Basics
Description
Coccidioidomycosis is an endemic systemic mycosis resulting in both asymptomatic and life-threatening disseminated infections. �
Epidemiology
- Coccidioides spp. are dimorphic fungi that live in the soil.
- Endemic to the southwestern United States (southern California, Arizona, western and southern Texas, New Mexico), northern Mexico, and parts of South and Central America
- Infection is acquired from exposure to aerosolized spores (arthroconidia) usually during recreational or occupational activities; clusters of cases may involve dust storms and earthquakes.
- The average incubation period is 10-16 days (range 1-4 weeks).
- There is no person-to-person spread.
- 60% of acute infections are subclinical (asymptomatic).
Incidence
- 25,000-150,000 new infections per year in the United States
- Highest rate of infection in the summer and early fall
Prevalence
Seropositivity rates in children living in endemic area for 1 year approach 20%, whereas rates in children living in endemic area for 10 or more years approach 80%. �
Risk Factors
- The course of illness is highly variable and depend on host immune response and amount of exposure.
- Risk factors for disseminated infection:
- Immunosuppression (especially organ transplant recipients, those receiving immunosuppressive therapies and immunomodulators, and those with HIV infection)
- Male gender (adult)
- Neonates, infants, and the elderly
- Filipino, African American, Native American, Hispanic ethnicity
- Pregnancy
- Risk of dissemination is less in children than in adults.
General Prevention
Infection control �
- No special isolation or precautions for the hospitalized patient
- Contaminated dressings from skin lesions should be handled and discarded with care.
- Inhalation of aerosolized spores from culture can be hazardous to laboratory personnel.
- Preventive efforts are aimed at dust control and trials to eliminate organisms from soil.
- Immunocompromised people should be counseled to avoid activities that may expose them to aerosolized spores in endemic areas.
Pathophysiology
- Spores (arthroconidia) are the infectious forms of Coccidioides organisms; they are released from the mold and propagate the mold in the soil.
- Inhalation of arthroconidia from disturbed, arid soil is the major route of infection.
- In tissues, arthroconidia enlarge to form spherules. Mature spherules release endospores that propagate in the host and continue the tissue cycle.
- Primary infection occurs in the lungs.
- Most patients have infection limited to a localized area of lung and hilar lymph nodes after mounting an intense inflammatory response with granuloma formation.
- Extrapulmonary dissemination occurs via lymphatic or hematologic spread and usually involves the skin, bones and joints, and central nervous system but can spread to virtually any organ system.
Etiology
- Coccidioides immitis and Coccidioides posadasii are the etiologic agents of coccidioidomycosis.
- Asymptomatic infection is the most common outcome, occurring in 60% of infected individuals.
- Primary pulmonary infection accounts for most symptomatic cases; nonspecific illness most common feature (cough, malaise, chest pain, fever); self-limited in most cases; may be accompanied by reactive rashes such as erythema multiforme or erythema nodosum
- Disseminated disease occurs in less than 1% of infected individuals and may manifest with
- Osteomyelitis: subacute or chronic and frequently involves more than 1 bone (40%). Common sites are the hands, feet, ribs, skull, and vertebrae.
- Meningitis: develops within 6 months of initial infection. Hydrocephalus is a common complication. Central nervous system vasculitis and intracerebral abscesses are rare.
- Cutaneous disease: Papules or pustular lesions that ulcerate are most common; most commonly seen on the face but can occur anywhere; regional adenitis is common.
Diagnosis
History
- Travel or residence in an endemic area is typical. Risk factors for disseminated infection should be sought.
- Acute pneumonia
- Fever, dry or productive cough, and pleuritic chest pain; hemoptysis is rare in children.
- Systemic symptoms include headache, malaise, arthralgias, sore throat, and fatigue; rash may be reported.
- Also known as "valley fever"�
- Myalgias, arthralgias, chills, night sweats, and anorexia suggest systemic dissemination.
- Headache, vomiting, and altered mental status suggest meningitis.
- Most infections (60%) are asymptomatic.
Physical Exam
- Signs of pneumonia and pleural effusions are often present with symptomatic pulmonary infection.
- Reactive rashes
- Contain no live organisms
- Erythematous maculopapular rash and erythema multiforme are seen in 50% of symptomatic children.
- Erythema nodosum and fever may occur following the onset of symptoms and correlate with the development of cell-mediated immunity (hypersensitivity reactions).
- Hypersensitivity reactions may occur in the absence of pulmonary symptoms.
- Hematogenous dissemination to the skin
- Lesions may consist of papules, nodules, abscesses, pustules, sinus tracts, and verrucous ulcers.
- May be single or multiple
- Can occur anywhere but are most common on the nasolabial folds
- Stridor is present with infection of the subglottic tissues.
- Signs of increased intracranial pressure are often seen with central nervous system infection. Classic signs of meningeal irritation and fever may be absent.
