RESUMEN

Con el objetivo de conocer las características de las fungemias en 285 pacientes oncológicos hospitalizados del 2012 al 2016 en el Instituto Nacional de Enfermedades Neoplásicas se realizó un estudio descriptivo retrospectivo. Se evaluó información demográfica, clínica y microbiológica. Las fungemias por C. albicans predominaron en pacientes con tumores sólidos y sin neutropenia, mientras las causadas por C. tropicalis predominaron en pacientes con neoplasias hematológicas y neutropenia. C. tropicalis fue el agente más aislado (47,0%). Las fungemias aumentaron con el tiempo en los pacientes sin neutropenia. Las fungemias causadas por C. albicans aumentan con la edad en pacientes con tumores sólidos sin neutropenia. Se concluye que las fungemias son mayormente causadas por C. tropicalis en pacientes con neoplasias hematológicas con neutropenia y por C. albicans en pacientes con tumores sólidos sin neutropenia. Además, las fungemias en pacientes sin neutropenia aumentan en el tiempo y las causadas por C. albicans, en tumores sólidos sin neutropenia, aumentan con la edad.

Palabras clave:
Epidemiología; Tendencias; Etiología; Micosis Invasivas; Candidemia; Hospitales de Cáncer

ABSTRACT

Retrospective descriptive study carried out to determine the characteristics of fungemia in 285 cancer patients hospitalized from 2012 to 2016 at the Instituto Nacional de Enfermedades Neoplásicas (INEN). Demographic, clinical and microbiological information was evaluated. Fungemia by C. albicans predominated in patients with solid tumors and without neutropenia, while those caused by C. tropicalis predominated in patients with hematological neoplasia and neutropenia. C. tropicalis was the agent isolated in most cases (47.0%). Fungemia increased over time in patients without neutropenia. Fungemia caused by C. albicans increases with age in patients with solid tumors without neutropenia. It is concluded that fungemia are mainly caused by C. tropicalis in patients with hematological neoplasia with neutropenia and by C. albicans in patients with solid tumors without neutropenia. In addition, fungemia in patients without neutropenia increases over time; and those caused by C. albicans increase with age in patients with solid tumors without neutropenia.

Keywords:
Epidemiology; Trends; Etiology; Invasive Mycoses; Candidemia; Cancer Care Facilities

INTRODUCTION

Fungemias are the most frequent invasive mycosis, with high morbidity and mortality, and have increased due to the growing number of immunocompromised patients, especially oncological cases ¹1. Paiva J, Pereira J, Tabah A, Mikstacki A, de Carvalho F, Koulenti D, et al. Characteristics and risk factors for 28-day mortality of hospital acquired fungemias in ICUs: data from the EUROBACT study. Critical Care. 2016; 20(1):53. doi: 10.1186/s13054-016-1229-1.
https://doi.org/10.1186/s13054-016-1229-... ^,22. Cornely O, Gachot B, Akan H, Bassetti M, Uzun O, Kibbler C, et al. Epidemiology and outcome of fungemia in a cancer Cohort of the Infectious Diseases Group (IDG) of the European Organization for Research and Treatment of Cancer (EORTC 65031). Clin Infect Dis. 2015; 61(3):324-331. doi: 10.1093/cid/civ293.
https://doi.org/10.1093/cid/civ293... . Fungemias vary according to certain demographic (age, gender, and geographical region) and clinical (underlying diseases, the primary focus of infection, and state of neutropenia) characteristics. Besides, etiology plays an important role in their occurrence³3. Gaona-Flores V, Campos-Navarro L, Cervantes-Tovar R, Alcalá-Martínez E. The epidemiology of fungemia in an infectious diseases hospital in Mexico city: a 10-year retrospective review. Med Mycol. 2016; 54(6):600-604. doi: 10.1093/mmy/myw017.
https://doi.org/10.1093/mmy/myw017... ^,44. Dong D, Li Z, Zhang L, Jiang C, Mao E, Wang X, et al. Clinical and microbiological investigation of fungemia from four hospitals in China. Mycopathologia. 2015; 179(5-6):407-414. doi: 10.1007/s11046-014-9855-0.
https://doi.org/10.1007/s11046-014-9855-... .

