Severe and invasive diseases are caused by Candida infection. More than 15 different Candida spp. cause disease in humans, but at least 95% of invasive disease is caused by C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei. These organisms cause serious disease referred to as invasive candidiasis. Invasive candidiasis embodies a variety of diseases caused by hematogenous spread of Candida to multiple viscera (e.g., kidney, brain, heart). These diseases include candidemia, disseminated candidiasis, meningitis, and endophthalmitis. Invasive candidiasis is a significant cause of morbidity and mortality for certain groups of patients. Further, invasive candidiasis is a very common fungus in patients with COVID-19. This coinfection can be associated with severe illness and death.

Systemic candidiasis

• History
  1. Fever unresponsive to broad-spectrum antibiotics
  2. History of prolonged indwelling intravenous (IV) catheter
  3. A personal history of any of the risk factors listed earlier
• Physical findings (general)
  1. Fever
  2. Hypotension
  3. Generalized malaise
  4. Tachycardia
  5. Change in mental status
  6. Signs of multiorgan system failure
• Specific diseases
  1. Candidemia
     1. A positive blood culture is the gold standard for the diagnosis of candidemia. Obtain blood cultures in patients suspected to have candidemia. Candida spp. must be isolated from at least one blood culture. A positive culture for Candida should be investigated thoroughly because of the increased risk of morbidity and mortality. Attributable mortality to candidemia in adults is 15% to 20%.
     2. Most common manifestation of invasive candidiasis.
     3. Physical examination may include fever, macronodular skin lesions, septic shock, Candida endophthalmitis.
  2. Disseminated candidiasis
     1. Seen in patients with neutropenia who have undergone cytotoxic chemotherapy for a hematologic malignancy
     2. Associated with multiple deep-organ infections or failure
     3. Blood culture positive
     4. Fever not responding to broad-spectrum antibiotics
     5. Physical examination: Discrete erythematous or palpable rash, sepsis/septic shock
  3. Endophthalmitis
     1. Iatrogenic/accidental or traumatic fungal infection of the eye (exogenous) or hematogenous seeding of the eye (endogenous); C. albicans accounts for about 90% of cases of endogenous endophthalmitis.
     2. Starts as choroidal lesion, progresses to vitreitis and endophthalmitis and eventually blindness.
     3. Physical examination shows fever. An early funduscopic examination by an ophthalmologist should be performed in all patients with candidemia. Funduscopic examination may show large and off-white cotton ball-like lesions with indistinct borders. Patients usually present with decreased visual acuity and occasional pain.
  4. Candida infection of the central nervous system
     1. Meningitis: Candida can spread hematogenously to the meninges during craniotomy or through ventriculoatrial/peritoneal shunts. Culture cerebrovascular fluid to establish diagnosis.
     2. Commonly found in long-term ICU patients.
     3. May manifest as meningitis, mycotic aneurysms, change in mental status.
     4. Physical examination reveals fever, neck rigidity, confusion, headache, and coma.
  5. Candidal musculoskeletal infections
     1. Candida infects the skeletal system, especially the joints as a result of trauma, joint injections, and other surgical interventions, such as IV drug use (hematogenous seeding).
     2. Previously uncommon; now relatively common probably because of increased frequency of candidemia and disseminated candidiasis.
     3. Knee and vertebral column (especially lumbosacral vertebral disks and vertebral bodies, which can lead to vertebral osteomyelitis, with or without diskitis) are involved.
     4. Physical examination is usually unremarkable but may show tenderness over involved area, fever, erythema, bone deformity, weight loss, and sometimes a draining fistulous tract.
  6. Candidal infections of the heart
     1. Usually found in patients with artificial heart valves, IV drug users, and patients with an indwelling central venous catheter.
     2. May manifest as infective endocarditis, myocarditis, or pericarditis.
     3. Physical examination reveals fever, hypotension, tachycardia, new or changing murmur, and signs and symptoms of heart failure.
  7. Hepatosplenic candidiasis (chronic systemic candidiasis)
     1. Seen in patients with hematologic malignancy and neutropenia; usually develops during recovery from a neutropenic state (normally after undergoing myeloablative chemotherapy).
     2. On examination, patients have low-grade fever, right upper quadrant pain, palpable/tender liver, splenomegaly, and rarely jaundice.
     3. MRI/US/Computed tomography (CT) may reveal multiple focal abnormalities in the liver, spleen, and kidneys.
  8. Candida peritonitis
     1. Associated with GI surgery: Perforations, acute necrotizing pancreatitis, peritoneal dialysis. Pancreatic abscess, gangrenous cholecystitis, and common bile duct obstruction are other GI manifestations of Candida infection. C. albicans is the commonly isolated species in intraabdominal Candida infection.
     2. Clinical manifestations include fever, chills, abdominal pain; nausea, vomiting, constipation.
     3. Physical examination reveals abdominal distention, abdominal pain, absent bowel sounds.
  9. Other forms of invasive candidiasis
     1. Candida splenic abscess.
     2. Candida cholecystitis.
     3. Renal candidiasis.
     4. Mediastinitis: Usually occurs after thoracic surgery. Clinical manifestations include chest wall erythema, sternal instability, and fever.
     5. Empyema: Common in patients with malignancies.
     6. Pneumonia (rare).
     7. Septic arthritis.

