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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 7
| Issue : 1 | Page : 24-31 |
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Risk Factors for development of invasive candidiasis in critically ill patients: A prospective observational study in intensive care unit of a tertiary hospital
Rudyanto Sedono1, Asri C Adisasmita2, Ratna Djuwita2, Amal Chalik Sjaaf3, Mardiati Nadjib3, Syahrizal Syarif2, Bachti Alisjahbana4, Anis Karuniawati5, Retno Wahyuningsih6
1 Department of Epidemiology, Faculty of Public Health, Universitas Indonesia, Jakarta; Department of Anesthesiology and Intensive Care, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo, Jakarta, Indonesia
2 Department of Epidemiology, Faculty of Public Health, Universitas Indonesia, Jakarta, Indonesia
3 Department of Health Policy and Administration, Faculty of Public Health, Universitas Indonesia, Jakarta, Indonesia
4 Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
5 Department of Microbiology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo, Jakarta, Indonesia
6 Department of Parasitology, Faculty of Medicine, Universitas Kristen Indonesia, Jakarta, Indonesia
| Date of Submission | 21-Nov-2022 |
| Date of Decision | 05-Jan-2023 |
| Date of Acceptance | 11-Jan-2023 |
| Date of Web Publication | 6-Mar-2023 |
Correspondence Address:
Rudyanto Sedono
Department of Anesthesiology and Intensive Care, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo, Jakarta
Indonesia
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/bjoa.bjoa_255_22
Background: Majority of invasive candidiasis in critically ill patients was developed after admission to intensive care unit. The aim of this study was to identify risk factors for development of invasive candidiasis among patients admitted to intensive care unit, especially considering the timing of laboratory, microscopic, and culture examinations. Materials and Methods: This was a prospective observational study in which critically ill patients were assessed on the first, fifth, and ninth day since admission to intensive care unit. Potential risk factors were demographic and clinical characteristic, clinical managements profile proportions, laboratory profile (leukocyte, platelet, erythrocyte sedimentation rate, C-reactive protein and procalcitonin), morphological change (from yeast to hypae or pseudohyphae in microscopic examination) and colonization increase (from serial culture examination). Results: A total of 115 subjects enrolled in this study. Multivariate analysis identified older age (HR 2.8, 95% CI 0.8–8.9), parenteral nutrition (HR 3.1, 95% CI 0.77–12.3), central venous catheter (HR 1.7, 95% CI 0.43–6.67), corticosteroid (HR 2.8, 95% CI 0.53–14.8), procalcitonin day-5 (HR 3.1, 95% CI 0.89–10.8), morphology change in the axilla and rectal swab (HR 5.1, 95% CI 1.6–18.51), and morphology change and colonization increase in rectal swab day-9 (HR 4.3, 95% CI 1.0–18.02) as independent risk factors of invasive candidiasis. Conclusion: In addition to several typical risk factors, procalcitonin test on day-5 as well as serial microscopic and culture examinations were associated with the development of invasive candidiasis, therefore potentially help in the diagnosis and treatment of critically ill patients in intensive care unit. Keywords: Critical illness, invasive candidiasis, procalcitonin, risk factors
How to cite this article:
Sedono R, Adisasmita AC, Djuwita R, Sjaaf AC, Nadjib M, Syarif S, Alisjahbana B, Karuniawati A, Wahyuningsih R. Risk Factors for development of invasive candidiasis in critically ill patients: A prospective observational study in intensive care unit of a tertiary hospital. Bali J Anaesthesiol 2023;7:24-31 |
How to cite this URL:
Sedono R, Adisasmita AC, Djuwita R, Sjaaf AC, Nadjib M, Syarif S, Alisjahbana B, Karuniawati A, Wahyuningsih R. Risk Factors for development of invasive candidiasis in critically ill patients: A prospective observational study in intensive care unit of a tertiary hospital. Bali J Anaesthesiol [serial online] 2023 [cited 2023 Mar 26];7:24-31. Available from: https://www.bjoaonline.com/text.asp?2023/7/1/24/371182 |
| Introduction | |  |
Invasive candidiasis is an important problem for critically ill patients admitted to intensive care unit (ICU) because it increases length of stay and mortality.[1] Majority of invasive candidiasis was developed in ICU; only approximately one tenth was discovered before admission to ICU.[2] The most common cause of invasive fungal disease is Candida, followed by Aspergillus and other fungi such as Mucor.[3],[4] Candida is a commensal organism in human body, and if accompanied by host or environmental factor, it can turn into pathogenic form. Candida infection begin with increase in colonization, changes in shape and production of enzymes that destroy host mucosa so that Candida can enter body tissues or blood vessels.[5],[6]
Diagnosis of invasive candidiasis still a challenging practice, especially in developing countries where only a handful of laboratories can provide fungal examinations.[7] Moreover, fungal culture examination requires several days of inoculation, hereby potentially delaying antifungal treatment. Most clinicians start anti-fungal treatment depending on the clinical condition of the patient and the presence of risk factors. Previous studies already identified several risk factors for developing invasive candidiasis,[8] however, only few consider laboratory or microscopic tests as independent factor. The objective of this study was to identify risk factors of invasive candidiasis in critically ill patient in ICU, especially when considering the timing of laboratory, microscopic, and culture examinations.