Within the varied etiology of fungemias, we find filamentous fungi and yeast-like fungi; which are the most predominant. Although Candida albicans (C. albicans) has long been the most common species to be isolated, other Candida species and yeasts other than Candida appear to emerge and displace C. albicans⁵5. Castanheira M. Fungemia surveillance in Denmark demonstrates emergence of non-albicans Candida species and higher antifungal usage and resistance rates than in other nations. J Clin Microbiol. 2018; 56(4):e01907-17. doi: 10.1016/j.diagmicrobio.2016.02.009.
https://doi.org/10.1016/j.diagmicrobio.2... ^,66. Capoor M, Gupta D, Verma P, Sachdeva H. Rare yeasts causing fungemia in immunocompromised and haematology patients: case series from Delhi. Indian J Med Microbiol. 2015; 33(4):576. doi: 10.1128/JCM.01907-17. doi: 10.4103/0255-0857.167320.
https://doi.org/10.1128/JCM.01907-17... . Besides, these pathogens have different sensitivity profiles to antifungal agents ⁷7. Castanheira M, Messer S, Rhomberg P, Pfaller M. Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program (2013). Diagn Microbiol Infect Dis. 2016; 85(2):200-204. doi: 10.1016/j.diagmicrobio.2016.02.009.
https://doi.org/10.1016/j.diagmicrobio.2... . Therefore, the associated epidemiology, and etiology have implications for the therapeutic management and outcome of fungemias. The demographic, clinical and etiological characteristics of fungi have been poorly described in our population. Knowing the characteristics of fungemias in hospitals will improve control mechanisms and treatment for these invasive mycoses.

The objective of this study is to determine the characteristics of fungemias in oncology patients hospitalized from 2012 to 2016 at the Instituto Nacional de Enfermedades Neoplásicas (INEN) in Peru.

THE STUDY

A retrospective descriptive study of fungemia cases diagnosed in the microbiology laboratory of INEN between January 2012 and December 2016. The information was obtained from the registry of the Microbiology Laboratory and the INEN computer system. All cases in which the etiological agent could be identified were included. Duplicate isolates corresponding to the same patient were excluded from the study.

Fungemia diagnosis was made by blood cultures processed in the automated system BD Bactec^TM Fx. The yeast identification was made by morphological analysis, according to Dalmau’s technique in rice extract agar; and by biochemical analysis, according to the chromogenic characteristics in CHROMagar medium and the characteristics of carbohydrate assimilation in the commercial API 20C AUX system (bioMérieux) ⁸8. Freydiere AM, Guinet R, Boiron P. Yeast identification in the clinical microbiology laboratory; phenotypical methods. Med Mycol. 2001; 39: 9-33. doi: 10.1080/mmy.39.1.9.33.
https://doi.org/10.1080/mmy.39.1.9.33... . Filamentous fungi were identified by their macroscopic and microscopic characteristics ⁹9. Larone DH, Larone DH. Medically important fungi: a guide to identification. New York: Elsevier; 1987..

Fungemia was defined as the isolation of fungi from blood or bone marrow ¹⁰10. Ascioglu S, Rex JH, De Pauw B, Bennett JE, Bille J, Crokaert F. et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002;34(1):7-14. doi: 10.1086/323335.
https://doi.org/10.1086/323335... . Additionally, demographic characteristics, such as age (age group) and gender were evaluated; as well as clinical characteristics, such as medical department, type of neoplasia, oncological diagnosis and state of neutropenia defined as count <1000 neutrophils/mm^{3 (11}11. Urabe, A. Clinical features of the neutropenic host: definitions and initial evaluation. Clin Infect Dis. 2004; 39(Supplement_1), S53-S55. doi: 10.1086/383055 .
https://doi.org/10.1086/383055... . Microbiological characteristics were also evaluated, such as etiology (grouped into C. albicans, non-albicans Candida, and other yeasts and filamentous fungi) and the sown sample.

Descriptive statistics were used, the results were summarized in frequencies and percentages, and in line and bar charts to evaluate the variables distribution. This study was performed with data from the registry of the microbiology laboratory and the computer system of the INEN, so it does not represent any risk for patients. The study was evaluated and approved by the INEN Research Committee.

RESULTS

During the five studied years, 36,923 blood cultures were performed, from which 285 (0.8%) turned out to be cases of fungemia, which increased over time. In 2012, 5,814 blood cultures were taken, and 34 cases were found (0.7%). In 2013, 6,400 blood cultures were taken, and 41 cases were found (0.6%). In 2014, 7,438 blood cultures were taken, and 59 cases were found (0.8%). In 2015, 7,861 blood cultures were taken, and 71 cases were found (0.9%). Finally, in 2016, 9,410 blood cultures were taken, and 80 cases (0.9%) were found to be fungemias.

Fungemias were more frequent in the age group from 0 to 19 years old (27.4%) and in the female population (54.4%). From the total, 56.5% patients had neutropenia; 64.6%, hematological neoplasias; 31.9%, diagnosed with acute lymphocytic leukemia; and 10.2% was from the Abdomen Medical Department. The demographic and clinical characteristics of the patients with fungemias distributed by etiology are described in Table 1.

