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Unseen Danger: Dust-Born Disease

Katherine Kelly, PharmD Intern and Jennifer K. Seltzer, PharmD

December 20, 2013

Coccidioidomycosis, or valley fever, is a fungal disease observed primarily in the southwestern United States.1 The majority of disease cases are reported in Arizona and California, but endemic areas include Texas, Nevada, Utah, New Mexico, Mexico, Central and South America.  While south Texas is considered an endemic area, the Texas Department of State Health Services does not classify coccidioidomycosis as a notifiable condition, and thus disease rates are underreported.2-4 The prevalence of valley fever has been increasing over the last several decades. In 2011, over 20,000 cases were reported (double that of tuberculosis), and it is estimated that more than 150,000 cases may be undiagnosed anually.1

Coccidioidomycosis is not ordinarily transmitted from person to person or animals to persons, even though the animal population is affected as well.1,4  Coccidioidomycosis is not a threat to a majority of those exposed, but 40% of cases include hospitalizations and complications.2  Severe coccidioidomycosis cases can develop into chronic pulmonary disease, osteomyelitis, or meningitis.1  Additionally, the common symptoms and presentation of coccidioidomycosis complicate diagnosis and differentiation from other conditions like influenza, leading to further underdiagnosis.2 Healthcare provider awareness of the disease is a key factor in prompt diagnosis and treatment to prevent complications.1,2
 
Coccidioidomycosis comes from the soil fungi, Coccidioides immitis and Coccidioides posadasii, which live in arid, low rainfall areas.1 People who reside in endemic areas or travel to these areas can be exposed to the fungus by inhaling Coccidioides arthroconidia (spores).1 Gautam et al.4, using serologic data from dogs across Texas, determined the high endemic areas are the western and south-western regions of the state.

Common risk factors for exposure are displayed in Table 1.1,5 Once Coccidioides arthroconidia are inhaled, the temperature and environment of the lungs enable them to develop into a spherule.  The spherules divide internally until they are filled with endospores and grow so large that the spherule bursts, releasing endospores into the surrounding tissue.1 These endospores can develop into additional spherules and can migrate to different parts of the body, including the joints, bones, skin, and central nervous system.5

Table 1. Risk Factors for Coccidioides Exposure1,5

  • Living in an endemic area (California, New Mexico, Arizona, Texas, Utah, Nevada)*
  • History of travel to an endemic area
  • Yard work, gardening, digging
  • Working in a dusty environment, such as a construction zone
  • Agricultural workers
  • Miners
  • Archaeologists
  • Military personnel performing training exercises in an endemic area
  • Dirt biking or other outdoor recreational activities that might cause dust inhalation
  • Being in an endemic area during a drought, dust storm, earthquake, or other natural disaster

 

*Has also been reported in: Delaware, Louisiana, Maryland, Michigan, Minnesota, Missouri, New Hampshire, Ohio, Rhode Island, and Wyoming

 

An estimated 30%-60% of people in endemic areas are exposed to the fungus at some time in their lives.1 About 60% of exposed people are asymptomatic, while the other 40% have symptoms that range in severity, some requiring hospitalization.5 Commonly reported symptoms, listed in Table 2, generally last longer than a week.5, 6 These symptoms are nondescript and are associated with a variety of other medical conditions, which can lead to underdiagnosis and delayed treatment. 

Table 2. Common Symptoms of Coccidioidomycosis5,6

  • Fever
  • Chills
  • Cough
  • Headache
  • Rash- trunk or extremities
    • Erythema nodosum
    • Erythema multiforme
  • Myalgias
  • Arthralgias
  • Shortness of breath
  • Malaise
  • Night sweats
  • Weight loss

 

In cases of severe disease, patients may develop chronic pulmonary infections or have the fungus disseminate to other parts of the body.1  Population groups at risk for having severe disease are listed in Table 3.5

Table 3.  High-Risk Populations for Severe or Disseminated  Coccidioidomycosis5,7

  • Elderly
  • HIV-infected individuals with CD4 counts less than 200/μL
  • Pregnant women in the third trimester
  • People receiving steroids or immune-compromising agents, like tumor necrosis factor-alpha (TNF-α) inhibitor therapy
  • Smokers
  • Other immunocompromising conditions (e.g., diabetes, chronic pulmonary disease, chronic renal failure, congestive heart failure)
  • African Americans
  • Asians
  • Filipinos
  • Solid Organ Transplant Patients

