Discussion
Galactomannan is a polysaccharide component of Aspergillus cell walls,and it is released during tissue invasion by Aspergillus hyphae. Beta-D-glucan (BDG) is present in the cell walls of almost all pathogenic fungi, such as Candida, Aspergillus, and several other genera (except Mucorales and Cryptococcus). These two serologic biomarkers have been introduced for the diagnosis of invasive aspergillosis (IA) over the last four decades.
The concentration of serum GM in vivo is determined not only by the rate of production and secretion by the growing fungus but also by the rate of uptake in the bloodstream, as well as the rate of elimination from the circulation. A meta-analysis from Mayo Clinic in 2018 shows that serum GM had a moderate mean sensitivity of 0.71 and high specificity of 0.89. Increasing the cut-off index increased specificity and decreased sensitivity. A serum GM cut-off of 1.0 seems to provide optimal sensitivity of 0.79 and specificity of 0.88[1]. In another study, the sensitivity, in particular, was very heterogeneous at the cut-off values of 0.5, 1.0, and 1.5 optical density index. Currently, due to the large number of false positives, a higher cut-off of 1.0 is proposed[2]. Even so, the GM test is difficult to be considered a gold standard of IA diagnosis.The major sources of circulating BDG are invasive fungal disease, iatrogenic contamination, intestinal translocation, intestinal contents: mycobiome and BDG translocation, hepatic function, bacterial infections, and manufacturing-associated contamination. A meta-analysis showed that the BDG assay in ICU patients at risk for IC or candidemia had a mean sensitivity of 0.81 and mean specificity of 0.60[1]. The negative predictive value of BDG is very high,and it could not identify Aspergillus infection.So the BDG test is clearly less close to being a diagnostic gold standard of invasive fungal disease than the GM testThe limitation of BDG-based tests lies in their inability to identify pathogenic microbial species.
Overall, serologic examination is not considered sufficient for a proven diagnosis. Microscopic examination, culture, and PCR sequencing are also required, according to the recent EORTC/MSG guidelines[3]. Invasive fungal diseases do not have specific symptoms, signs, or imaging findings. Some studies have evaluated the early diagnostic value of serum GM tests combined with computed tomography for invasive pulmonary aspergillosis. The diagnostic and follow-up performance of the two biomarkers were further improved by using them as a combination of tests (parallel analysis improves sensitivity and negative predictive value) or continuous monitoring (serial analysis improves specificity and positive predictive value). In this report, pain appeared earliest and persisted in the progression of the disease; imaging studies provided localization but were not diagnostic. At the early stage of the disease, the BDG assay and GM test showed a slight increase, but the presence of Candida in the sputum examination made us consider them as false positives. Fortunately, we persisted in monitoring the serological changes dynamically and made the decision to treat with voriconazole. Serological tests were sensitive and varied with the severity of the illness and remained valuable for observation even after the disappearance of symptoms and imaging changes.
It is known that treating Aspergillus infections in the central nervous system requires longer periods of drug therapy[4]. When the patient stopped taking the medication, the GM test values began to rise, raising concerns about a possible resurgence of aspergillosis. The current guidelines do not exhaustively describe these rare clinical cases, and the optimum duration of antifungal treatment and follow-up remains uncertain.
Only about half of all invasive fungal infections are diagnosed pre-death,the value of the GM test is not sensitive and specific enough to be considered a diagnostic gold standard, according to many sources.However, when used it in combination with BDG, CT, and MR imaging and observed dynamically,it demonstrates significant value during the course of Aspergillus infections and therapeutic management.