Bronchobiliary fistula secondary to hepatic malignancy with Exophiala dermatitidis infection: a case report

Abstract

Background

Bronchobiliary fistula (BBF) is a rare but severe complication following the treatment of hepatic malignancies. Exophiala Dermatitidis(E. Dermatitidis), a dematiaceous fungus, is an opportunistic pathogen that predominantly affects immunocompromised individuals. However, its role in BBF-associated infections has not been previously documented.

Case presentation

A 79-year-old man who was diagnosed with metastatic hepatic malignancy three years prior presented with a fever that persisted for seven days and dyspnoea for two days; a comprehensive evaluation was initiated on admission. Bronchoscopy revealed the presence of BBF, and imaging revealed hepatic and subphrenic abscesses. Ultrasound-guided drainage of the hepatic abscess was performed, and both the abscess aspirate and bronchoalveolar lavage fluid yielded E. dermatitidis on culture. Based on the clinical and microbiological findings, a diagnosis of BBF-related E. dermatitidis infection was established. The patient was treated with voriconazole (VRCZ) in conjunction with drainage. Antimicrobial therapy achieved the remission of symptoms, and the patient was discharged. Five months later, the disease recurred, necessitating readmission. Given the end-stage malignancy, profoundly poor performance status, and dismal prognosis, after exhaustive discussion, the family opted to forgo further active treatment.

Conclusions

This case highlights for the first time that BBF may serve as a unique conduit for the dissemination of E. dermatitidis, underscoring the importance of considering rare pathogens in patients with hepatic abscesses complicated by pulmonary infections. A prompt microbiological evaluation and targeted antifungal therapy are essential for optimal outcomes.

Clinical Trial

This article is a case report; therefore, I declare that a clinical trial number is not applicable.

Background

BBF is an aberrant communication between the biliary tract and the bronchial tree [1] and was first described by Peacock in 1850 [2]. It is classified as congenital or acquired [3]. Congenital BBF is extremely rare and is usually diagnosed in infancy, although some cases escape recognition until adulthood [1]. Acquired BBF more commonly follows trauma, surgery, hydatid liver disease, or malignancy [3, 4]. Bile expectoration (bilioptysis) is the primary symptom of patients with BBF. Disease history is also important in a preliminary diagnosis [4]. E. dermatitidis is a dematiaceous [5] yeast-like environmental fungus [6] that frequently colonizes the airways of patients with cystic fibrosis [7]. It causes superficial, cutaneous/subcutaneous, or systemic mycoses, with skin lesions being most common [8]. Deep infection typically presents as chronic necrotizing pneumonia after the inhalation of conidia and may progress to disseminated disease in either immunocompetent or immunocompromised hosts [9]. However, simultaneous hepatic abscess and pulmonary infection caused by E. dermatitidis in the setting of BBF has not been reported. We describe such a case to alert clinicians to this unusual pathogen.

Case presentation

A 79-year-old man was admitted on 7 March 2025 with a 1-week history of fever and 2-day progressive dyspnoea. On 1 March, he developed intermittent fever (maximum of 38.5 °C) and a dry cough with scant white sputum after a presumed cold; no chills or rigors were reported. From March 3 to 5, he was treated at a local health clinic with anti-infective therapy, antipyretics, and other symptomatic supportive care (specific medications unknown), resulting in a normalization of body temperature. On March 5, the patient experienced worsening dyspnoea, accompanied by increased cough producing yellowish-white mucoid sputum and chest tightness; nausea and vomiting were absent. The patient presented to the emergency department of our hospital on March 7. An emergency thoraco-abdominal CT (Fig. 1A) showed chronic liver disease with multiple abnormal lesions, consistent with a posttreatment metastatic hepatic malignancy. Postoperative changes associated with colon surgery included an infected lesion in the right middle lobe complicated by abscess formation, bilateral bronchiectasis with infection, inflammatory changes in the bilateral bronchiole, and a small air-containing cyst adjacent to the right trachea. For further evaluation and management, he was admitted with a diagnosis of bronchiectasis accompanied by an infection.

Fig. 1.