| Materials & Methods | | |
This study was a prospective observational cohort study which conducted in intensive care unit of a tertiary teaching hospital in Indonesia from September 2021 until January 2022. This study had been approved by Ethics Committee of Dr. Cipto Mangunkusumo Hospital with regards to the protection of human rights and welfare in medical research, under the ICH-GCP standard procedures (ethical approval number KET-678/UN2.F1/ETIK/PPM.00.02/2021) and The Research and Community Engagement Ethical Committee Faculty of Public Health Universitas Indonesia (ethical approval number KET-325/UN2.F10.D11/PPM.00.02/2021). All subjects or their family provided a written consent prior to the study.
Inclusion criteria were ICU patients aged 18-70 years old who were predicted to stay more than two days, sequential organ failure assessment (SOFA) scores more than two. Exclusion criteria were post-cardiac surgery, pregnancy, immunocompromise, malignancy, and patients who declared themselves out of the study. Patients with Candida positive culture results on the first day of examination were dropped out of the study. Subjects were observed until death or discharge from ICU. On the first, fifth, and ninth day of admission to ICU, samples were taken from blood, skin swabs, and rectal swabs for laboratory examination, direct microscopic examination, and fungal culture.
A dedicated parasitologist was responsible to carry out fungal microscopic and culture examination without being informed of patient identity. For microscopic examination, axillary skin and rectum swabs were fixated with 10% KOH solution. Candida was identified under light microscope with 100 and 400 times of magnification. Under microscope, the presence of Candida spp. was further classified into yeast, pseudohypae, or hypae. For culture examination, blood, axillary and rectal samples were inoculated in Sabouraud dextrose agar plate. The plates were sealed and incubated at room temperature, and then were evaluated 24-72 hours later. The presence of Candida colonization was also counted by semiquantitative means. Blood samples were also sent to laboratory examination including platelet count, neutrophil count, leukocyte count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin (PCT).
Independent variables were the use of broad-spectrum antibiotics for more than 13 days, nutrition parenteral for more than 7 days, catheter venous central for more than 10 days, major surgery, digestive surgery, mechanical ventilation for more than 72 hours, hemodialysis, corticosteroid, sepsis, SOFA score more than 5, PCT <1 ng/mL, CRP <75 mg/L, neutrophil <1,000 cells/mm3, leucocyte <10.000 cells/mm3, ESR >15 mm, body temperature <36°C or >38°C. Increased colonization was defined as increased Candida species colonization samples obtained from rectal and/or axilla from day-1 to 5 or from day-5 to 9. Change of morphology was defined as presence of change from yeast to hyphae or pseudo hyphae from day-1 to 5 or from day-5 to 9. Subjects were followed until death or discharged from ICU. Diagnosis of invasive candidiasis in this study was referred to either proven or probable criteria of 2021 EORTC/MSGERC during admission in ICU.[5]
To create predictive model, variables from univariate were selected based on the value of OR >1 and p-value <0.05. Univariates analysis was used for determining mean, median, modus, and proportion. Bivariate analysis was used Kaplan-Meier and log-rank for independent variable related time. This variable was included in the global test and a p-value of 0.9979 was obtained, which means that the variable was fulfill the proportional hazard assumption. The backward method was used for selecting risk factors. Multivariate analyses used Cox regression. Statistical analysis was performed using STATA v15.0 (StataCorp. 2017. Stata: Release 15. Statistical Software. College Station, TX: StataCorp LLC).
