AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Coccidioides immitis, the etiologic agent responsible for coccidioidomycosis and the more well-known San Joaquin Valley Fever, is a dimorphic fungus. It has a mold and a yeast form and is endemic to the Southwestern United States and other lower Sonoran climates of Central America and South America. It was first described in the late 1800s; however, most cases at that time were consistent with more severe cases of C immitis infection, and many of the more benign cases were not recognized until 1929, with an unintentional exposure of a medical student at Stanford University. The medical student subsequently developed a respiratory tract infection and lived, sparking interest that resulted in the eventual connection between C immitis and San Joaquin Valley Fever.

Pathophysiology

C immitis infections occur when inhaled arthroconidia (spores) are deposited in the lower airways and subsequently change morphology to a spherule. These spherules enlarge, divide, and rupture, releasing hundreds of 2-5 micron spherule particles, which similarly reproduce. During primary infection, a mononuclear infiltrate may develop followed by subsequent conversion to polymorphonuclear predominance.

Th1-helper cells are important in the development of effective immunity. Observational data and experimental models show that lack of Th1 cells or predominance of Th2 cells results in higher rates of disseminated disease (eg, human immunodeficiency virus [HIV], acquired immunodeficiency syndrome [AIDS], certain lymphomas, posttransplant states, chronic steroid dependence).¹ C immitis infection can also occur by direct inoculation (eg, from contaminated penetrating objects).

Other rare case reports have been documented, such an infected lung transplant case and sexually transmitted cases. Some of the phagocytized arthroconidia are theorized to be transported back to draining lymph nodes by macrophages and can cause lymphangitis. The inoculating dose responsible for infection is small and may be 10 or less arthroconidia.

Frequency

United States

C immitis infection rates are typically quoted in the 100,000 per year range within the United States. Peak incidence occurs during the summer to early fall months and is related to the variations in weather and spore formation. In particular, outbreaks have been documented during earthquakes and wind storms, which agitate arthroconidia and cause them to become airborne.

Historically, people at greatest risk for contact include farmers, construction workers, and archaeologists; the Northridge earthquake and outbreaks among archaeologists highlight these events.^{2, 3} Thus, otherwise healthy persons exposed to high spore burdens have a higher likelihood of more severe disease. C immitis cases are by no means confined to the Southwestern United States; in fact, cases have been reported in travelers who visited endemic areas. This illustrates the need for careful history taking and possible exposure in endemic areas.

International

Affected areas include the lower Sonoran areas, which are characterized by semiarid climates with hot summers and alkaline soil. These areas include northern Mexico, Central America, and South America.

Mortality/Morbidity

C immitis infection is rarely fatal, except in those who may be extremely immunocompromised. Residual pulmonary disease occurs in 5-10% of patients, and only about 1% of patients progress to disseminated disease.

Any person with impaired cellular immunity has a greater risk for disseminated disease. Individuals with HIV or AIDS are particularly susceptible to more severe disease, especially those with CD4 counts of less than 250. The risk of dissemination is also increased during pregnancy; the risk is slightly higher with each progressive trimester. Patients with lymphoma, those who have undergone solid organ transplant, and patients receiving long-term corticosteroid treatment also have a higher risk of dissemination. Recent advances in immunosuppressive therapy with tumor necrosis factor (TNF)-alpha inhibitors have also been proposed as a risk factor for advanced or disseminated disease.⁴

Race

Filipinos, blacks, and Hispanics have an increased risk of disseminated disease compared with whites.⁵ Studies have shown that genotypic variations in human leukocyte antigen (HLA) either confer increased risk or reduced risk of dissemination. Hispanics with A or B type blood groups also have a slightly higher risk for advanced and/or disseminated disease compared with the population as a whole.⁶

Low income has been associated with a predisposition for severe pulmonary infection and disseminated disease. The role of health care access in this observation is unknown.

Sex

Incidence is equal in males and females.