 

HIV = Human Immunodeficiency Virus

Since symptoms are indistinguishable from other viral or bacterial infections, about 30% of coccidioidomycosis infections are misdiagnosed as bacterial community-acquired pneumonia.1,7,8   Routine tests may show nonspecific results, such as increased white blood count, peripheral eosinophilia, and elevated erythrocyte sedimentation rate.9  Chest x-rays or CT scans of the lungs can be used to investigate signs of infiltration of Coccidioides, but distinguishing the pathogen from others based on radiograph alone is difficult.1  Tests for coccidioidomycosis should be considered in endemic areas and especially when treatment for bacterial infections fails.7  Although Coccidioides readily grows on culture media within seven days, culturing the organism poses a high risk to laboratory workers and should be handled using Biosafety Level 3 containment.8  IgM and IgG enzyme immunoassays (EIA) are the most sensitive serologic assay, while immunodiffusion tests are the most specific serologic assay for Coccidioides.8,9  EIA tests may be used in combination with immunodiffusion tests when confirmation is needed.8,9 

Both the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) have published guidelines for management of coccidioidomycosis and have made similar recommendations.  Treatment is based on disease manifestation and patient immune system status.  Treatment options include azole antifungals and amphotericin B.  Table 4 summarizes the ATS recommendations for managing different coccidioidomycosis manifestations.7

 

Table 4. ATS Coccidioidomycosis Treatment Recommendations7

Primary Pulmonary Disease

  • No therapy for most patients
  • If patient has risk factors for disseminated disease (listed in Table 3) or has had infection for >6 weeks, consider standard therapy* for 3-6 months or longer
  • Follow-up should last a year to assure complete resolution

Persistent Pulmonary Disease

 

Nodules

  • No treatment for nonimmunocompromised patients
  • Consider standard therapy* for periods of significant immunosuppression in compromised individuals

 

Cavities

  • No treatment for nonimmunocompromised patients
  • Consider standard therapy* for:
    • 3-6 months in patients with severe symptoms (pleuritic chest pain, productive cough, or hemoptysis)
    • 12-18 months in immunocompromised individuals
    • Could treat for longer or until cavity/symptoms stabilize

Diffuse Pulmonary

  • Amphotericin B treatment† until clinical improvement, followed by standard therapy* for at least a year
  • For those with ongoing immune suppression, consider long-term maintenance with an azole

Disseminated Disease

 

Non-Meningeal

  • Standard therapy* for at least a year and until clinical stabilization
  • In severe cases, amphotericin B treatment† until clinical improvement, followed by standard treatment* for at least another year

Meningeal

  • Lumbar puncture for any patients presenting with meningitis symptoms
  • High dose fluconazole (400-1000 mg/d) or itraconazole (400-600 mg/d) for life
  • Intrathecal amphotericin B may be required in some severe cases, when azoles fail, or when rapid response is desired
  • Experts should be consulted in managing coccidioidal meningitis

* Standard Therapy: 400 mg/day orally of fluconazole or itraconazole
Intravenous liposomal amphotericin B (5 mg/kg/day) or amphotericin B (0.7-1.0 mg/kg/day)

There are few clinical trials assessing antimicrobial treatment for valley fever.  Compared to conventional amphotericin B, liposomal amphotericin B has not demonstrated greater efficacy in treating coccidioidomycosis but has shown reductions in renal and other toxicities.7  Additionally, investigators evaluated fluconazole and itraconazole efficacy for non-meningeal coccidioidomycosis in a randomized, double-blind trial and found no significant differences between treatment groups. Itraconazole, however, did show a significant benefit in patients with bone infections following 12 months of therapy but not at 8 months.11 Therefore, ATS guidelines suggest that itraconazole may be preferred in patients with disseminated infection in the bones and joints.7  Some smaller studies and case reports suggest that posaconazole or voriconazole may be beneficial in patients with severe or refractory disease.7,11-15 Nikkomycin Z is an antifungal agent that inhibits the enzyme that makes chitin, a fungal cell wall component.16 This orphan drug is being studied at the University of Arizona, where phase 1 trials have been completed.16,17  However, due to lack of funding, a phase 2 study was terminated early.17  Researchers hope to gain enough funding to restart clinical trials with this promising agent.16 Research to develop a vaccine for valley fever is also being conducted.1,18   

