Invasive Candidiasis: Risk Assessment for Predictor of Infection

Abstract

Candidiasis is an infection caused by the Candida species. Invasive candidiasis is a severe and invasive form of infection, with manifestations that can be found in the blood (candidemia) or other organs (disseminated candidiasis). Early antifungal therapy is important for the management of invasive candidiasis and may reduce mortality. To date, the diagnosis of invasive candidiasis has been difficult and the criteria for empiric antifungal therapy have not been clearly defined. Risk assessment was developed as a clinical predictor to identify patients at risk of invasive candidiasis, provide appropriate and timely antifungal therapy, and avoid wasteful use of antifungal drugs. Risk assessments can be established based on the epidemiology of each health service or currently published risk assessments.

1. Introduction

The location of infection is a common feature of fungal infections. These are classified as superficial, subcutaneous, and systemic which is also known as deep-seated. Several causes have been suggested for the sudden emergence of yeast species as causative agents of invasive infections. One of them is Candida species which is yeast fungi and normal flora. Candida species live in the mouth, throat, intestines, and vagina. However, colonization of Candida species can cause invasive candidiasis in at-risk patients. This infection can get into the blood and internal organs and also has the capability of spreading widely throughout the body. Candida infection in the blood is called candidemia, while in internal organs it is called disseminated candidiasis. Infected internal organs include the brain, heart, eyes, bones, or other parts of the body [1, 2].

Numerous impediments in the diagnosis of invasive candidiasis may delay the beginning of treatment. An atypical, dubious, and nonspecific early presenting symptoms driving the suspicion of a fungal infection, reduces the chance of making the proper clinical diagnosis [3]. The gold standard for the diagnosis of invasive candidiasis is cultured, but positive findings may be observed in cases of late infection. The drawbacks of culture are that it takes longer to receive examination results and cannot identify organ infections. Alternatively, it needs histopathology from normally sterile sites or organs, although necessitates invasive procedures and is often challenging. Since diagnosis of invasive candidiasis has many confinements, an approach to diagnosing invasive candidiasis can involve assessments that measure the risk of bacterial infections [3, 4]. In this chapter, we will discuss the definition, epidemiology, risk factors, pathogenesis, classification, diagnosis, management, and risk assessment of invasive candidiasis.

2. Invasive candidiasis

2.1 Definition

A fungal infection called candidiasis is brought on by this species. Candida species are 4−6 μm unicellular yeasts. Despite having thin cell walls, their structures include glycoproteins, β-glucan, chitin, and plasma membrane [5, 6]. The 1940s saw a rise in cases of candidiasis, which was correlated with the mass use of antibiotics, an increase in HIV infections, the use of therapeutic modalities for advanced life support, and specific surgical procedures like organ transplantation and prosthetic device implantation [7].

Almost all organs can become infected by Candida species. There are two different kinds of candidiasis invasive and superficial candidiasis. Superficial candidiasis refers to mild infections of the skin, nails, and mucous membranes, which the symptoms are paronychia and onychomycosis. Examples of skin symptoms of superficial candidiasis are perianal candidiasis and intertriginous candidiasis. Among the mucosal surfaces where superficial candidiasis might present include oral, perlece, candidiasis vaginitis and vulvovaginitis, candidiasis balanitis, and balanoptysis. A condition known as disseminated candidiasis occurs when Candida species enters the bloodstream and travels to several organs, resulting in symptoms including candidemia. Disseminated candidiasis can harm the heart, brain, eyes, bones, and other organs [1, 2].

2.2 Epidemiology

Seventy to ninety percent of fungal infections are caused by Candida species [4]. Candida albicans can be found in a variety of settings, including hospitals, food, animals, and inanimate items. Non-albicans species may live in environments with or without animals. In laboratories, contamination by Candida species occurs relatively seldom. In the past, substantial mistakes in patient care have resulted from a lack of comprehension of this idea. For example, positive cultures have been mistaken for skin or laboratory contamination. Typically found on the skin, in expectorated sputum, in the female vaginal canal, and in the urine of patients with indwelling Foley catheters, Candida species are human commensals. Healthcare workers are significantly more likely to be skin carriers [7].

