Pediatric Coccidioidomycosis

Author: 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 Coauthor(s): Catherine O'Keefe, DNP, APRN, Assistant Professor of Nursing and Pediatric Nurse Practitioner, Pediatric Infectious Diseases, Creighton University Medical Center

Introduction
Background

Coccidioides species is a species of dimorphic fungi endemic in the soil of the southwestern United States and some areas of Mexico, Central America, and South America. Inhalation of spores results in coccidioidomycosis, which is an acute pulmonary infection that is often asymptomatic but may manifest as a flulike illness or pneumonia. Occasionally, severe progressive pneumonia or residual pulmonary sequelae can result.1,2,3 Although occurring rarely, dissemination is most commonly observed in a host with underlying immunosuppression or other risk factors. Common sites of dissemination include skin, bone, joint, and meninges.3 Amphotericin and oral azoles are the mainstays of antifungal therapy for coccidioidomycosis. Duration of therapy for the infection is often prolonged and may last several months to years, with lifelong suppression needed in certain patients.1,2,3,4
Pathophysiology

Coccidioides species is found in a saprophytic or vegetative phase in the soil and in laboratory culture and in a parasitic or tissue phase in the host.1 In the saprophytic phase, the organism is described as mycelia with branching septate hyphae. The aerial mycelia contain rectangular spores (ie, arthroconidia) surrounded by nonviable cells, thus creating a fragile structure. Upon fragmentation of the hyphae, the infectious arthroconidia become airborne spores (spherules) measuring 8-30 m in diameter.4 These spores are inhaled by the host and reach the pulmonary alveoli; however, they also can be introduced into skin or soft tissue by inoculation into wounds or by trauma. Pulmonary infection can result from inhalation of a single spore in humans. Increased exposure occurs with disruption of soil, which can occur with earthquakes, wind or dust storms, farming, construction, archeological excavations, or with drought following heavy rains. High inoculum exposures are more likely to result in symptomatic disease. Primary infection most often occurs in the dry months of the summer or fall. Person-to-person transmission does not occur. Rare cases of infection from contaminated fomites (eg, contaminated plaster cast, dusty clothing) have been reported.5

The incubation period of coccidioidomycosis averages 10-16 days, with a range from less than 7 to 30 days.2 The spores enlarge to spherules that are round double-walled structures measuring approximately 20-100 m in diameter. The spherules undergo internal division within 48-72 hours until they are filled with hundreds to thousands of offspring (ie, endospores). Rupture of the spherules leads to the release of endospores, which mature to form more spherules.5 The spherules and endospores are not infectious. Most Coccidioides species infections remain confined to the lung and hilar nodes. The body responds to the presence of the endospores with activation of complement and release of chemotactic factors. An intense, primarily neutrophilic, inflammatory reaction follows; however, the recruited neutrophils and macrophages are unable to kill the organisms because the spherules are resistant to phagocytosis. T-cell mediated immunity is important for killing and clearing of the organism; therefore, deficiencies in this arm of the immune system render the host of the fungus extremely vulnerable to disease and dissemination.5 With dissemination, cell-mediated immunity can become impaired further, often resulting in anergy to skin tests. The mechanism for this effect on cell-mediated immunity is unclear, although many theories have been postulated. Antigen overload, suppressor cells, formation of immune complexes, and elaboration of immunosuppressive substances by the fungi may contribute to the impairment in cell-mediated immunity.5 Eventually, immunity may recover with treatment and control of the coccidioidomycosis.
Frequency United States

Incidence averages approximately 150,000 cases of coccidioidomycosis per year. This estimate is greater than the 100,000 cases per year previously cited in the literature as a result of population increases in southern Arizona and central California, where the organism is endemic.6,4 Coccidioides species is endemic in soil in the southwestern United States, including California (especially the San Joaquin Valley), western Texas, New Mexico, and the deserts of Arizona. In endemic areas, the annual risk of infection is 2-4% among healthy individuals. The organism's habitat is characterized as the lower Sonoran life zone, with an arid-to-semiarid climate, alkaline dry soil, hot summers, moderate-to-low rainfall of 5-20 in/y, and inability to grow at altitudes greater than 3700 feet.1,6,7 Coccidioidomycosis can be observed in nonendemic areas due to travel, population mobility, immunosuppression, and reactivation. Diagnosis often is delayed in nonendemic areas because coccidioidal infection initially is not considered in the differential.2,3,5,8 Domesticated, zoo, and wild animals can also be infected with Coccidioides species. Coccidioidal disease has a significant socioeconomic impact in the United States. An otherwise healthy individual diagnosed with symptomatic coccidioidomycosis may miss more than 1 month of school or work. Recent estimates of antifungal medication costs range from $500020,000 per person per year of therapy for the disease.3,9

