Based on the clinical and mycological findings, we report a case of invasive aspergillosis of the biliary tract caused by A. fumigatus.
Fungal infections of the biliary tract are uncommon. Typically, these infections are caused by Candida spp., which can lead to biliary obstruction and cholangitis.
Typically, invasive aspergillosis is found in immunosuppressed patients. Although, there is a growing awareness that patients without classical risk factors could be affected by invasive aspergillosis, e.g. patients with COPD or liver cirrhosis, mortality in these patients is still high because of potential atypical presentation, which is associated with delay in diagnosis and therapy.
Aspergillus spp. are ubiquitously found in the environment and acquisition and transmission is typically through the airborne route. Therefore, the lung is the most common site of invasive aspergillosis, but primary infection of non-pulmonary sites can occur in rare circumstances [3].
Based on the described case of Aspergillus spp. Cholangitis, we performed a literature review using the PubMed database to identify biliary involvement in invasive aspergillosis. Only three case reports describing aspergillosis of the biliary tract could be identified (Table 1) [8,9,10].
Table 1 Clinical course, therapy and risk factors for Aspergillus cholangitis of cases identified in the literature review Involvement of the gastrointestinal tract in aspergillosis represents a possible site of infection and may occur via hematogenous dissemination from a primarily pulmonary site or via direct ingestion [11, 12]. This could be excluded by radiological diagnostic and via negative GM in bronchoalveolar lavage-fluid in our case.
One case describes aspergillosis of the liver without signs of pulmonary- or disseminated aspergillosis but presence of classical risk factors for invasive aspergillosis: Acute myeloid leukaemia with chemotherapy and neutropenia [9].
The presented patient in our case was not neutropenic but in the literature, visceral aspergillosis without clinical pulmonary involvement is conceivable rather only in severely neutropenic patients [1, 13].
The other possibility, as reported in the cases of biliary tract invasive aspergillosis, is attributable to invasive procedures at the biliary tract like surgery and external drainage (PTCD).
The reported patients in these cases underwent hepato-biliary surgery before development of Aspergillus cholangitis [8, 10]. In one case portoenterostomy explicitly served as a bidirectional conduit between intrahepatic biliary system and the small intestine allowing intestinal flora to access the intrahepatic biliary system (see Table 1).
In our case, we assume ascension of the pathogen after ERCP and stent implementation from the small intestine.
In the gastrointestinal tract, especially the small intestine is the most affected organ in reported cases of visceral aspergillosis, causing intestinal ischemia and peritonitis or liver affection through the portal venous system [1, 9, 10, 15,16,17].
For diagnosis and screening purposes, GM-antigen tests in serum are recommended but their sensitivity is significantly lower in non-neutropenic patients [5, 14] as neutropenia could cause an increased fungal load and facilitate angioinvasion. Also, serum neutrophils may eliminate GM [15]. Moreover, the value of GM-antigen testing has not been studied in the context of invasive aspergillosis of the digestive tract based on the rarity of this infection site [11, 16].
There is the possibility of false positive results in GM-testing in patients with piperacillin-tazobactam therapy (due to its derivation from natural compounds produced by the genus Penicillium [17]) and after translocation from the gastrointestinal tract after nutritional intake of GM-containing food which also includes certain enteral nutritional supplement [18]. These settings however were not present in our case.
In our case GM detection (Platelia™ Aspergilllus Ag, Bio-Rad Laboratories, Munich, Germany) was performed in BAL-fluid and in serum samples. Results were reported as ODI with a cut-off of 0.5 [5]. Moreover, primary microbiological bile cultures were performed on Columbia agar, Schaedler agar, chocolate agar (prepared culture media, Becton Dickinson, Sparks, MD, USA) and thioglycolate broth (Oxoid™ Thermo Fisher Scientific™, Waltham, MA, United States of America) as enrichment culture. In addition, culture of vortexing fluid of removed bile duct stent components was performed to increase diagnostic sensitivity and to establish association of Aspergillus growth with stent components. Aspergillus was then sub-cultured on sabouraud-dextrose-agar (Oxoid™ Thermo Fisher Scientific™, Waltham, MA, USA) for species identification: macroscopic, microscopic and via MALDI-TOF (Bruker Daltronics GmbH, Leipzig, Germany).
Yet, in our case, serial serum GM-antigen testing showed the response to antifungal therapy and helped to establish the diagnosis of extra-pulmonary aspergillosis in the first place emphasising the potential value of this diagnostic tool for extrapulmonary aspergillosis.
Treatment of extrapulmonary aspergillosis could be challenging and antifungal resistance is increasing.
Therefore, phenotypic screening for azol-resistance was performed using RPMI (Becton Dickinson, Sparks, MD, United States of America) agar plates supplemented with voriconazole and itraconazole and an antifungal-free agar as growth control. Azole susceptible isolates would have been identified by growth on the antifungal-free agar and absence of growth on plates containing azoles [19].
To date, the antifungal agents licenced for the first line treatment of invasive aspergillosis include voriconazole, isavuconazole and amphotericin B and its lipid formulations. However, as also stated in the latest ESCMID-ECMM-ERS guidelines, liposomal amphotericin B is usually the first therapeutic option in patients with liver insufficiency. In this case, we used liposomal amphotericin B because of the need for continuous renal replacement therapy and the impaired liver function to reach stable drug concentrations [16, 17]
The role of new antifungals in liver insufficiency e.g. isavuconazole has to be evaluated in future studies as promising data in patients with neutropenia or allo-HSCT are already available.