Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults

INTRODUCTION — The term candidemia describes the presence of Candida species in the blood. Candida in a blood culture should never be viewed as a contaminant and should always prompt a search for the source. In all cases, candidemia requires treatment with an antifungal agent; it should never be assumed that removal of a catheter alone is adequate therapy for candidemia. (See "Management of candidemia and invasive candidiasis in adults".)

Clinical issues related to the clinical manifestations and diagnosis of candidemia will be reviewed here. The epidemiology, pathogenesis, and treatment of candidemia are discussed separately. Candida endocarditis; hepatosplenic candidiasis (chronic disseminated candidiasis); Candida endophthalmitis; Candida infections of the central nervous system, bladder, and kidneys; empiric treatment of presumed invasive candidiasis; and an overview of Candida infections are also presented elsewhere. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis" and "Management of candidemia and invasive candidiasis in adults" and "Candida endocarditis and suppurative thrombophlebitis" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)" and "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species" and "Candida infections of the central nervous system" and "Candida infections of the bladder and kidneys" and "Overview of Candida infections".)

Candidemia in neonates and children is discussed in detail separately. (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" and "Prevention of Candida infection in neonates" and "Candidemia and invasive candidiasis in children: Clinical manifestations and diagnosis" and "Candida infections in children" and "Candidemia and invasive candidiasis in children: Management".)

CLASSIFICATION — Candidemia may be only the most obvious manifestation of invasive infection with Candida species. Some experts have proposed dividing invasive Candida infections into three subgroups: candidemia without deep-seated or visceral involvement, candidemia with deep-seated or visceral Candida infection, and deep-seated (visceral) candidiasis without candidemia [1]. In at least one study, each entity was responsible for approximately one-third of cases [2]. The diagnosis of invasive candidiasis is made most easily in those patients with positive blood cultures, but the low sensitivity of blood cultures means that some patients with deep-seated infection may be missed. More rapid techniques for identifying yeasts in blood cultures and refinement of non–culture-based techniques are active areas of investigation. (See 'Diagnosis' below.)

EPIDEMIOLOGY — Candidiasis is an increasingly important nosocomial infection. Although Candida albicans is the most common cause of candidemia, there has been increased isolation of non-albicans species of Candida in recent years. Patients in the intensive care unit and those who are immunocompromised are most at risk for the development of candidemia.

The epidemiology of and risk factors for candidemia are discussed in detail separately. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)

CLINICAL MANIFESTATIONS — The clinical manifestations of candidemia vary from minimal fever to a full-blown sepsis syndrome that resembles severe bacterial infection. Invasive candidiasis is defined by hematogenous spread to multiple viscera (eg, eye, kidney, heart valves, brain).

Clinical clues on physical examination that point to possible hematogenous spread of Candida include characteristic eye lesions (chorioretinitis with or without vitritis), skin lesions, and, much less commonly, muscle abscesses.

The frequency of eye lesions in patients with candidemia is variable. Early studies found that more than 20 percent of cases of candidemia had associated eye lesions; subsequent estimates are closer to 2 percent, with few cases of vitritis [3]. This discrepancy may be attributable to timing of examination; in the setting of early involvement, only chorioretinitis may be present. These issues are discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Epidemiology and risk factors'.)

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 1) to others that are nodular, several centimeters in diameter, and appear necrotic in the center (picture 2). In severely neutropenic patients, the lesions may be macular rather than pustular. In patients with negative blood cultures, the recognition of these lesions as a manifestation of candidemia and subsequent punch biopsy may lead to the diagnosis. (See 'Diagnosis' below.)

Less commonly, patients describe soreness in a discrete muscle group caused by Candida microabscesses. Examination reveals a tender muscle that may be warm and swollen (picture 3).

In addition to these typical peripheral sites of involvement, signs of multiorgan system failure may be present due to involvement of the kidneys, heart, liver, spleen, lungs, eyes, and brain (picture 4).

Other manifestations of invasive candidiasis and approach to empiric treatment are discussed in detail separately. (See "Overview of Candida infections" and "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis" and "Candida infections of the central nervous system" and "Candida osteoarticular infections" and "Candida endocarditis and suppurative thrombophlebitis" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)" and "Management of candidemia and invasive candidiasis in adults".)

DIAGNOSIS — The gold standard for the diagnosis of invasive candidiasis and candidemia is a positive culture. Blood cultures should be obtained in all patients with suspected candidemia. Not infrequently, patients will have blood cultures drawn without a specific concern for Candida infection, and then diagnosis is made when the cultures yield Candida species. In patients with focal findings (eg, skin lesions or parenchymal involvement), biopsy should be performed for staining, culture, and histopathologic evaluation. Non-culture-based methods are used increasingly to aid in the diagnosis of invasive Candida infections for which blood cultures often are negative. (See 'Nonculture methods' below.)

