The advancement of Medicine brought new medications, therapeutics, invasive diagnostic methods and surgical approaches have in different pathologies. However, new obstacles emerge to defy our scientific knowledge. Rare pathogens until then unknown take advantage of health fragility in humans to cause infections with alarming proportions.

Cryptococcus spp. other than C. neoformans and C. gattii were previously considered to be saprophytes and non-pathogenic to humans; however, opportunistic infections associated with rare Cryptococcus spp., such as Cryptococcus laurentii and Cryptococcus albidus, have increased over the past four decades.1Cryptococcus laurentii belongs to the phylum basidiomycota of the fungi and is an encapsulated saprobic yeast and can be widely isolated from various types of environments.2 It is widely distributed throughout the world, including the Caribbean, Antarctic and the Himalayas and can be acquired from air, water, wood, soil, pigeon excrements as well as various foods, such as cheese, fruit, pork products, bean, and wine.3 Since 2015, the species name Cryptococcus laurentii was replaced by Papiliotrema laurentii. This nomenclature was based on phylogenetic analyses based on the sequencing of seven genes and regions such as ITS rRNA gene, the D1/D2 domains of the large subunit (LSU or 26S) rRNA gene, the small subunit (SSU or 18S) rRNA gene, two subunits of RNA polymerase II (RPB1 and RPB2), translation elongation factor 1-α (TEF1) andcytochrome b (CYTB).

With increasing immunosuppression due to antineoplastic therapy, organ transplantation, catheter insertion, dialysis and other invasive diagnostic and therapeutic procedures, systemic fungal infections are observed more frequently.4 Non-neoformans cryptococci have been reported to cause infection in many organs. The bloodstream and central nervous system are the most common sites of non-neoformans cryptococcal infection.5 Due to the rarity of cases involving P. laurentii, a standard treatment has not yet been established. Commonly, amphotericin B with flucytosine is recommended.6

The aim of this paper was to report a case of a female patient with pyloric obstructive cancer with catheter-related Papiliotrema laurentii bloodstream infection and systematically review the available evidence on P. laurentii infection in humans.

A 68-year old female patient, previously diagnosed with type 2 diabetes, arterial hypertension, non-alcoholic fatty liver disease, with a previous history of breast cancer which was treated with radical mastectomy, radiotherapy and chemotherapy a decade ago, sought care due to weight loss (20 % of total body mass - over 40 pounds), incoercible vomiting, weakness, hypoglicemia and upper abdominal pain.

She was admitted to the hospital for investigation. CAT-scan showed gastric distension. Upper digestive endoscopy showed submucosal obstructive pyloric malignancy (Fig. 1), but superficial biopsies came back negative for cancer. Colonoscopy was incomplete due to inadequate colonic preparation - the patient vomited manitol. Magnetic resonance showed a pyloric-duodenal mass, suggestive of submucosal pyloric cancer. A two-week parenteral nutrition (PN) was initiated with the purpose of improving nutrition prior to surgery. Patient gained five pounds while on PN. In the 12th day of PN, the patient began to present fever. Blood cultures were drawn and ampicillin-sulbactam was initiated with little response.

Fig. 1.

Infiltrative submucosal gastric neoplasm in the pylorus (circle).

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Five days thereafter, the patient presented with bacteremia. Catheter and peripheral cultures drawn during fever came back positive for Papiliotrema laurentii, with antifungigram pending. Identification of the isolate was performed on the Vitek 2 ( YST card - BioMérieux, Marcy l'Etoile, France) automated identification system, which reported P. laurentii. The concern regarding misdiagnosis by Vitek systems was minimized since the P. laurentii culture had been sent to two different laboratories and regrown for the antifungigram, which confirmed the first and second P. laurentii diagnosis with the same resistance profile. The isolate sent to the second lab was again identified by the same Vitek 2 (BioMérieux, Marcy l'Etoile, France) yeast identification card with testing staff blinded to previous Vitek 2 and antifungigram results. Xiao et al. cited that compared to the gold standard (identification of ITS- internal transcribed spacer), Vitek 2 can correctly identify 81.0 % of P. laurentii isolates.7 Fluconazole, piperacillin-tazobactam and vancomycin replaced ampicillin-sulbactam and the site of the catheter was switched. In five days, fever subdued and after 5-day negative control blood cultures, partial gastrectomy with Y-en-Roux gastroenteric anastomosis was performed (Fig. 2). With an adequate evolution, patient began to eat orally and PN was reduced gradually.

Fig. 2.

Surgical resection of neoplasm (circle).

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Five days after surgery, fever was again noted and catheter and peripheral cultures were positive for P. laurentii and Candida parapsilosis. The first was susceptible to flucytosine (intermediary), fluconazole, amphotericin B, voriconazole, and resistant to micafungin and caspofungin. The latter was susceptible to flucytosine, fluconazole, amphotericin B, voriconazole, micafungin and caspofungin. Transesophageal echocardiogram was negative for infective endocarditis. Vancomycin and piperacillin-tazobactam were already finished and patient was on monotherapy with fluconazole 800 mg once a day. Catheter site was switched again and amphotericin B 50 mg once a day was associated, with resolution of fever. After 14 days of combined therapy and negative peripheral cultures, patient was discharged with a dosage of 800 mg oral fluconazole daily. A post-operative control CAT-scan and an upper digestive endoscopy were performed, showing no signs of recurrence of the neoplasm (Fig. 3).

