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Candidemia and invasive candidiasis in children: Clinical manifestations and diagnosis

Candidemia and invasive candidiasis in children: Clinical manifestations and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Sep 21, 2023.

INTRODUCTION — The term candidemia describes the presence of Candida species in the blood. Candida in a blood culture should prompt a search for the source; it should never be viewed as a contaminant. Invasive candidiasis encompasses both candidemia and deep-seated (ie, visceral) candidiasis (which may occur with or without candidemia) [1].

The epidemiology, pathogenesis, clinical manifestations, and diagnosis of candidemia and invasive candidiasis in children will be discussed here. An overview of candidal infections and management of candidemia and invasive candidiasis in children, candidal infections in neonates, and candidal infections in adults are discussed separately:

(See "Candida infections in children".)

(See "Candidemia and invasive candidiasis in children: Management".)

(See "Epidemiology and risk factors for Candida infection in neonates" and "Clinical manifestations and diagnosis of Candida infection in neonates" and "Treatment of Candida infection in neonates".)

(See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis" and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Management of candidemia and invasive candidiasis in adults".)

EPIDEMIOLOGY — Beyond the neonatal period (ie, in children >28 days), Candida spp are important pathogens in critically ill patients and patients with immunocompromising conditions [2-4]. The epidemiology of Candida infections in neonates is discussed separately. (See "Epidemiology and risk factors for Candida infection in neonates".)

The overall incidence of candidemia in population-based studies ranges from 1 to 17.5 cases per 100,000 persons [5-10]. The incidence is increased in children younger than one year and in older adults [9,10]. In population-based surveillance in the United States in 2017, the estimated incidence of candidemia was 7.7 per 100,000 in infants <1 year of age and 0.3 per 100,000 in children age 1 through 18 years [9]. In surveillance from a single tertiary care children's hospital, Candida accounted for 5 percent of episodes of bloodstream infections between 2002 and 2012 [11].

The infecting strain usually is part of the host's colonizing flora [12], although acquisition of Candida auris appears to be exogenous [13,14]. Health care-associated acquisition of Candida species has been described but is rare. In health care-associated cases, contaminated solutions and the hands of health care workers have been implicated [12,15].

The distribution of Candida spp causing invasive candidiasis varies geographically and temporally. Although Candida albicans is isolated most frequently, nonalbicans species are increasingly isolated at some institutions [4-6,16-19]. In children, Candida parapsilosis is the predominant nonalbicans species in most geographic regions [4,5,20,21].

C. auris candidemia remains rare in children but has been reported in children in Venezuela, Colombia, India, South Africa, and South Korea [22-24]. It has been associated with serious infection, multidrug resistance, health care outbreaks, and misidentification [14].

In adults, Candida glabrata is the predominant nonalbicans species in Canada, northern Europe, and the United States, whereas C. parapsilosis is more prominent in Asia, southern Europe, and South America [7]. Increasing use of fluconazole may contribute to the increasing prevalence of nonalbicans species, but other factors may also play a role [20].

RISK FACTORS — Immunosuppressed children, children in intensive care units, children with central venous catheters, and neonates are most at risk for the development of candidemia. Risk factors in neonates are discussed separately. (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Risk factors for invasive candidiasis'.)

Risk factors for invasive candidiasis in children beyond the neonatal period and adolescents include [3,5,25-28]:

Central venous catheter

Immune suppression (eg, hematologic malignancy; solid organ or stem cell transplantation; antineoplastic chemotherapy; neutropenia; long-term glucocorticoids)

Damage to the gastrointestinal mucosa (eg, related to antineoplastic chemotherapy or immune modulators, abdominal surgery, gastrointestinal perforation or anastomotic leak)

Broad-spectrum antibiotics

Parenteral nutrition

Kidney failure requiring hemodialysis

Mechanical ventilation

Genetic susceptibility [29-31]

Injection drug use [32,33]

A multivariate model using several of the above risk factors failed to predict candidemia in a multicenter case control study [34].

PATHOGENESIS — Candida gains access to the bloodstream by three major routes:

Through the gastrointestinal tract mucosal barrier (most common mechanism for candidemia) – Candida species are part of the normal bowel flora; predisposing factors (eg, broad-spectrum antibiotics, immune suppression, gastrointestinal surgery) lead to overgrowth and subsequent leakage into the bloodstream. (See 'Risk factors' above.)