• Fig. 1 illustrates the pathogenesis of invasive candidiasis.
• Several species of Candida exist in nature.
• Medically significant include:
  1. C. albicans: Together with C. glabrata, they account for 70% to 80% of Candida in invasive candidiasis.
  2. C. glabrata: Together with C. albicans, they account for 70% to 80% of Candida in invasive candidiasis.
  3. C. parapsilosis: Associated with indwelling vascular catheters and prosthetic devices.
  4. C. tropicalis: Especially in leukemic patients.
  5. C. krusei: Resistant to fluconazole and ketoconazole.

• Sepsis (bacterial)
• Septic shock
• Cryptococcosis
• Aspergillosis

• Laboratory studies are nonspecific. It is often necessary to perform several diagnostic tests to achieve maximum accuracy.
• High index of suspicion is needed.
• Candidemia/disseminated candidiasis: Candidemia represents the tip of the iceberg with respect to the more invasive forms of candidiasis. Central lines often contribute to the propagation of candidemia. From the blood, infection can spread to almost any organ.
  1. Blood culture is the gold standard of diagnosis. They are helpful but have low positive yield. Only 40% to 60% of patients with infection have positive culture. 95% of blood cultures that are positive for Candida spp. become positive within 96 hours. Candida in a blood culture is not a contamination, and the source of the infection should be sought.
  2. Diagnosis also can be made from normally sterile sites. Specific species identification is necessary because only 10% of known Candida spp. produce disease in humans.
  3. The T2 magnetic resonance assay of whole blood can be performed on blood samples even after initiation of antifungal therapy.
  4. Serum (1,3) beta-D-glucan detection assay: High specificity and high positive predictive value. It can also be used for diagnosing invasive candidiasis when blood cultures are negative.
  5. New techniques allow for quick identification of Candida spp. in blood. These include:
     1. Peptide nucleic acid fluorescence in-situ hybridization (PAN-FISH).
     2. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI TOF MS).
• Hepatosplenic candidiasis (focal):
  1. Elevated serum alkaline phosphatase.

• Imaging studies are generally not required or useful.
• Ultrasound is useful for diagnosing hepatosplenic abscess. “Bull’s eye or target lesions” are observed in the liver and spleen.
• CT scanning may be used to diagnose hepatosplenic candidiasis, as well as intraabdominal/renal abscesses.
• Transesophageal echocardiogram is useful to rule in or rule out Candida endocarditis.

• Several factors affect prognosis: Infection site, degree of immune suppression, and how quickly diagnosis and therapy are initiated
• Overall mortality rate: 30% to 40%

• Always involve an infectious disease specialist.
• Referral to specialist will depend on the organ involved. For example:
  1. Endocarditis will require a cardiothoracic surgeon.
  2. Endophthalmitis will require an ophthalmologist.

• Prolonged periods, mainly in the hospital, of antifungal treatment may be necessary.
• Closely monitor patients on amphotericin B because of the high incidence of side effects. Check basic metabolic panel, magnesium, and CBC at least twice a week.

Basic preventive measures are similar to those used for nosocomial infections. This includes:

• Maximizing hand hygiene recommendations:
  1. Handwashing
  2. Using alcohol/chlorhexidine solution
• Adhering strictly to recommendations for placement and care of central lines and catheters
• Judicious use of antimicrobials
  1. Notes on Candida auris:
     1. The Centers for Disease Control and Prevention issued warnings in 2016 about the emergence of C. auris, a multidrug-resistant Candida sp. It is resistant to fluconazole and amphotericin B in 93% and 35% of patients, respectively.
     2. It has caused invasive health care-associated infections in many countries and has high mortality rates.
     3. Initial treatment is with echinocandin. Patient should be closely followed with cultures.
     4. Special infection control precautions should be followed for patients infected with or colonized by C. auris.

Antifungal prophylaxis should be limited to patients in whom it has proved beneficial: Patients with GI anastomotic leakage, patients undergoing transplantation of the pancreas or small bowel, selected patients undergoing liver transplantation who are at high risk for candidiasis, and extremely low-birth-weight neonates in settings with a high incidence of neonatal candidiasis.

• Inform them about the risk factors for invasive candidiasis.
• Inform them of the seriousness of the disease and the associated high morbidity/mortality rates, thus requiring aggressive treatment.
• Side effects and toxicities associated with treatment.

Candidiasis (Patient Information)

Candidiasis, Cutaneous (Related Key Topic)