A1: An infected lesion in the right middle lobe complicated by abscess formation and a small air-containing cyst adjacent to the right trachea. A2: Bilateral bronchiectasis with infection and inflammatory changes in the bilateral bronchiole. A3: Abnormal intrahepatic density foci are visible. B: The right middle lobe of the lung contains abundant yellow, bile-stained secretions. C1: Dilatation and tortuosity of the intrahepatic biliary tree. C2: Mildly hypoenhancing subcapsular region in the right hepatic lobe

Approximately 10 years earlier, the patient had undergone treatment for colon cancer, with an uneventful postoperative course. Three years earlier, a metastatic hepatic malignancy was detected; he underwent repeated radiofrequency ablation and interventional procedures at a tertiary hospital in Shanghai. The most recent interventional procedure was performed 10 days before the current admission. Hypertension had been diagnosed 1 year earlier; he was reportedly taking two antihypertensive agents (details unknown). The patient had no history of diabetes mellitus, chronic hepatitis, or drug/food allergy. On admission, his physical examination revealed a body temperature of 36.4 °C, pulse of 84 beats per minute, respiratory rate of 20 breaths per minute, and blood pressure of 150/76 mmHg. He was alert without signs of scleral icterus or labial cyanosis. No superficial lymphadenopathy was noted on examination, and the nodes were not tender upon palpation. The jugular veins showed no distension, and the trachea was midline. The thoracic cage was normal, with symmetrical expansion and no intercostal retraction. The tactile fremitus was equal bilaterally; percussion revealed diffuse dullness. Auscultation disclosed coarse breath sounds and crackles or wheezes. The cardiac rhythm was regular, with no detectable murmurs or other pathological sounds. The abdomen was soft and nontender, with no hepatosplenomegaly palpable below the costal margins. Moderate oedema of the lower limbs was present, and the joints showed no signs of deformity. The results of the neurological examination were unremarkable, with no abnormalities detected.

Diagnosis and treatment: Routine blood tests revealed a white blood cell (WBC) count of 18.1 × 10^9/L, a lymphocyte count of 0.6 × 10^9/L, a neutrophil count of 16.1 × 10^9/L, a red blood cell count of 4.11 × 10^12/L, a haemoglobin concentration of 127 g/L, and a C-reactive protein (CRP) concentration of 142.87 mg/L. Emergency biochemical tests revealed an alanine aminotransferase concentration of 71 U/L, an aspartate aminotransferase concentration of 88 U/L, an albumin concentration of 30.1 g/L, a creatinine concentration of 45 µmol/L, a total bilirubin concentration of 70.7 µmol/L, a direct bilirubin concentration of 48.2 µmol/L, and an indirect bilirubin concentration of 22.5 µmol/L. Based on computed tomography (CT) imaging and the patient’s clinical history, pulmonary infection was confirmed, and bronchiectasis with lung abscess and superimposed pneumonia was the working diagnosis. Empirical therapy was started: 1.0 g of intravenous meropenem every 8 h for anti-infection, ambroxol for mucolysis, 0.30 g of acetylcysteine nebulized bid, 2 mL of terbutaline nebulized bid, 2 mg of budesonide nebulized bid, and diuretics and potassium supplements. The treatment was adjusted, and further tests were performed as the condition evolved. On 8 March 2025, the patient expectorated moderate yellow–green sputum. On 19 March 2025, bronchoscopy (Fig. 1B) revealed bile-like secretion overflowing from the lateral segment of the right middle lobe, suggesting BBF and a clinical correlation was advised. Bronchoscopy indicated BBF; imaging revealed hepatic and subdiaphragmatic abscesses, and thus percutaneous drainage of the abdominal purulent foci was recommended. On 20 March, ultrasound-guided hepatic abscess puncture and catheter drainage were performed under ultrasound guidance, and the drainage fluid total bilirubin concentration was 74.3 µmol/L. Blood cultures obtained on March 7 were negative. Microscopy of bronchoalveolar lavage fluid, bronchial brushing and aspirate samples showed yeast-like fungal spores; acid-fast bacilli were not detected. On 25 March, E. dermatitidis was isolated from both abscess fluid and bronchoalveolar lavage fluid, and a diagnosis of BBF complicated by E. dermatitidis infection was established. On 25 March, MRI was performed (Fig. 1C) to determine the status after multiple treatments for hepatic malignancy. Multiple foci with abnormal signals were observed within the liver along with a mildly hypoenhancing subcapsular region in the right hepatic lobe. Based on multiple abnormal enhancing lesions and in the right hepatic lobe, a clinical correlation was recommended. Intra- and extrahepatic biliary duct dilatation were observed. Thickening and enhancement of the common bile duct wall in the upper segment with focal luminal narrowing suggested a clinical correlation. On 26 March, antifungal treatment with 200 mg of oral VRCZ every 12 h was initiated; Yunnan Baiyao capsules (0.25 g orally twice daily) were added to minimize haemoptysis. After 4 days of VRCZ treatment, the patient improved, with minimal cough and sputum, no chills or fever, and a stable condition. He was discharged on oral VRCZ treatment, and outpatient follow-up was scheduled. On April 3, the VRCZ trough concentration was 4.0 mg/L.On April 3, antifungal treatment with 100 mg of oral VRCZ every 12 h was initiated. On April 10, the VRCZ trough concentration was 3.0 mg/L. On September 7, 2025, the patient was readmitted with a two-day history of dyspnoea, cough, and low-grade fever. At this point, the patient had completed 5 months of VRCZ therapy. Given the advanced malignancy, extremely poor performance status, and anticipated dismal prognosis, after thorough physician–patient communication, the family ultimately opted to forgo further therapeutic interventions.