Compared to the fungemias caused by non-albicans Candida, those caused by C. albicans had a higher prevalence rate in patients from the Abdomen Medical Department (17.2% versus 8.0%). When Candida species were analyzed in these patients, it was found that C. albicans alone was more frequent than C. tropicalis (17.2% vs. 5.2%).

Fungemia by C. albicans (54.0%) was more frequent than those caused by non-albicans Candida (31.6%) and other yeasts (14.8%) in patients with solid tumor. On the analysis of hematological neoplasms and Candida species, C. tropicalis was found to be more frequent than C. albicans (77.6% versus 46.0%).

C. albicans was more frequently isolated than non-albicans in patients with non-Hodgkin’s lymphoma (20.3% vs. 9.1%) and genitourinary tumor (18.8% vs. 8.6%). When non-Hodgkin’s lymphoma and Candida species were analyzed, C. albicans alone was more frequent than C. glabrata (20.3% vs. 0.0%). In genitourinary tumors, C. albicans was more frequent than C. tropicalis (18.8% versus 6.7%).

In contrast, there was a lower proportion of C. albicans (10.9%) compared to non-albicans Candida (37.4%) and other yeasts (44.5%) in patients with acute lymphocytic leukemia (ALL). When ALL and Candida species were analyzed, it was found that C. albicans was less frequent than C. tropicalis (10.9% vs. 44.8%) and other Candidas (10.9% vs. 35.3%).

Fungemias by C. albicans had a higher proportion (71.9%) than those caused by non-albicans Candida (34.2%) and other yeasts (40.7%) in patients without neutropenia. When these patients and the Candida species were analyzed, C. albicans was more frequent than C. tropicalis (71.9% vs. 26.1%) and other Candidas (71.9% vs. 29.4%).

Furthermore, when analyzing the type of neoplasia and the degree of neutropenia, it was found that patients with solid tumors without neutropenia were more frequent than those having neutropenia (67.5% vs 10.6%).

Candidemia (251 cases) represented 88.1% of the fungemias, and non-albicans Candida was isolated in 65.6% (187) of the cases. C. tropicalis was isolated in most cases at 47.0% (134 cases). Other yeasts were isolated in 9.5% (27) of the cases and filamentous fungi in 2.5% (7) of the cases (Table 2).

Non-albicans Candida predominated during the five reviewed years, although it had a decrease in frequency, from 73.5% in 2012 to 60.6% in 2015. The frequency of C. albicans increased from 14.7% in 2012 to 31.0% in 2015. Other yeasts and filamentous fungi remained below 14.0% and 4.0%, respectively (Figure 1).

Variations in fungemia frequency and in the degree of neutropenia were found and were related to the time elapsed. Fungicides in patients without neutropenia increased from 23.5% in 2012 to 55.0% in 2016. In addition, we analyzed the variation in the frequency of fungemias and the type of neoplasia and did not find a sustained increase over time.

Fungemia frequencies varied in relation with age, according to the type of neoplasia, oncological diagnosis, degree of neutropenia, and etiology. Fungemias in patients with solid tumors and gastrointestinal cancer increased with age, from 17.9% in the 0-19 years age group to 75.4% in the 60+ years age group, and from 2.5% in the 0-19 years age group to 50.8% in the 60+ years age group, respectively. Similarly, fungemias in patients without neutropenia increased from 34.6% in the 0-19 years age group to 81.5% in the 60+ years age group. Finally, fungemias by C. albicans increased from 16.7% in the 0-19 years age group to 29.2% in the 60 or more years age group (Figure 2).

DISCUSSION

The type of neoplasia and the degree of neutropenia seem to be related to the etiology of fungemias. The predominance of fungemias by C. albicans in patients with solid tumors and the predominance of fungemias by non-albicans Candida, (mainly C. tropicalis in ALL) and other yeasts in hematological neoplasias may be due to the origin of the infection. In solid tumors the origin is mainly endogenous, while in hematological neoplasias the origin would be by non-commensal yeasts ¹²12. Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut?. Clin Infect Dis. 2001; 33(12):1959-1967. doi: 10.1086/323759.
https://doi.org/10.1086/323759... ^,1313. Bassetti M, Peghin M, Carnelutti A, Righi E, Merelli M, Ansaldi F. et al. Clinical characteristics and predictors of mortality in cirrhotic patients with candidemia and intra-abdominal candidiasis: a multicenter study. Intensive Care Med. 2017; 43(4):509-518. doi: 10.1007/s00134-017-4717-0.
https://doi.org/10.1007/s00134-017-4717-... . Likewise, we find a higher frequency of C. albicans in genitourinary and abdominal tumors since C. albicans is common in these anatomical regions and causes postoperative complications in abdominal surgeries ¹⁴14. Bassetti M, Righi E, Ansaldi F, Merelli M, Scarparo C, Antonelli M, et al. A multicenter multinational study of abdominal candidiasis: epidemiology, outcomes and predictors of mortality. Intensive Care Med. 2015; 41(9):1601-1610. doi: 10.1007/s00134-015-3866-2.
https://doi.org/10.1007/s00134-015-3866-... ^,1515. Bergamasco M, Garnica M, Colombo A, Nucci M. Epidemiology of candidemia in patients with hematologic malignancies and solid tumours in Brazil. Mycoses. 2013; 56(3):256-263. doi: 10.1111/myc.12013.
https://doi.org/10.1111/myc.12013... .