Via an intravascular catheter, particularly a central venous catheter – Candida colonization of the vascular catheter can occur at either the insertion site or the hub, and lead to subsequent candidemia. Candidemia that originated in the gut or skin also can colonize the catheter during bloodstream infection. Colonization of the catheter may lead to the formation of a biofilm, from which fungi are subsequently released, resulting in persistent candidemia while the catheter is in place [7].

From a localized focus of infection (eg, pyelonephritis) – Bloodstream invasion is relatively uncommon from a localized focus of infection but has been well described with ascending Candida urinary tract infection associated with either intrinsic obstruction (eg, from a fungus ball) or extrinsic compression preventing the flow of infected urine. (See "Candida infections of the bladder and kidneys" and "Candida infections in children", section on 'Urinary tract infections'.)

Candida may disseminate from the localized infection, leading to metastatic infections in the lung, liver, spleen, kidneys, bone, or eye (ie, deep-seated infections). Deep-seated infections may remain localized or lead to secondary candidemia [7]. Other focal Candida infections in children are discussed separately. (See "Candida infections in children", section on 'Invasive focal infections'.)

CLINICAL MANIFESTATIONS — The clinical manifestations of candidemia and invasive candidiasis vary from minimal fever to a fulminant sepsis with multiorgan system failure that is indistinguishable from severe bacterial infection. In patients with fulminant sepsis, necropsy reveals widespread visceral microabscesses that are especially prominent in the kidneys (picture 1), heart, liver, spleen, lungs, and brain.

Clinical clues to candidemia include characteristic ocular lesions, skin lesions, and, less commonly, muscle abscesses.

Ocular involvement – Characteristic chorioretinal findings include focal, glistening, white, infiltrative, often mound-like lesions on the retina (picture 2A). A vitreal haze suggests extension to the vitreous (endophthalmitis); sometimes fluffy white balls or "snowballs" in the vitreous are noted (picture 2B). (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Clinical manifestations'.)

After the neonatal period, ocular candidiasis is uncommon; it may be seen in children who are immunocompromised. In a retrospective review, among 254 children with candidemia who had a dilated retinal examination, only eight patients (3.2 percent) had ophthalmologic involvement: four had chorioretinitis only and four had involvement of the vitreous in addition to chorioretinitis [35]. Neonatal chorioretinitis is discussed separately. (See "Clinical manifestations and diagnosis of Candida infection in neonates", section on 'Ocular involvement'.)

Chorioretinitis and endophthalmitis can be caused by pathogens other than Candida. (See 'Differential diagnosis' below.)

Skin lesions – Invasive candidal skin lesions tend to appear suddenly as clusters of painless pustules on an erythematous base; they can occur on any area of the body. The lesions vary from tiny pustules that can be easily missed (picture 3A) to nodular lesions several centimeters in diameter, which appear necrotic in the center (picture 3B). In severely neutropenic patients, the lesions may be macular rather than pustular.

Specimens from skin lesions (eg, scrapings from the base of a pustule, punch biopsy) can be obtained for laboratory identification to distinguish Candida from other causes of pustular skin lesions. (See 'Culture and stain of biopsy material' below and 'Differential diagnosis' below.)

Muscle pain – Soreness in a discrete muscle group is less common than chorioretinitis or skin lesions. Examination reveals a tender muscle that may be warm and swollen. Biopsy shows microabscesses in the muscle, and special stains may show budding yeasts.

Clinical manifestations of deep-seated candidal infections that may or may not be associated with candidemia are described separately. (See "Candida infections in children", section on 'Invasive focal infections'.)

EVALUATION

Clinical suspicion — Although many children with invasive candidiasis have no obvious clinical manifestations, we suspect candidemia or invasive candidiasis in children with risk factors who have [36]:

Unexplained fever or signs of severe sepsis while receiving adequate antibiotics

Skin lesions suggestive of invasive candidiasis (eg, multiple, nontender, erythematous, pustular or nodular lesions (picture 3A-B))

Eye findings suggestive of invasive candidiasis (picture 2A-B)

Multiple focal liver or spleen lesions on imaging for persistent fever [37,38]

Decisions regarding empiric treatment with antifungal therapy in children with suspected candidemia (whether or not they have suggestive examination findings) are discussed separately. (See "Candidemia and invasive candidiasis in children: Management", section on 'Empiric antifungal therapy for at-risk patients'.)

