eMedicine Specialties > Infectious Diseases > Fungal Infections

Candidiasis: Differential Diagnoses & Workup

Author: Jose A Hidalgo, MD, Assistant Professor, Universidad de San Marcos Medical School; Attending Physician, Department of Internal Medicine, Division of Infectious Diseases, Guillermo Almenara Hospital
Coauthor(s): Jose A Vazquez, MD, FACP, FIDSA, Consulting Staff, Division of Infectious Diseases, Henry Ford Hospital; Professor, Department of Internal Medicine, Wayne State University School of Medicine
Contributor Information and Disclosures

Updated: Jan 11, 2010

Differential Diagnoses

Abdominal Abscess
Aspergillosis
Cryptococcosis
Sepsis, Bacterial
Septic Shock

Other Problems to Be Considered

Cutaneous candidiasis - Dermatitis (contact, allergic), folliculitis
Gastrointestinal tract candidiasis - Esophagitis due to herpes simplex virus, herpes zoster, induced by radiation, gastroesophageal reflux disease
Respiratory candidiasis - Bacterial pneumonia, viral pneumonia, tracheitis, Aspergillus pneumonia
Genitourinary tract candidiasis - Bacterial cystitis or pyelonephritis
Candidemia - Bacterial sepsis, bacterial endocarditis
Disseminated candidiasis - Bacterial meningitis, bacterial sepsis, bacterial endocarditis, tuberculosis
Chronic mucocutaneous candidiasis - HIV-seropositive state, chronic granulomatous disease
Hepatosplenic candidiasis - Hepatic abscess, cholelithiasis, cholecystitis, acalculous cholecystitis, ascending cholangitis, graft versus host disease, granulomatous hepatitis, relapsed malignancy

Workup

Laboratory Studies

Unfortunately, results from the routine laboratory studies are often nonspecific and not very helpful. Clinicians are required to act definitively and early based on a high index of suspicion. In the past, many patients with life-threatening candidiasis died without receiving antifungal therapy. Systemic candidiasis should be suspected in patients with persistent leukocytosis and either persistent neutropenia or other risk factors and who remain febrile despite broad-spectrum antibiotic therapy. To be effective, antifungal therapy should be provided early and empirically in such high-risk patients. Cultures of nonsterile sites, although not useful for establishing a diagnosis, may demonstrate high degrees of candidal colonization. Always consider positive culture results from sterile sites to be significant and evidence of infection.