Alert
- Clinicians in endemic areas should maintain a high level of clinical suspicion of primary as well as disseminated infection.
- Diagnosis in nonendemic areas may be missed owing to low clinical suspicion or missed travel history.
- False-negative serologic results may occur during the initial weeks of infection or in an immunocompromised host.
Diagnostic Tests & Interpretation
Lab
- Direct examination and culture
- Cytologic examination of bronchoalveolar fluid is diagnostic in only about 1/3 of persons and is less sensitive than culture. Visualization of large spherules is possible in stained specimens of sputum, tracheal aspirates, urine, or tissue biopsy. They are rarely seen in CSF.
- The organisms can be detected by culture in experienced laboratories. The yield is highest from purulent material. The yield from other sources, such as pleural fluid, blood, and gastric aspirates, is lower.
- A DNA probe can identify Coccidioides species in cultures.
- Coccidioidin or spherulin skin intradermal testing has been used as an epidemiologic tool in the past but is no longer commercially available.
- Serologic studies
- Serve as valuable diagnostic and prognostic tools but may be hampered by false-negative results early in the course of infection and in immunocompromised hosts; false-positive reactions occur as a result of cross-reactivity with other endemic mycoses.
- C. immitis-specific IgM antibody is detectable in 75% of patients 1-3 weeks after symptom onset and usually is absent after 6 months. False-positive results are seen in 15% of patients with cystic fibrosis.
- IgG is detected by the complement fixation (CF) assay from serum or CSF. It is positive in 50% of patients at 4 weeks and 83% at 3 months following symptomatic primary infection. In general, higher titers reflect more extensive infection, and rising CF antibody concentrations are associated with worsening disease.
- Enzyme immunoassay (EIA) for qualitative detection of IgM and IgG is sensitive but can yield false-positive results. It can be useful for screening, but a positive EIA should be confirmed with another test.
- Hematologic findings include elevated erythrocyte sedimentation rate, leukocytosis, and eosinophilia (in 10%).
- Other studies
- CSF findings in meningitis include hypoglycorrhachia and pleocytosis with mononuclear cell predominance.
Imaging
Radiologic studies �
- Chest radiograph may reveal well-circumscribed nodules, lobar or patchy pulmonary infiltrates, pleural effusions, cavitary lesions, and hilar adenopathy.
- Radiographs of involved bones may reveal lytic lesions. Scintigraphy or MRI of bone is more sensitive for the diagnosis of osteomyelitis.
Differential Diagnosis
- Other pulmonary mycoses (e.g., Histoplasma capsulatum, Aspergillus fumigatus, and Blastomyces dermatitidis)
- Mycobacterium tuberculosis (lung or CSF)
- Mycoplasma pneumoniae
- Influenza and other viral infections that present as bronchopneumonia
- Skin lesions may mimic other endemic mycoses, tuberculosis, actinomycetes, or syphilis.
Treatment
Medication
- Uncomplicated or minor disease is self-limited and should not be treated with antifungal therapy (>95% of cases).
- Treatment of uncomplicated respiratory infection is recommended for infants, pregnant women, and patients with continuous fever for >1 month, >10% weight loss, extensive or progressive pulmonary disease, or immunodeficiency (either from HIV or as a result of immunosuppressive medications). Use either oral fluconazole or itraconazole for 3-6 months.
- Diffuse pneumonia or immunocompromised host: Start therapy with amphotericin B and replace with oral fluconazole or itraconazole when clinical improvement is demonstrated. The total length of therapy should be at least 1 year, and for patients with severe immunodeficiency, oral azole therapy should be continued as secondary prophylaxis.
- Disseminated infection, nonmeningeal: Treat with oral fluconazole or itraconazole. Amphotericin B may be used initially, especially for patients with severe or rapid progression of disease. The duration of therapy may be longer than for those with pneumonia only.
- Meningitis: Oral fluconazole is preferred (12 mg/kg/24 h once daily or divided b.i.d., max 800-1,000 mg/24 h). Itraconazole (10-20 mg/kg/24 h divided b.i.d.-t.i.d., max 600 mg/24 h) for 3 days, 4-10 mg/kg/24 h divided b.i.d. (max 400 mg/24 h) thereafter, is an alternative agent. Therapy should be continued indefinitely.
- Intrathecal amphotericin B may be useful in central nervous system infections for those who fail to respond to azole therapy.
- Surgical debridement is used for localized and persistent lesions in bone and lung.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Patients with mild primary respiratory tract infections who are not treated with antifungal therapy should be assessed at 3-6 months intervals for up to 2 years to ensure that their clinical and radiographic findings have resolved.
- Periodic assessment should be done for all patients treated with antifungal therapy throughout their treatment and after cessation of antifungal therapy.
- Patients who are being treated for meningeal infections should undergo CSF assessment every 3 months for life.
- Rising or unchanging CF titers while the patient is receiving treatment may indicate treatment failure, most often due to noncompliance or an occult focus that may require surgical drainage.
