Coccidioidomycosis Workup

  • Author: Duane R Hospenthal, MD, PhD; Chief Editor: Burke A Cunha, MD   more...
 
Updated: Dec 8, 2011
 

Approach Considerations

Because most patients recover spontaneously, pursuing documentation of coccidioidal infection is not imperative unless the patient is immunocompromised or has signs of severe progressive disease or dissemination. Diagnosis requires isolation of the organism in culture, identification on histologic specimens, or serologic testing.

The diagnostic evaluation is guided by the patient's clinical presentation and the clinician’s index of suspicion. General laboratory tests include a complete blood count (CBC) and erythrocyte sedimentation rate (ESR). Typical results are a normal white blood cell count or mild lymphocytosis, monocytosis, and/or eosinophilia (>5%) and an elevated ESR.

The specific laboratory tests include the following:

  • Immunoglobulin testing
  • Culture
  • Polymerase chain reaction (PCR) testing
  • Skin testing

Observation of Coccidioides in a clinical specimen establishes the diagnosis. Specimens may include any of the following:

  • Sputum
  • Bronchoalveolar lavage fluid
  • Blood
  • Urine
  • Bone marrow
  • Lymph nodes
  • Skin lesions
  • Cerebrospinal fluid
  • Biopsy specimens

Coccidioides urinary antigenemia has been found positive in more than 70% of immunocompromised patients with HIV/AIDS or solid organ transplant; no reports on its sensitivity in less compromised or immunocompetent patients are available.[46] One study has suggested an association between low serum mannose-binding lectin (MBL) levels and symptomatic coccidiodomycosis.[47]

Chest radiography is indicated, with further imaging studies as appropriate. Lumbar puncture is mandatory in patients with suspected meningitis.

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Serologic Studies

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.[6, 2, 3, 7, 4, 48, 49] As false positives are rare, 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.

Serologic tests for coccidioidomycosis measure titers of immunoglobulin M (IgM) or immunoglobulin G (IgG). These tests can also be performed on cerebrospinal fluid (CSF) upon suspicion of coccidioidal meningitis.

Immunoglobulin M

The appearance of immunoglobulin M (IgM) or precipitin antibody against Coccidioides is the most sensitive serologic indication of early infection. IgM is detected in approximately half of all coccidioidal infections within the first week and in approximately 90% by 3 weeks.

The IgM antibody fades over several weeks. In most patients, these antibodies dissipate within 6 months. However, IgM may persist and/or reappear under certain circumstances (eg, chronic cavitary coccidioidomycosis or systemic reinfection associated with ventriculoperitoneal shunt placement).

Methods of IgM detection are as follows:

  • Tube precipitin - Older test, not currently in use
  • Immunodiffusion tube precipitin - Better specificity; requires more time to perform than latex agglutination or enzyme immunoassay
  • Latex agglutination - Rapid and highly sensitive but lacks specificity; higher false-positive rate and positive results require confirmation with another test (ie, immunodiffusion tube precipitin)
  • Enzyme immunoassay (EIA) - Highly sensitive but lacks specificity; positive result requires confirmation with immunodiffusion tube precipitin

IgM has only qualitative significance, as the magnitude does not correlate with dissemination or extent of disease. Also, a high rate of false-positives is noted, especially in conditions that stimulate humoral immunity.

Immunoglobulin G

Immunodiffusion and complement fixation (CF) methods can detect coccidioidal immunoglobulin G (IgG). IgG antibodies detected via CF become positive in 85-90% of patients by 3 months after infection onset, persist 6-8 months, and disappear as infection resolves. However, in some cases IgG can persist for years.

In contrast to IgM, for which quantification is uninformative, the CF titer is useful as a quantitative measure of the extent and progression of disease. The CF IgG titer may be low or absent in mild or asymptomatic disease or in immunosuppressed patients. Approximately 95-100% of patients with titers of 1:16 or less do not have disseminated disease. High titers (ie, 1:32 or higher) persist in severe, untreated extrapulmonary or disseminated disease.

Coccidioidal CF titers in the serum and cerebrospinal fluid can be followed to monitor the effect of treatment on disease and predict relapses.

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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 3-5 days of inoculation on laboratory media, even when spherules are not present on direct examination. However, the morphology of the colonies (white and cottony mold) is not adequate for identification 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 has been replaced by nucleic acid probes. Culture of the organism and definitive identification takes up to 3 weeks.

