Invasive aspergillosis (IA) is increasingly prevalent, with a high mortality rate. Early diagnosis and treatment can improve survival; however, diagnosing IA at an early stage remains challenging. Galactomannan (GM), a component of the Aspergillus cell wall, is released into the extracellular milieu as the fungal hyphae grow. In 1995, Stynen et al. first reported the use of a double‑sandwich enzyme‑linked immunosorbent assay (ELISA) to detect GM antigen in serum, demonstrating high sensitivity and establishing the diagnostic utility of this method for IA. The monoclonal antibody–based double‑sandwich ELISA developed by Bio‑Rad was approved by the U.S. Food and Drug Administration in 2003 and has since been widely adopted worldwide. Currently, clinical testing for GM in serum and bronchoalveolar lavage fluid (BALF) helps screen patients with high‑risk factors for IA and those with clinical suspicion, thereby facilitating the early diagnosis of IA.

I. Serum GM Assay

In patients with hematologic malignancies and those undergoing stem cell transplantation, invasive aspergillosis (IA) is highly prevalent. In diagnosing IA, serum galactomannan (GM) demonstrates high sensitivity and specificity; most studies report values of approximately 90% for both parameters. Similar findings have been observed in pediatric cohorts. A meta-analysis published in 2006, which included 27 randomized controlled trials—limited to patients with hematologic malignancies, bone marrow transplant recipients, and solid organ transplant recipients—reported that, for both confirmed and clinically suspected cases, GM testing yielded a sensitivity of 61% and a specificity of 93%. Furthermore, the analysis indicated that GM testing exhibited significantly higher sensitivity and specificity for detecting IA in patients with hematologic malignancies and those undergoing bone marrow transplantation compared with solid organ transplant recipients. These results underscore that GM’s diagnostic performance varies across populations with differing immune statuses.

Serum GM also plays a crucial role in determining the optimal timing for initiating empirical antifungal therapy in patients with febrile neutropenia. A prospective study published in 2011 combined peripheral blood GM testing with chest HRCT to guide the initiation of antifungal treatment, reducing the proportion of patients receiving empirical antifungal therapy by 14% while preserving 12‑week survival. In 2013, The Lancet reported a multicenter, open-label, parallel-group, randomized controlled trial that compared “peripheral blood GM plus PCR” (122 patients) with the conventional diagnostic approach of “culture plus histology” (118 patients). The results showed that the “peripheral blood GM plus PCR” strategy significantly decreased the rate of empirical antifungal therapy without compromising short-term survival.

Serum GM can also help assess the efficacy and prognosis of invasive aspergillosis (IA) in immunocompromised patients. In 2008, a meta-analysis by U.S. researchers demonstrated that serum GM is a prognostic factor for IA outcomes in patients with hematologic malignancies; at cut-off values of 0.5, 1.0, and 1.5, the corresponding correlation coefficients with prognosis were 0.80, 0.87, and 0.90, respectively. A 2009 study published in Cancer, focusing on neutropenic patients, found that among GM‑positive IA cases, using “conversion to negative (cut-off 0.5) sustained for 2 weeks” as the criterion for treatment success yielded concordance between the calculated success rate and the actual clinical success rate after 6 weeks of antifungal therapy. A 2011 study in CID likewise showed that adopting “conversion to negative (cut-off 0.5) sustained for 2 weeks” as the standard for treatment success exhibited remarkable agreement with the EORTC/MSG guidelines. Furthermore, a 2010 study in JCM reported that both the baseline GM level prior to antifungal therapy and the degree of GM decline after one week of treatment are independent predictors of prognosis in IA patients. In 2012, research published in JCM suggested that changes in GM levels within two weeks following antifungal therapy directly reflect treatment efficacy: among patients who were GM‑positive at baseline, a GM reduction exceeding 35% after one week indicates favorable therapeutic response; whereas in patients who were GM‑negative at baseline, the emergence of GM positivity within two weeks post‑treatment portends poor outcomes and prognosis.

The diagnostic value of serum GM is relatively lower in patients without neutropenia, non‑hematologic malignancies, and those who have not undergone bone marrow transplantation and are classified as IA. A Korean study found that its diagnostic sensitivity was only 23%, with a specificity of 76% and a positive predictive value of just 1.6%. Similarly, Finnish researchers reported that, among patients at no risk of IA, the diagnostic utility of GM testing is very limited. Furthermore, serum GM exhibits low diagnostic accuracy for chronic necrotizing pulmonary aspergillosis (CNPA).

The definition of the cutoff value for serum GM testing has undergone a lengthy evolution, with an overall trend toward progressively lowering the threshold to enhance diagnostic sensitivity. Since 2003, when the U.S. FDA approved setting the serum GM cutoff at 0.5, this standard has been widely adopted in clinical practice, including in China.

II. Diagnostic Value of BALF-GM for Invasive Pulmonary Aspergillosis (IPA)

BALF‑GM demonstrates excellent sensitivity and specificity for diagnosing invasive pulmonary aspergillosis (IPA) in patients with hematologic malignancies and those undergoing stem cell transplantation. In 2007, a study published in CJM on IPA in non‑lung solid organ transplant recipients reported that BALF‑GM achieved nearly 100% sensitivity and specificity at a cutoff of 1.0, outperforming both serum GM assays and BALF fungal cultures, with a negative predictive value of 100% but a lower positive predictive value (41.7%). A 2009 study published in CID focusing on IPA in patients with hematologic malignancies found that BALF‑GM exhibited sensitivity and specificity exceeding 90% at a cutoff of 1.0. Furthermore, a 2010 meta‑analysis in Chest indicated that BALF‑GM yields approximately 90% sensitivity and specificity for diagnosing IPA, and its combination with BALF‑PCR can further enhance diagnostic sensitivity and specificity.

Currently, there are limited studies on the role of BALF‑GM in the diagnosis of IPA in patients without severe immunosuppression. A small‑sample study conducted in the United States in 2007 reported a sensitivity of 100% and a specificity of 88% for BALF‑GM at a cutoff value of 1.0. In contrast, for serum GM, the sensitivity was 60% and the specificity 91% at a cutoff of 0.5, and 40% and 91.7% at a cutoff of 1.0. To date, no consensus has been reached regarding the optimal cutoff value for BALF‑GM; most studies place it between 0.5 and 1.5. Moreover, because the procedure for obtaining BALF specimens has not yet been standardized, determining an appropriate cutoff remains challenging.

In addition, GM testing still faces several limitations. For instance, intravenous administration of β‑lactam antibiotics such as piperacillin–tazobactam can lead to false‑positive results for serum GM and BALF‑GM; empirical or prophylactic antifungal therapy, as well as increased lavage fluid volume, can reduce the diagnostic sensitivity of BALF‑GM and even produce false‑negative findings; and consumption of high‑protein foods, such as milk that may contain GM, can result in false‑positive outcomes. Therefore, GM testing should continue to be interpreted in conjunction with clinical and radiologic findings.

In summary, for patients with severe immunodeficiency, both serum and BALF GM assays are effective tools for the early diagnosis of invasive aspergillosis. For high-risk patients or those suspected of having IA, serial serum GM monitoring twice weekly is recommended. Furthermore, dynamic serum GM monitoring plays a crucial role in assessing treatment response and prognosis. However, for patients without severe immunosuppression, the diagnostic utility of GM remains to be further investigated.

Excerpted from the Respiratory Disease Branch of the Chinese Medical Association