Age

All age groups can be affected. Congenital infection is rarely a factor in childhood coccidioidomycosis. In disseminated disease, the mortality rates in neonates and infants are much higher than those seen in children, adolescents, and adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The natural history of C immitis infection is usually one of a self-limited respiratory tract infection, which occurs 1-3 weeks after exposure. Most cases (60%) are subclinical and never reach the attention of a physician.

Common symptoms are nonspecific and include fever, cough, chest pain, fatigue, dyspnea, headache, arthralgias, and/or myalgias. Skin manifestations are also seen in a small percentage of cases. In addition to the above symptoms, infection can progress to various presentations. The triad of fever, erythema nodosum, and arthralgias is commonly referred to as San Joaquin Valley Fever or desert rheumatism.

Primary pulmonary infection may progress to overt pneumonia, chronic lung infections, hematogenous spread, disseminated disease, and meningitis. Clinical suspicion and eliciting a history of possible exposure or travel to an endemic area are important.

Physical

• Pulmonary
• • In addition to the asymptomatic infection and benign or unrecognized respiratory infections, coccidioidomycosis can also progress to various degrees of pneumonia. Disease can range from segmental or lobar pneumonias to diffuse reticulonodular infiltrates; it can also progress to complete respiratory failure.
  • A small percentage of patients may present with asymptomatic pulmonary nodules that may be confused with malignancy. Although asymptomatic, these nodules may persist over time and can degenerate into thin-walled cavitations, which may erode into adjacent small airways, resulting in hemoptysis or pneumothorax.
  • Chronic pulmonary patterns may also develop, including chronic fibrocavitary lesions.
  • Physical examination findings are generally nonspecific but can include rales, pleural rubs, wheezing, and decreased breath sounds from effusions.
• Dermatologic
• • Various dermatologic sequelae can result. The best known is erythema nodosum, which presents as tender, erythematous nodules on the anterior lower extremities. These nodules are immune complexes consistent with immune complex phenomena.
  • Disseminated infection can also result in ulceration and fistulas from underlying infection. Lesions can also present as ulcerations or verrucous lesions with a predilection for the nasolabial area.
• CNS
• • As in other organ systems, infection can present in various ways and CNS is no exception. The most serious form of disseminated disease is meningitis. As with other etiologies of meningitis, symptoms typically include fever, headache, meningismus, nausea, vomiting, and altered mental status.
  • Basilar meninges are often affected, and inflammation may result in a noncommunicating hydrocephalus, increased intracranial pressure, and subsequent death if left untreated. Cranial nerve palsies, abscesses, and vasculitides are also described complications of CNS infection.
• Cardiovascular
• • Cardiovascular complications are rare and account for an extremely small percentage of clinical presentations. However, when they do occur, they can be devastating.
  • Pericardial effusions are a rare but recognized occurrence and can produce cardiovascular compromise and tamponade in extreme cases.
• Musculoskeletal
• • The most common manifestations with respect to the musculoskeletal system include osteomyelitis, septic arthritis, and synovitis. Septic arthritis and synovitis often need to be clinically differentiated.
  • Arthritis is usually monoarticular but can be migratory in nature. Typically, the weightbearing joints are affected (eg, knees). Arthrocentesis samples typically reveal an exudative effusion. The presence of organisms varies, and reports suggest that direct visualization of organisms is rare but can occur in up to half of cases.
  • Although osteomyelitis can occur from direct inoculation of bone from contaminated penetrating objects, it is more commonly due to hematogenous spread and disproportionately affects the vertebra; paraspinal abscesses are a possible complication. Other common sites of involvement include the tibia, femur, skull, and bones of the hands and feet. Lesions in the larger bones typically appear as radiopaque lesions, whereas smaller bones tend to have an appearance more typical of osteomyelitis.
• Disseminated disease: Disease can present in virtually any organ system. In addition to the above, patients with disseminated disease may present in septic shock.

Causes

Coccidioidomycosis is caused by C immitis, a soil fungus particularly adapted to arid conditions.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Histoplasmosis
Blastomycosis
Paracoccidioidomycosis
Other fungi
Lung abscess
Lymphoma
Other causes of cough, fever, and fatigue
Old granuloma

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

Guide diagnostic evaluation by index of suspicion and patient's clinical presentation. Various tests may aid or confirm the diagnosis.

