key findings

In this study, we investigated the role of serum AGA detection in lung transplant recipients, examining both its incidence and clinical implications. Approximately 24% of patients tested positive for AGA, with most cases occurring within the first 100 days post-transplant. Although AGA positivity was not an independent predictor of long-term survival, it did independently predict respiratory infections including bacterial and fungal, which were themselves significantly associated with overall survival. Furthermore, the AGA-positive group exhibited higher short-term morbidity—including an increased incidence of PE, prolonged hospitalization, and tend to reduce one-year survival (90.5% vs. 83.1%, P=0.09)—suggesting that AGA may serve as a valuable biomarker for identifying high-risk lung transplant recipients who could benefit from closer monitoring and timely intervention for those complications.

Strengths and limitations

While AGA has historically been used to diagnose IPA (21), our data suggests a broader role in signaling immunological stress. In particular, the strong correlation between AGA positivity and infectious rates underscores the likelihood that fungal antigenemia may signify an exaggerated inflammatory milieu. Several mechanisms could explain this association: (I) subclinical fungal colonization or early Aspergillus invasion could lead to an enhanced immune response, paving the way for secondary bacterial or opportunistic infections (22,23); (II) immune dysregulation inherent to high-intensity immunosuppression could simultaneously raise susceptibility to fungal and non-fungal pathogens (24,25); (III) inflammatory cross-talk might occur between fungal components and the host immune system, thereby heightening systemic inflammatory pathways and potentiating endothelial dysfunction, which could also contribute to thrombotic events such as PE (26,27). In this study, several patient- and procedure-related factors were associated with an increased risk of AGA positivity, including older recipient age, CKD, and prolonged ischemic time. The observation that female donor status was protective against AGA positivity raises compelling questions about sex-specific immunologic differences that warrant further investigation (28). However, this apparent protective association should be interpreted with caution, as our study was not powered to robustly evaluate donor-sex effects; the relatively small number of female donors and potential residual confounding raise the possibility of a chance finding that requires validation in larger, multicenter cohorts. From a clinical standpoint, identifying these risk factors is crucial, as it enables a risk-stratified approach in which patients who meet these high-risk criteria could be monitored more rigorously for AGA positivity and other early postoperative complications. In addition, these findings suggest that antifungal prophylactic strategies may need to be augmented in select high-risk individuals, such as by ensuring timely therapeutic drug monitoring, extending the duration of prophylaxis, or intensifying adjunctive therapies when appropriate.

Despite the robust analyses, the limitations inherent to a retrospective, single-center design must be acknowledged. Selection bias, potential under- or over-diagnosis, and variations in clinical practice patterns over time may have influenced the results. Furthermore, the relatively modest proportion of AGA-positive patients (24%) constrained our ability to analyze specific long-term outcomes with greater statistical power. Additionally, the potential for false-positive AGA due to cross-reactivity remains a concern and could lead to misinterpretation. It is also important to note that donor culture results were not included in our analysis; consequently, some AGA positivity might be attributable to donor-derived fungal antigenemia. Because AGA testing was ordered at clinicians’ discretion, detection bias is possible: patients with longer ICU or hospital stays may undergo more frequent testing, increasing the likelihood of AGA detection. Although our multivariable models included markers of illness severity (e.g., length of stay), we did not systematically capture the number and timing of AGA assays per patient; therefore, residual ascertainment bias may persist. Finally, our analyses involved multiple comparisons across a large set of variables. We did not apply formal multiplicity adjustments; therefore, P values should be interpreted as exploratory and hypothesis-generating. In addition, unmeasured confounding (e.g., provider practice patterns, undocumented colonization) may have influenced associations despite adjustment.

Comparison with similar research

Although previous studies in solid organ transplant settings have primarily concentrated on AGA as a diagnostic marker for IPA (29,30), our work advances the understanding of AGA’s significance in LTx by highlighting its potential prognostic value. To our knowledge, there have been limited systematic investigations of AGA’s relevance to non-Aspergillus–related complications—such as bacterial infections or thrombotic events. Our findings align with the notion that positive AGA can be a proxy for broader immunological stress rather than solely an indicator of an active Aspergillus infection. Future research would benefit from a comparative approach that examines whether integrating AGA measurements into routine postoperative care enhances early detection of complications and improves outcomes, especially in centers with varying immunosuppressive regimens and prophylactic strategies.

Early and routine AGA testing could be pragmatically incorporated into standardized surveillance protocols, particularly in the first year when lung transplant recipients are most vulnerable. By flagging patients who may be entering a heightened inflammatory or infectious phase, clinicians could deploy additional diagnostic steps—such as bronchoscopy, imaging, or targeted microbiological testing—and respond with appropriate interventions (e.g., augmenting antifungal prophylaxis, adjusting immunosuppression, or closer monitoring for thromboembolic phenomena). Such strategies must be carefully balanced against the risk of over-treating patients with false-positive AGA results, underscoring the importance of parallel clinical assessments and confirmatory diagnostic measures.

Implications and actions needed

Building on our study’s findings, future research should adopt a prospective, multicenter design that specifically addresses the nuances observed in our lung transplant cohort—including the potential influence of donor-derived fungal antigenemia and the impact of varied immunosuppressive protocols. Given protocol heterogeneity across centers, future multicenter studies should compare induction regimens and antifungal prophylaxis (including drug choice, duration, and therapeutic drug monitoring practices) to determine their impact on AGA positivity and related complications. Under universal antifungal prophylaxis, risk profiles differ for early candidiasis and early/late invasive mold infections, emphasizing the need for risk-stratified, multicenter protocol comparisons (31). In this context, studies should prospectively collect donor culture data alongside recipient AGA measurements to delineate the origin of antigen positivity more clearly. Moreover, randomized controlled trials tailored to our study framework are warranted to assess whether an early intervention protocol—guided by prompt AGA screening and subsequent targeted management—can effectively mitigate the high rates of infections, thromboembolic events, and reduced one-year survival observed in our population. This focused approach will not only validate our current observations but also pave the way for precision-focused strategies to improve outcomes in lung transplant recipients.

Conclusions

Our results indicate that serum AGA positivity is a clinically relevant biomarker in LTx, closely linked to early postoperative complications and diminished one-year survival. Although it does not independently predict long-term mortality, its strong association with infections and thromboembolic events highlights a potential role for AGA in risk stratification. Routine, protocolized AGA surveillance—especially in the first-year post-transplant—may allow clinicians to detect early warning signals of clinical deterioration and address modifiable risk factors more swiftly. Further prospective research is needed to solidify the utility of AGA monitoring as part of a comprehensive, precision-focused approach to improving lung transplant outcomes.

Acknowledgments

The authors would like to thank Ms. Elena Susan for her assistance in submitting this manuscript.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1105/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1105/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1105/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1105/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Northwestern University (STU00207250 and STU00213616), and the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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