International

Coccidioides species (specifically C posadasii) is also found in northern Mexico and some parts of Central and South America; all areas are located between 40 latitude, north and south.2,10,11
Mortality/Morbidity

Mortality is extremely uncommon with primary coccidioidomycosis. Approximately 90-95% of infections resolve without sequelae; however, 5-10% have severe or progressive pneumonia, including nodules or peripheral thin-walled cavities, with a smaller proportion resulting in chronic pulmonary or extrapulmonary disease. Dissemination is uncommon (approximately 0.5% of infections in whites), typically involves infection of the skin, bone or joint, lymph nodes, or CNS, and is associated with increased morbidity and mortality. In the host who is immunocompromised, the risk of dissemination is much higher (up to 30-50%), and mortality can be as high as 70% even with appropriate therapy.2,3,5
Race

No race predilection for primary infection with Coccidioides species is observed. Dissemination is more common in Filipinos and blacks and possibly in other Asians, Hispanics, and Native Americans. The risk of dissemination is 175 times greater in Filipinos and 10 times greater in blacks than in non-Hispanic whites.4 Some studies have suggested genetic bases to the predisposition to dissemination, including a possible association with blood group type B.12
Sex

Increased incidence of primary coccidioidal infection may be apparent in older boys and men because of occupational exposure. Women who are pregnant, especially during the third trimester and in the peripartum period, are at higher risk for dissemination than the general population.4,13,14
Age

In general, dissemination is less common in children than in adults. Neonatal infection is rare14 ; however, infants can experience severe disease within the first few months of life, especially if exposed to a large respiratory inoculum.

Clinical
History

In patients with suspected coccidioidomycosis, a history of travel or residence in an endemic area is very important in establishing the risk of exposure. The exposure may be as limited as driving through an endemic area.1,2,3,4,5,15,16
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Patients with primary pulmonary coccidioidal infection may have the following:

Fever Localized adventitious breath sounds Mild respiratory distress Arthritis and rash (classic rash is erythema multiforme [EM] or erythema nodosum [EN]) In general, a patient with disseminated coccidioidomycosis may have signs of the following: o Chronic illness o Weight loss o Fever o Lymphadenopathy: The physical examination depends on the site of involvement and is relatively nonspecific.
o o o o

Physical

In most patients with coccidioidal infection, the primary infection is in the lungs. In 60-65% of individuals affected with coccidioidomycosis, primary pulmonary infection is asymptomatic. Extrapulmonary primary infections can occur with trauma causing a puncture wound from a contaminated object. Laboratory workers and children are especially at risk for cutaneous or soft tissue lesions, including chancres, with regional lymphadenitis.1,2,3,4,5,15,16
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Pulmonary coccidioidomycosis15 o Pulmonary coccidioidomycosis may be difficult to differentiate from other acute or subacute respiratory infections with fever. Most symptomatic primary infections are not easily diagnosed as coccidioidomycosis unless classic findings (eg, EM, EN) are present in an endemic area. o 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. Primary coccidioidomycosis3,4 o Symptomatic patients with primary coccidioidomycosis have a range of presentations from brief upper respiratory infection or flulike illness to lobar pneumonia. The most common symptoms are cough, fever, fatigue, chest pain, dyspnea, and hemoptysis. More severe manifestations include pleural effusions, pericarditis, and rare presentations mimicking bacterial pneumonia and sepsis. o Skin manifestations are common with primary infection. More than 50% of children with primary coccidioidomycosis develop rashes that begin as diffuse, evanescent, maculopapular rashes or urticaria. The host may develop EM or EN after 3-21 days. EM is more common in children. Although nonspecific, EN is the classic presentation in an endemic area. Prognostically, EN is suggestive of low risk of dissemination since it correlates with development of cell-mediated immunity. EN occurs less often in persons outside of endemic areas and occurs infrequently in blacks, Hispanics, and Filipinos. In adults, females are affected with EN much more frequently than males. o Other common symptoms of primary coccidioidomycosis include arthralgias, arthritis, and myalgias. The syndrome of valley fever includes fever, arthralgias, and EN or EM. Headaches and anorexia also can be present. Infants and older children can present with stridor from laryngeal infection. o Primary infection of the newborn rarely occurs. Infection of the genital tract of the mother can result in placental involvement, coccidioidal endometritis, and aspiration of

