Coccidioidomycosis

Glenn G. Fort, M.D., M.P.H.

Basic Information

Definition

Coccidioidomycosis is an infectious disease caused by inhaling the spores of the fungus Coccidioides immitis. Clinical syndromes range from subclinical pulmonary disease to pneumonia and disseminated disease mostly in immunocompromised hosts. Most cases occur in the southwest part of the U.S.

Synonyms

San Joaquin Valley fever
Valley fever

ICD-10CM CODES
B38.9	Acute pulmonary coccidioidomycosis
B38.3	Cutaneous coccidioidomycosis
B38.89	Other forms of coccidioidomycosis
B38.2	Pulmonary coccidioidomycosis, unspecified
B38.4	Coccidioidomycosis meningitis
B38.1	Chronic pulmonary coccidioidomycosis

Epidemiology & Demographics

Incidence (In U.S.)

Estimated annual infection rate is 150,000 persons, predominantly in the southwest U.S., and appears to be rising because of increased population and construction in the area. In 2011, the incidence in endemic states rose to 42.6 cases per 100,000 population from 5.3 cases per 100,000 in 1998.

Peak Incidence

Seasonal in endemic areas with the highest risk being in the dry season after a rainy season as the mold lies a few inches below desert surface in soil and can become aerosolized.

Prevalence

28.65 cases per 1 million population in the southwest U.S. in 2002 based on patients requiring hospital admission.

Predominant Sex

•

Males, between the ages of 25 and 55 yr
•

Clinical disease more severe in older children and adults

Physical Findings & Clinical Presentation

•

The clinical manifestations vary widely according to the host, severity of the illness, and location of dissemination.
•

Asymptomatic infections or illness consistent with a nonspecific upper respiratory tract infection in at least 60%.
•

Symptoms of primary infection—cough, malaise, fever, chills, night sweats, anorexia, weakness, and arthralgias (desert rheumatism)—in remaining 40% within 3 wk of exposure.
•

Erythema nodosum and erythema multiforme more common in women.
•

Scattered rales and dullness on percussion.
•

Spontaneous improvement within 2 wk of illness, with complete recovery usual.
•

Pulmonary nodules and cavities in <10% of those patients with primary infection; half of these patients are asymptomatic.
•

In a small portion of these patients: a progressive pneumonitis, often with a fatal outcome.
•

Immunocompromised or diabetic patients may progress to chronic pulmonary disease.
•

Over many years, granulomas rupture, leading to new cavity formation and continued fibrosis, often accompanied by hemoptysis.
•
Disseminated or extrapulmonary disease in approximately 0.5% of acutely infected patients.
1. 1.
  
  Early signs of probable dissemination: fever, malaise, hilar adenopathy, and elevated ESR persisting in the setting of primary infection.
2. 2.
  
  Most organs are susceptible to dissemination, with the heart and GI tract generally spared.
•
Musculoskeletal involvement: bone lesions often unifocal, ribs, long bones, and vertebral lesions are common.
1. 1.
  
  Joint lesions predominantly unifocal, most commonly involving the ankle and knee, and often accompanying adjacent sites of osteomyelitis.
•

Meningeal involvement: headache, fever, weakness, confusion, lethargy, cranial nerve defects, seizures; meningeal signs often minimal or absent.
•
Cutaneous involvement (Fig. E1): variable lesions—pustules, papules, plaques, nodules, ulcers, abscesses, or verrucous proliferative lesions.

FIG.E1

Cutaneous coccidioidomycosis. Multiple verrucous papules and plaques in a patient with cutaneous coccidioidomycosis disseminated from a primary pulmonary infection.

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.
1. 1.
  
  Dissemination and fatal outcomes most common in men, pregnant women, neonates, immunocompromised hosts, and individuals of dark-skinned races, especially those of African, Filipino, Mexican, and Native American ancestry.

Etiology

•

Coccidioides immitis is endemic to North and South America.
•

In the U.S., endemic areas coincide with the Lower Sonoran Life Zone, with semiarid climate, sparse flora, and alkaline soil in Arizona, California, New Mexico, and Texas.
•

Fungus exists in the mycelial phase in soil, having barrel-shaped hyphae (arthroconidia). Arthrospores are aerosolized and deposit in the alveoli, and then fungus converts to thick-walled spherules.
•

Internal spherical spores (endospores) are released through spherule rupture and mature into new spherules (parasitic cycle).
•

Fungus incites a granulomatous reaction in host tissue, usually with caseation necrosis.

