Abstract
Introduction
Cryptococcosis is a significant opportunistic fungal infection, particularly affecting immunocompromised individuals. Papillotrema laurentii has been increasingly reported in recent years, especially in immunosuppressed patients. This study aims to provide guidance on the diagnosis and treatment of P. laurentii-related infections or colonization, along with a review of the existing literature.
Materials and Methods
Patients with <P. laurentii isolated in any culture sample between 2017 and 2022 were included in this study. A literature search was conducted using the electronic databases Scopus, Web of Science, MEDLINE (PubMed), and Google Scholar.
Results
Over the past 5 years, P. laurentii was identified in culture samples from nine patients in our hospital. A literature review revealed 35 publications reporting a total of 40 cases of P. laurentii infection between 1998 and 2022. The most common risk factors included the use of broad-spectrum antibiotics and the presence of invasive devices or catheters.
Conclusion
Although P. laurentii is considered a rare pathogen, it can cause infections of various organ systems. Therefore, clinicians should be aware that this uncommon fungal species may act as an infectious agent, particularly in patients receiving broad-spectrum antibiotics or steroid therapy.
Introduction
Papillotrema laurentii, formerly known as Cryptococcus laurentii, is an encapsulated basidiomycetous yeast. Cryptococcosis is a major opportunistic fungal infection, primarily affecting immunocompromised patients[1]. However, in approximately 30% of cases, no identifiable predisposing factors are present[2]. The most common pathogenic species associated with Cryptococcosis are C. neoformans and C. gattii. Notably, around 80% of reported cases of non-neoformans or non-gattii Cryptococcosis have been attributed to C. laurentii and C. albidus[3].
Although P. laurentii is generally considered a saprophytic and rare yeast, reports of invasive infections have increased in recent years[4, 5]. Documented infections caused by P. laurentii include involvement of the lungs, central nervous system, bloodstream, urinary tract, and musculoskeletal system[6]. While this species is typically regarded as non-pathogenic to humans, such infections have been reported.
This study aims to investigate P. laurentii infections or colonization detected in our hospital and review the existing literature to emphasize the clinical relevance of C. laurentii-related infections and provide guidance for their diagnosis and treatment.
Materials and Methods
Patients with P. laurentii isolated from any culture sample between 2017 and 2022 were included in this study. Demographic and clinical data were obtained from the hospital database. Infection was defined as the proliferation of the microorganism in the host leading to disease symptoms due to invasion, whereas colonization was characterized by the presence of the microorganism without causing a disease response. Sputum samples were assessed using the Bartlett classification. According to this method, active inflammation was defined by the presence of 10-25 or more leukocytes at 10x magnification and fewer than 10 epithelial cells in the same field. A literature search was conducted using the electronic databases Scopus, Web of Science, MEDLINE (PubMed), and Google Scholar. Among the identified studies, 3 were retrospective cohort studies, 7 were systematic reviews, and 31 were case reports. No restrictions were placed on language or publication date. Both pediatric and adult populations were included, and reference lists of the retrieved studies were manually reviewed. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines.
Ethical Approval
The study protocol was approved by the Ethics Committee of Kocaeli University Faculty of Medicine (approval number: GOKAEK-2023/11.27, dated: 16.06.2023).
Statistical Analysis
Statistical analysis was performed using IBM SPSS Statistics 20.0 (IBM Corp., Armonk, NY, USA). The Kolmogorov-Smirnov test was used to assess the normality of data distribution. Continuous variables were presented as mean ± standard deviation, while categorical variables were expressed as frequency (percentage). Since the assumption of normal distribution was not met, the Wilcoxon signed-rank test was used for comparisons between pretreatment and posttreatment values. Relationships between categorical variables were analyzed using the chi-squared test. A p-value of <0.05 was considered statistically significant.
Results
Over the past 5 years, P. laurentii was identified in culture samples from nine patients in our hospital. Of these, seven patients exhibited clinical findings indicative of infection, while two were classified as cases of colonization. A literature review identified 35 publications reporting a total of 40 cases of P. laurentii infection between 1998 and 2022 (Table 1). Among the infected patients, 66% were male, with a mean age of 48.3±7.085 years (range, 15-77 years). A summary of cases identified in our hospital and those reported in the literature is presented in Table 1.
Case Presentations
Case 1
A 42-year-old female patient with a history of asthma and hypothyroidism was admitted with fever and shortness of breath. She was started on ceftriaxone, clarithromycin, and treatment for an asthma attack. Chest computed tomography (CT) revealed several pulmonary nodules. Gram staining of a bronchoalveolar lavage (BAL) sample showed active inflammation based on Bartlett classification, with leukocytes and yeast cells present. P. laurentii was isolated in the BAL fungal culture. After 3 months of fluconazole treatment, follow-up CT showed a reduction in nodule size.