infected amniotic fluid by the fetus. Both congenital and perinatal transmission of Coccidioides species have been reported. o Although the illness, especially the fatigue, may persist for weeks to months, 90-95% of primary pulmonary infections resolve without sequelae. Of patients with primary coccidioidomycosis, 5-10% have persistent pulmonary nodules or cavities on chest radiography. The cavitary pulmonary lesions often are thin-walled, asymptomatic, and resolve spontaneously. Cavities larger than 6 cm in diameter are at greater risk for rupture and require surgery. o Occasionally, the pneumonia can be severe or progressive or dissemination can occur. In addition, chronic pulmonary infection can occur, particularly in hosts who are immunocompromised or those with underlying diabetes. Children rarely develop chronic pulmonary lesions. Disseminated coccidioidomycosis17 o Consider disseminated coccidioidomycosis in individuals with persistent fevers or malaise; chronic pulmonary infiltrates or nodules; or skin, soft tissue, or bone lesions in the appropriate epidemiologic setting. o A higher risk of infection is suggested after a large inoculum exposure to soil, such as from windstorms, digging, farming, and construction. o Approximately 0.5-1% of individuals with coccidioidomycosis develop disseminated disease. Dissemination usually occurs weeks to months after the initial infection but may occur after 1 year in a host who is immunocompromised. In addition, reactivation of treated primary disease may occur at any time in a host who is immunosuppressed. o Widespread miliary disease is very rare but may progress rapidly and is often fatal. The presence of diffuse reticulonodular or miliary pulmonary infiltrates from coccidioidomycosis suggests an underlying immunodeficiency. Hosts who are immunocompromised can have concurrent aggressive primary pulmonary disease and dissemination. o Infection in the host who is immunocompromised is fulminant, especially with T-cell dysfunction in patients with HIV18 , solid organ transplantation19,20 , and/or lymphoma. Patients who are immunosuppressed from high-dose corticosteroid or anti-tumor necrosis factor (TNF) therapy are also at increased risk for dissemination. Patients with organ transplants are at the greatest risk for disseminated coccidioidomycosis in the first year posttransplant. Ten percent of patients who are HIV positive and reside in endemic areas contract active coccidioidal disease each year. In particular, adults infected with HIV with CD4 counts less than 250 are at significant risk for active disease. o Signs of dissemination include persistent fever, toxicity, and development of extrapulmonary lesions. Coccidioides species has a predilection for the lungs, skin, soft tissue, joints, and CNS, especially the meninges. o The skin is the most common site of extrapulmonary disease.21 In most types of disseminated disease, the skin eventually is involved. The classic skin manifestation of coccidioidomycosis is a verrucous granuloma at the nasolabial fold. Other typical lesions include granulomatous papules, nodules, and plaques, especially on the head. These lesions can progress to subcutaneous involvement, sinus tracts, abscesses, and chronic ulcers. Differential diagnoses of coccidioidal skin lesions include tuberculosis, syphilis, other fungi, actinomycetes, sarcoid, warts, and squamous cell carcinoma. o Coccidioidomycosis also affects joints, causing synovitis. Knees are the most common joints involved, followed by ankles and wrists. Infection of the bone typically causes a chronic osteomyelitis, often draining to soft tissue and creating fistulae. Long bones, as