Approach to laboratory diagnosis — The tests available to detect invasive candidiasis have important limitations; accurate diagnosis may require multiple tests [1,7,39].

We suggest the following approach to laboratory diagnosis in children with suspected candidemia:

All patients – Obtain aerobic blood cultures (routine bacterial cultures) of adequate volume based on the patient's weight from peripheral and central catheters whenever feasible. Repeat daily blood cultures are of limited clinical utility if the initial culture or set of cultures are of adequate volume and the patient's clinical condition is unchanged. The sensitivity of detection varies by pathogen and disease [40], as well as blood culture volume. The optimal volume for detection of Candida is not known. Although many institutions have their own guidelines for blood culture volume, general guidelines for adequate volume according to the patient's body weight are as follows [41]:

≤1 kg – 2 mL (only one aerobic culture is obtained)

1.1 to 2 kg – 2 mL for first culture and 2 mL for second culture (each culture is aerobic only)

2.1 to 12.7 kg – 4 mL for first culture and 2 mL for second culture (each culture is aerobic only)

12.8 to 36.3 kg – 10 mL for first culture and 10 mL for second culture (each culture is aerobic only)

>36.3 kg – 20 to 30 mL for first culture set and 20 to 30 mL for second culture set; each culture set may require two or more aerobic culture bottles depending upon the manufacturer

Patients with pustules or other skin lesions (picture 3A-B) – Scrape the base of the pustule with a scalpel and submit obtained material for Gram stain and culture. Obtain a punch biopsy for culture, fungal stains, and histopathologic examination.

Patients with parenchymal involvement (eg, brain, kidney) – Obtain biopsy for culture, fungal stains, and histopathologic examination.

Microbiologic studies

Blood cultures — A blood culture positive for Candida is the reference standard for the diagnosis of candidemia. Culture is the only method that allows susceptibility testing. Candida in a blood culture should prompt immediate treatment and a search for the source (eg, central venous catheter, gastrointestinal tract, deep-seated infection); it should never be viewed as a contaminant. (See "Candidemia and invasive candidiasis in children: Management", section on 'Choice of antifungal therapy'.)

Candida can be detected with blood culture systems commonly used for the detection of bacteria, but the reported sensitivity can be low. In studies performed before the advent of modern blood culture techniques, blood cultures were positive in only approximately 50 percent of patients found to have disseminated candidiasis at autopsy [1]. Similar autopsy-based studies have not been reported since the advent of modern blood culture techniques (eg, lysis-centrifugation [Dupont Isolator tube], changes in culture media used in the BACTEC and BactiAlert systems). However, with newer automated blood culture systems and weight-based recommendations for obtaining appropriate volumes of blood for culture, the rate of detection likely is improved.

It can take several days to establish the diagnosis of candidemia with blood cultures: one to two days for the Candida to grow and another one to two days for speciation [42]. New techniques are helping to shorten the interval to identification:

Peptide nucleic acid (PNA) fluorescence in situ hybridization (FISH) technology is a commercially available system that can identify yeasts as being C. albicans or C. glabrata within two hours of obtaining a positive blood culture [43].

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) identifies protein patterns of many types of organisms accurately and quickly and is increasingly used for the rapid identification of Candida species isolated from blood cultures [44].

Culture and stain of biopsy material — Culture or histopathologic examination of biopsy samples from skin or other sites of involvement may lead to identification of Candida. Gram stain may demonstrate budding yeast (picture 4). Punch biopsies of skin or tissue biopsy will show microabscesses, and special stains for fungi (eg, Gomori methenamine silver, periodic acid-Schiff) will show budding yeasts and sometimes pseudohyphae or hyphae characteristic of Candida.

Isolation of Candida from skin or parenchymal biopsy is a reference standard for the diagnosis of candidiasis. As with blood cultures, the sensitivity of cultures from parenchymal samples is relatively low, reflecting the difficulties in choosing the best site for sampling and the variability in distribution and burden of viable organisms [1].

