Approach
Systemic candidiasis can be difficult to diagnose, particularly when initial blood cultures are negative. Blood cultures are the simplest means for diagnosis and remain the gold standard, yet they lack sensitivity. Physicians usually become aware of systemic candidiasis as a result of positive blood cultures. Empiric therapy is appropriate when other causes of fever have been excluded in patients at high risk of fungal infection who are not responding to antibacterial agents despite negative blood cultures.[32] Infectious diseases consultation is recommended in such cases.
Clinical evaluation
The presence of clinical risk factors and evidence of colonization with Candida are factors that should be considered when suspecting systemic candidiasis. Clinical features may include persistent fever despite several days of empiric antibiotics, or evidence of candidal endophthalmitis on fundoscopy (cream-colored lesions in the posterior vitreous), or the patient may already be critically ill with sepsis.
Physical findings of sepsis caused by systemic candidiasis are identical to bacterial sepsis. There are no unique clinical findings to distinguish between bacterial and fungal septic shock. Early signs and symptoms of sepsis or systemic inflammatory response syndrome (SIRS) are often overlooked or are attributed to underlying nonseptic conditions (e.g., cancer or organ trauma), and a high index of suspicion is required for early recognition.[37]
Symptoms may be nonspecific and include fever, chills, and constitutional upset (e.g., fatigue, confusion, anxiety). SIRS is characterized by the presence of 2 or more of the following:
Temperature >100.4°F (38°C) or <96.8°F (36°C)
Heart rate >90 bpm
Respiratory rate >20 breaths/minute
WBC count >12,000/microliter or <4000/microliter
A high index of suspicion for sepsis should be considered in a patient who presents with the following:
Temperature >101°F (38.3°C) or <97°F (36.1°C)
Tachycardia >90 bpm; tachypnea >20 breaths/minute; hypotensive
Altered mental status
Chills and/or rigors
Septic shock due to Candida is typically diagnosed when sepsis has progressed, producing alterations in consciousness, hypotension, and organ failure with high mortality.[38] Delayed diagnosis is associated with increased morbidity and may occur if the primary infection site is not found, no pathogen is identified, or comorbid conditions (e.g., cancer, dementia, or HIV) modify or mask clinical signs.
Initial evaluation should include assessment of the airway and consciousness level (Glasgow Coma Scale). On exam, the patient may be febrile (>101°F [38.3°C]) or hypothermic (<97°F [36.1°C]).[37]
In neutropenic patients, hematogenous dissemination may result in a rash that can be maculopapular to nodular, and often erythematous. Hemorrhagic rash with small-vessel vasculitis can also be seen. Involvement of different organs can also be identified by testing or imaging in acute disseminated candidiasis. Chronic disseminated candidiasis is a separate disseminated entity usually involving the liver and spleen in patients recovering from neutropenia (often prolonged). Clinical features usually include fever, abdominal pain, abnormal liver function tests (LFTs) - specifically elevated alkaline phosphatase - and variable hepatosplenomegaly with typical target abscesses known as “bull’s eye” lesions on imaging.
A thorough physical exam is recommended, including a focused exam of potentially affected organ systems. Potential sites of focal Candida infections with invasive or disseminated candidiasis include:[3][39][40]
Intra-abdominal infection: including abscesses or peritonitis
Endovascular infection: including endocarditis and cardiac device infections
Osteoarticular infection: including vertebral osteomyelitis with or without discitis
Ocular infection: including endophthalmitis, choroiditis, retinitis
Central nervous system (CNS) infection: although rare, Candida is the most common cause of fungal CNS infection which can be seen in patients with CNS devices and with immunocompromise
Isolated kidney infection: may occur in the setting of urinary catheterization or urologic procedures
Candida pneumonia is very rare and occurs mainly in immunocompromised patients from hematogenous spread.