well as bones of the hands, feet, pelvis, and skull, may be involved. Approximately 60% of incidents of coccidioidomycosis are limited to a single bone, with 20% involving 2 bones and 10% involving 3 bones. Vertebral osteomyelitis can affect any part of the vertebra, sparing the disc, but putting the patient at risk of meningitis.22 Approximately 50% of patients with disseminated coccidioidomycosis acquire CNS disease. It can occur acutely with primary infection or later with dissemination and can be the only site of dissemination. CNS coccidioidomycosis can present with headache, vomiting, nuchal rigidity, change in mental status, lethargy, confusion, ataxia, diplopia, and focal neurologic signs.23 Coccidioidal meningitis is usually chronic with insidious onset, in contrast to meningitis from bacterial causes. Typically a granulomatous and suppurative basilar process, coccidioidal meningitis can also involve the brain parenchyma and spinal cord with granulomas and abscesses. Hydrocephalus is a common sequela and is often present at initial diagnosis in children. Although the skin, lungs, joints, soft tissue, and meninges are the most common sites for coccidioidal dissemination17 , infection of almost every other organ system has been reported. At autopsy, involvement of the liver, spleen, kidney, adrenal glands, psoas muscle, heart, thyroid, and prostate has been noted. These infected sites rarely are responsible for the presenting signs or symptoms. Infection of the thyroid gland has been reported to result in a thyroid abscess and thyrotoxicosis.  Ocular coccidioidomycosis can present as a lacrimal gland fossa mass or with eye pain, photophobia, and other symptoms of chorioretinitis or iridocyclitis.  Hepatic infection is usually asymptomatic but can be part of a hepaticpulmonary syndrome with a brief hepatitis-like illness, hepatic granulomas, and eosinophilia.  Coccidioidal infection of the biliary tree is uncommon but has been reported to present as abdominal pain and obstructive jaundice. Intestinal obstruction and peritonitis have also been reported to be secondary to coccidioidal infection.  Coccidioidal infection of the genitourinary tract can result in nodules or granulomas, abscesses, or fistulae in the kidney, ureter, bladder, prostate, epididymis, or testes.

Differential Diagnoses
Actinomycosis Lymphadenopathy

Acute Lymphoblastic Leukemia Lymphoproliferative Disorders Acute Myelocytic Leukemia Aspergillosis Meningitis, Aseptic Meningitis, Bacterial

Atypical Mycobacterial InfectionMycoplasma Infections Blastomycosis Brucellosis Catscratch Disease Nocardiosis Osteomyelitis Parainfluenza Virus Infections

Chronic Granulomatous Disease Pneumococcal Infections Fever Without a Focus Histiocytosis Histoplasmosis Influenza Legionella Infection Respiratory Syncytial Virus Infection Sarcoidosis Toxoplasmosis Tuberculosis Wegener Granulomatosis

Workup
Laboratory Studies

The following studies may be indicated in coccidioidomycosis:

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Nonspecific laboratory tests o Nonspecific laboratory tests include an elevated erythrocyte sedimentation rate (ESR), leukocytosis, and eosinophilia (>5% in 27% of patients with coccidioidomycosis). o Patients with coccidioidal meningitis may have cerebrospinal fluid (CSF) pleocytosis with a mononuclear predominance, decreased glucose, and elevated protein. o One study has suggested an association between low serum mannose-binding lectin (MBL) levels and symptomatic coccidiodomycosis.24 Serology1,2,3,4,5,25,26 o Serologic testing is helpful for confirmation of the diagnosis and prognostication of coccidioidal infection. False-positive serology tests are rare. o Coccidioidal immunoglobulin M (IgM) is present in 75% of patients with acute infection and is more sensitive than complement fixation (CF) for early infection. IgM usually appears within 1-3 weeks after the onset of symptoms and lasts 3-4 months; however, IgM may persist and/or reappear with reactivation. o Methods to evaluate coccidioidal IgM include latex agglutination, enzyme immunoassay, immunodiffusion, tube precipitins, and immunoelectrophoresis. IgM only is useful qualitatively, as the magnitude does not correlate with dissemination or extent of disease. o Immunodiffusion and CF methods can detect coccidioidal immunoglobulin G (IgG). The CF titer is useful as a quantitative measure of the extent and progression of disease. Most titers are positive by 3 months after infection onset, persist 6-8 months, and disappear as infection resolves. o The CF titer may be low or absent in mild or asymptomatic disease or in immunosuppressed patients. Approximately 95-100% of patients with titers less than or equal to 1:16 do not have disseminated disease. High titers greater than or equal to 1:32 persist in severe, untreated extrapulmonary or disseminated disease. o Coccidioidal CF titers of the serum and cerebrospinal fluid can be followed to monitor the effect of treatment on disease and predict relapses. Culture

Culture of Coccidioides species from infected tissue or fluids often is possible within 3-4 days of inoculation on laboratory media, even when spherules are not present on direct examination. o In culture, the spherules can convert to arthroconidium and grow in the lab in the infectious mycelial phase; therefore, notify the laboratory of the possibility of coccidioidomycosis so that appropriate precautions and equipment may be used. o After the cultures begin to grow, a chemiluminescent DNA probe can identify the organism. Susceptibility testing of Coccidioides species in one report revealed uniform susceptibility to most antifungal agents.27
o