It is nevertheless feasible for human-to-human transmission to happen even if the bulk of Candida infections are endogenous in origin. Examples are perinatal thrush, which can be contracted from a mother’s vagina, and male circumcision infections from a spouse’s Candida vaginitis-related balanitis. Not to mention, there’s growing evidence that a hospital environment can be the source of a Candida infection. Molecular biology techniques significantly advance our knowledge of Candida epidemiology [7].

Of all the pathogens, Candida species is the most common, accounting for 17 percent of infections [3]. There has been a shift in the epidemiology of Candida species throughout the last two decades. Two-thirds of infections were formerly caused by C. albicans, which was the primary pathogen [4]. The sixth to tenth most common pathogen in Europe is a type of Candida [3]. Over the last few decades, non-albicans species have proliferated and are now responsible for up to 50% of infections; these species include Candida glabrata, Candida krusei, Candida tropicalis, and Candida parapsilosis [4].

Many variables, including individual risk factors, the prevalence of molecularly different Candida species specific to certain healthcare contexts, and local antifungal usage, frequently control the preponderance of non-albicans Candida species in most locations. C. glabrata is the second species that is most often seen in non-epidemic areas in the US and northwest Europe. Additionally, recipients of solid organ transplants and those over 60 are more likely to be members of this species. In comparison to C. glabrata, C. parapsilosis and/or C. tropicalis are significantly more prevalent in Southern Europe, India, and Pakistan. Out of all the five primary species of Candida, C. krusei is the least common. Data released in the previous 5 years indicate that C. albicans remains the most frequent species in South America. Notwithstanding country-specific variations, C. parapsilosis is the most prevalent non-albicans species [8].

A third of cases of candidemia were found in the intensive care unit (ICU) by Marchetti et al. [9]. ICUs had 5–10 times higher rates of candidiasis cases (2–6.7 per 1000 hospitalized patients) than standard wards. Five to 15% of patients have Candida species colonization when they are admitted to the intensive care unit (ICU). This percentage rises to 50–80% during treatment. Five to thirty percent of patients have invasive candidiasis five to 12 days after admission. Patients in the intensive care unit who stay longer than 7 days frequently develop multifocal colonization. The most common loci were the gastric (45.6%), oropharyngeal (34.3%), trachea (23.4%), perirectal area (21.2%), and urinary tract (18.7%). The relative risk of invasive candidiasis was significantly higher in patients with positive test findings for stool specimens (7.5% vs. 3.2%, p = 0.019) or urine (9.2% vs. 5.2%, p = 0.032) [4, 10].

While Candida species is the third and fourth most often isolated pathogen from blood cultures in the United States, accounting for 8–10% of bloodstream infections, it only causes 2–3% of bloodstream infections in Europe [3]. A previous research, Extended Prevalence of Infection in Intensive Care (EPIC) II (2011), found that 6.87 cases of candidemia occurred for every 1000 ICU patients [5]. The European ICU project (EUCANDICU, 2019) conducted a multinational, multicenter, retrospective examination in 23 ICUs across nine European nations as part of its first phase of research on intra-abdominal candidiasis and candidemia. The frequency of invasive candidiasis in ICUs in Europe was 7.07 episodes per 1000 ICU admissions, resulting in a crude 30-day mortality rate of 42% [11]. Invasive candidiasis has a mortality rate that ranges from 40 to 60% and can even reach 100% [3].

2.3 Risk factors

In the skin and mucosa, oropharynx, vagina, and large intestine, Candida species are found in their natural form. Neonates may colonize throughout the birthing process. Numerous risk factors for the development of invasive candidiasis are listed in Table 1. Pathogenic exposure to Candida species might occur during hospitalization or an ICU stay. Earlier colonization may have caused Candida organisms to translocate across the mucosa. Risk factors with a possible mechanism through immunosuppression may result from prematurity and elderly (extreme age), malnutrition, neutropenia, HIV or AIDS, malignancy or other comorbidities, the use of corticosteroids, and chemotherapy. Meanwhile, the use of vascular catheters or ventilators, contaminated total parenteral nutrition, and major surgery or extensive burns can facilitate fungal colonization and direct vascular access [6].

Possible cause of infection	Risk factor
Pathogenic exposure	Hospitalization or ICU
Translocation through the mucosa	Previous colonization
Immunosuppression	Premature and elderly
	Malnutrition
	Neutropenia (<500 cells/μL)
	Dialysis
	Malignancy
	HIV, AIDS
	Corticosteroids
	Chemotherapy
Facilitates fungal colonization Intravascular access	Broad spectrum antimicrobial
	Use of vascular catheter (CVC)
	Use of ventilators
	Use of TPN
	Major surgery or extensive burns
Genetics	Mutation in dectin-1, CARD 9, CD82, TLR1, or TLR2
	SNP at CD58, LCE4A-C1orf68, or TAGAP
	Vav protein

Table 1.