Discussion and conclusions

BBF is an aberrant communication between the biliary system and the bronchial tree. Its rarity has precluded a formal elucidation of its pathogenesis. The prevailing pathophysiological model proposes that increased intrabiliary pressure precipitates an inflammatory focus in the subdiaphragmatic space, with eventual transdiaphragmatic rupture into the bronchial tree [10, 11]. Furthermore, locally destructive processes—most notably neoplastic transdiaphragmatic infiltration or subphrenic abscess perforation—may result in direct biliary–bronchial communication [12]. A systematic 40-year literature review encompassing 110 patients treated between 1980 and 2023 revealed that single-modality therapy involving endoscopic retrograde cholangiopancreatography (ERCP), surgery, drainage, or embolization achieved success rates of 87.2% for benign aetiologies of BBF and 59.5% for malignant aetiologies of BBF, irrespective of the underlying aetiology. In contrast, dual- or multimodal strategies (e.g., ERCP plus percutaneous drainage, embolization, or surgery) increased the success rate to 100%. Consequently, dual or multimodal interventions significantly outperform monotherapy, regardless of the underlying aetiology [13].

The formation of a BBF in the present case created a distinctive pathophysiological milieu that facilitated E. dermatitidis infection. Under physiological conditions, bile is sterile, and its bile salt composition exerts antimicrobial activity. The patient, who had undergone multiple sessions of radiofrequency ablation and transarterial chemoembolization for metastatic hepatic malignancy, harboured several well-recognized predisposing factors for BBF; the cumulative effects of these insults ultimately culminated in fistula formation. This fistulous tract functioned as a bidirectional conduit: on the one hand, microbe-laden bile or purulent abscess contents could reflux into the bronchial tree, directly inoculating the lower airways and precipitating pneumonia; on the other hand, respiratory secretions could traverse the same channel in the opposite direction, entering the hepatic parenchyma. This dual trafficking accounts for the isolation of an identical E. dermatitidis strain from both the hepatic abscess aspirate and the bronchoalveolar lavage fluid.

How the environmental fungus E. dermatitidis established hepatic abscessation is the pivotal question of this case. We postulate the following trajectory: environmental conidia were inhaled and initially colonized the bronchial mucosa; thereafter, the biliary–bronchial fistula served as an aberrant conduit, allowing the descent of the organism from the airway into the pyogenic liver cavity. The abscess milieu—hypoxic, necrotic and nutritionally rich—mimic the ecological niche that E. dermatitidis preferentially occupies. Members of the genus Exophiala grow vigorously at 4–47 °C; notably, E. dermatitidis is the only Exophiala species that proliferates at 40°C [14, 15]. Moreover, the organism tolerates a pH of 2.5–12.5 and a NaCl concentration of up to 17%, enabling it to survive and multiply in bile and purulent exudate and thereby perpetuating a persistent infectious focus [14].