Nonculture methods — Nonculture methods include beta-D-glucan and other antigen assays and polymerase chain reaction (PCR). Nonculture methods, alone or in combination with blood cultures may increase the identification of invasive candidiasis [1]. However, these methods are not well studied in children and we generally do not use them.

Specific for Candida

Commercial PCR assays – The T2Candida is a US Food and Drug Administration-approved magnetic resonance-based system that is able to detect Candida colony-forming units and identify five Candida species (C. albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. krusei) directly from blood cultures within as few as three to five hours [45-48], but data in children are limited [49-51] and further study of the clinical utility in pediatric patients is necessary. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'T2Candida'.)

The Septifast assay is another commercially available rapid PCR test that can be used on whole blood without preculture to detect and identify Candida species within six hours. However, it is unavailable in the United States and requires further study in children.

Noncommercial PCR assay – Experience with PCR assays for invasive candidiasis in children is limited. PCR assays can identify individual species of Candida. However, a standardized PCR assay for Candida that has been validated in multicenter studies is not yet available.

The reported sensitivity of noncommercial ("in-house") PCR assays for the detection of candidemia is similar to that of blood cultures; however, in occasional cases PCR helped to establish the diagnosis of invasive candidiasis when cultures were negative [39,52-54].

Newer real-time PCR assays appear to be more sensitive than blood cultures and the beta-D-glucan assay in detecting invasive candidiasis in adult patients [39]; combining PCR with blood cultures may further increase the sensitivity.

Antigen and antibody assays – Assays for several Candida cell wall components (eg, mannan), cytoplasmic antigens, and the metabolite arabinitol have been investigated, but most are not sufficiently sensitive for diagnosis invasive candidiasis [51,55-58].

Not specific for Candida

Beta-D-glucan – Experience with beta-D-glucan assays for the diagnosis of candidemia in children is limited.

Beta-D-glucan is present in the cell wall of many fungi, including Candida. An assay that detects beta-D-glucan is commercially available and increasingly used in the diagnosis of fungal infections [59-62]. Although the beta-D-glucan assay is sensitive in detecting invasive fungal infections (75 to 80 percent) [63] and in patients with candidemia (approximately 80 percent) [60], it is not specific for Candida; a positive test requires identification of the infecting organism [7].

Diagnosis — The diagnosis of proven candidemia or invasive candidiasis is confirmed by positive blood culture or isolation of Candida from skin or parenchymal tissue biopsy in an immunocompromised or immunocompetent patient [64].

A diagnosis of probable invasive candidiasis can be made in immunocompromised children with a risk factor (eg, neutropenia, hematopoietic cell or solid organ transplant recipient), an episode of candidemia in the previous two weeks, and [64]:

At least one of the following clinical features:

Small abscesses in the liver, spleen, brain, or meningeal enhancement on magnetic resonance imaging or computed tomography

Progressive retinal exudates or vitreal opacities on ophthalmologic examination

Evidence of Candida infection, either:

Positive T2Candida

Beta-D-glucan ≥80 ng/L detected in at least two consecutive serum samples, provided that other etiologies have been excluded

DIFFERENTIAL DIAGNOSIS — The major considerations in the differential diagnosis of candidemia and invasive candidiasis include bacterial sepsis and localized bacterial infection (eg, endocarditis). Bacterial and candidal sepsis or focal infection cannot be differentiated clinically. Microbiologic evaluation is necessary to establish the diagnosis. (See "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)

Pustular skin lesions, which may be suggestive of candidemia (picture 3A-B), occur in other infectious and noninfectious conditions. The skin lesions of candidemia usually are painless, but painlessness is nonspecific and Gram stain, culture, or histopathologic examination may be necessary to establish a diagnosis. (See "Approach to the patient with pustular skin lesions".)

Endophthalmitis, another finding suggestive of candidemia (picture 2A-B), may be caused by bacteria and other fungi. Cultures, special stains, and other microbiologic studies are necessary to establish the diagnosis. (See "Bacterial endophthalmitis", section on 'Diagnosis' and "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Diagnosis'.)