Risk factors.

AIDS: Acquired Immunodeficiency Syndrome, CVC: central venous catheters, HIV: Human Immunodeficiency Virus, ICU: Intensive Care Unit, SNP: single nucleotide polymorphism, TLR: toll-like receptor, TPN: total parenteral nutrition.

Novel insights into immunity and the development of next-generation human antifungal therapies as components of tailored therapy have led to the introduction of a new chapter on risk factors. Mutations, single nucleotide polymorphisms (SNPs), and specific proteins like the Vav protein can all have an impact on invasive candidiasis [8].

2.4 Pathogenesis

Among the virulence factors that cause candidiasis include the capacity to switch (move from the yeast phase to the hyphal phase in infected organs), biofilm development, adherence by adhesins, and synthesis of extracellular hydrolytic enzymes including phospholipase and aspartyl protease [5, 7]. Although the yeast form is present on the surface of the epithelium and is necessary for the spread of systemic infections, the invasive form, hyphae, is necessary to infiltrate the epithelium and enter phagocytic cells [12, 13]. Extracellular hydrolytic enzymes play a critical role in overgrowth by facilitating tissue adhesion and allowing for host infiltration through penetration [13].

Mucous membranes and undamaged skin serve as the host’s primary defensive mechanism against Candida species [7]. The immune response in the mucosa and epithelium enables the host to discriminate between invasive hyphal forms and yeast colonization [14]. Mitogen-activated protein kinase (MAPK) is triggered by hyphal growth, or it may be identified by looking for pathogen-associated molecular patterns (PAMP) of Candida species, such as β-glucan. After this realization, there is an inflammatory reaction. T-helper (Th17) differentiation requires macrophage IL-1 production, which is stimulated by hypopha development [13].

Candida species invasion might potentially exploit the host in cases of skin maceration or mucosal damage [7, 15]. In the process of colonizing, Candida species will accept host nutrients and attach to epithelium. Candida species use hydrolytic enzymes and hypha formation to cause surface infections and break down proteins in their hosts. In the event of immunological escape, Candida species have the ability to penetrate the tissue and adhere to the vascular endothelium [2, 15].

When endothelial adhesions form, the infection may penetrate organs and activate the coagulation system. Candida species are identified by leukocytes and can activate the complement system once they enter the bloodstream. Complement receptor 3 (CR3) and Fc gamma receptor (FcγR) are neutrophil receptors that recognize Candida species and establish signaling cascades that activate effector mechanisms like phagocytosis. Monocytes, as well as macrophages and dendritic cells found in numerous organs, play the role of mononuclear phagocytes. The cell identifies Candida species mostly through dectin-1 and induces IL-6 and tumor necrosis factor-α (TNF-α) release. Candida species are recognized by natural killer (NK) cells via pathogen recognition receptors (PRR), specifically NKp30. Perforin, which is secreted by NK cells, directly kills candida. Following that, NK cells produce granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFN-γ), both of which influence other immune cells [14].

2.5 Classification

The European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) introduced the revised definition of fungal disease. The definitions assigned 3 levels of probability to the diagnosis of invasive fungal infection, namely “proven,” “probable,” and “possible” invasive fungal infection. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only [16].

The suggested definition of proven invasive candidiasis needed conclusive confirmation of the pathogen in a typically sterile location. It should include at least one of the following aspects [16]:

1. Histopathologic, cytopathologic, or direct microscopic examination of material obtained by needle aspiration or biopsy from a normally sterile site that shows budding cells consistent with Candida species (presence of pseudo-hyphae and/or true hyphae is highly suggestive of Candida species, but these structures are not present in all Candida species and may be seen in other organisms, such as Trichosporon species, Geotrichum species, and Magnusiomyces capitatus [previously known as Geotrichum capitatum], as a result, validation using culture or PCR is required).

2. Candida species recovery by culture of a material acquired through a sterile technique (including a recently implanted [24 hours] drain) from a typically sterile location with a clinical or radiologic abnormality associated with an infectious disease process.

