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Coccidioidomycosis (Infectious Diseases): Differential Diagnoses & Workup

Author: Edward L Arsura, MD, Chair, Department of Medicine, Chief Medical Officer, Richmond University Medical Center
Coauthor(s): Duane R Hospenthal, MD, PhD, Chief, Infectious Disease Service, San Antonio Military Medical Center, Brooke Army Medical Center; Professor of Medicine, Uniformed Services University of the Health Sciences; Ana Paula Oppenheimer, MD, MPH,, Staff Physician, Department of Medicine, Richmond University Medical Center
Contributor Information and Disclosures

Updated: Jun 25, 2008

Differential Diagnoses

Acute Respiratory Distress Syndrome
Paracoccidioidomycosis
Blastomycosis
Pericarditis, Acute
Brucellosis
Pericarditis, Constrictive
Cryptococcosis
Pneumonia, Bacterial
Enteropathic Arthropathies
Pneumonia, Community-Acquired
Eosinophilia
Pneumonia, Fungal
Eosinophilic Pneumonia
Pneumonia, Viral
Histoplasmosis
Pott Disease (Tuberculous Spondylitis)
Hodgkin Disease
Pulmonary Eosinophilia
Hypercalcemia
Sarcoidosis
Legionnaires Disease
Septic Arthritis
Lymphoma, B-Cell
Septic Shock
Mycetoma
Solitary Pulmonary Nodule
Mycoplasma Infections
Tuberculosis
Myelophthisic Anemia

Other Problems to Be Considered

Bacterial lung abscesses with thick-walled cavities with extensive surrounding infiltrates
Chlamydial and mycoplasmal infections
Cold abscesses of skin tuberculosis
Pneumocystis jiroveci pneumonia in persons with HIV infection or AIDS

Workup

Laboratory Studies

  • Routine laboratory examination
    • Elevated ESR
    • Blood eosinophilia
  • Direct examination
    • The diagnosis can be made by observing spherules (≤70 μm in diameter) that contain endospores in clinical material of any body fluid, including sputum or lesion smears and biopsy material.
    • Identification on smears may be made by using calcofluor white or cytologic stains.
    • Identification in biopsy material may be made by using standard hematoxylin and eosin or fungal stains (silver or periodic acid-Schiff).
  • Cultures
    • The most definitive method for diagnosis is isolation of the organism from clinical specimens. The fungus grows well on most common laboratory media within 5 days. Identification of colonial morphology, a white and cottony mold, is not adequate because other organisms have similar mycelial forms.
    • Observation of typical arthroconidia may be used to identify the Coccidioides organism.
    • Identification can be confirmed with a commercially available nucleic acid (gene) probe. Confirmation with exoantigen testing may also be performed, although this test is no longer in common use because of the availability of nucleic acid probes.
    • Arthroconidia are infectious and therefore pose a significant risk to laboratory personnel. Always warn laboratory personnel in advance if coccidioidomycosis is suspected.
  • Serology
    • For more than half a century, detection of antibodies to coccidioidal antigens has been used to establish the diagnosis of coccidioidomycosis and to monitor patients undergoing therapy. A positive serologic result is very likely to be clinically relevant in the appropriate clinical setting; however, a negative result does not exclude the diagnosis.
    • Repeat testing following a negative result improves sensitivity.
    • The 2 major antigens used to detect antibodies are the tube-precipitating (TP) antigens, so named because of the tube precipitant button at the bottom of the test tube when the test was originally performed, and the complement-fixation antigen, which reacts with immunoglobulin (Ig) G.
      • TP antibodies are serum IgM antibodies to mycelial-phase antigens that appear in more than 85% of patients with primary infection and are most commonly detected with enzyme immunoassay (EIA).
      • IgM antibodies are found early in infection, detected within the first week after the onset of symptoms, and peak after several weeks. In most patients, these antibodies dissipate within 6 months. A concern with IgM EIA antibodies is that the false-positive rate may be high, especially in conditions that stimulate humoral immunity.
      • IgG antibodies detected via complement fixation appear later, with results becoming positive in 85-90% of patients. However, serum positivity may occur only after 2 months of illness. The antibody usually disappears after several months.
      • Quantification of IgM antibodies is of no prognostic value, whereas the degree of elevation of complement-fixation antibody, IgG, is proportional to the disease extent. A titer of 1:32 or higher is a marker of dissemination.
      • These tests can be performed on CSF upon suspicion of coccidioidal meningitis.
    • Polymerase chain reaction (PCR) is a better alternative to handling highly virulent cultures of the organism, which can be performed only in biosafety level-3 laboratories and takes about 3 weeks to yield results. PCR amplification has been used successfully to identify the highly specific Ag2/PRA antigen gene of C posadasii in inappropriate samples of sputum5 and can be applied to both clinical specimens and cultures.6,7 The MBP-1 gene for both Coccidioides species and the SOW-gp82 gene for C posadasii have also been identified with high sensitivity and high specificity via PCR.8
  • Skin testing
    • The assessment of cutaneous reactivity to coccidioidal antigens has limited diagnostic utility because of its low sensitivity and specificity in endemic areas. Results in infected individuals may be falsely negative because of a lack of immune response, and results may be falsely positive in healthy individuals because of previous infection.
    • This delayed-type hypersensitivity reaction appears 2-21 days after the onset of symptoms and precedes the appearance of serologic markers.
    • Cutaneous reactivity to coccidioidal antigens has epidemiologic and prognostic implications. The lack of delayed-type hypersensitivity is a negative prognostic factor in infected individuals.