• CBC count: CBC count may reveal leukocytosis with eosinophilia, lymphocytosis, or monocytosis.
• Direct observation: Observe for direct evidence of spherules of C immitis from various aspirates, body fluids, or biopsy samples. Various fungal stains may increase sensitivity.
• Skin testing: Delayed-type hypersensitivity test results may become positive as early as 1-3 weeks. Although reactivity may endure for a lifetime, it may wane in some individuals, particularly those who may be anergic.
• Immunoglobulin testing: Serology tube precipitin assays for immunoglobulin (Ig) M may detect acute infection. IgM reactivity usually does not persist for more than 6 months. Complement fixation is useful in detecting IgG immunity and is particularly useful in evaluating the extent and response to meningeal disease.
• Culture: Culture may be performed, but results are usually delayed because of a 5- to 7-day incubation period.
• Immunoprecipitant assays
• Immunodiffusion

Imaging Studies

• Chest radiography should be routinely performed to check for signs of pulmonary infection. Findings may be normal or may include the following:
• • Infiltrates
  • Nodules
  • Cavity
  • Mediastinal or hilar adenopathy
  • Pleural effusion
• Radiography of affected areas is performed to check for osteomyelitis.

Procedures

If unable to obtain a diagnosis by skin testing or serology, consider performing the following:

• Bronchoscopy
• Fine-needle biopsy
• Open-lung biopsy
• Pleural biopsy
• Bone/skin/node biopsy

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Emergency Department Care

• Therapy is rarely started in the emergency department (ED); however, infectious disease consultants often expedite therapy in endemic areas.
• Therapies include amphotericin B and azoles, including ketoconazole and fluconazole.

Consultations

• Report cases to infectious disease and local health departments.
• Consultation with a pulmonologist is indicated.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In general, the severity and tempo of the disease usually dictates tempo of treatment. In patients with suspected or documented uncomplicated primary infection, treatment varies from careful observation to long-term azole therapy.

Some authors have suggested that empiric treatment may decrease the rate of disseminated infection, but this has not been proven in any controlled studies and no conclusive guidelines specify which uncomplicated infections need treatment. However, groups who are at risk for dissemination (eg, blacks, Filipinos, individuals with HIV or AIDS, individuals with diabetes mellitus, women in the third trimester of pregnancy) warrant more aggressive treatment. Typically, this may be accomplished with fluconazole except in pregnant women because azole antifungals are teratogenic. Pregnant women with suspected infection may be treated with amphotericin B. Currently, few randomized controlled trials have specifically looked at the efficacy of the different azoles. Galgiani et al compared fluconazole with itraconazole in a randomized controlled trial.⁷ Although no statistically significant difference was noted, itraconazole was associated with better outcomes in musculoskeletal disease.

Patients with more advanced disease require more aggressive treatment. In particular, patients who exhibit signs of meningitis need either intravenous antibiotic therapy with amphotericin unless otherwise contraindicated or high-dose azole therapy with or without intrathecal amphotericin. Some case reports have suggested that voriconazole or posaconazole may be therapeutic options in these patients;^{8, 9} however, these reports are only anecdotal to date, and no comparative studies have been performed. Caspofungin in combination with fluconazole has been cited as beneficial in a case report of a 31-year-old Korean man with coccidioidal pneumonia.¹⁰ Steroids may be somewhat beneficial in patients with vasculitis.

Drug Category: Antifungal agents

The mechanism of action in these agents may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

Indications for admission include the following:

• Immunocompromised conditions
• Dissemination
• Any need for symptomatic support or intravenous therapy

Complications

• Severe cases are fatal, particularly if associated with meningitis.
• Obstruction of pulmonary tissue due to scarring or cavities may occur.

Prognosis

• Most cases are self-limited and resolve within a few months.
• Prognosis is poor if the patient has a weak cell-mediated immunity or high IgG.
• Relapse of extrapulmonary or disseminated disease is common.

