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. Empirical 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.[22] Infectious diseases consultation is recommended in such cases.
Clinical assessment
The presence of clinical risk factors and evidence of colonisation with Candida are factors that should be considered when suspecting systemic candidiasis. Clinical features may include persistent fever despite several days of empirical antibiotics, or evidence of candidal endophthalmitis on fundoscopy (cream-coloured 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 non-septic conditions (e.g., cancer or organ trauma), and a high index of suspicion is required for early recognition.[25]
Symptoms may be non-specific and include fever, chills, and constitutional upset (e.g., fatigue, confusion, anxiety). SIRS is characterised by the presence of 2 or more of the following:
Temperature >38°C (>100.4°F) or <36°C (<96.8°F)
Heart rate >90 bpm
Respiratory rate >20 breaths/minute
WBC count >12 x 10^9/L (>12,000/microlitre) or <4 x 10^9/L (>4000/microlitre).
A high index of suspicion for sepsis should be considered in a patient who presents with the following:
Temperature >38.5°C (101°F) or <36.1°C (97°F)
Tachycardia >90 bpm; tachypnoea >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.[26] 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 examination, the patient may be febrile (>38.5°C [101°F]) or hypothermic (<36.1°C [97°F]).[25]
In neutropenic patients, haematogenous dissemination may result in a rash that can be maculopapular to nodular, and often erythematous. Chronic disseminated candidiasis usually involves the liver and spleen in patients recovering from neutropenia (often prolonged). Clinical features usually include fever, abnormal liver function tests (LFTs), and variable hepatosplenomegaly.
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. Fungal blood cultures may be used to supplement routine blood cultures. They have been considered to be more sensitive than routine blood cultures, but advancements in automated blood culture systems have made these specialised cultures largely unnecessary for most patients.
Other baseline laboratory tests recommended in the setting of sepsis are an ABG, FBC (with differential), electrolytes, LFTs, coagulation studies (INR, PTT), serum glucose, creatinine, and urea.[25]
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.
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.[27][28][29][30] However, it has a good negative predictive value. Commercial testing kits are available.
A novel diagnostic test, T2 magnetic resonance assay, uses magnetic resonance to detect specific Candida species directly from blood specimens with a sensitivity of down to 1 colony-forming unit (CFU)/mL.[31][32] Turnaround time is 3 to 5 hours, making this a promising technology.
Tissue biopsy of normally sterile sites can help establish the diagnosis, in particular of skin lesions. Gram stain and culture should be performed in addition to histopathology. 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 polymerase chain reaction (PCR), and increased sensitivity compared with blood cultures, it is not widely commercially available.[33]
The US Centers for Disease Control and Prevention (CDC) recommends that Candida isolates obtained from a normally sterile site are identified to the species level so that appropriate measures can be taken, particularly when C auris is isolated. In the US, the Food and Drug Administration (FDA) has approved use of a matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry system to identify C auris.[34] Cultures from patient samples are ionised and matched to a reference organism database for identification.
Use of this content is subject to our disclaimer