The American Academy of Ophthalmology (AAO) no longer recommends a dilated funduscopic exam to exclude occult ocular involvement in all non-neutropenic patients with documented candidemia unless they are symptomatic.[41] However, the Infectious Diseases Society of America guidelines alongside several other infectious disease experts still recommend a fundoscopic exam in patients with candidemia, because rates of eye involvement may be higher than those reported by the AAO, and this could have implications on treatment.[32][42][43]
Initial tests
Blood cultures are the most common method of establishing the diagnosis, although sensitivity ranges from 20% to 80% in patients with systemic candidiasis, and they may take several days to become positive (most Candida species will grow within 96 hours with some species growing faster than others).[44] Volume of blood, frequency of sampling, and antifungal administration may influence the sensitivity of the blood cultures. Large volumes of blood and repeated cultures are recommended. With advancements in automated blood culture systems, Candida is typically recovered on routine blood cultures. The role of fungal blood cultures in the diagnosis of candidiasis is unclear and fungal blood cultures seem to be largely unnecessary for most patients. These may be used to supplement routine blood cultures especially if other fungal infection is included in the differential.[45]
Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) as well as peptide nucleic acid fluorescent in situ hybridization (PNAFISH) are now more readily available methods that can improve time to identification of the Candida species. MALDI-TOF is approved to identify different Candida species including Candida auris.[46] Cultures from patient samples are ionized and matched to a reference organism database for identification.
FilmArray Blood Culture Identification Panel (BCID) is a Food and Drug Administration (FDA) approved polymerase chain reaction (PCR) multiplex that identifies 24 different pathogens including 5 species of Candida (Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis and Candida parapsilosis) and can also facilitate rapid identification of Candida species on positive blood cultures.[47]
Other baseline laboratory tests recommended in the setting of sepsis are an arterial blood gas, complete blood count (with differential), electrolytes, liver function tests, coagulation studies (international normalized ratio, partial thromboplastin time), serum glucose, creatinine, and BUN.[37]
Imaging
Imaging tests should be performed based on clinical scenarios (e.g., abdominal imaging if clinical suspicion for intra-abdominal candidiasis) to help guide potential further diagnostics. Imaging should be considered when focal infection is suspected or to look for evidence of dissemination in the setting of persistent candidemia. Abdominal imaging is indicated routinely in neutropenic patients with candidemia when looking for evidence of dissemination. Ultrasound, computed tomography (CT) scan, and magnetic resonance imaging are all imaging modalities that can be utilized. Echocardiography can be used in the setting of repeatedly positive blood cultures or other findings suggestive of endocarditis. 18F-FDG-PET/CT may have a role in identifying the extent of dissemination in immunocompromised patients and in follow-up to response to therapy, particularly in cases of chronic hepatosplenic candidiasis.[48][49]
Further tests
Various culture-independent diagnostic assays for invasive candidiasis are available to enhance the ability to detect infection. The serum 1,3-beta-D-glucan assay is perhaps the best known and most widely available of these tests. It is not specific for candidiasis though as many other fungi have beta-D-glucan present, and false positives are common.[50][51][52][53] However, it has a good negative predictive value. Commercial testing kits are available.
A relatively novel nonculture-based diagnostic test is the T2 magnetic resonance assay. This is a PCR-based assay that uses magnetic resonance to detect specific Candida species directly from blood specimens with a sensitivity of down to 1 colony-forming unit (CFU)/mL.[54][55] Turnaround time is 3-5 hours, making this a promising technology. It has been approved by the FDA for the diagnosis of Candida bloodstream infections. This is performed on whole blood and sent simultaneously with cultures. The test seems to have excellent positive and negative predictive values of 91.7% and 99.6%.[44][56]
Tissue biopsy of normally sterile sites can help establish the diagnosis, in particular of skin lesions. Gram stain and fungal culture should be performed in addition to histopathology. Additional fungal stains that can be performed include periodic acid-Schiff stain and Grocott-Gomori methenamine silver stain. It is considered definitive evidence of invasive candidiasis, regardless of source, if a positive result is determined.
There is no commercially available Candida antibody test and such a test would be unlikely to be clinically useful.
Emerging tests
Although there have been reports of successful use of PCR, and increased sensitivity compared with blood cultures, it is not widely commercially available.[57]
Use of this content is subject to our disclaimer