Diagnosis

Differential Diagnosis

•
Acute pulmonary coccidioidomycoses:
1. 1.
  
  Community-acquired pneumonias caused by Mycoplasma and Chlamydia spp.
2. 2.
  
  Granulomatous diseases, such as Mycobacterium tuberculosis and sarcoidosis
3. 3.
  
  Other fungal diseases, such as Blastomyces dermatitidis and Histoplasma capsulatum
•

Coccidioidomas: true neoplasms

Workup

Coccidioidomycosis is definitively diagnosed by isolation of the organism in culture. Suspected in patients with a history of residence or travel in an endemic area, especially during periods favorable to spore dispersion (e.g., dust storms and drought followed by heavy rains)

Laboratory Tests

•
Definitive diagnosis based on demonstration of the organism by culture from body fluids or tissues. It should be noted that culture can take days to several weeks to grow.
1. 1.
  
  Greatest yield with pus, sputum, synovial fluid, and soft tissue aspirations, varying with the degree of dissemination.
2. 2.
  
  Possible positive cultures of blood, gastric aspirate, pleural effusion, peritoneal fluid, and CSF but less frequently obtained.
3. 3.
  
  Lab personnel are at risk of infection by inhalation on opening culture plates so lab should be notified the disease is suspected, but it is not contagious from person to person.
•
Serologic evaluations: useful for diagnosing and monitoring the course of therapy. They are the preferred method for diagnosing primary coccidioidal infections.
1. 1.
  
  Enzyme-linked immunoassays measure IgM and IgG antibodies and are used as a screening test. If positive, then an immunodiffusion test is used that also measures IgM and IgG. EIA tests have a high sensitivity but are less specific than the immunodiffusion test.
2. 2.
  
  Elevated serum complement-fixing antibody (CFA) titers ≥1:32 strongly correlated with disseminated disease, and their detection in the CSF is an especially important aid in diagnosing coccidioidal meningitis.
3. 3.
  
  Coccidioidal serum and urine assays are available but insensitive. They can be useful in diagnosing disease in severely immunocompromised persons (e.g., persons with AIDS) whose serologic tests are negative and in those with extensive disease.
4. 4.
  
  Coccidioidal antigen levels in CSF appear to be more sensitive than the antibody tests in CSF (93% vs. 85%) and much better than CSF culture.
•

CBC to reveal eosinophilia, especially with erythema nodosum.
•

Routine chemistries: usually normal but may reveal hyponatremia.
•

Elevated serum levels of IgE; associated with progressive disease.
•

CSF cell counts and chemistry: pleocytosis with mononuclear cell predominance associated with hypoglycorrhachia and elevated protein level.

Imaging Studies

Chest radiography:

•

Reveals unilateral infiltrates, hilar adenopathy, or pleural effusion in primary infection
•

Shows areas of fibrosis containing usually solitary, thin-walled cavities that persist as residua of primary infection
•

Possible coccidioidoma, a coinlike lesion representing a healed area of previous pneumonitis

Treatment

Nonpharmacologic Therapy

•

Supportive care in mild symptomatic disease
•

In patients with extrapulmonary manifestations involving draining skin, joint, and soft tissue infection: local wound care to avoid possible bacterial superinfection

Acute General Rx

•

In general, drug therapy is not required for patients with asymptomatic pulmonary disease and most patients with mild symptomatic primary infection.
•
Chemotherapy is indicated under the following circumstances:
1. 1.
  
  Severe symptomatic primary infection
2. 2.
  
  High serum CFA titers
3. 3.
  
  Persistent symptoms >6 wk
4. 4.
  
  Prostration
5. 5.
  
  Progressive pulmonary involvement
6. 6.
  
  Pregnancy
7. 7.
  
  Infancy
8. 8.
  
  Debilitation
9. 9.
  
  Concurrent illness (e.g., diabetes, asthma, COPD, malignancy)
10. 10.
  
  Acquired or induced immunosuppression
11. 11.
  
  Racial group with known predisposition for disseminated disease
•
Fluconazole
1. 1.
  
  Most commonly, oral therapy with 400 mg/day up to 1.2 g/day appears to be the drug of choice for meningeal and deep-seated mycotic infections.
2. 2.
  
  In patients with AIDS, fluconazole may be considered the drug of choice for initial and maintenance therapy.
3. 3.
  
  All patients with coccidioidal meningitis should continue azole therapy indefinitely.
•
Itraconazole
1. 1.
  