In culture, C occidioides spherules can convert to arthroconidia, which are highly contagious. For that reason, cultures should be performed only in Biosafety level 3 laboratories.

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Polymerase Chain Reaction Testing

PCR assays are used to detect a target gene after DNA extraction from biopsy specimens.[50] In the clinical setting, Coccidioides PCR serum testing was found to have very high specificity and negative predictive value.[51] PCR testing is a safer and faster alternative to handling highly virulent cultures of Coccidioides.

PCR amplification has been used successfully to identify the highly specific Ag2/PRA antigen gene of C posadasii in appropriate samples of sputum.[52] This technique can be applied to both clinical specimens and cultures.[53, 54] 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.[55]

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Skin Testing

Skin testing for diagnosis of coccidioidomycosis involves the intradermal injection of a coccidioidal antigen preparation (eg, coccidioidin, spherulin). The induration of the skin is measured at 24 hours and 48 hours after the injection. An induration greater than 5 mm is considered reactive. Erythema at the injection site does not aid in the diagnosis of coccidioidomycosis. The skin test becomes positive 10-45 days after infection or 2-21 days after symptom onset, preceding the appearance of serologic markers.

Coccidioidin and spherulin are no longer available in the United States. However, Ampel et al found that archived coccidioidin from the 1970s retains its potency and specificity.[56]

The assessment of cutaneous reactivity to coccidioidal antigens has limited diagnostic utility due to low sensitivity and specificity in endemic areas.[4] A dermal delayed-type hypersensitivity reaction to coccidioidin is highly specific for coccidioidal infection. However, a positive result may not be related to current disease because, in most persons, this skin test result remains positive for life after infection. In addition, a low level of cross-reactivity with blastomycosis and histoplasmosis occurs.

Results in infected individuals may be falsely negative because of a lack of immune response. Anergy is common in patients with disseminated disease, even without underlying immunosuppression.

Although skin testing has important limitations when it is used as a screening procedure for recent infections with C immitis, cutaneous reactivity to coccidioidal antigens has epidemiologic and prognostic implications. In patients in whom coccidioidomycosis is diagnosed with the help of other tests, the results on skin testing of a lack of delayed-type hypersensitivity is a negative prognostic factor.

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Radiography and Other Imaging Studies

Obtain chest radiography in all patients with suspected or confirmed coccidioidomycosis, to check for signs of pulmonary infection. Radiographs may be normal or may show a variety of nonspecific changes[6, 2, 3, 7, 4, 8, 5, 57, 58, 39] :

Computed tomography or magnetic resonance imaging scanning, and possibly positron-emission tomography (PET) scanning may also be valuable. For discussion of imaging studies in coccidioidomycosis, see Imaging Studies in Coccidioidomycosis.

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Lumbar Puncture

Perform lumbar puncture in patients with fever, headache, nuchal rigidity, meningismus, mental status changes, or ataxia.[9, 57] Many physicians perform lumbar puncture in all patients with extrapulmonary disease or significantly elevated CF IgG titers.

CSF analysis typically reveals a lymphocytic pleocytosis with elevated protein levels and hypoglycorrhachia. In as many as 70% of patients, coccidioidal meningitis is associated with eosinophils in the CSF. Coccidioidomycosis is the most common cause of eosinophilic pleocytosis in the United States.

The diagnosis is aided by the detection of complement-fixating antibodies in the CSF. Coccidioidal meningitis preferentially involves the basilar meninges.

Demonstration of elevated CF titers in CSF establishes the diagnosis of coccidioidal meningitis. CF IgG is present in 90% of patients with coccidioidal meningitis. Elevated CSF CF titers can also be seen with isolated epidural coccidioidal involvement, but only the CSF total protein value is elevated in that situation.

False-positive CSF CF titers are rare but can occur in patients with very high serum CF titers and no meningeal involvement. Rarely, patients with meningitis as their only site of coccidioidal infection have positive CSF CF titers with negative serum CF titers.