E. dermatitidis infection predominantly affects immunocompromised hosts. Published studies have identified congenital CARD9 deficiency, prolonged corticosteroid or immunosuppressive therapy, malignancy, solid-organ or haematopoietic stem-cell transplantation, and AIDS as high-risk factors [16, 17]. In addition to patients with cystic fibrosis, affected cohorts include immunosuppressed individuals, elderly individuals, and, intriguingly, immunocompetent persons of Asian ancestry [18]. Although pulmonary disease caused by E. dermatitidis occurs worldwide, cases exhibit pronounced geographic clustering, with the overwhelming majority reported in East Asia [19]. In addition to cystic fibrosis, bronchiectasis is now recognized as a predisposing condition [19]; structural airway damage and mucus stasis create a permissive niche for fungal colonization and subsequent invasion. Our patient—an elderly Asian man with metastatic hepatic malignancy and bronchiectasis—belongs to the well-defined, high-risk population for E. dermatitidis infection. The patient had a history of hepatic malignancy and underwent multiple sessions of radiofrequency ablation and interventional therapy. These factors collectively contributed to the formation of the BBF. Repeated local interventions combined with long-term immunosuppression may have created a unique ecological niche for opportunistic infections.

The pathogenicity of E. dermatitidis is linked to virulence factors, morphological plasticity, and biofilm formation. Virulence factors include melanin and carotenoids, among others [18, 20]. Melanin, a complex cell-wall polymer, blocks phagocyte-derived hydrolases and reactive oxygen species, enabling immune evasion [21]. Carotenoids shield sensitive molecules and organelles from oxidative damage [20]. E. dermatitidis senses environmental cues—temperature, nutrient availability, and oxidative stress—to activate transcriptional regulators such as the WdSTUA gene and the Rho GTPase WdCdc42p gene, driving reversible yeast–hypha–sclerotic body transitions. The yeast form facilitates haematogenous dissemination, hyphae increase tissue penetration, and thick-walled sclerotic bodies confer resistance to both macrophage attack and antifungal agents [21]. Kirchhoff et al. demonstrated that E. dermatitidis assembles biofilms within 48 h; initial surface adherence is followed by extracellular matrix production that impedes antifungal penetration and thwarts host immune effectors, culminating in chronic, therapy-refractory infection [22].

Evidence for treating E. dermatitidis infection remains confined to case series and small retrospective cohorts; consequently, no standardized guidelines exist regarding the optimal antifungal agent or duration of therapy [5]. The current consensus suggests an individualized strategy that integrates the infection site, host immune status, and early therapeutic response [8]. The joint guidelines of the European Society of Clinical Microbiology and Infectious Diseases and the European Confederation of Medical Mycology (ESCMID-ECMM) recommend VRCZ, itraconazole (ITCZ) and posaconazole (PSC). Regarding the treatment duration, the literature suggests that diseases caused by dematiaceous fungi typically require prolonged therapeutic courses, ranging from several weeks to months or longer. Surgery remains an integral component of comprehensive management for localized lesions such as subcutaneous nodules and solitary pulmonary nodules, as well as deep-seated infections, including cerebral abscesses [6, 23]. Several studies have demonstrated the potent in vitro activities of VRCZ, PSC, ITCZ and amphotericin B (AMB) against E. dermatitidis originating from different geographical regions worldwide [24–27]. Many scholars have increasingly advocated for a combination of surgical resection and prolonged antifungal therapy to achieve a definitive cure and prevent dissemination [8, 28, 29].