  • Mucocutaneous candidiasis
    • For a wet mount, scrapings or smears obtained from skin, nails, or oral or vaginal mucosa are examined under the microscope for hyphae, pseudohyphae, or budding yeast cells.
    • A potassium hydroxide smear, Gram stain, or methylene blue is useful for direct demonstration of fungal cells.
    • Cultures from affected nails may help identify the etiologic agent responsible for onychomycosis versus other noninfectious causes.
  • Candidemia and disseminated candidiasis18
    • Blood cultures are helpful but yield positive results in only 50-60% of cases of disseminated infection.
    • Urinalysis may be helpful and may show either colonization or renal candidiasis.
    • The serum (1,3)β-D-glucan detection assay (Glucatell, Fungitell) is a nonculture assay that was approved for use in the United States in May 2004. This assay measures the level of β-glucan (a fungal cell wall component). In a large multicenter study, the assay yielded a high specificity and positive predictive value with highly reproducible results.19
    • Cultures of nonsterile sites, although not useful for establishing a diagnosis, may be useful for initiating antifungal therapy in patients with fever that is unresponsive to broad-spectrum antimicrobials. Therefore, appropriate interpretation is required. Positive results from blood cultures and cultures from other sterile sites always imply the presence of invasive disease. Positive results from sterile sites should always be taken as significant and should always prompt treatment.
    • Gastrointestinal, respiratory, and urinary tract cultures that are positive for Candida may not always represent invasive disease. However, these should be considered sites of colonization.
  • Cutaneous candidiasis: Using a wet mount, scrapings or smears obtained from skin or nails can be examined under microscopy for hyphae, pseudohyphae, or budding yeast cells. Potassium hydroxide smears are also useful.
  • Genitourinary candidiasis: A urinalysis should be performed. Evidence of WBCs, RBCs, protein, and yeast cells is common. Additionally, urine fungal cultures are useful.
  • Respiratory tract candidiasis
    • Sputum Gram stain may demonstrate WBCs and yeast cells.
    • Sputum cultures may demonstrate Candida species.
    • Lung biopsy is mandatory to definitively establish the diagnosis of respiratory tract candidiasis because of the high frequency of yeast colonization of the respiratory tract.
  • Gastrointestinal candidiasis: Endoscopy with or without biopsy is necessary to establish the diagnosis.
  • Focal hepatosplenic candidiasis: Serum alkaline phosphatase levels are commonly elevated.
  • Species identification
    • C albicans, C dubliniensis, and Candida stellatoidea can be identified morphologically via germ-tube formation (hyphae are produced from yeast cells after 2-3 h of incubation) or biochemical assays.
    • CHROMagar Candida allows for the presumptive identification of several Candida species by using color reactions in specialized media that demonstrate different colony colors depending on the species of Candida.
    • API20C and API32C are biochemical assays that allow for the identification of the different Candida species with more precision. These assays evaluate the assimilation of numerous carbon substrates and generate profiles used in the identification of different fungal species.
    • The C albicans peptide nucleic acid (PNA) fluorescence in situ hybridization (FISH) test can be used to identify C albicans in 24-48 hours when the probe is added to smears that are made directly from the blood culture bottle and followed by hybridization. A newer version of this test now allows for the simultaneous identification of either C albicans or C glabrata.20
  • Antifungal susceptibility testing
    • In vitro susceptibility testing for Candida species is now standardized using the Clinical Laboratory Standards Institute (CLSI) microbroth dilution (CLSI M27-A2, 2002) or the disk diffusion (CLSI M44-P, 2003) methodology. This was formerly known as the National Committee for Clinical Laboratory Standards (NCCLS) microbroth dilution.
    • These methods may be helpful in guiding difficult therapeutic decisions. Most of the difficult decisions involve antifungal-refractory oral or esophageal candidiasis in patients with advanced HIV disease.
  • Nonculture Candida detection assays
    • The Candida mannan assay yields a sensitivity of 31-90% (less for non-albicans Candida species).
    • The Candida heat labile antigen assay yields a sensitivity of 10-71%.
    • The D-arabinitol assay yields a sensitivity of 50% but is not useful for infection with C krusei or C glabrata.
    • The enolase assay yields a sensitivity of 55-75%, which improves with serial testing.
    • The (1,3)β-D-glucan assay is an amebocyte lysis assay with a sensitivity of 75-100% and a specificity of 88-100%. It is a broad-spectrum assay that detects Aspergillus, Candida, Fusarium, Acremonium, and Saccharomyces species. β-D-glucan is a cell wall component in a wide variety of fungi and can be detected based on its ability to activate factor G of the horseshoe crab coagulation cascade. The Fungitell assay may be used in the evaluation of invasive fungal infections caused by the fungi mentioned above. The assay does not detect infections caused by Cryptococcus neoformans or Zygomycetes.
    • Molecular assays such as the polymerase chain reaction (PCR) assay and DNA probes are still under development and in the early investigational phases, but they appear promising.

Imaging Studies

  • Imaging studies are not required or useful in the diagnosis of cutaneous candidiasis, oropharyngeal candidiasis (OPC), or vulvovaginal candidiasis (VVC).
  • Chest radiography may be useful in differentiating a bacterial pneumonia as the cause of fever in patients who are hospitalized. Patients with bronchopneumonia due to hematogenous candidiasis usually have multilobar involvement.
  • Esophagography/upper gastrointestinal studies may be useful for detecting abnormalities in the esophagus and stomach. Unfortunately, these studies are not helpful in determining the microbiologic etiology of the infection.
  • Ultrasonography may be useful for diagnosing hepatosplenic abscess. The classic bull's eye or target lesions are observed in the liver and spleen.
    • Echogenic foci with degrees of shadowing
    • Intra-abdominal abscess formation
    • Cholelithiasis
    • Renal abscess
    • Renal fungus balls
  • CT scanning with contrast enhancement may be useful for diagnosing the following:
    • Hepatosplenic candidiasis
    • Intra-abdominal abscess or peritonitis
    • Renal abscess
    • Pyelonephritis
  • Echocardiography may be useful for excluding or including Candida endocarditis as a possible diagnosis. It is extremely useful because fungal endocarditis is frequently associated with large vegetations that are easily observed on standard echocardiograms.

Procedures

  • In patients with candidemia or disseminated candidiasis, obtaining a tissue biopsy of the involved areas is frequently helpful in establishing the presence of Candida infection and invasion.
  • Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy provide adequate tissue for diagnosis of pulmonary candidiasis.
  • Endoscopy provides direct examination of the esophagus and stomach, one of the organ systems most commonly infected with Candida species. It is also necessary for excluding other causes of esophagitis.
  • Echocardiography may be useful for excluding or including Candida species as a cause of endocarditis. It is extremely useful because fungal endocarditis is frequently associated with large vegetations that are easily observed using standard echocardiography.

