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Multiple organ dysfunction syndrome and death secondary to Cyberlindnera fabianii

Cyberlindnera fabianii is a yeast present in soil rarely associated with invasive infection. Due to advanced diagnostic and therapeutic techniques, pathogenicity is increasingly recognized. A 37-year-old male with B cell lymphoma on rituximab developed multiple organ dysfunction syndrome secondary to C. fabianii bacteremia. Specialized species identification techniques were required after failure of standard methods. Despite extracroporeal membrane oxygenation (ECMO) the patient died on day 26 after admission.


Introduction
Over the last decade there has been a reduction in mortality associated with B cell lymphoma due to improved recognition and treatment. Mortality is often a result of a complication of treatment or development of an infection. Fungemia carries a high risk of mortality in these immunocompromised patients [1,2]. Though less frequently pathogenic than Candida, Cyberlindnera fabianii is a causative organism that is increasingly being recognized. It is an ascomycetous yeast of the Saccharomycetaceae family [3]. Past names for the organism include: Lindnera fabianii and Pichia fabianii [4]. In a review of the literature, we identified nineteen published cases or case series [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. These cases noted the invasive capability of C. fabianii, with associated sepsis often following bacterial infection.

Case
A 37-year-old male with no prior medical history was admitted to the medical ICU on day 0 with septic shock. The patient complained of a toothache on day −4, for which he went to an urgent care on day −1 and was started on amoxicillin clavulanate for a possible tooth abscess. He required vasopressor support and was placed on broad spectrum antimicrobial coverage with vancomycin, meropenem, clindamycin, and micafugin. The initial laboratory work-up was significant for neutropenia (ANC 70/μL), lactic acidosis, acute kidney injury, ischemic hepatitis (shock liver), and coagulopathy.
Due to encephalopathy, the patient required endotracheal intubation and mechanical ventilation on day 0. He was transitioned to veno-arterial ECMO on day 1 due to worsening septic shock with septic cardiomyopathy. Blood and sputum cultures from day 0 were positive for pan-susceptible Escherichia coli. The patient underwent three full volume plasma exchanges on days 1, 2, and 3 with stabilization in coagulation markers, progressive decline in vasopressor requirement, and clearance of lactate. Flow cytometry revealed a clonal expansion of B cells with a phenotype suggesting marginal zone lymphoma. Rituximab was started on day 8, along with intravenous methylprednisolone.The monoclonal B cell population was not present on repeat flow cytometry on day 20.
On day 16, while still on ECMO, the patient had increasing vasopressor requirements. Blood cultures from day 16 demonstrated yeast despite active treatment with micafungin, so voriconazole was added on day 19. Transthoracic echocardiography (TTE) on day 19 revealed a left ventricular apical thrombus. The yeast was initially identified as Candida pelliculosa by the Vitek system. Blood cultures were sent to a reference laboratory where Cyberlindnera fabianii was identified by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) on day 24. Amphoteracin B lipid complex was added to the antifungal regimen on day 24 due to species identification and persistent fungemia despite treatment with voriconazole and micafungin. The patient continued to require increasing vasopressor support and eventually died on day 26 after transitioning to comfort care.