Imaging Studies
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Radiography1,2,3,4,5,15,16,17,21,22 o In primary pulmonary infection, the chest radiograph depicts nonspecific changes, including segmental or lobar infiltrates, hilar adenopathy, and small pleural effusions. o Five percent of patients may have nodules, cavitation, bronchiectasis, or calcifications depicted on the radiograph. The cavitary pulmonary lesions are often thin-walled, asymptomatic, and resolve spontaneously. Cavities larger than 6 cm in diameter are at greater risk for rupture and require surgery. o In certain patients with coccidioidomycosis, especially immunocompromised patients, the chest radiograph can reveal diffuse nodular densities. Nodules and adenopathy can be difficult to differentiate from malignancy or other infectious processes. o Radiographic changes in primary pulmonary coccidioidomycosis often resolve spontaneously, albeit slowly. o In patients with osteomyelitis, bone radiographs may show lytic lesions, periosteal elevation, and bony destruction.
o

Coccidioidal osteomyelitis of the right elbow. Plain film radiograph. Photograph by Preeyacha Pacham, MD. CT/MRI
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The high-resolution CT scan can further delineate extent of pulmonary and lymph node involvement.

Pulmonary nodule from infection with Coccidioides species. CT scan of the chest. Photograph by Preeyacha Pacham, MD. [ CLOSE WINDOW ]

Pulmonary nodule from infection with Coccidioides species. CT scan of the chest. Photograph by Preeyacha Pacham, MD.
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MRI may help better delineate the extent of bone, joint, and overlying soft tissue involvement, including sinus tracts or fistulae. A bone scan may detect multiple sites of bony involvement. CT or MRI of the brain in patients with CNS involvement may demonstrate meningeal enhancement, granulomas, or abscesses. In addition, patients often have signs of hydrocephalus on imaging. Therefore, MRI may be better in this respect to evaluate the patency of the aqueduct of Sylvius.

Other Tests
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Skin tests5

Skin testing is not helpful in making the diagnosis of coccidioidomycosis because it cannot distinguish between past and acute infection; however, skin tests can be useful as epidemiologic or research tools. A positive skin test is 5 mm or more of induration observed 48 hours after intradermal application. The skin test becomes positive 10-45 days after infection or 2-21 days after symptom onset. Anergy is common in patients with disseminated disease, even without underlying immunosuppression. In addition, a low level of cross-reactivity with blastomycosis and histoplasmosis occurs.

Procedures
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Perform lumbar puncture in patients with fever, headache, nuchal rigidity, meningismus, mental status changes, or ataxia.16,17 Bronchoscopy with bronchoalveolar lavage, needle aspiration, and/or lung biopsy may be indicated with persistent or progressive infections, especially in hosts who are immunocompromised. Synovial biopsy may be needed to document coccidioidal dissemination to a joint.

Histologic Findings
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Histopathologic specimens of affected tissues may reveal the pathognomonic spherules on hematoxylin-eosin or silver stains.

Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD. [ CLOSE WINDOW ]

Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD.
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Spherules may be observed in tracheal aspirates; purulent material; biopsies of lymph nodes, skin, or organs; joint fluid; urine; and, less commonly, cerebrospinal fluid. Tissue lesions consist of granulomas with abundant giant cells and histiocytes, with or without acute inflammation. Caseous necrosis, fibrous changes, and rare calcification can also be found.

Treatment
Medical Care

Antifungal therapy is not usually necessary for uncomplicated acute primary coccidioidomycosis. For many patients, management of uncomplicated acute primary coccidioidal pneumonia mainly relies on periodic reassessment of symptoms and resolution of any radiographic findings. However, some experts propose treatment of all symptomatic patients; currently the data from prospective controlled trials in this area are insufficient. Initiation of therapy is warranted for specific situations, such as for patients with severe progressive pulmonary disease or with concurrent risk factors for dissemination.10,1,2,3,4,5,15,16,17,18,21,22,23
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Indicators of severity of illness for which to consider therapy of acute primary pulmonary infection include the following:3 o Continuous fever for longer than 1 month o Night sweats for longer than 3 weeks o Weight loss greater than 10% o Prominent or persistent hilar adenopathy