Since Coccidioides spores are airborne, coccidioidomycosis is a difficult disease to prevent. Wearing safety masks and avoiding dusty environments may provide some protection to high-risk individuals.1 Recognition and awareness in endemic areas could lead to prompt diagnosis and treatment of severe cases before the disease disseminates.  Texas healthcare professionals and populations living in west or southwest Texas should be aware of risk factors and potential complications from this fungus.  Future research involves studying weather patterns that affect the fungus, epidemiology trends across the United States, and better treatment options.1  

 

 

REFERENCES

  1. Centers for Disease Control and Prevention. Coccidioidomycosis (Valley Fever). Available at: http://www.cdc.gov/fungal/coccidioidomycosis. Accessed November 18, 2013.
  2. Centers for Disease Control and Prevention. Increase in reported coccidioidomycosis--United States, 1998-2011. MMWR Morb Mortal Wkly Rep. 2013;62:(12):217-221.
  3. Texas Department of State Health Services.  Notifiable conditions list. Available at: http://www.dshs.state.tx.us/idcu/investigation/conditions. Accessed November 19, 2013.
  4. Gautam R, Srinath I, Clavijo A, et al. Identifying Areas of High Risk of Human Exposure to Coccidioidomycosis in Texas Using Serology Data from Dogs. Zoonoses Public Health. 2013;60:(2):174-81.
  5. Chiller, T. Coccidioidomycosis. Centers for Disease Control and Prevention. Available at: http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/coccidioidomycosis. Accessed November 19, 2013.
  6. California Department of Public Health Division of Communicable Disease Control. Quick tips on coccidioidomycosis (valley fever) for healthcare providers. Available at: http://www.cdph.ca.gov/HealthInfo/discond/Documents/VFPhysicianGuide.pdf. Accessed November 19, 2013.
  7. Limper AH, Knox KS, Sarosi GA, et al. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183:(1):96-128.
  8. Ampel NM. The diagnosis of coccidioidomycosis. F1000 Med Rep. 2010;2.
  9. Galgiani, JN. Laboratory diagnosis of coccidioidomycosis. In: UpToDate, Kauffman, CA (Ed), UpToDate, Waltham, MA, 2013.
  10. Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis. 2005;41:(9):1217-23.
  11. Anstead GM, Corcoran G, Lewis J, et al. Refractory coccidioidomycosis treated with posaconazole. Clin Infect Dis. 2005;40:(12):1770-6.
  12. Stevens DA, Rendon A, Gaona-Flores V, et al. Posaconazole therapy for chronic refractory coccidioidomycosis. Chest. 2007;132:(3):952-8.
  13. Catanzaro A, Cloud GA, Stevens DA, et al. Safety, tolerance, and efficacy of posaconazole therapy in patients with nonmeningeal disseminated or chronic pulmonary coccidioidomycosis. Clin Infect Dis. 2007;45:(5):562-8.
  14. Kim MM, Vikram HR, Kusne S, et al. Treatment of refractory coccidioidomycosis with voriconazole or posaconazole. Clin Infect Dis. 2011;53:(11):1060-66.
  15. Cortez KJ, Walsh TJ, Bennett JE. Successful treatment of coccidioidal meningitis with voriconazole. Clin Infect Dis. 2003;36:(12):1619-22.
  16. Galgiani, JN. The Search for the Cure for Valley Fever Nikkomycin Z Development at the University of Arizona. Available at: https://www.vfce.arizona.edu/resources/pdf/bio5_summary_nikz_development_plan.pdf. Accessed November 21, 2013.
  17. ClinicalTrials.gov. Available at: http://clinicaltrials.gov. Accessed: November 21, 2013.
  18. Cole GT, Hurtgen BJ, Hung CY. Progress toward a human vaccine against coccidioidomycosis. Curr Fungal Infect Rep. 2012;6:(4):235-44.

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