Imaging Studies

  • Obtain chest radiography in all patients with suspected or confirmed coccidioidomycosis. The most common finding is a localized infiltrate. Less-common findings include diffuse reticulonodular disease, pleural effusion, hilar adenopathy, single or multiple cavities (thin-walled and usually apical), miliary disease, or pneumothorax with associated pleural effusion.
  • Perform neuroimaging studies in patients with suspected meningitis.
  • MRI is more sensitive than other studies for CNS involvement, yielding positive findings in approximately 75% of patients with coccidioidal meningitis, whereas CT scanning yields only 42%. The 3 most common findings include hydrocephalus with ventricular enlargement, basilar meningitis, and vascular occlusion. The detection of hydrocephalus and vascular occlusion has negative prognostic implications.
  • Skeletal images usually reveal an osteolytic lesion in patients with symptomatic bone disease. The MRI appearance of coccidioidomycosis varies; findings may include heterogeneous marrow signal intensity and soft tissue involvement.
  • In patients with confirmed skeletal involvement or highly suspected osseous dissemination, a bone scan should be obtained to assess concurrent silent or multifocal osteomyelitis. Abnormal uptake on a bone scan should be investigated further with additional imaging modalities, such as CT scanning or MRI.
  • CT imaging provides information on bony destruction that is more precise than that on MRI, but CT imaging yields less information on spinal and soft tissue damage. MRI is the preferred modality if spinal cord impingement is considered. Both modalities are useful in establishing the extent of disease and in planning surgical debridement of the infected area.

Procedures

  • Lumbar puncture (This is mandatory in patients with suspected meningitis. Many physicians perform lumbar puncture in all patients with extrapulmonary disease or significantly elevated compliment-fixation titers.)
  • Bronchoscopy
  • Fine-needle biopsy (Open lung biopsy and video-assisted thoracoscopy [VATS] are usually unnecessary because the diagnosis can be obtained with noninvasive or minimally invasive procedures.)
  • Pleural, bone, skin, and lymph node biopsy, when indicated

Histologic Findings

The predominant tissue reaction is granulomatous. In acute lesions, macrophages and polymorphonuclear neutrophils may be numerous. As lesions become chronic, fibrosis ensues. Caseation may occur.

The characteristic tissue form of the organism is the spherule. Pathogenicity of the organism is largely related to the resistance of the spherule to eradication by host defenses. Spherules and endospores produce no known toxins, and, as new spherules are propagated in infected tissue, progressive suppuration and tissue necrosis occur. Neutrophils and mononuclear cells attempt phagocytosis of the organism, and giant cells are formed to attack larger fungal structures.

More on Coccidioidomycosis (Infectious Diseases)

Overview: Coccidioidomycosis (Infectious Diseases)
Differential Diagnoses & Workup: Coccidioidomycosis (Infectious Diseases)
Treatment & Medication: Coccidioidomycosis (Infectious Diseases)
Follow-up: Coccidioidomycosis (Infectious Diseases)
Multimedia: Coccidioidomycosis (Infectious Diseases)
References
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Further Reading

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Keywords

coccidioidomycosis, primary pulmonary coccidioidomycosis, primary coccidioidomycosis, chronic coccidioidomycosis, valley fever, desert fever, San Joaquin Valley fever, California fever, Coccidioides immitis, C immitis, Coccidioides posadasii, C posadasii, desert rheumatism, cocci, coccidioidal granuloma, coccidioidal nodule, coccidioidal cavity, coccidioidal mycosis, coccidioidal meningitis, coccidioidal pneumonia

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Contributor Information and Disclosures

Author

Edward L Arsura, MD, Chair, Department of Medicine, Chief Medical Officer, Richmond University Medical Center
Edward L Arsura, MD is a member of the following medical societies: American College of Physician Executives, American College of Physicians, American Federation for Medical Research, American Heart Association, American Medical Association, California Medical Association, Society of General Internal Medicine, and Southern Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Duane R Hospenthal, MD, PhD, Chief, Infectious Disease Service, San Antonio Military Medical Center, Brooke Army Medical Center; Professor of Medicine, Uniformed Services University of the Health Sciences
Duane R Hospenthal, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Society for Infectious Diseases, International Society of Travel Medicine, and Medical Mycology Society of the Americas
Disclosure: Nothing to disclose.

Ana Paula Oppenheimer, MD, MPH,, Staff Physician, Department of Medicine, Richmond University Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Thomas Herchline, MD, Professor of Medicine, Wright State University Boonshoft School of Medicine; Medical Director, Public Health, Dayton and Montgomery County, Ohio
Thomas Herchline, MD is a member of the following medical societies: American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Pharmacy Editor

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

Managing Editor

Thomas M Kerkering, MD, Chief of Infectious Diseases, Virginia Tech, Carilion School of Medicine, Roanoke, Virginia
Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society
Disclosure: Nothing to disclose.

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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