Fig. 3.

Post-operative control: gastroenteric anastomosis with no lesion or gastric food residue.

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This study was carried out in accordance with the recommendations contained in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA-P) guidelines.8 Our systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), maintained by York University, on 14 January 2019 [registration No. CRD42019122125 (www.crd.york.ac.uk/prospero/)].

P. laurentii has a high degree of interspecies heterogeneity and has been divided into phylogenetic groups I and II. Physiologic and biochemical characteristics of the species in the complex are similar. Nevertheless, the species in phylogenetic group I, such as Cryptococcus flavescens and Cryptococcus aureus, can be distinguished from phylogenetic group II by their combination of assimilation patterns of d-glucosamine, Nacetyl-d-glucosamine, DL-lactic acid, 1,2-propanediol and sodium nitrite and vitamin requirements.34Cryptococcus neoformans and P. laurentii share many common traits and structures – the hemolytic capacity of P. laurentii is an intrinsic characteristic that optimizes its infective capacity and increases its growth in blood.35

The likelihood of cryptococcal infection is highly increased in patients with impaired cell-mediated immunity, including lymphoproliferative disorders, HIV infection (CD4 counts < 100 cells/μl) and hematologic malignancies.36 Other risk factors are: use of steroid or chemotherapy,37 organ transplantation, impaired humoral immunity such as hyper-IgM syndrome,38 non-HIV lymphopenia,39 invasive devices40 and direct or indirect exposures to pigeon excreta.41 From our analysis, the presence of invasive catheters, immunosuppression and neoplasms were significant risk factors associated to P. laurentii infection.

P. laurentii has been reported to cause infections in many organ systems.42 The bloodstream and central nervous system were the most common sites of infection, although some other sites such as keratitis43 have been reported. Fever was the most common clinical finding, present in most cases. Choices and duration of treatment for P. laurentii infections depended on the anatomical involvement, host-immune status, and severity of infection. Recommendations regarding treatment for infections are limited, due to the small number of empirically treated cases and the absence of controlled trial data. Amphotericin B alone was used for most treatments, with a high rate of cure (80 %). The most used regimen was an induction period of 14 days followed by maintenance fluconazole, with a cure rate of 75 %. Nonetheless, 10 patients were treated with monotherapy with fluconazole, with a cure rate of 90 %.

A joint clinical guideline published in 2013 by the European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group (ESCMID) and the European Confederation of Medical Mycology (ECMM) for the diagnosis and management of rare invasive yeast infections is the available consensus on how to manage these infections. For non-neoformans and non-gattii Cryptococcus infections it is recommended the use of amphotericin B with or without flucytosine for the induction of CNS and severe infections or fluconazole in a dose over 400 mg daily if demonstrated in-vitro sensitivity. For non-CNS and non-severe infections, 400 mg of daily fluconazole can be used for induction and maintenance treatment, reserving amphotericin B for less azole susceptible species. Due to intrinsic resistance, echinocandins are not recommended.44

Susceptibility testing was reported for only 13 isolates, including our isolate. One was found to be resistant in vitro to amphotericin B and other to fluconazole. Although our isolate was not resistant in vitro to fluconazole, monotherapy failed, justifying a switch to amphotericin B followed by maintenance therapy with fluconazole. Clinical correlations between susceptibility testing results and treatment outcome are lacking.19

The cure rate of the infection was 82.8 %, and the most effective drug was amphotericin B, used in 44.8 % of the cured cases. Although this infection generally occurs in patients with multiple co-morbidities, it does not appear to be very severe, with a high response rate to commonly used therapy for resistant yeast.22,45

A very important concern regarding our reported case must be brought into attention: there is a report of misdiagnosis by Vitek systems, confounding candida species, such as C. parapsilosis, with P. laurentii.7 We do not believe this was the case, since the culture had to be sent to a different lab and regrown for the antifungigram, which confirmed the first and second C. laurentii diagnosis with the same resistance profile and the C. parapsilosis diagnosis in a different system.

In conclusion, P. laurentii, generally considered a non-infective saprobe, may cause relevant fungemia and other infections, especially in immunocompromised and oncologic patients. Central catheters seem to be a particular risk factor for fungemia with this yeast. The main clinical manifestation is fever, blood cultures are useful for diagnosis, and induction treatment with amphotericin B followed by maintenance fluconazole seems to achieve a significant success rate.

All authors have nothing to disclose.

All authors contributed to study concept and design, and drafting of the manuscript; All authors contributed to acquisition of data, analysis and interpretation of data; Michelin L contributed in revising the final manuscript; Soldera J and Corso LL contributed to statistical analysis; Soldera J contributed to study supervision; all authors contributed to critical revision of the manuscript for important intellectual content.