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Large (>50% of one lung) or bilateral pulmonary infiltrates Complement fixation (CF) titers greater than or equal to 1:16 Persistent symptoms for longer than 2 months Inability to work Age older than 55 years Risk factors for dissemination for which treatment should be initiated include the following: o Primary infection during infancy o Primary infection during pregnancy, especially in the third trimester, or immediately postpartum o Immunosuppression o Chronic debilitation or underlying disease, including diabetes mellitus or preexisting cardiopulmonary disease o High inoculum exposures o Certain ethnicities, such as Filipino or black Typical antifungal therapy of acute primary pulmonary coccidioidomycosis in these high-risk groups consists mainly of oral azoles at the recommended adult doses (usually 200-400 mg/d) for 3-6 months duration (see Medication). During pregnancy, amphotericin B is the treatment of choice because the azoles may be teratogenic. Initially treat patients with diffuse pulmonary disease (ie, miliary or reticulonodular infiltrates) with amphotericin B or high-dose fluconazole for several weeks until definite signs of improvement are observed. If there is rapid deterioration or significant hypoxia, amphotericin B is used more frequently. After clear evidence of improvement emerges, therapy may be changed to an oral azole to complete a prolonged course of antifungal therapy. Because these patients are often immunocompromised, the total duration of therapy should be at least 1 year, with secondary prophylaxis continuing indefinitely for subgroups of patients who are severely immunodeficient. Persons with asymptomatic pulmonary nodules or cavities often do not warrant antifungal therapy in the absence of immunosuppression. Individuals with symptomatic or enlarging cavities may respond to oral azole therapy or oral antibacterial therapy, if bacterial superinfection of the cavity is present. However, symptoms may recur upon cessation of therapy and the cavities usually do not resolve with antifungal therapy. Antifungal therapy, often in conjunction with surgical treatment, is recommended for patients with ruptured coccidioidal cavities. Individuals with chronic progressive fibrocavitary pneumonia may be treated with prolonged azole therapy for at least 1 year. Persons with progressive pulmonary disease not responding to medical therapy with oral azoles may benefit from a higher dose of azole, an alternative azole, or amphotericin B and/or surgical resection. All patients with disseminated coccidioidomycosis warrant prolonged antifungal treatment. Therapy for nonmeningeal extrapulmonary disease can be initiated with oral azoles unless the disease is rapidly progressive or in a critical location (such as the vertebral column); in such situations, the alternative therapy is amphotericin B. Some authors suggest initial therapy with amphotericin B until significant clinical, radiographic, and laboratory test (in particular, CF titers) improvements are documented, followed by completion of the antifungal regimen with an oral azole. Fluconazole and itraconazole are the most commonly used azoles, at doses from 4002000 mg/d for fluconazole, and up to 800 mg/d for itraconazole. In patients who warrant amphotericin B therapy but have drug-related toxicities, lipid amphotericin B formulations can be considered and have been effective in animal models,
o o o o o

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although no human clinical trials have assessed their efficacy. Combination therapy with amphotericin B and an azole has been reported, but no clinical trials have demonstrated its superiority to single agent treatment, and antagonism with combination therapy has been reported for other fungal infections. The preferred regimen for individuals with meningeal disease is administration of oral fluconazole, although itraconazole also has been reported to be effective. Adult dosages of fluconazole for meningitis range from 400-1000 mg/d and for itraconazole from 400-600 mg/d. Intrathecal amphotericin B23,28 has been used in conjunction with an oral azole, both initially and as an alternative regimen after failure with azole therapy alone. The dose of intrathecal amphotericin B ranges from 0.1-1.5 mg per dose. Lifelong antifungal therapy must be continued in patients with CNS involvement23 with Coccidioides species because of high relapse rates (ie, up to 75%) with oral azoles. CNS vasculitis is a life-threatening complication of coccidioidal meningitis. Short-term treatment with high-dose IV corticosteroids has been reported with varying results in regards to benefit.

Surgical Care
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Surgery is indicated for the following conditions: asymptomatic persistent pulmonary cavities, especially if enlarging or adjacent to the pleura; symptomatic localized or persistent pulmonary infections, including empyema and bronchopleural fistulae; and cavities associated with rupture or hemoptysis. In patients with chronic osteomyelitis, drainage of sequestrum in bones and debridement of adjacent purulent soft tissues often is necessary. Joint involvement can be managed by incision and drainage, although occasionally synovectomy and arthrodesis are needed. Immobilization of limbs affected by the disease may be necessary. The benefit of irrigation and local instillation of amphotericin B to joints, cavities, or abscesses affected by coccidioidomycosis is controversial, and no clear data supporting this practice are available. Hydrocephalus from CNS involvement often requires shunt placement for management.