3. Candida species have been found in blood cultures.

The presence of at least one clinical criteria was used to define probable invasive candidiasis in the ICU (compatible ocular findings by fundoscopic examination, hepatosplenic lesions by computed tomography [CT], clinical or radiological (non-pulmonary) abnormalities consistent with an infectious disease process that are otherwise unexplained) plus at least 1 mycological criterion (positive serum 1,3-β-d-glucan in 2 consecutive samples, recovery of Candida in an intra-abdominal specimen obtained surgically or within 24 hours from external drainage), plus at least 1 of the following host factors [16].

The presence of at least one clinical criterion (fundoscopic evaluation of compatible ocular findings, computed tomography [CT] of hepatosplenic lesions, clinical or radiological (non-pulmonary) abnormalities associated with an infectious illness process but are otherwise inexplicable), at least one mycological criterion (positive serum 1,3-β-d-glucan levels in two consecutive tests; Candida recovery in an intra-abdominal specimen acquired surgically or within 24 hours of external drainage), and at least one of the following host variables was used to define probable invasive candidiasis in the ICU [16]:

1. Prednisone equivalent of 20 mg or higher per day glucocorticoid therapy

2. Neutrophil abnormalities, qualitative or quantitative (inherited neutrophil deficit, absolute neutrophil count 500 cells/μL)

3. Impairment of gut wall integrity (for example, recent abdominal surgery, chemotherapy, biliary tree abnormalities, repeated intestinal perforations, ascites, mucositis, acute pancreatitis, parenteral feeding)

4. Impaired cutaneous barriers to bloodstream infection (for example, the existence of a central vascular access device or hemodialysis)

5. Candida colonization is defined as the recovery of Candida species in cultures collected from two or more of the following sources: respiratory tract secretions, feces, skin, wound sites, urine, and drains left in place for 24 hours or longer

6. Hematopoietic stem cell transplantation (HSCT)

7. Solid-organ transplant (SOT)

2.6 Diagnosis

Clinical signs and symptoms, radiographic findings, culture, and histological abnormalities are all used to diagnose fungal infections. Clinical manifestation of invasive candidiasis is generally not specific and does not differ from another infection origin. It has a slow clinical course with vague signs and symptoms. Accurate diagnosis has lagged behind that caused by conventional pathogens such as bacteria and viruses. Proven invasive candidiasis usually requires confirmation with gold-standard methods [7, 17].

Although the culture-based method is the gold standard, it has limitations such as being insensitive and taking longer to acquire test findings [3, 17]. This approach has several drawbacks and may delay the initiation of proper treatment. Culture-based diagnostic approaches can only detect 50% of cases, and positive findings are possible in situations of late infection. The relevance of increased Candida recovery from places such as sputum, urine, feces, and skin is difficult to evaluate because the organisms can frequently be retrieved from these sites without producing infection [7].

Besides low sensitivity, taking specimens from sterile sites may be harmful to patients, therefore histological diagnosis is often challenging [3]. Commercial reagents for identifying and distinguishing Candida species thus develop for non-cultural diagnosis of invasive candidiasis. However, they are still not widely accessible at this time [18]. Despite the development of a considerable number of papers on the serologic diagnosis of disseminated candidiasis over at least three decades, disagreements over the use of various serodiagnostic methods persist [7]. Also, polymerase chain reaction (PCR) has lower reliability in the diagnosis of invasive candidiasis.

There is no single, fast, validated serodiagnostic test that is routinely used to diagnose invasive candidiasis at the moment. The β-glucan measurement is yielding a wealth of information. Because of false positives with this test, its greatest benefit may be in its substantial negative predictive value. Serial judgments may be useful in predicting therapeutic outcomes and serving as indicators of treatment effectiveness [7]. Radiological examination is also not specific for detecting certain infections. Halos or macronodules may not always be found, for example in patients with immunosuppression [3].

2.7 Treatment

The timing of antifungal medication in invasive candidiasis is critical to treatment effectiveness. The European Society of Clinical Microbiology and Infectious Disease (ESCMID) recommends four strategies for the management of invasive candidiasis, namely prophylactic, pre-emptive, empiric, and targeted therapy [4].