Patient Education

• Educate populations at high risk (eg, immunocompromised, pregnant women, African Americans, Filipinos, those with diabetes) on avoidance of high-risk activities (eg, construction, archeological digs).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider this or other fungal infections in patients in whom other therapies have failed and in those who appear to have a chronic illness or are resident of (or traveler to) endemic regions is a pitfall.
• Recently, coccidioidomycosis has regained interest due to its potential as a bioterrorism weapon.¹¹ C immitis is listed in some texts as a potential agent for biological warfare. Although the exact outcome of an attack is unknown, C immitis possesses some properties that could make it attractive as a weapon. In particular, spores can be disseminated and aerosolized rather easily. However, the infectivity in this capacity is unknown and effects are probably limited.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Ampel NM. Combating opportunistic infections: coccidioidomycosis. Expert Opin Pharmacother. Feb 2004;5(2):255-61. [Medline].
2. CDC. Coccidioidomycosis following the Northridge earthquake--California, 1994. JAMA. Jun 8 1994;271(22):1735. [Medline].
3. Schneider E, Hajjeh RA, Spiegel RA, et al. A coccidioidomycosis outbreak following the Northridge, Calif, earthquake. JAMA. Mar 19 1997;277(11):904-8. [Medline].
4. Bergstrom L, Yocum DE, Ampel NM. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum. Jun 2004;50(6):1959-66. [Medline].
5. CDC. Increase in coccidioidomycosis--Arizona, 1998-2001. MMWR Morb Mortal Wkly Rep. Feb 14 2003;52(6):109-12. [Medline].
6. Louie L, Ng S, Hajjeh R, et al. Influence of host genetics on the severity of coccidioidomycosis. Emerg Infect Dis. Sep-Oct 1999;5(5):672-80. [Medline].
7. Galgiani JN, Catanzaro A, Cloud GA. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. Nov 7 2000;133(9):676-86. [Medline].
8. Prabhu RM, Bonnell M, Currier BL. Successful treatment of disseminated nonmeningeal coccidioidomycosis with voriconazole. Clin Infect Dis. Oct 1 2004;39(7):e74-7. [Medline].
9. Anstead GM, Corcoran G, Lewis J. Refractory coccidioidomycosis treated with posaconazole. Clin Infect Dis. Jun 15 2005;40(12):1770-6. [Medline].
10. Park DW, Sohn JW, Cheong HJ. Combination therapy of disseminated coccidioidomycosis with caspofungin and fluconazole. BMC Infect Dis. 2006;6:26. [Medline].
11. Deresinski S. Coccidioides immitis as a potential bioweapon. Semin Respir Infect. Sep 2003;18(3):216-9. [Medline].
12. Blair JE, Smilack JD, Caples SM. Coccidioidomycosis in patients with hematologic malignancies. Arch Intern Med. Jan 10 2005;165(1):113-7. [Medline].
13. Catanzaro A. Coccidioidomycosis. In: Manual of Clinical Problems in Pulmonary Medicine. 5^th ed. Lippincott Williams & Wilkins; 2000.
14. Comrie AC. Climate factors influencing coccidioidomycosis seasonality and outbreaks. Environ Health Perspect. Jun 2005;113(6):688-92. [Medline].
15. Deresinski SC, Mirels LF, Kemper CA. Coccidioides immitis. In: Infectious Diseases. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:2227-46.
16. Galgiani J. Coccidioides immitis. In: Principles and Practice of Infectious Diseases. New York, NY: Churchill Livingstone; 2000:2746-57.
17. Jones JL, Fleming PL, Ciesielski CA, et al. Coccidioidomycosis among persons with AIDS in the United States. J Infect Dis. Apr 1995;171(4):961-6. [Medline].
18. Rosenstein NE, Emery KW, Werner SB. Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995-1996. Clin Infect Dis. Mar 1 2001;32(5):708-15. [Medline].

Article Last Updated: May 27, 2008