On the other hand, the high frequency of fungemia by C. albicans in non-neutropenic patients and by C. tropicalis in neutropenic patients can be explained by the relationship between the type of neoplasia and the degree of neutropenia. Fungemia by C. albicans occurs in solid tumors without neutropenia, while C. tropicalis appears in hematological neoplasias with neutropenia. Some studies show that non-neutropenia is more frequent in patients with solid tumors than in hematological neoplasias ¹⁶16. Gustinetti G, Mikulska M. Bloodstream infections in neutropenic cancer patients: a practical update. Virulence. 2016; 7(3):280-297. doi: 10.1080/21505594.2016.1156821 .
https://doi.org/10.1080/21505594.2016.11... ^,1717. Noskin G. Management of Infectious Complication in Cancer Patients. Boston, MA: Springer; 2007..

The diversity in the type and frequency of fungemias etiology determines the appropriate antifungal therapy. Candidemias were the most frequent fungemias, with predominance of non-albicans Candida, being C. tropicalis the most isolated one. The high frequency of the non-albicans Candida, C. tropicalis, as the cause for fungemias has already been described in some studies of our region ¹⁸18. Colombo A, Nucci M, Park B, Nouér S, Arthington-Skaggs B, da Matta D, et al. Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in eleven medical centers. J Clin Microbiol. 2006; 44(8):2816-2823. doi: 10.1128/JCM.00773-06 .
https://doi.org/10.1128/JCM.00773-06... ^,1919. Tang H, Liu W, Lin H, Lai C. Epidemiology and prognostic factors of candidemia in cancer patients. PLoS One. 2014; 9(6):e99103. doi: 10.1371/journal.pone.0099103 .
https://doi.org/10.1371/journal.pone.009... . The possible association between cancer and fungemias by C. tropicalis may explain its etiological predominance ¹⁹19. Tang H, Liu W, Lin H, Lai C. Epidemiology and prognostic factors of candidemia in cancer patients. PLoS One. 2014; 9(6):e99103. doi: 10.1371/journal.pone.0099103 .
https://doi.org/10.1371/journal.pone.009... .

Possible trends were found, and these appear to be clinically correlated, but further evaluation is needed. The increase in fungemia duration in patients without neutropenia would indicate that neutropenia is less necessary for the development of these invasive mycoses. This increase would not be due to an increase in solid tumors as these remain invariable over time. The continuous increase of fungemia cases according to age in patients with solid tumors (particularly gastrointestinal tumors) may be due to characteristics of these neoplasias. Patients with solid tumors are older than those with hematological neoplasias ²⁰20. Puig-Asensio M, Ruiz-Camps I, Fernández-Ruiz M, Aguado J, Muñoz P, Valerio M, et al. Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain. Clin Microbiol Infect. 2015; 21(5):491-e1. doi: 10.1016/j.cmi.2014.12.027 .
https://doi.org/10.1016/j.cmi.2014.12.02... .

Finally, the continuous increasing number of fungemias by C. albicans in patients without neutropenia, which increases with age, can be explained by the relationship between these two characteristics and solid tumors, something already described in previous paragraphs. Solid tumors are more frequent in older adults and, at the same time, are related to fungemias by C. albicans and not having neutropenia.

Our study had some limitations, such as data retrospectively collected and the small sample for some categories of the variables considered, which prevented an inferential analysis. Also, fungal identification was performed at the phenotypic level, although molecular techniques provide a more reliable identification, they are expensive, complex, and not very applicable to hospital laboratories.

In conclusion, our findings suggest that fungemias are predominantly caused by C. tropicalis, mainly in patients with hematological neoplasias with neutropenia, while fungemias by C. albicans predominate in patients with solid tumors without neutropenia. Besides, as years go by, prevalence of fungemias increase in patients without neutropenia. As age increases, prevalence of fungemias by C. albicans increase in patients with solid tumors without neutropenia.

Future studies are advised to assess the antifungal sensitivity of isolates, the association with risk factors for fungemia occurrence and the outcome of fungemias. This will allow us to understand the current scenario of fungemias in cancer patients and to take appropriate control and treatment measures.

References

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