Histologic Findings

Fixed tissues can be stained with hematoxylin and eosin. In addition, fungal hyphae may be demonstrated with Grocott silver-methenamine, methylene blue, or periodic acid-Schiff staining. The classic appearance demonstrates the Candida species as either round or ovoid yeast cells, hyphae, or pseudohyphae.

More on Candidiasis

Overview: Candidiasis
Differential Diagnoses & Workup: Candidiasis
Treatment & Medication: Candidiasis
Follow-up: Candidiasis
Multimedia: Candidiasis
References
Further Reading
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Further Reading

Bodey GP (Ed). Candidiasis. Pathogenesis, diagnosis and treatment. 2nd ed. New York, NY; Raven Press; 1993.

Calderone RA (Ed). Candida and candidiasis. Washington, DC; ASM Press; 2002.

NCCLS. Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Proposed Guideline. NCCLS document M44-P [ISBN 1-56238-488-0]. NCCLS, Pennsylvania, USA 2003

NCCLS. Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Second Edition. NCCLS document M27-A2 [ISBN 1-56238-469-4]. NCCLS, Pennsylvania, USA 2002.

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Keywords

candidiasis, Candida albicans, C albicans, fungal infection, candidal infection, candidosis, fungus infection, Candida, mucocutaneous candidiasis, candidemia, disseminated candidiasis, candidal colonization, candidiasis syndromes, intertrigo, paronychia, onychomycosis, oral thrush, mucosal candidiasis, systemic candidiasis, hepatosplenic candidiasis, fungemia, granulocytopenia, oropharyngeal candidiasis, OPC esophageal candidiasis, vulvovaginal candidiasis, VVC, cutaneous candidiasis syndromes, chronic mucocutaneous candidiasis

Addison disease, membranous candidiasis, erythematous candidiasis, chronic atrophic candidiasis, nonesophageal gastrointestinal candidiasis, respiratory tract candidiasis, laryngeal candidiasis, genitourinary tract candidiasis, candidal endophthalmitis, intravascular catheter-related candidiasis, fungal endocarditis, renal candidiasis, Candida peritonitis, Candida esophagitis, Candida folliculitis, Candida balanitis, Candida cystitis, Candida tracheobronchitis, Candida pneumonia, Candida splenic abscess, Candida hypersplenism
Candida cholecystitis, Candida arthritis, Candida osteomyelitis, Candida costochondritis, Candida myositis, Candida myocarditis-pericarditis, Candida endocarditis fungal meningitis, Candida parapsilosis , C parapsilosis, Candida glabrata , C glabrata, Candida tropicalis , C tropicalis
Candida krusei , C krusei, Candida kefyr, C kefyr, Candida dubliniensis , C dubliniensis, Candida guilliermondi , C guilliermondi, Candida lusitaniae , C lusitaniae

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Contributor Information and Disclosures

Author

Jose A Hidalgo, MD, Assistant Professor, Universidad de San Marcos Medical School; Attending Physician, Department of Internal Medicine, Division of Infectious Diseases, Guillermo Almenara Hospital
Jose A Hidalgo, MD is a member of the following medical societies: HIV Medicine Association of America and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Coauthor(s)

Jose A Vazquez, MD, FACP, FIDSA, Consulting Staff, Division of Infectious Diseases, Henry Ford Hospital; Professor, Department of Internal Medicine, Wayne State University School of Medicine
Jose A Vazquez, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Society for Microbiology, Infectious Diseases Society of America, International Immunocompromised Host Society, and Medical Mycology Society of the Americas
Disclosure: pfizer Grant/research funds Independent contractor; Johnson & Johnson Grant/research funds Independent contractor; Schering Plough Grant/research funds Independent contractor; Merck Grant/research funds Independent contractor; Pfizer Honoraria Speaking and teaching; Basilea Grant/research funds Independent contractor

Medical Editor

David Hall Shepp, MD, Program Director, Fellowship in Infectious Diseases, Department of Medicine, North Shore University Hospital; Associate Professor, New York University School of Medicine
David Hall Shepp, MD is a member of the following medical societies: Infectious Diseases Society of America
Disclosure: Gilead Sciences Salary Management position

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Ronald A Greenfield, MD, Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine
Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist  Speaking and teaching

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

 
 
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