Discussion
In Table 1  own, of Cyberlindnera fabianii following an English literature search [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. C. fabianii does not appear to demonstrate a predilection for a specific age group. However, severe immunosuppression, major surgery, antimicrobial therapy, and low birth weight appear to be associated with increased propensity for infection. Prior antifungal therapy was present in 7 cases at the time of species identification, suggesting that treatment of C. fabianii requires proper identification and determination of susceptibility. Clinical presentation appears to be relatively nonspecific with fever being the most common presentation. Multiple cases noted nonspecific rises in C reactive protein and variable alterations in the manual differential. Based on review of our case and prior cases, no specific clinical or laboratory data are associated with new onset fungal infection with C. fabianii. In 12 of 20 cases (60%), fungemia was present. In all cases, specialized diagnostic testing was required to identify the correct organism. Therapies included all antifungal classes-azoles, echinocandins, formulations of amphotericin, and flucytosine-as well as source control when possible. Eight of the 20 patients (40%) died of multiple organ dysfunction syndrome.
Our patient had many of the risk factors identified in previous cases including immunosuppression (new diagnosis of B-cell lymphoma), neutropenia, chemotherapy (rituximab), mechanical ventilation, ECMO support, and antibiotic therapy (for preceding E. coli bacteremia). Classically, cellular immune mechanisms prevent cellular invasion by yeast with modest contribution from the humoral immune response [1]. There is no clear theory to explain B-cell lymphoma or rituximab, a chimeric anti-CD20 monoclonal antibody that induces B cell depletion through lysis, phagocytosis, and cell cycle arrest, would result in increased risk of rare opportunistic fungemia. Based on prior research the influence of rituximab on fungal infections remains unclear [19][20][21].
The presence of macro disruptive procedures (mechanical ventilation, ECMO, CRRT) seems to increase the likelihood of Cyberlindnera to cause systemic disease. Our patient presented with gram negative septic shock requiring salvage therapy with veno-arterial ECMO. Because of the high incidence and mortality of Candida sepsis, it is a strong recommendation of the Extracorporeal Life Support Organization (ELSO) Infectious Disease task force that clinicians lower the threshold for antifungal therapy for critically ill septic patients on ECMO [22]. Our case demonstrates that we should extend this vigilance to include rare non-Candida yeast species that may require different therapy in this population.
Growth of C. fabianii on Dalmau plate culture produces spherical ovoid budding yeast cells with occasional pseudohyphae. Microscopy demonstrates spheroidal to ellipsoidal budding blastoconidia with an absence of pseudohyphae [3]. The use of routine diagnostic kits for the identification of yeast has limited ability to identify Cyberlindnera [9,11,23]. We suspect Cyberlindnera infections are often undiagnosed due to a failure to complete definitive fungal identification. In our case, the organism was initially misidentified as Candida pelliculosa by the Vitek system. Cultures were sent to a reference lab for further identification due to the rarity of that species. Prior cases have also demonstrated misidentification as Candida utilis [9]. Diagnosis of our yeast required use of MALDI-TOF MS.
C. fabianii has been described as a yeast with low virulence and a rare cause of blood stream infection and sepsis. However, our case as well as others (Table 1) have noted the organism to grow from multiple sites with a poor response to treatment with antifungal therapy. Antifungal susceptibility testing should be pursued as strains of the yeast can have varied minimum inhibitory concentrations. Prior cases also noted the rapid development of resistance in isolates following the initiation of therapy, particularly to azoles [6,16]. In our case, fungemia developed while on micafungin and persisted while on both micafungin and voriconazole. Harboring of the fungus in the intra-atrial thrombus and ECMO circuit were presumably also barriers to clearance of the blood. Past C. fabianii isolates demonstrated strong biofilm production [9], which likely contributed to the organism's persistence in ECMO recipients.

Conclusion
A high index of suspicion is necessary for rare opportunistic yeast species in immunocompromised, critically ill patients, especially in those requiring life support devices such as ECMO. Cyberlindnera fabianii is an emerging pathogen that can be associated with fungemia, sepsis and multiple organ dysfunction syndrome. Antibiotic therapy is a risk factor, and C. fabianii has the ability to breakthrough antifungal prophylaxis and empiric treatment. Given that automated identification systems can misidentify this organism as a Candida species, we emphasize the importance of reference testing, either with MALDI-TOF MS or fungal sequencing. Accurate identification of the yeast is essential in treatment, as Cyberlindnera has varying antifungal susceptibilities, which must guide therapy. It requires source control due to its resistance pattern and biofilm production. In certain patients, C. fabianii can be highly virulent with infection resulting in considerable mortality.

Conflict of interest
There are none.