  400 to 600 mg/day achieves 90% response rate in bone, joint, soft tissue, lymphatic, and genitourinary infections.
2. 2.
  
  Itraconazole may be more efficacious than fluconazole in the treatment of skeletal (bone) infections but has more drug-drug interactions than fluconazole, and must be taken with fatty food and an acidic beverage to increase absorption.
•

Alternative regimens include posaconazole, a triazole agent that can be used as delayed release tablets or IV vs. suspension, or voriconazole: 6 mg/kg po q 12 hrs × 2, then 4 mg/kg po BID for patients weighing more than 40 kg.
•

For pulmonary infections, treatment with either fluconazole or itraconazole, given for 6 to 12 wk, appears to be equal in efficacy.
•
Treatment of coccidioidomycosis complicated by meningitis:
1. 1.
  
  Subacute or chronic meningitis presenting with headache, cranial nerve palsies, or focal neurological deficits.
2. 2.
  
  CSF findings include high-protein, lymphocytic pleocytosis and low glucose, and a CSF cocciodiodal antigen may be more sensitive than antibody tests or CSF culture to detect meningeal involvement.
3. 3.
  
  Treatment can be with fluconazole: 400 to 1200 mg po once a day; itraconazole: 400 to 800 mg po divided two to four times daily; or voriconazole: 6 mg/kg po/IV q 12 hrs × 24 hrs, then 4 mg/kg po q 12 hrs.
4. 4.
  
  Alternative regimens with amphotericin B: for refractory cases can use intrathecal amphotericin B: 0.1 to 1.5 mg/dose, daily to weekly, or can use liposomal amphotericin B: 3 to 5 mg/kg IV daily.
5. 5.
  
  Patients who respond to azol therapy should continue for life, as relapses are common and potentially life-threatening.
•

For osteomyelitis, soft tissue closed-space infections, and pulmonary fibrocavitary disease: surgical debridement, drainage, or resection, respectively, in addition to oral azole therapy or parenteral administration of amphotericin B.

Chronic Rx

For chronically immunocompromised patients, lifelong therapy with oral azoles or amphotericin B. Azoles should be avoided in women during the first trimester of pregnancy because of their teratogenic potential.

Disposition

•

Prognosis for primary symptomatic infection is good.
•

Immunocompromised patients are most likely to have disseminated disease and higher morbidity and mortality.
•

Risk factors for poor outcome in patients with active coccidioidomycosis are described in Table E1.

TABLEE1 Risk Factors for Poor Outcome in Young Patients With Active CoccidioidomycosisFrom Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.

Primary Infections

Severe, prolonged (≥6 wk), or progressive infection

Risk Factors for Extrapulmonary Dissemination

Primary or acquired cellular immune dysfunction (including patients receiving tumor necrosis factor inhibitors)

Neonates, infants, older adults

Male sex (adult)

Filipino, African, Native American, or Latin American ethnicity

Late-stage pregnancy and early postpartum period

Standardized complement fixation antibody titer >1:16 or increasing titer with persisting symptoms

Blood group B

HLA class II allele-DRBI∗1301

Referral

•

To surgeon for the evaluation of chronic hemoptysis, enlarging cavitary lesions despite chemotherapy and intrapleural rupture, osteomyelitis, and other synovial or soft tissue closed-space infections
•

For neurosurgical consultation in patients with meningeal disease to establish the delivery route of intrathecal drug therapy

Pearls & Considerations

Comments

•

Although coccidioidomycosis is a great imitator, a diagnosis will become apparent if a high degree of suspicion is maintained and appropriate testing (serologic testing, cultures, and histology) is performed.
•

Infected body fluids contained within a closed moist environment (e.g., sputum in a specimen cup) provide the opportunity for the fungus to revert to its hyphal form whereby spores may be made airborne on opening of the container. This is a biohazard for laboratory personnel. Purulent drainage into a cast, allowing conversion of fungus to the saprophytic phase, has been responsible for acute disease when the cast was opened and the spores were unintentionally made airborne.
•

Patients with a remote history of exposure, especially if immunosuppressed by medication or disease, may reactivate primary disease and suffer rapid dissemination.
•

Although cardiac disease is rare, constrictive pericarditis in the setting of disseminated coccidioidomycosis has been documented and is potentially fatal.
•

Organ transplant recipients may develop disease if the transplant donor has unrecognized active coccidioidomycosis at the time of death.

Ferri – Coccidioidomycosis