For cutaneous and subcutaneous infections, several investigators have proposed the use of AMB plus ITCZ as the backbone regimen, with 5-flucytosine (5-FC) added when increased fungicidal activity is needed [28]. To date, no consensus guidelines specify the optimal regimen or duration of therapy for an E. dermatitidis pulmonary infection. Case reports have documented favourable clinical outcomes in hosts without underlying comorbidities who were treated with fluconazole (FCZ) monotherapy for 3–4 months [30]; however, this evidence is limited to sporadic cases and lacks controlled validation. Conversely, relapse after five months of ITCZ monotherapy was documented in one patient who achieved remission only after the ITCZ treatment was extended to 12 months, suggesting that ≥ 1 year of therapy may be needed to eradicate pulmonary pathogens [31]. In noncystic fibrosis, both ITCZ and VRCZ produce favourable responses, yet the optimal duration remains undefined [32]. For relapsing or refractory pneumonia, combination antifungal therapy should be considered [31]. In invasive E. dermatitidis infection, the hydroxypropyl-β-cyclodextrin formulation of PSCZ markedly increases drug solubility and oral bioavailability, optimizing its pharmacokinetic profile. The resulting increase in tissue penetration makes this formulation a highly promising therapeutic option for such invasive infections [33]. In profoundly immunosuppressed hosts with a refractory or disseminated E. dermatitidis infection, the combination of terbinafine (TRB) and PSCZ has produced clear synergistic effects in vitro, providing a rational salvage regimen [34]. Central nervous system involvement requires agents with robust blood–brain barrier penetration; VRCZ, which achieves high cerebrospinal fluid and brain tissue levels, is the regimen of choice. Catheter-related bloodstream infections mandate prompt central line removal plus systemic antifungal therapy [8].

Drug susceptibility testing revealed that the infection in our patient was sensitive to 5-FC, FCZ, VRCZ, and AMB. After being diagnosed with E. dermatitidis infection, the patient was treated with VRCZ, which continued for five consecutive months. During the treatment course, the patient underwent therapeutic drug monitoring (TDM), with VRCZ trough concentrations meeting recommendations provided in the guideline [35]. However, the therapeutic response remained suboptimal, with progressive clinical deterioration. Ultimately, the patient and his family decided to discontinue treatment.

We hypothesize that treatment failure resulted from a multifactorial interplay of pathogen-related, host-related, and treatment-related factors. First, E. dermatitidis, a dematiaceous yeast-like fungus, exhibits a robust biofilm-forming capacity. Once established in vivo, these biofilms significantly impede antifungal penetration and concurrently attenuate host immune clearance. VRCZ monotherapy displayed limited efficacy, particularly against biofilm-encased fungal cells. Furthermore, in a local microenvironment characterized by a high bile salt concentration and heavy fungal burden, VRCZ exposure may selectively induce resistance, further compromising therapeutic efficacy. Second, during the treatment course, the patient received only percutaneous hepatic abscess drainage and VRCZ antifungal therapy, without ERCP or BBF occlusion. Consequently, the fistula remained patent, enabling continuous physical reinoculation of E. dermatitidis from the respiratory tract into the liver. This persistent cross-contamination rendered antifungal monotherapy ineffective, as the eradication of the pathogen in one compartment was repeatedly undermined by seeding from the other compartment. This milieu provided ideal conditions for fungal colonization and recurrent infection. Additionally, in light of the patient’s advanced-stage cancer and poor prognosis, the family ultimately elected to discontinue treatment. These multifactorial elements collectively resulted in unsuccessful treatment.