Case 2
A 34-year-old female patient with a history of cryoglobulinemic vasculitis was admitted to the clinic with pneumonia, presenting with a 10 day history of cough and sputum production. She had been using prednisolone intermittently for 2 years. Chest CT showed pleural effusion adjacent to consolidation in the lower lobe of the right lung, along with a cavitary lesion. Additionally, tree-in-bud nodules and ground-glass opacities were observed in the lower lobe of the left lung. Fluconazole was added to her antibiotic regimen. Gram staining of sputum samples showed numerous leukocytes but no microorganisms. P. laurentii was isolated in the sputum culture. After 6 months of fluconazole therapy, follow-up chest CT revealed the resolution of the ground-glass opacities, consolidation, cavity, and pleural effusion.
Case 3
A 77-year-old male patient with no known comorbidities was hospitalized with Coronavirus Disease 2019 (COVID-19), confirmed by a Severe Acute Respiratory Syndrome Coronavirus 2 Polymerase Chain Reaction, tests. Chest CT showed diffuse bilateral ground-glass opacities, and his oxygen saturation was 75% on room air. He was started on antibiotics and pulse steroid therapy (250 mg for 3 days, followed by 40 mg of prednisolone). On the seventh and eighth days of hospitalization, he received two doses of tocilizumab. P. laurentii was isolated in a blood culture 8 days after pulse steroid therapy and 1 day after tocilizumab administration. The patient died on the same day.
Case 4
A 43-year-old male patient with no known medical conditions underwent surgery for a duodenal perforation. He was started on meropenem and tigecycline. On the second day of hospitalization, Enterococcus faecalis and P. laurentii were isolated from the culture of the fluid collected from the surgical drain. Gram staining of the fluid showed numerous leukocytes and yeast cells. Fluconazole was added to his treatment regimen. The surgical drain was removed after 28 days of treatment, and the patient was discharged in full recovery.
Case 5
A 67-year-old female patient with a history of diabetes mellitus, hypertension, and coronary artery disease was admitted to the Nephrology Department with postrenal acute kidney injury and required hemodialysis. She presented with dysuria, fatigue, and nausea. A pigtail catheter had been inserted approximately 1 year earlier. Urine culture from the patient, who had pyuria, revealed P. laurentii at a concentration of 105 colony-forming units (CFU) . The pigtail catheter was replaced, and the patient completed a 7 day course of fluconazole before being discharged. Follow-up urine culture was negative, and pyuria was no longer present.
Case 6
A 47-year-old male patient with hypertension was admitted to the intensive care unit with fever, shortness of breath, and cough. He developed acute kidney injury and required hemodialysis. A renal biopsy confirmed acute tubulointerstitial nephritis, for which he received 60 mg of prednisolone for 3 days. Two days later, P. laurentii was isolated in a sputum culture. However, as there was no evidence of active inflammation based on the Bartlett classification and no microorganisms detected in Gram staining, the isolate was considered a case of colonization. The patient was discharged after completing antibiotic treatment.
Case 7
A 15-year-old male patient with Duchenne muscular dystrophy underwent surgery in the Orthopedics Department for fractures of the right femur and humerus. On the sixth day of hospitalization, P. laurentii was isolated from a wound culture obtained from the surgical site. However, as leukocytes were absent in the sample, the isolate was considered a case of colonization rather than infection.
Case 8
A 77-year-old male patient with a history of mitral valve replacement and a previous cerebrovascular stroke was admitted with a 45 day history of fever. Transesophageal echocardiography revealed an oscillating mass on the mitral valve. He was started on broad-spectrum antibiotics and was managed with a urinary catheter. One month later, after catheter removal, urine analysis showed 55 leukocytes, and urine culture yielded P. laurentii at a concentration of 105 CFU. The patient reported worsening fatigue and reduced oral intake, and his C-reactive protein level was elevated to 33 mg/l (normal upper limit: 5 mg/l). He was diagnosed with cystitis and started on fluconazole. Follow-up urine culture was negative. However, the patient died during surgical intervention for endocarditis.
Case 9
A 33-year-old male patient with nasopharyngeal cancer was hospitalized with pneumonia. P. laurentii was isolated from a BAL sample. Gram staining of the BAL sample revealed leukocytes, yeast cells, and Gram-positive cocci. The patient was initially treated with amphotericin B for 5 days, followed by fluconazole. His treatment was completed in 14 days, leading to a full recovery.