Culture and stain of biopsy material — Directed biopsy of sites of involvement often leads to a definitive diagnosis. Material obtained by scraping the base of a pustule should be submitted to the microbiology laboratory for Gram stain (picture 5) and culture. More commonly, a punch biopsy is performed and the tissue is submitted for culture and for histopathologic examination using special stains for fungi.

Punch biopsies of skin or tissue biopsy will show microabscesses, and special stains will show budding yeasts and often pseudohyphae or hyphae that are characteristic of Candida species.

Blood cultures — The most straightforward method to detect candidemia is to grow the organism from the blood; however, in one study, blood cultures were positive in only approximately 50 percent of patients found to have disseminated candidiasis at autopsy [1].

There have been many studies comparing the sensitivity of different blood culture systems for the detection of yeasts [4,5]. The introduction of the lysis-centrifugation method (Isolator tube) improved the detection of yeasts when compared with other blood culture systems. Subsequent changes in the culture media used in the BACTEC and BactiAlert systems, allowing enhanced growth of yeasts, have made these systems as sensitive as the lysis-centrifugation technique for detecting Candida species in blood.

A drawback of all blood culture systems for the diagnosis of candidemia is that one to three days are required for growth and an additional one to two days for identification of the organism after subculture onto agar medium. For a seriously ill patient, more rapid and more sensitive techniques are essential.

Several techniques have been developed that decrease the time to identification of the most common Candida species once a blood culture bottle shows growth and yeasts are seen on the smear of the bottle contents. Using the technique of peptide nucleic acid fluorescence in situ hybridization (PNA-FISH), C. albicans and Candida glabrata can be identified within hours of a blood culture becoming positive for yeast [6,7].

Another technique is matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Using this technique, proteins released from Candida spp are detected and compared with a large database of proteins from many species of yeast [8]. MALDI-TOF MS is performed on colonies that have grown from a blood culture bottle, and results can be read in as short a period as 30 minutes.

The emerging species Candida auris requires specialized methods for identification, and it could therefore be misidentified as another yeast (most commonly Candida haemulonii but also Candida famata, Candida sake, Candida catenulata, unspecified Candida species, Rhodotorula glutinis, Saccharomyces cerevisiae) when using traditional biochemical methods [9]. A MALDI-TOF MS assay is available for the identification of C. auris [10]. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis", section on 'C. auris emergence'.)

A study that compared the performance of blood cultures with the polymerase chain reaction (PCR) and the beta-D-glucan assay is discussed below. (See 'Polymerase chain reaction' below.)

Nonculture methods — Over the last several decades, substantial efforts have been directed at the development of non-culture-based method for the diagnosis of candidemia [11].

Beta-D-glucan assay — The beta-D-glucan assay has proven useful for diagnosis of invasive candidiasis [12]. However, beta-D-glucan is present in the cell wall of many fungi and is not specific for Candida [13-17]. Additionally, false positive beta-D-glucan tests have been noted following intravenous therapy with immunoglobulins and albumin, in the presence of gauze packing materials used in surgery, and with disruption of gut integrity that can occur with chemotherapy-induced mucositis, in the presence of septic shock, and with intestinal ischemia [18]. Therefore, the beta-D-glucan assay should not be used as a definitive test for diagnosis of invasive candidiasis; its interpretation should be guided by clinical and microbiologic data. In the appropriate clinical circumstances, the assay can be useful for detection of deep-seated invasive candidiasis (eg, intra-abdominal candidiasis) when blood cultures are negative [19].

Consistent with a high sensitivity but low specificity, a negative beta-D-glucan test has high negative predictable value and has been shown to be sufficient to guide discontinuation of empiric antifungal therapy in the intensive care unit setting [18,20,21]. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Choosing a regimen'.)

In one systematic review including 10 studies, the sensitivity and specificity of beta-D-glucan were 81 and 60 percent, respectively [17]. In an earlier study including 107 patients who had proven candidiasis, between 78 and 81 percent had positive beta-D-glucan assay results (depending on the chosen cutoff for a positive result) [14]. A subsequent Japanese autopsy series that included 41 patients with invasive fungal infection who had a beta-D-glucan assay performed noted positive and negative predictive values of 70 and 98 percent, respectively (using a cut-off of 60 picograms/mL) [15].

Use of blood cultures together with a beta-D-glucan assay or polymerase chain reaction has been associated with higher diagnostic sensitivity than blood cultures alone [22]. This is discussed further below. (See 'Polymerase chain reaction' below.)

T2Candida — In 2014, the US Food and Drug Administration (FDA) cleared the T2Candida panel and T2Dx instrument (T2Candida) for the detection of bloodstream infection caused by C. albicans, Candida tropicalis, Candida parapsilosis, and C. glabrata/Candida krusei. The T2Candida assay can detect as few as 1 to 3 colony-forming units/mL from a blood specimen within three to five hours, far more quickly than blood cultures. The assay breaks yeast cells apart, releasing deoxyribonucleic acid (DNA); copies the target DNA; and detects the amplified DNA using magnetic resonance technology. This technology enhances the early detection of candidemia [23].