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Bronchoscopy

Bronchoscopy is a useful diagnostic procedure in suspected coccidioidal infection if results from other studies (eg, sputum, serologies) are not diagnostic. Successful identification of C immitis (and Mycobacterium tuberculosis) using endoscopic ultrasonography has been reported.[59]

Bronchoscopy may be able to double the yield (compared with sputum) in patients with parenchymal infiltrates and cavitary lesions. In one small series, bronchoscopy established a diagnosis of coccidioidal infection in almost 70% of such cases.[60]

Bronchoscopy is especially useful in patients with tracheal or endobronchial coccidioidal infection, in whom the appearance of lesions can range from erythematous plaques to submucosal nodules to endobronchial masses, and diagnosis is established histologically or from culture.

Bronchoscopy with bronchoalveolar lavage, needle aspiration, and/or lung biopsy may be indicated with persistent or progressive infections, especially in hosts who are immunocompromised.

Bronchoscopy has a very low yield in solitary pulmonary nodules secondary to coccidioidomycosis and is not recommended in these patients.

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Biopsy

Peripheral solitary pulmonary nodules secondary to coccidiomycosis are especially amenable to diagnosis by percutaneous transthoracic needle biopsy. Most percutaneous transthoracic needle biopsies are CT guided, which allows direct visualization of the needle into the lesion. Specimen fungal stains demonstrating spherules or culture growing C immitis are diagnostic. Cytology of the specimen should be obtained to rule out malignancy.

Closed pleural biopsy may be diagnostic in patients with coccidioidal pleural effusions. Identification of spherules infiltrating the pleural is diagnostic. Culture of pleural biopsy specimens has the highest yield, with isolation of C immitis of in all cases in one small series. The typical pleural effusion is exudative and lymphocytic with modest eosinophilia. Pleural fluid cultures have a low yield, with isolation of C immitis in less than 20% of patients.

Surgical biopsy may be required if the diagnosis cannot be established using the aforementioned approaches. Surgical biopsy is best suited for sampling lymph nodes or parenchymal lung disease. Cervical mediastinoscopy can access most mediastinal lymph nodes and video-assisted thoracoscopy can be used to obtain parenchymal lung tissue.

In extrapulmonary coccidiomycosis, fine-needle aspiration provides a quick and less invasive diagnosis if easily accessible subcutaneous lymph nodes are noted on examination.[61]

Synovial biopsy may be needed to document coccidioidal dissemination to a joint.

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Histologic Findings

The diagnosis of coccidioidomycosis can be made by observing spherules (≤70 μm in diameter) that contain endospores in specimens of any body fluid, including sputum or lesion smears and biopsy material. (See the images below.) Direct examination of sputum is less sensitive than cultures for the identification of spherules.

Sputum smears can be stained with potassium hydroxide [KOH]. Spherules are also identified on smears by using calcofluor white or cytologic stains. Spherules are identified in biopsy specimens using standard stains such as hematoxylin and eosin or Papanicolaou stains. Other useful stains for tissue specimens include periodic acid-Schiff stain (PAS) or Gomori methenamine silver stain.

Pulmonary cocci spherule (Hematoxylin-eosin stain)Pulmonary cocci spherule (Hematoxylin-eosin stain). Pulmonary cocci spherule, periodic acid-Schiff staPulmonary cocci spherule, periodic acid-Schiff stain.

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

Coccidioidal spherules rupturing and releasing endCoccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD. A granuloma with coccidioides immitis spherule (prA granuloma with coccidioides immitis spherule (pretracheal lymph node biopsy). A ruptured Coccidioides immitis spherule (pretrachA ruptured Coccidioides immitis spherule (pretracheal lymph node biopsy). Gomori methenamine silver stain of Coccidioides imGomori methenamine silver stain of Coccidioides immitis spherule (pretracheal lymph node biopsy). Periodic acid-Schiff stain of Coccidioides immitisPeriodic acid-Schiff stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
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Contributor Information and Disclosures
Author

Duane R Hospenthal, MD, PhD  Professor of Medicine, Uniformed Services University of the Health Sciences; Physician, Infectious Disease Service, San Antonio Military Medical Center (formerly Brooke Army Medical Center)

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 Human and Animal Mycology, International Society for Infectious Diseases, International Society of Travel Medicine, and Medical Mycology Society of the Americas

Disclosure: Nothing to disclose.

Coauthor(s)

Kelley Struble, DO  Fellow, Department of Infectious Diseases, University of Oklahoma College of Medicine

Disclosure: Nothing to disclose.

Ana Paula Oppenheimer, MD, MPH  Fellow, Section of Infectious Diseases, Wake Forest University Baptist Medical Center

Disclosure: Nothing to disclose.