| Results | | |
A total of 115 subjects were enrolled, 68 male and 47 female, aged 18–70 years old. During ICU stay, 19 subjects (16.5%) developed invasive fungal infection: 4 subjects were proven and 15 subjects were probable invasive candidiasis. We divided potential risk factors into four groups: demographic and clinical characteristic, clinical managements profile proportions, laboratory profile proportions, and Candida morphological change and colonization increase [Table 1][Table 2][Table 3][Table 4]. From bivariate analysis, subjects with older age, female, used broad-spectrum antibiotic, parenteral nutrition, CVC, corticosteroid, sepsis, SOFA score, PCT day-5, CRP day-1, CRP day-5, leukocyte day-1, leukocyte day-5, leukocyte day-9, body temperature day-5, and body temperature day-9 prior to admission were associated with invasive candidiasis. Those factors were included in the multivariate analysis. | Table 1: Demographic and clinical characteristic proportions and the crude hazard ratios (95% CI) for invasive candidiasis
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 | Table 2: Clinical managements profile proportions and the crude hazard ratios (95%CI) for invasive candidiasis
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 | Table 3: Laboratory tests profile proportions and the crude hazard ratios (95%CI) for invasive candidiasis
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 | Table 4: Candida morphological changes and colonization increase (from axilla and/or rectal swabs) and the crude hazard ratios for invasive candidiasis
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Cox proportional hazard assumption was used for relationship between the survival time of patients and one or more predictor variable. After backward method, risk factors for multivariate analysis were tested with global test and the results on all variables resulted in P = 0.9979, meaning that all variables were confirmed to proportional hazard assumption [Table 5]. | Table 5: Cox proportional hazard multivariate analysis for invasive candidiasis
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Multivariate analysis confirmed that age more than 60 years old, parenteral nutrition, central venous catheter, corticosteroid, PCT day-5, Candida morphology change in axillary and rectal swab, and combined morphology change and colonization increase in rectal swab day-9 were associated with invasive candidiasis [Table 6].
| Discussion | | |
Invasive fungal infections were associated with considerable mortality, morbidity, and healthcare cost. Critically ill patients are particularly vulnerable, with 62.5% of invasive candidiasis was developed during ICU admission.[1] For surgical patients, 89.2% of those cases were diagnosed in ICU setting.[9] Prompt identification of invasive fungal infection is essential so that antifungal treatment can be administered rapidly. However, early diagnosis is not always easy. Positive blood cultures are found in only 50–70% of all cases of candidemia, and the results require several days of inoculation, potentially delays definitive treatment.[10] Furthermore, more sophisticated assay such as β-D-glucan (BDG) was not readily available in developing countries.[7] This study was aimed to identify more responsive, traditional, and widely available risk factors of invasive candidiasis such as laboratory marker or serial microscopic and culture examination.
Prolonged ICU duration was associated with invasive candidiasis. However, critical care patients in Asia had relatively shorter stays of ICU admission to develop invasive fungal infection.[11] Al-Dorzi conducted a prospective cohort study in two tertiary centers and reported that invasive candidiasis was developed on a median of five days after ICU admission (25th and 75th percentiles = 1 and 8 days, respectively).[1] On the basis of those findings, we conducted serial testing of laboratory, microscopic, and culture on day-1, day-5, and day-9, which was around time considered as development and pathogenesis of Candida in host tissue.