ADDITIONAL EVALUATION — We individualize decisions about ophthalmologic examination for children with candidemia and/or invasive candidiasis according to clinical features. Although sight-threatening ocular abnormalities, including chorioretinitis and endophthalmitis, may occur in as many as 8 percent of children with candidemia [19,35,65], professional societies disagree about the value of routine ophthalmologic examination to screen for intraocular infection in patients with candidemia [66,67].

Immune-compromised or critically ill children with confirmed candidemia – We obtain formal ophthalmologic examination, even in those without ocular symptoms [35,66,68].

In children who are immune compromised due to neutropenia, the examination should optimally be performed within one week of neutrophil recovery because findings may be minimal during the period of neutropenia [66].

Immune-competent children with confirmed candidemia – These children do not require ophthalmologic examination if they have only one positive blood culture for Candida and respond rapidly to antifungal therapy. (See "Candidemia and invasive candidiasis in children: Management".)

Children with invasive candidiasis without documented candidemia – We individualize decisions about ophthalmologic examination according to the child's clinical course, immune status, and associated symptoms. Examination is usually warranted if the child is immune compromised, has associated systemic symptoms, or responds poorly to antifungal therapy.

Neonates – The evaluation of neonates with candidemia is discussed separately. (See "Clinical manifestations and diagnosis of Candida infection in neonates".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)

SUMMARY

Terminology – The term candidemia describes the presence of Candida species in the blood. Candida in a blood culture should prompt a search for the source; it should never be viewed as a contaminant. Invasive candidiasis encompasses both candidemia and deep-seated (ie, visceral) candidiasis (which may occur with or without candidemia). (See 'Introduction' above.)

EpidemiologyBeyond the neonatal period (ie, in children >28 days), Candida spp are important pathogens in critically ill patients and patients with immunocompromising conditions. The incidence of invasive candidiasis is increased in children younger than one year compared with older children. (See 'Epidemiology' above.)

The infecting strain is usually part of the host's colonizing flora. The distribution of Candida species causing invasive candidiasis varies geographically. Candida albicans is most common, but nonalbicans species are increasingly isolated. In children, Candida parapsilosis is the predominant nonalbicans species in most geographic regions. (See 'Epidemiology' above.)

Risk factors – Risk factors for invasive candidiasis include immune suppression, damage to the gastrointestinal mucosa, antineoplastic chemotherapy, central venous catheter, receipt of broad-spectrum antibiotics, parenteral nutrition, kidney failure requiring hemodialysis, and mechanical ventilation. (See 'Risk factors' above.)

Clinical manifestations and clinical suspicion – Although many children with invasive candidiasis have no obvious clinical manifestations, we suspect invasive candidiasis in children with risk factors who have (see 'Clinical manifestations' above and 'Clinical suspicion' above):

Unexplained fever or signs of severe sepsis while receiving adequate antibiotics

Skin lesions suggestive of invasive candidiasis (eg, multiple, nontender, erythematous, pustular or nodular lesions (picture 3A-B))

Eye findings suggestive of invasive candidiasis (picture 2A-B)

Multiple focal liver or spleen lesions on imaging for persistent fever

Approach to diagnosis – The tests available to detect invasive candidiasis have important limitations; accurate diagnosis may require multiple tests. We obtain blood cultures of adequate volume from all patients with suspected invasive candidiasis, and other specimens for culture or biopsy as indicated (eg, scrapings from the base of pustules for Gram stain and culture, biopsy of skin or other focal lesions for culture, fungal stains, and histopathologic examination). (See 'Approach to laboratory diagnosis' above.)

The diagnosis of candidemia or invasive candidiasis is confirmed by positive blood culture or isolation of Candida from skin or parenchymal biopsy. The sensitivity of these methods can be low. (See 'Diagnosis' above and 'Microbiologic studies' above.)

Candida in a blood culture should prompt immediate treatment and a search for the source (eg, central venous catheter, gastrointestinal tract, deep-seated infection). (See 'Blood cultures' above and "Candidemia and invasive candidiasis in children: Management", section on 'Choice of antifungal therapy'.)

Infants and children with candidemia who are immune compromised or critically ill generally should undergo a formal ophthalmologic examination for chorioretinitis, whether or not they have ocular symptoms. (See 'Additional evaluation' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Carol A Kauffman, MD, who contributed to an earlier version of this topic review.

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Topic 5976 Version 25.0

References

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