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.

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.

Additional Contributors

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Itzhak Brook, MD, MSc Professor, Department of Pediatrics, Georgetown University School of Medicine

Itzhak Brook, MD, MSc is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Immunocompromised Host Society, International Society for Infectious Diseases,Medical Society of the District of Columbia, New York Academy of Sciences, Pediatric Infectious Diseases Society, Society for Ear, Nose and Throat Advances in Children, Society for Experimental Biology and Medicine, Society for Pediatric Research, Southern Medical Association, and Surgical Infection Society

Disclosure: Nothing to disclose.

David FM Brown, MD Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital

David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Archana Chatterjee, MD, PhD Professor of Pediatrics, Medical Microbiology and Immunology, and Pharmacy, Division of Pediatric Infectious Diseases, Chief of Division of Pediatric Infectious Diseases, Creighton University School of Medicine; Hospital Epidemiologist and Medical Director of Infection Control, Children's Hospital

Archana Chatterjee, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, International Society for Infectious Diseases, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Michele M Cheung, MD Consulting Staff, Department of Pediatrics, Division of Pediatric Infectious Diseases, University of California, San Francisco, School of Medicine

Michele M Cheung, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

John E Cho, MD Staff Physician, Providence Tarzana Medical Center

John E Cho, MD is a member of the following medical societies: American College of Chest Physicians, California Medical Association, and Phi Beta Kappa

Disclosure: Nothing to disclose.

James de la Torre, MD Resident Physician, Department of Emergency Medicine, LAC+USC Medical Center

Disclosure: Nothing to disclose.

Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Director, Public Health, Dayton and Montgomery County, Ohio

Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha, Infectious Diseases Society of America, and Infectious Diseases Society of Ohio

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine

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.

Joseph Kim, MD Chairman, Department of Emergency Medicine, Western Medical Center; Clinical Instructor, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Zab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

Disclosure: Nothing to disclose.

Catherine O'Keefe, DNP, APRN Assistant Professor of Nursing and Pediatric Nurse Practitioner, Pediatric Infectious Diseases, Creighton University Medical Center

Catherine O'Keefe, DNP, APRN is a member of the following medical societies: American Academy of Nurse Practitioners, National Association of Pediatric Nurse Practitioners, and Nebraska Nurse Practitioners

Disclosure: Nothing to disclose.

Michael Peterson, MD Chief of Medicine, Vice-Chair of Medicine, University of California, San Francisco, School of Medicine; Endowed Professor of Medicine, University of California, San Francisco-Fresno, School of Medicine

Michael Peterson, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Allison J Richard, MD Assistant Professor of Emergency Medicine, Keck School of Medicine of the University of Southern California; Associate Director, Division of International Medicine, Attending Physician, Department of Emergency Medicine, LAC+USC Medical Center

Disclosure: Nothing to disclose.

Mark R Schleiss, MD American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Barry J Sheridan, DO Chief Warrior in Transition Services, Brooke Army Medical Center

Barry J Sheridan, DO is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Guy W Soo Hoo, MD, MPH Clinical Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Director, Medical Intensive Care Unit, Pulmonary and Critical Care Section, West Los Angeles Healthcare Center, Veteran Affairs Greater Los Angeles Healthcare System

Guy W Soo Hoo, MD, MPH is a member of the following medical societies: American Association for Respiratory Care, American College of Chest Physicians, American College of Physicians, American Thoracic Society, California Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Peggy Weintrub, MD Chief, Division of Pediatric Infectious Diseases, Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine

Peggy Weintrub, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

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Soft tissue abscess due to cocci.
Pulmonary cocci spherule (Hematoxylin-eosin stain).
Pulmonary cocci spherule, periodic acid-Schiff stain.
Erythema nodosum can be observed in coccidioidomycosis, tuberculosis, histoplasmosis, drug reactions, and streptococcal infections.
A Coccidioides immitis spherule containing daughter cysts. Courtesy of Thomas Matthew.
Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules containing endospores, which propagate infection in human tissues. Courtesy of Thomas Matthew.
A granuloma with coccidioides immitis spherule (pretracheal lymph node biopsy).
A ruptured Coccidioides immitis spherule (pretracheal lymph node biopsy).
Gomori methenamine silver stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
Periodic acid-Schiff stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD.
 
 
 
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