The goal of prophylactic antifungal therapy is to prevent the occurrence of invasive candidiasis in high-risk patients. For prophylactic therapy, most use fluconazole. Prophylactic use is rarely recommended for ICU patients. Pre-emptive therapy is antifungal therapy given from the start to patients with colonization and risk of candidiasis [19]. Pre-emptive therapy is given if there is microbiological evidence of invasive candidiasis, but clinical signs of fungal infection are absent or fit into the probable and possible categories, taking into account risk factors of invasive candidiasis in patients [4].

According to ESCMID recommendations, empiric therapy is given when persistent fever is present and there is a risk of fungal infection, but there is no microbiological evidence of invasive candidiasis, or only an increase is found during a risk assessment. Treatment was administered for a minimum of 14 additional days after the first negative culture result. De-escalation or switching to oral therapy is carried out after 10 days, taking into account the clinical picture [4].

Management can be adjusted to the therapeutic target if the culture results and sensitivity of Candida species are known. Patients are treated for a minimum of 14 days after the first negative culture result. De-escalation or switching to oral therapy can be done after 10 days, taking into account the clinical picture. Antifungals are given with therapy as recommended and within the antifungal spectrum [4].

3. Invasive candidiasis risk assessment

Invasive candidiasis risk assessment combines several risk factors into a scoring system to predict invasive candidiasis. This assessment has a good negative predictive value (NPV). It is useful for determining the risk of invasive candidiasis, and distinguishing patients with or without invasive candidiasis, which can address the possibility of antifungal overuse or underuse, increased healthcare costs, and the development of antifungal resistance [6].

3.1 Colonization index

The colonization index is the ratio of the number of colonizations in body areas other than blood, compared to the total number of cultures (Table 2). In the calculation, only the same Candida species strain is considered when calculating invasive candidiasis [19]. This risk assessment was made based on research by Pitett et al. [16]. Colonization was defined as finding Candida species in ≥3 specimens taken from ≥1 area on 2 consecutive screenings continuously [9]. Surveillance is carried out twice a week with specimens of oropharyngeal secretions, tracheal secretions, gastric fluid, perineum, feces, urine, surgical wounds, abdominal drains, and catheter insertion areas [20]. Data from 29 patients who met the inclusion criteria and were at high risk of candidiasis, there were 11 patients (38%) developed severe infections, 8 of them showed candidemia, while the other 18 patients showed colonization [19, 20]. All patients who developed candidiasis had colonization on average 6 days before candidiasis [17].

Index	Formulas
Colonization index, CI	$CI=\frac{\text{Number of colonization areas}}{\text{Number of culture areas}}$
	Colonization	0.47
	Invasive candidiasis	0.7
Corrected colonization index, CCI	$CCI=\frac{\text{Number of colonization areas}}{\text{Number of culture areas}}\text{X}\frac{\text{Number of areas with colony growth}}{\text{Total positive areas}}$
	Colonization	<0.35
	Invasive candidiasis	≥0.4

Table 2.

Description of colonization index.

Source: [20].

Risk factors that differentiate colonization from infection are the duration of previous antimicrobial therapy, disease severity according to the APACHE II, and Candida species. Based on logistic regression analysis, disease severity according to the APACHE II and Candida species colonization were independent factors for predicting invasive candidiasis. Colonization of Candida species precedes infection, with the same Candida species strain even though it is isolated from different areas of the body, and this pattern persists for up to 140 days [20, 21]. The colonization index of patients without infection and patients with infection, respectively, is 0.47 and 0.7, with a positive predictive value (PPV) of 66–100% [4, 20, 21].

The colonization index is corrected (Corrected Colonization Index, CCI), the ratio of the number of colonizations compared to the number of culture areas, multiplied by the ratio of the number of areas with fungal growth compared to positive areas, as seen in Table 2. CCI values ​​<0.35 were found in colonization, and ≥0.4 in candidiasis. Sensitivity, specificity, NPV, and PPV are 100%. In multiple logistic regression analysis, independently only the APACHE II score and CCI score could predict the development of invasive candidiasis [20].

3.2 Paphitou rule

Paphitou rule includes criteria for hemodialysis, TPN use, diabetes mellitus, and use of broad-spectrum antimicrobials for ICU patients as shown in Table 3. The criteria were obtained based on a retrospective study by Paphitou et al. [22] of 327 patients who were treated in the surgical ICU for ≥4 days and had a risk of invasive candidiasis 11.0%. Patient data was collected from a week before entering the ICU until the third day of treatment in the ICU. Patients with combination diabetes mellitus, new-onset hemodialysis, TPN use, or broad-spectrum antimicrobial use had an invasive candidiasis rate of 16.6% versus 5.1% for patients who did not have these characteristics. Of the 52% of patients treated ≥4 days in the ICU, 78% of patients showed invasive candidiasis [22].