- All azoles inhibit P450 enzymes. Consider drug-drug interactions when the patient is taking other medications.
Prognosis
- Most infections are asymptomatic (60%) or mild (35%) and self-limited.
- Primary infection of the lungs is usually self-limited, with a course of illness lasting 1-3 weeks; complications (see below) may prolong the course.
- Fatigue can last for several months.
- Dissemination is infrequent (see earlier section for risk factors). Morbidity and mortality have improved with use of antifungal therapy, but immunocompromised patients still have a poor prognosis after the development of disseminated infection. The mortality rate is 70% in HIV-infected patients with diffuse pulmonary coccidioidomycosis.
- Meningitis, untreated, is nearly always fatal within 2 years of diagnosis.
Complications
- Localized complications of primary pulmonary infection are infrequent and include pleural effusions and pericarditis.
- ~5% of lung infections result in residual pulmonary sequelae, usually nodules or abscess cavities. 1/3 of these cavities spontaneously resolve within 2 years. Hemoptysis and rupture of the abscess, with formation of an empyema, are potential complications in patients with unresolved cavities.
- Extrapulmonary dissemination usually develops within a year after the initial infection but may appear much later if immunity is impaired (e.g., HIV infection, malignancy, immunosuppressive or immunomodulatory therapy).
- Hospital admission seems to be more common in patients with comorbid conditions and frequently necessitates surgical intervention.
- Hydrocephalus may occur with central nervous system involvement.
Additional Reading
- Ampel �NM. New perspectives on coccidioidomycosis. Proc Am Thorac Soc. 2010;7(3):181-185. �[View Abstract]
- Chu �JH, Feudtner �C, Heydon �KH, et al. Hospitalizations for endemic mycoses: a population based national study. Clin Infect Dis. 2006;42(6):822-825. �[View Abstract]
- Deresinski �SC. Coccidioidomycosis: efficacy of new agents and future prospects. Curr Opin Infect Dis. 2001;14(6):693-696. �[View Abstract]
- Fisher �BT, Chiller �TM, Prasad �PA, et al. Hospitalizations for coccidioidomycosis at forty-one children's hospitals in the United States. Pediatr Infect Dis J. 2010;29(3):243-247. �[View Abstract]
- Galgiani �JN, Ampel �NM, Catanzaro �A, et al. Practice guidelines for the treatment of coccidioidomycosis. Clin Infect Dis. 2000;30(4):658-661. �[View Abstract]
- Montenegro �BL, Arnold �JC. North American dimorphic fungal infections in children. Pediatr Rev. 2010;31(6):e40-e48. �[View Abstract]
- Nguyen �C, Barker �BM, Hoover �S, et al. Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol Rev. 2013;26(3):505-525. �[View Abstract]
- Shehab �ZM. Coccidioidomycosis. Adv Pediatr. 2010;57(1):269-286. �[View Abstract]
- Smith �JA, Kauffman �CA. Endemic fungal infections in patients receiving tumour necrosis factor-alpha inhibitor therapy. Drugs. 2009;69(11):1403-1415. �[View Abstract]
Codes
ICD09
- 114.9 Coccidioidomycosis, unspecified
- 114.5 Pulmonary coccidioidomycosis, unspecified
- 114.1 Primary extrapulmonary coccidioidomycosis
- 114.0 Primary coccidioidomycosis (pulmonary)
- 114.9 Coccidioidomycosis, unspecified
- 114.3 Other forms of progressive coccidioidomycosis
ICD10
- B38.9 Coccidioidomycosis, unspecified
- B38.2 Pulmonary coccidioidomycosis, unspecified
- B38.3 Cutaneous coccidioidomycosis
- B38.7 Disseminated coccidioidomycosis
- B38.89 Other forms of coccidioidomycosis
SNOMED
- 60826002 Coccidioidomycosis (disorder)
- 417018008 Pulmonary coccidioidomycosis (disorder)
- 23247008 Primary extrapulmonary coccidioidomycosis (disorder)
FAQ
- Q: Do all patients with symptomatic primary respiratory infection due to C. immitis require treatment?
- A: No. Because >95% of initial pulmonary infections are self-limited, treatment is not always required. Patients with concurrent risk factors (e.g., HIV, organ transplant, or high doses of corticosteroids) or evidence of unusually severe infections should always be treated. Factors suggesting increased severity of infection include weight loss of >10%, symptoms for 3 or more weeks, infiltrates involving more than half of 1 lung or portions of both lungs, and CF antibody to C. immitis >1:16.
- Q: What is the best option for treatment of the child with coccidioidal meningitis?
- A: Fluconazole has become the treatment of choice because of its ease of administration, excellent central nervous system penetration, and safety profile. Other azoles such as ketoconazole and itraconazole appear to also be effective in adults. Intravenously and intrathecally administered amphotericin B is considered a 2nd-line agent because of its inconvenience and adverse effect profile.