Medication
Historically, amphotericin B has been the drug of choice to treat disseminated coccidioidomycosis. More recently, oral azoles have provided a desirable alternative for both initial therapy and completion of courses after amphotericin therapy. The benefits of azoles include oral formulations and fewer adverse effects. Large, multicenter, nonrandomized clinical trials have studied the response of chronic pulmonary and disseminated coccidioidal infections to oral azoles (eg, fluconazole, itraconazole, ketoconazole) and have found adequate treatment efficacy but high relapse rates upon cessation of therapy. Other azoles (eg, voriconazole) may also be effective against Coccidioides species. Research on the use of immunomodulators to improve T-cell response to coccidioidal infection is still underway. A new triazole antifungal, posaconazole (Noxafil), was recently approved by the US Food and Drug Administration (FDA).3,29,30

Polyene antifungal

These agents are used for rapidly progressing coccidioidal infection and disease unresponsive to oral azole therapy.

Amphotericin B (Fungizone, AmBisome, Abelcet)

Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. DOC for rapidly progressing coccidioidal infection and disease nonresponsive to PO azole therapy. Liposomal amphotericin should be used when significant nephrotoxicity is a risk with conventional amphotericin B therapy. Intrathecal amphotericin B has been used for coccidioidal meningitis.
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Dosing

Adult

Primary pulmonary (amphotericin B lipid complex or liposomal): 5 mg/kg/day IV; infuse IV at rate of 2.5 mg/h Meningitis (amphotericin B deoxycholate [conventional]): 0.1-1.5 mg/dose IT; administered at intervals from daily to weekly, increasing dose to patient's tolerance
Pediatric

Administer as in adults
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Interactions Antineoplastic agents may enhance potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine

Contraindications Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Severe renal dysfunction can result; administer NS bolus or PO sodium chloride before each dose; monitor serum electrolytes (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); IT administration may cause pain with administration, headache, paresthesias, nerve palsies, and arachnoiditis Premedication with acetaminophen and/or diphenhydramine may reduce infusion-related symptoms and may be repeated at appropriate dosing interval if infusion is prolonged; hydrocortisone (mixed with amphotericin solution) has also been used to reduce infusion-related symptoms
Azole antifungals

Oral azoles have been used in the treatment of disseminated coccidioidomycosis and primary pulmonary infections in high-risk groups. Overall, the initial response rate is 50-60% with azole therapy, although relapse rates may be as high as 50%. A preliminary report from the Mycoses Study Group found no statistically significant difference in efficacy between fluconazole and itraconazole. How well azoles perform in rapidly progressive disease is not clear.

Fluconazole (Diflucan)

Fungistatic activity. Synthetic PO antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Used in treatment of primary pulmonary infections in high-risk groups and of disseminated coccidioidomycosis. Preferred over ketoconazole because of better response rates and less GI and endocrine adverse effects. Available in PO susp.
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Dosing

Adult

400 mg/d PO/IV; doses as high as 800-1000 mg/d have been reported
Pediatric

10-12 mg/kg/d PO/IV; not to exceed 400 mg/d

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Interactions

Levels may increase with hydrochlorothiazide; levels may decrease with long-term coadministration of rifampin; coadministration of fluconazole may decrease phenytoin clearance; may increase concentrations of theophylline, tolbutamide, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration; increases in cyclosporine concentrations may occur when administered concurrently
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Contraindications Documented hypersensitivity, pregnancy, concurrent QT-prolonging drugs, congenital long QT pts or conditions that incur QT prolongation risk

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Monitor closely if rashes develop and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) in patients with underlying medical conditions (eg, AIDS, malignancy) and in those taking multiple concomitant medications; not recommended for mothers who are breastfeeding
Itraconazole (Sporanox)

Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. Used to treat primary pulmonary infections in high-risk groups and disseminated coccidioidomycosis. Preferred over ketoconazole because of better response rates and less GI and endocrine adverse effects. IV form available, but long-term usage is not established. Also available in PO solution. The PO solution provides better, more consistent absorption than the capsule. Take capsules with full meal to improve absorption, but take oral solution on empty stomach, if possible.
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Dosing

Adult

400 mg/day PO
Pediatric

5-10 mg/kg/day PO; not to exceed 400 mg/day

Interactions Strong CYP3A4 inhibitor; antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (ie, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered)

Contraindications Documented hypersensitivity; pregnancy; concurrent QT-prolonging drugs or congenital long QT