Variable
Hemodialysis
Use of TPN
Diabetes mellitus
Use of broad-spectrum antimicrobials

Table 3.

Paphitou rule.

TPN: total parenteral nutrition.

Source: [22].

3.3 Candida score

Candida score is an inclusive risk assessment of four risk factors for invasive candidiasis, as in Table 4. These criteria are research-based Leon et al. [10] prospectively involved 1107 adult ICU patients treated between April 2006 and June 2007 in 36 ICUs in Spain, France, and Argentina. This study confirmed that the Candida score is a risk assessment to differentiate patients with severe sepsis or septic shock who would benefit from early antifungals (Candida score > 3). Empirical antifungals are given if Candida score > 3, whereas if Candida score ≤3, no invasive candidiasis, and no antifungals [10].

Variable	Mark
Use of TPN	1
Operation	1
Multifocal Candida species	1
Severe sepsis	2

Table 4.

Candida score.

TPN: total parenteral nutrition.

Source: [10].

The research of Leroy et al. [23] is a continuation of the research of Leon et al. [24], with subjects of 1669 adult ICU patients treated in 73 Spanish ICUs from May 1998 to January 1999. Four proven risk factors for invasive candidiasis were identified, namely total parenteral nutrition, surgery, multifocal Candida species colonization, and severe sepsis [23].

The four risk factors that constitute these variables are coded 1 if present, 0 if absent, and the Candida score is calculated according to the formula [23]:

Candida score = 0.908× (total parenteral nutrition) + 0.997 × (surgery) + 1.112 × (multifocal Candida species colonization) + 2.038 × (severe sepsis).

Based on receiver operating characteristics (ROC) and area under the ROC curve, a score of >2.5 can identify patients at risk of proven invasive candidiasis, with a sensitivity of 81%, specificity of 74%, NPV of 98%, and PPV of 16%, as seen in Table 5.

Variable	Value-based on
	Leon et al. [24]	Leroy et al. [23]
Use of TPN	0.908	1
Operation	0.997	1
Multifocal Candida species	1112	1
Severe sepsis	2038	2
Candida score for invasive candidiasis	>2.5	>3

Table 5.

Candida score is based on research by Leon et al. [24] and Leroy et al. [23].

TPN: total parenteral nutrition.

Source: [23, 24].

Li et al. [25] validated the revised Candida score model’s clinical usefulness and comparative effectiveness, utilizing the Sepsis 3.0 criteria, in assessing critically sick patients over the conventional sepsis/severe sepsis model. The foundation for predicting the presence of invasive candidiasis should be Sepsis 3.0, given the clinical significance of organ failure in ICI.

3.4 Ostrosky-Zeichner rule

Ostrosky-Zeichner rule is a risk assessment based on a retrospective study by Ostrosky-Zeichner et al. [26] which was carried out on 2890 patients hospitalized ≥4 days at 9 hospitals in the United States and Brazil [25]. Initially, the major criteria for the Ostrosky-Zeichner rule were the use of systemic antimicrobials (days 1–3), and the use of a central venous catheter (days 1–3). Minor criteria are TPN use (days 1–3), any dialysis (days 1–3), any major surgery (days −7–0), pancreatitis (days −7–0), steroid use (days −7–3), or use of other immunosuppressives (days −7–0). These criteria can identify patients at high risk of invasive candidiasis. Invasive candidiasis among patients of the study subjects was 9.9%, with a relative risk of 4.36, sensitivity of 34%, specificity of 90%, PPV of 10%, and NPV of 97% (Table 6) [22, 27].

Major criteria	Minor criteria
Systemic antimicrobial use (days 1 - 3); CVC use (days 1 - 3)	TPN use (days 1 - 3); Each dialysis (days 1-3); Any major surgery (days −7 - 0); Pancreatitis (day −7 - 0); Steroid use (days −7 – 3); Use of other immunosuppressives (days −7–0)
Modification
Use a ventilator for at least 48 hours
Criteria	Sensitivity	Specificity	PPV	NPV
3 majors + >1 minor
Without modification to major criteria	34	90	10	97
With modifications to the major criteria	50	83	10	97

Table 6.