Systematic Review
The first documented case of P. laurentii-associated infection was a cutaneous infection reported in 1977. Between 1977 and 2023, 43% of all identified cases were recorded. Among 40 reported cases of P. laurentii infection, 65.7% occurred in male patients, with a mean age of 39.4±3.928 years (age range, 0-88 years). The most frequently reported infection was fungemia, followed by meningitis and pneumonia. Less common infections included enteritis, skin ulcers, septic arthritis, endophthalmitis, lung abscesses, peritonitis, and mucositis. Notably, two cases of enteritis, one case of septic arthritis, and one case of endophthalmitis were newly reported in recent years (Figure 1). Broad-spectrum antibiotic use and the presence of invasive devices or catheters were frequently identified as risk factors in the literature[7, 8]. Treatment primarily involved fluconazole and amphotericin B. Among the 39 patients with available prognosis data, 33 (84.6%) recovered, while 5 (12.8%) died due to P. laurentii infection, and 1 (2.6%) succumbed to an underlying condition. Of the five patients who died from P. laurentii infection, two had fungemia, one had both meningitis and cutaneous infection, one had meningitis, and one had mucositis (Figure 2).
Comparison of Our Cases with Published Data
The average age of our patients was 48.3 years, while the mean age of cases reported in the literature was 39.4 years. This difference was not statistically significant (p=0.302). Male predominance was observed in both our study and the literature, with no significant difference between the two groups (p=0.641).
In our study, pneumonia was the most frequently observed clinical manifestation, whereas fungemia was the most common presentation in the literature. Consistent with previous findings, broad-spectrum antibiotic use and the presence of invasive devices or catheters were identified as key risk factors for Cryptococcosis. A comparison of our hospital data with published cases is provided in Table 2.
Discussion
This study presents seven cases of infection and two cases of colonization caused by P. laurentii, a rare human pathogen. To the best of our knowledge, this is the first report documenting P. laurentii cases in Türkiye. While immunocompromised individuals are generally considered at higher risk for P. laurentii infections, cases can also occur in immunocompetent patients.
Although P. laurentii has traditionally been regarded as a saprophyte and an uncommon human pathogen, reports of invasive infections have increased in recent years[9]. This rise may be linked to the growing number of immunocompromised individuals and the widespread use of immunosuppressive therapies[1]. Similarly, our findings align with the literature, as our cases also involved invasive infections.
Non-neoformans cryptococci are capable of infecting various organ systems. A study by Khawcharoenporn et al.[1] reported that bloodstream infections (39%) were the most common, followed by central nervous system infections (32%). In our study, one patient (14%) developed a bloodstream infection after receiving corticosteroids and cytokine blockers for COVID-19. Priscilla et al. also reported P. laurentii isolation from sputum culture under similar clinical conditions[10]. Additionally, a study of 30 COVID-19 patients found that corticosteroid and cytokine blocker therapy (e.g., tocilizumab) increased the risk of opportunistic cryptococcal infections[10].
In our study, pulmonary Cryptococcosis was identified in three cases (42%). Cryptococcal lung disease can present in various forms, ranging from asymptomatic colonization to severe pneumonia with respiratory failure. Radiological findings may include pulmonary nodules, masses, segmental or lobar consolidation, reticulonodular infiltrates, mediastinal or hilar lymphadenopathy, and, less commonly, pleural effusion[9]. However, individuals with advanced HIV tend to exhibit more severe imaging abnormalities. Most case series have reported interstitial infiltrates as the predominant finding, while pleural effusions, cavitary lesions, adenopathy, and alveolar opacities are less frequently observed[11]. Additionally, endobronchial colonization has been documented in patients with chronic pulmonary disease, as seen in one case from our study[12]. The presence of yeast in urine cultures of asymptomatic individuals is typically regarded as colonization.
Current guidelines recommend that treatment for asymptomatic candiduria should focus on eliminating risk factors and should only be considered for patients at risk of disease progression[10].
Invasive device use was identified as a risk factor in our study. Similarly, a review highlighted the presence of invasive devices as a significant risk factor for P. laurentii infection. One case report described P. laurentii as the causative agent of peritoneal dialysis-associated peritonitis[13]. However, in our study, peritonitis developed in one patient, and the isolation of the pathogen after surgery may have been influenced by broad-spectrum antibiotic use or the presence of an invasive device.
Conclusion
In summary, an evaluation of these nine cases indicates that P. laurentii, though considered a rare pathogen, can cause infections in multiple organ systems. Successful treatment can be achieved with appropriate antifungal therapy initiated based on thorough clinical evaluation and culture results. However, delays in treating systemic infections may result in fatal outcomes. Therefore, it is important to recognize that this rare pathogen can act as an infectious agent, particularly in patients receiving broad-spectrum antibiotics or steroid therapy.