This case has several limitations. First, no microbiological investigation was performed at recurrence on September 7, 2025. The patient experienced significant dyspnoea and was unable to cooperate with sputum collection. Additionally, the family declined invasive procedures and elected to forgo further treatment, resulting in discharge within several hours of admission. Consequently, we could not determine whether this recurrence represented a relapse of E. dermatitidis infection, secondary bacterial pneumonia, tumour progression, or a combination of these factors. Second, the VRCZ TDM was incomplete. Although TDM was performed on April 3 (4.0 mg/L) and April 10 (3.0 mg/L), no follow-up monitoring was conducted thereafter. Furthermore, potential drug‒drug interactions affecting VRCZ metabolism were not systematically assessed. For this Asian patient with hepatic malignancy, both a Cytochrome P450 2C19 (CYP2C19) poor metabolizer status and hepatic dysfunction could increase the drug exposure risk, making longitudinal TDM particularly critical. Third, although percutaneous hepatic abscess drainage achieved initial symptomatic relief, drainage alone may be insufficient to eradicate the fistula in complex cases with BBF. We did not perform early ERCP for biliary evaluation or attempt BBF occlusion, potentially missing the optimal window for fistula resolution, which may have contributed to the eventual treatment failure. The conservative strategy was based on the patient’s high surgical risk and initial response to drainage; however, the complexity of pyogenic abscess with BBF in the context of underlying hepatic malignancy may have been underestimated. Future similar cases should consider an early combined endoscopic intervention, which might improve the clinical outcomes.

These limitations reflect the clinical reality of managing invasive fungal infections in patients with advanced malignancy. Future studies should attempt to obtain microbiological documentation at recurrence whenever possible and implement standardized TDM protocols (weekly monitoring during the first month, with immediate testing at suspected recurrence) along with CYP2C19 genotyping where available to guide dosing.

We report an exceedingly rare case of deep-seated E. dermatitidis infection secondary to malignant liver tumour-related BBF, where treatment failure resulted from the convergence of multiple adverse factors. The pathological process simultaneously produced hepatic abscesses and pneumonia, with the BBF creating a direct “shortcut” that allowed this environmentally dematiaceous fungus to translocate from the respiratory tract to the liver. However, biofilm-related antifungal resistance and persistent BBF established the pathological foundation for an intractable infection, while the terminal stage of malignancy compounded by the family’s decision to forgo further treatment critically undermined therapeutic possibilities and precluded a microbiological investigation at recurrence. Clinicians should maintain a high index of suspicion. In immunocompromised patients with BBF who fail to respond to conventional antibacterial therapy, diagnostic reasoning must be broadened to include uncommon fungal pathogens, and a microbiological work-up should be pursued aggressively whenever feasible. Future similar cases should implement standardized TDM protocols and consider an early combined endoscopic intervention, which might improve the clinical outcomes. Throughout the entire clinical trajectory, a tightly integrated multidisciplinary team is central to optimize the outcomes in these challenging scenarios.

Abbreviations

BBF

Bronchobiliary fistula

E. dermatitidis

Exophiala dermatitidis

CT

Computed tomography

MRI

Magnetic resonance imaging

WBC

White blood cell

CRP

C-reactive protein

MALDI‒TOF MS

Matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry

SDA

Sabouraud dextrose agar

ERCP

Endoscopic retrograde cholangiopancreatography

CARD9

Caspase recruitment domain-containing protein 9

ESCMID-ECMM

European Society of Clinical Microbiology and Infectious Diseases/European Confederation of Medical Mycology

FCZ

Fluconazole

VRCZ

Voriconazole

PSCZ

Posaconazole

AMB

Amphotericin B

ITCZ

Itraconazole

5-FC

5-Flucytosine

TRB

Terbinafine

TDM

Therapeutic drug monitoring

CYP2C19

Cytochrome P450 2C19

Author contributions

All the authors contributed to the study’s conception and design. Conception and design: QZ. Material preparation and data collection: HZS, YZ, QYZ, FX, QFD, ZC, WSD, DL. Manuscript drafting: HZS. Critical revision of the article: QZ. All the authors read and approved the final manuscript.

Funding

No financial support relevant to this article was obtained.

Data availability

The information used in preparing this case report was extracted from the electronic medical records of the Ruian People’s Hospital, WenZhou, Zhejiang, China. A link to these records is not provided to maintain patient privacy and anonymity. This report does not contain patient data that could compromise patient privacy. The data can be provided by the corresponding author upon reasonable request.

Declarations

Ethical approval and consent to participate

This study was an observational study. This study was approved by the Ethics Committee of the Ruian People’s Hospital (Approval No. YJ2025148).

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The patient provided written informed consent for the reporting of his personal and clinical details.

Competing interests

The authors declare no competing interests.