In a study that included 1801 patients, T2Candida had an overall sensitivity of 91 percent and correctly categorized nearly 100 percent of negative specimens as negative for the presence of yeast [24].

In a multicenter study of 152 patients with candidemia detected by blood cultures, follow-up blood samples were collected for T2Candida testing and repeat blood cultures [25]. Median time between collection of diagnostic blood cultures and follow-up specimens was 56 hours (range 16 to 148 hours). The T2Candida assay was positive in 69 of 152 patients (45 percent), whereas follow-up blood cultures were positive in 36 of 152 patients (24 percent). T2Candida sensitivity was 89 percent as positive results were obtained in 32 of 36 patients with positive cultures. The presence of an antifungal reduced the sensitivity of the T2 assay but to a lesser amount than that seen for blood cultures; in 112 patients who were already receiving antifungal therapy, the T2Candida assay was positive in 56 (50 percent) but blood cultures were positive in only 24 (21 percent).

Polymerase chain reaction — One current focus of non-culture methods is on the development of a PCR assay for candidemia and invasive candidiasis [26]. For the detection of candidemia, the sensitivity of PCR has been previously reported to be similar to that of blood cultures [27-29] and, in occasional cases of invasive candidiasis, PCR has assisted in establishing the diagnosis when cultures were negative [27]. The main drawback is that no PCR assay has been standardized and none are routinely available.

A study compared the performance of a real-time PCR assay, the beta-D-glucan assay, and blood cultures for diagnosing invasive candidiasis in 55 patients with invasive candidiasis (17 with candidemia, 33 with deep-seated candidiasis, and 5 with both) and 73 hospitalized controls [22]. The PCR assay was more sensitive than the beta-D-glucan assay for diagnosing invasive candidiasis (80 versus 56 percent) but had comparable specificity (70 versus 73 percent). The PCR assay and the beta-D-glucan assay had similar sensitivity for candidemia, but PCR was more sensitive for deep-seated candidiasis (89 versus 53 percent). Both PCR and the beta-D-glucan assay were more sensitive than blood cultures among patients who had invasive candidiasis. In patients with invasive candidiasis, the sensitivity of blood cultures combined with PCR or the beta-D-glucan assay was 98 and 79 percent, respectively. Thus, these two non–culture-based assays, when combined with blood cultures, have the potential to increase the sensitivity of culture methods for invasive candidiasis.

Antibody assays — To date, no sensitive and specific Candida antibody assay has been developed that is useful for diagnosis. Because Candida are part of the normal microbiota, healthy persons have antibodies against these organisms, thereby decreasing the specificity of the assay. Additionally, an immunosuppressed host may be unable to generate a vigorous antibody response to Candida infection, thereby decreasing the sensitivity of the assay in this high-risk population.

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 AND RECOMMENDATIONS

●Significance of positive blood culture – Candida in a blood culture should never be viewed as a contaminant and should always prompt a search for the source. (See 'Introduction' above.)

●Definition and symptoms of candidemia – Candidemia is defined as the presence of Candida spp in the bloodstream. The clinical manifestations of candidemia vary from minimal fever to a full-blown sepsis syndrome that is indistinguishable from severe bacterial infection.

●Definition and symptoms of invasive candidiasis – Invasive candidiasis is defined as hematogenous spread to multiple viscera (eg, eye, kidney, heart valves, brain). A positive blood culture for Candida spp is not necessary to make the diagnosis of invasive candidiasis. (See 'Clinical manifestations' above.)

Clinical clues on physical examination to hematogenous spread of Candida include characteristic eye lesions (chorioretinitis with or without vitritis), skin lesions, and, much less commonly, muscle abscesses. (See 'Clinical manifestations' above.)

●Diagnosis – The gold standard for the diagnosis of candidemia is a blood culture growing Candida spp; blood cultures should be obtained in all patients with suspected candidemia. However, blood cultures can be negative in patients with invasive candidiasis, and the diagnosis in such cases is often based on clinical suspicion. (See 'Blood cultures' above.)

•Role of biopsy – In patients with focal findings (eg, skin lesions or parenchymal involvement), biopsy should be performed for staining, culture, and histopathologic evaluation. (See 'Diagnosis' above and 'Culture and stain of biopsy material' above.)

•Role of beta-D-glucan – When available, we suggest obtaining a beta-D-glucan assay as an adjunct to blood cultures and biopsy. It appears to be particularly useful in patients with deep-seated candidiasis (eg, intra-abdominal candidiasis), given the low sensitivity of blood cultures in this setting. However, beta-D-glucan is present in the cell wall of many fungi, and there are other non-fungal causes of false-positive beta-D-glucan tests; therefore, this assay is not specific for Candida spp. (See 'Diagnosis' above and 'Beta-D-glucan assay' above.)