Ostrosky-Zeichner rule.

CVC: central venous catheter, TPN: total parenteral nutrition.

Source: [22].

3.5 Nebraska medical center rules

Nebraska Medical Center rules is a risk assessment based on research by Hermsen et al. [28]. The criteria included in the Nebraska Medical Center rule risk assessment include those shown in Table 7. Hermsen et al. [28] conducted a retrospective matched case-control study from May 2003 to June 2008 to evaluate the sensitivity, specificity, PPV, and NPV of each criterion. These criteria include adults being treated in the ICU for ≥4 days, and invasive candidiasis matched with three controls based on age, gender, and date of ICU admission. If a score ≥2.45 is found, it is likely invasive candidiasis, with a sensitivity of 84.1%, specificity of 60.2%, PPV of 4.7%, and NPV of 99.4% [28].

Variable	Score
Broad spectrum antimicrobial	1.5
Use of CVC	0.9
TPN use (days 1–3)	0.9
Use of steroids 7 days before entering the ICU until day 3	0.4
Abdominal surgery	0.9
Length of stay before being in the ICU x 0.039
Nebraska Medical Center rules for invasive candidiasis	≥2.45

Table 7.

Nebraska Medical Center rules.

CVC: central venous catheter, TPN: total parenteral nutrition, ICU: Intensive Care Unit.

Source: [28].

3.6 Candidemia rule

The Candidemia rule is a risk assessment for candidemia in hospitalized patients with severe sepsis and septic shock, based on research conducted by Guillamet et al. [29]. The use of TPN, previous antimicrobial exposure, referral from an outside hospital or admission from a nursing home, mechanical ventilation, and the presence of a central venous catheter are independent predictors of candidemia, while the lung as a source of infection is protective, as seen in Table 8. Candidemia rule value <3 indicates no invasive candidiasis, while ≥3 indicates the presence of invasive candidiasis. These clinical prediction criteria for candidemia in hospitalized patients with severe sepsis and septic shock are better than previous risk assessments [29].

Variable	Score
Antimicrobials in the previous 30 days	2
CVC use >48 hours before positive blood culture	2
Use of TPN	2
Referral from nursing home	2
Referral from another hospital	1
Use of ventilators	1
Lungs as a source of severe sepsis or septic shock	−6
Candidemia rule for invasive candidiasis	≥3

Table 8.

Candidemia rule.

CVC: central venous catheter, TPN: total parenteral nutrition.

Source: [29].

The study involved 2066 hospitalized patients with severe sepsis or septic shock who had positive blood cultures for Candida species. Severe sepsis and septic shock were proven by positive blood culture. Septic shock is characterized by the need for vasopressors (norepinephrine, vasopressin, dopamine, epinephrine, or phenylephrine). Candidemia is characterized by ≥1 positive blood culture result for Candida species, while bacteremia is when a positive blood culture is found for pathogenic bacteria. A central venous catheter is considered a risk factor if it was inserted a minimum of 48 hours before a positive blood culture. Immunosuppressive conditions included in the analysis included hematologic or solid organ malignancies, bone marrow transplantation, acquired immunodeficiency, long-term or high-dose corticosteroid administration, and chemotherapy and/or radiation therapy. This study also included criteria for a history of hospitalization in the previous 90 days, administration of antimicrobials, and bloodstream infections in the previous 30 days in the analysis. Antimicrobials that are suitable for treatment are preparations that have in vitro activity against the isolated organism and are administered at the correct dose during the first 24 hours after a positive blood culture result [29].

4. Conclusion

Invasive candidiasis, which includes both candidemia and deep-seated tissue candidiasis, is the most prevalent fungal illness among hospitalized patients. Early identification of invasive candidiasis is crucial in severely sick patients in particular. In individuals with invasive candidiasis at high risk, there is evidence of a correlation between delayed antifungal medication and higher mortality. For the purpose of starting preventative antifungal medication, many bedside technologies have been created for early invasive candidiasis detection. In addition to test diagnosis for invasive candidiasis, a risk assessment can be performed. Systemic candidiasis frequently occurs in the absence of candidemia, hence these two conditions must be combined. To foresee invasive candidiasis, it is suggested that a new risk prediction score be created using the logit model equation, which includes risk variables that take into account our own demography.