This study identified older age, parenteral nutrition, central venous catheter, and corticosteroid as independent risk factors of developing invasive candidiasis. It was in concordance with other studies: those risk factors along with broad spectrum antibiotics, blood transfusion, candida colonization, mechanical ventilation, bacteremia, HIV, sepsis, renal replacement therapy, shock, abdominal surgery, hematological disease, neutropenia, transplantation, immunosuppresion, malignancies, diabetes mellitus, urinary catheter, and liver or pulmonary diseases had been known as risk factors for invasive fungal disease.[12],[13],[14],[15],[16],[17]
Parenteral nutrition is well-known risk factor for invasive candidiasis. Candida could multiply in a variety of parenteral nutrition, even in some where bacteria could not grow. Parenteral nutrition is composed of lipid and amino acids and can promote biofilm formation and germination of Candida species. Due to its hypertonicity, administration of parenteral nutrition is preferred using a central venous catheter. Moreover, prolonged implanted medical devices such as central venous catheter provide a potential source of candidemia.[18],[19],[20] The use of a central venous catheter has the potential entry of Candida spp. into the bloodstream. In addition, Candida albicans can form biofilms on host-associated abiotic surfaces, allowing colonization.[21],[22] Corticosteroid was also one of established risk factors of invasive candidiasis, due to suppression of host cellular immune response, thus predisposing fungal infection.[23]
One of important findings of this study was association between PCT < 1 ng/mL on day-5 with development of invasive candidiasis. To date, there were only a handful of studies investigating diagnostic role of PCT in invasive candidiasis. Dou, et al. conducted a systematic review and meta-analysis including 8 studies with a total of 474 episodes of suspected fungal infection with 155 (32.7%) probable or proven invasive candidiasis. They concluded that PCT offered good diagnostic accuracy for discrimination between invasive candidiasis and bacterial infection or noninfectious conditions.[24]
There were several studies investigating PCT as diagnostic tool to predict Candida infection. However, they were inconclusive because of limited sample sizes and inconsistent cut-off values. Several studies showed the correlation between a low PCT level (< 2 ng/mL) and Candidiasis and high negative predictive values of PCT for Candida isolation. Nevertheless, its role in antifungal treatment in clinical practice is not established yet.[25]
Other important and novel findings of this study were the importance of serial morphology and culture examinations in the development of invasive candidiasis. Morphological change in the axilla and rectal swab (any change from two consecutive examinations), as well as change of morphology and increase of colonization in rectal swab (from day-5 to day-9 of admission) were associated with development of invasive candidiasis.
The fungus grows in two main different forms: yeast or filaments. Yeasts are single oval-shaped budding cells, whereas filaments consist of elongated cells attached end-to-end. There are two types of filamentous morphologies: pseudohyphae and hyphae. Pseudohyphae have elliptical shape, with constrictions at cell junctions and usually more branches. In contrast, hyphae possess parallel-sided cell walls, true septae without many constrictions, and generally have less branches.[26] The yeast form of Candida spp. is not necessary for virulence, but this form is known to play essential roles in several important processes including colonization, rapid dissemination, cell-surface adhesion, and biofilm formation. On the other hand, hyphal cells are more involved in invasive infections.[27]
A balanced host microflora helps to control Candida colonization and possibly prevents the formation of hyphae. An unbalanced microflora along with malfunctioning immune system are unable to control Candida population size therefore the host becomes susceptible to candidiasis. With addition of nutrient availability, pH, and temperature, this microflora can be stimulated into hypha formation. The pathogenesis can lead into a more serious conditions where the fungi disseminate into different internal organs, which is invasive candidiasis.[28]
Majority of studies have suggested a strong correlation between the ability of Candida to undergo a reversible yeast-filament transition and virulence. Studies on clinical isolates have shown a clear correlation between the invasion of reconstituted oral mucosal surfaces with increased number of hyphal filaments. Moreover, Candida albicans strains locked in either the yeast or filamentous form were highly attenuated for virulence in a mouse model of systemic candidiasis. In contrast, allowing a yeast-locked strain to transition to filaments at various time points during systemic infection could promote fungal virulence. The ability to switch between various morphologies aids in adaptation and persistence in different niches inside a host.[27]
Candida colonization had been considered an important risk factor of invasive candidiasis.[29] In addition, multiple-site colonization with Candida spp. is commonly recognized as a major predictor for invasive fungal infection in critically ill patients and the colonization density could be a predictive value for the diagnosis of systemic candidiasis.[30],[31],[32] However, to our knowledge, currently there were no published study investigating the relationship between serial microscopic examinations or semiquantitative culture examinations and development of invasive candidiasis in critically ill patients. Direct microscopic examination under KOH fixation was a simple, cheap, and reliable method to find the presence of Candida spp. in swab specimen. This method could play a central role in diagnosis and treatment of invasive candidiasis in the future, especially in developing countries where more sophisticated diagnostic tools were not readily available.
There were several study limitations. Firstly, this study was conducted at one center in a relatively short time space. Larger sample size could be achieved with more centers involved. Secondly, the timing of serial testing could be expanded for more than nine days.
| Conclusion | | |
In conclusion, older age, parenteral nutrition, central venous catheter, corticosteroid administration, PCT < 1 ng/mL on day-5, morphology change of Candida in axilla and rectal swab, as well as morphology and colonization increase of Candida in rectal swab on day-9 were associated with invasive candidiasis. Future study should be aimed at understanding the mechanism by which these risk factors affect the occurrence of invasive candidiasis, and whether a scoring system could be made for prediction and prevention of invasive candidiasis in those patients.
Financial support and sponsorship
Not applicable.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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