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Black Box Warnings Congestive heart failure (CHF): Negative inotropic effects reported with IV administration; reassess therapy if signs or symptoms of CHF occur during administration Contraindicated drug interactions: Potent CYP450 3A4 inhibitor; serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death reported when administered with drugs metabolized by this isoenzyme system, including cisapride, pimozide, quinidine, dofetilide, or levomethadyl acetate Other precautions Caution in hepatic insufficiencies; level can be checked after 2 wk of therapy to document adequate absorption; GI distress, headache, dizziness, rash, and hypokalemia
Ketoconazole (Nizoral)

Fungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death. Has been used in treatment of coccidioidomycosis, although fluconazole and itraconazole are preferred because of low response rates (<40%) with ketoconazole. In addition, may have greater GI and endocrine adverse effects at high doses.
y

Dosing

Adult

400-800 mg/day PO; if 800 mg/day needed, administer in divided doses bid
Pediatric

>2 years: 3.3-6.6 mg/kg/day PO; not to exceed adult dose y Interactions
Strong CYP3A4 inhibitor; isoniazid may decrease bioavailability; coadministration with rifampin decreases effects of either drug; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels; ventricular arrhythmias reported when ketoconazole was coadministered with cisapride (restricted distribution in the US), terfenadine, or astemizole (no longer on US market) due to accumulation of these drugs

y Contraindications
Documented hypersensitivity

y Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in hepatic insufficiencies; has been associated with fatal hepatotoxicity; high doses may suppress adrenocortical function; jaundice, GI distress, rash, alopecia, adrenocortical insufficiency, diminished libido, impotence, menstrual irregularities, and gynecomastia

Follow-up
Further Outpatient Care
y

Treatment of patients with primary pulmonary coccidioidomycosis relies on periodic monitoring of symptoms and radiographic studies to assess residual disease (eg, nodules, cavities) and identify signs of early dissemination. Continue follow-up care for at least 1-2 years or until resolution of all coccidioidal disease occurs. The identification of progressive pulmonary disease or dissemination warrants initiation of antifungal therapy as outlined in Medication. Follow-up care of patients with disseminated coccidioidomycosis includes periodic monitoring of the complement fixation (CF) titer until it is less than 1:8. Also, monitor other abnormal laboratory or radiographic studies at regular intervals. Initially, monitor CF titers at monthly intervals until a consistent decrease has been documented. Relapses of coccidioidomycosis can be predicted by recurrence of symptoms,

y y

physical findings, and increases in the CF titer. Cerebrospinal fluid (CSF) abnormalities and CF titers may persist for months despite therapy. Development of hydrocephalus in a patient with coccidioidal meningitis who is otherwise stable and improving does not imply failure of antifungal therapy. Monitor routine health maintenance as well as reviews of all medications for potential drug interactions with the prescribed antifungal therapy. Periodically evaluate adverse effects of antifungal medications by history and laboratory testing.

Deterrence/Prevention
y y

Infection with Coccidioides species can be minimized with dust control measures at construction or archaeological sites and in areas with large amounts of soil disruption. Within the hospital, isolation precautions are not necessary because person-to-person transmission of the disease does not occur; however, draining wounds may pose an infectious risk from aerosolization of organisms growing in the dressing or cast material. Enforce proper disposal of contaminated materials.2 Primary prophylaxis for patients with HIV in endemic areas is not recommended routinely. However, indefinitely continue suppressive therapy after active disease (ie, secondary prophylaxis) with oral itraconazole (200 mg twice a day) or fluconazole (400 mg each day). For patients with organ transplants and a history of coccidioidomycosis, antifungal treatment at the time of engraftment has been proposed, although no formal recommendations exist. No vaccines to prevent coccidioidomycosis currently are used in humans. A killed spherulederived vaccine was found to be efficacious in experimental animals but not protective in humans. Multiple Coccidioides species cell-surface antigens have been investigated for their ability to stimulate protective T-cell mediated immune responses. Currently, recombinant DNA techniques to develop vaccines using the proline-rich31 and other antigens from the Coccidioides spherule appear promising.

Miscellaneous
Medicolegal Pitfalls
y

Delay in diagnosis of disseminated coccidioidomycosis may occur, given the insidious nature of the disease; however, no medicolegal issues specific to the diagnosis or management of coccidioidomycosis exist.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Michele M Cheung, MD and Peggy Weintrub, MD to the development and writing of this article.