Korean J Transplant 2023; 37(3): 155-164
Published online September 30, 2023
© The Korean Society for Transplantation
Department of Laboratory Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence to: Yeon-Joon Park
Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Prompt and accurate diagnosis of invasive aspergillosis (IA) is crucial for immunocompromised patients, including those who have received a solid organ transplant (SOT). Despite their low sensitivity, microscopic detection and conventional culture are considered the 'gold standard' methods. In conjunction with conventional culture, culture-independent assays such as serum galactomannan testing and Aspergillus polymerase chain reaction (PCR) have been incorporated into the diagnostic process for IA. The recently revised consensus definitions from the European Organization for Research and Treatment of Cancer and the Mycosis Study Group have adjusted the threshold for positive galactomannan testing based on the sample type, and have excluded 1,3-β-D-glucan testing as a mycological criterion. Following extensive standardization efforts, positive Aspergillus PCR tests using serum, plasma, or bronchoalveolar lavage fluid have been added. However, there are limited studies evaluating the clinical utility of these culture-independent assays for the early diagnosis of IA in SOT recipients. Therefore, further research is required to determine whether these assays could aid in the early diagnosis of IA in SOT recipients, particularly in relation to the organ transplanted. In this review, we examine the culture-independent diagnostic methods for IA in SOT recipients, as well as the clinical utility of these assays.
Keywords: Invasive aspergillosis, Galactomannan, Polymerase chain reaction, Transplant
Invasive fungal disease (IFD) is associated with poor allograft outcomes and increased mortality in solid organ transplant (SOT) recipients who are on immunosuppressive medications. The primary risk factors for IFD development in SOT recipients include: (1) technical and anatomical abnormalities, such as the proficiency in operative and perioperative management, the use of vascular access devices, drainage catheters, and endotracheal tubes; (2) the extent of environmental exposures, whether community-based or hospital-acquired; and (3) the overall state of immunosuppression, which can be influenced by cytomegalovirus and other herpesviruses, steroid treatment for rejection, immunosuppressive medications or monoclonal antibodies, and renal failure . The most common IFDs in SOT recipients are invasive candidiasis (IC) and invasive aspergillosis (IA) . The incidence of fungal infections varies depending on the type of SOT. IC is most commonly reported in liver transplant recipients, while IA is most prevalent in lung transplant recipients [3,4]. A recent study reported the overall incidence of IA by transplanted organ as follows: less than 1% for liver transplant recipients, between 0.7% and 4% for renal transplant recipients, between 4% and 23% for lung transplant recipients, and between 1% and 14% for heart transplant recipients . Despite the overall low incidence of IA in SOT recipients, the 1-year mortality rate following IA diagnosis ranges from 19% to 40%, and the rates of graft loss are notably high [6-8].
A prompt and accurate diagnosis is crucial for the appropriate treatment and improved outcomes of IA. In 2008, the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) established criteria to classify potential IA cases into proven, probable, and possible categories. This classification was based on host factors, clinical criteria, and mycological criteria, and was intended for research purposes. The definition proposed for proven IA includes definitive evidence of
Here, we review the currently available culture-independent diagnostic approaches for IA in SOT recipients and highlight the clinical usefulness of antifungal susceptibility testing with
Most fungi have BDG as a significant and characteristic constituent of their cell walls. Detecting BDG in the bloodstream can be useful in diagnosing IFD, including clinically important fungi like
Limited data are available on the effectiveness of BDG testing in diagnosing IFD in SOT recipients. Several studies have shown that the sensitivity and specificity of BDG testing using serum in SOT recipients range from 58% to 100% and from 9% to 83%, respectively [17-21] (Table 2). The precise cut-offs for optimal accuracy of BDG testing in diagnosing IFD may vary depending on the host and the pathogen . Furthermore, a number of studies have evaluated the use of BDG testing as a diagnostic tool using bronchoalveolar lavage (BAL) fluid, but found it to have poor specificity [20,23]. Several factors have been identified that can interfere with the results of the BDG test. These include bloodstream infections with microorganisms such as
Galactomannan, a key component of
At present, the manufacturer suggests utilizing a cut-off optical density index (ODI) value of 0.5 for both serum and BAL fluid in galactomannan testing. To mitigate the issue of false positives, the updated version of the EORTC/MSG criteria suggests considering higher cut-offs of 1.0 for a single plasma, serum, BAL fluid, or CSF sample. If both serum and BAL fluid yield positive galactomannan results, the diagnostic criteria can be applied using cut-off values of ≥0.7 for serum and ≥0.8 for BAL fluid to support the diagnosis .
While serum and BAL galactomannan testing have proven to be valuable diagnostic tools for IA in patients with hematologic malignancies , their role in SOT recipients lacks established evidence due to the considerable variation in their performance in such individuals [35,36]. According to a meta-analysis, among SOT recipients, serum galactomannan testing exhibited low sensitivity (0.22; 95% confidence interval [CI], 0.03–0.60) and comparable specificity (0.84; 95% CI, 0.78–0.88). In contrast, bone marrow transplant recipients exhibited higher sensitivity and specificity, with values of 0.82 (95% CI, 0.70–0.90) and 0.86 (95% CI, 0.83–0.88), respectively . For SOT recipients, the limited number of studies made it difficult to estimate overall accuracy (Table 3) [37-41]. In this context, the sensitivity in SOT recipients is notably low, possibly due to limited angioinvasion in these patients who have better immune capabilities compared to those with neutropenia in hematologic malignancy patients . The lack of neutropenia in patients may lead to a reduced fungal burden, potentially due to their intact ability to clear fungal mannan from the bloodstream via macrophages [43,44]. In hematologic patients, galactomannan testing with BAL fluid showed higher sensitivity and specificity compared to serum [45-47]. According to a Cochrane review evaluating galactomannan testing with BAL in immunocompromised patients, an ODI cut-off value of 0.5 demonstrated a diagnostic sensitivity of 0.88 (95% CI, 0.75–1.00) and specificity of 0.81 (95% CI, 0.71–0.91) in 12 studies, while an ODI cut-off value of 1.0 showed a sensitivity of 0.78 (95% CI, 0.61–0.95) and specificity of 0.93 (95% CI, 0.87–0.98) in 11 studies . For SOT recipients, several studies have demonstrated the diagnostic accuracy of galactomannan testing with BAL fluid for the diagnosis of IA [40,41,49]. Although galactomannan testing with BAL fluid offers greater sensitivity than serum, the optimal cut-off value for galactomannan testing in BAL fluid remains a topic of ongoing debate.
In lung transplant recipients, where
Several researchers have investigated the diagnostic performance of
Most studies have focused on patients with hematologic malignancies, leaving a gap in the literature regarding the evaluation of
The extensive and prolonged use of broad-spectrum azoles has significantly contributed to the widespread emergence of azole-resistant
Under the revised EORTC/MSG criteria, the introduction of two consecutive positive
By comprehensively implementing these culture-independent assays in routine diagnosis, we can potentially optimize the management of IA, which could ultimately lead to improved treatment outcomes for SOT recipients.
No potential conflict of interest relevant to this article was reported.
This study was supported by research grant from the Korean Society for Transplantation (2023-00-03004-008).
Conceptualization: IYY. Visualization: IYY. Writing–original draft: IYY. Writing–review & editing: all authors. All authors read and approved the final manuscript.
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