Pediatric Coccidioidomycosis

8/7/2019 Pediatric Coccidioidomycosis

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Pediatric Coccidioidomycosis

Author: Archana Chatterjee, MD, PhD, Professor of Pediatrics, Medical Microbiology andImmunology, and Pharmacy, Division of Pediatric Infectious Diseases, Chief of Division of

Pediatric Infectious Diseases, Creighton University School of Medicine; Hospital Epidemiologistand Medical Director of Infection Control, Children's HospitalCoauthor(s): Catherine O'Keefe, DNP, APRN, Assistant Professor of Nursing and PediatricNurse Practitioner, Pediatric Infectious Diseases, Creighton University Medical Center

Introduction

Background

Coccidioides species is a species of dimorphic fungi endemic in the soil of the southwesternUnited 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 oftenasymptomatic but may manifest as a flulike illness or pneumonia. Occasionally, severeprogressive pneumonia or residual pulmonary sequelae can result.1,2,3

Although occurring rarely, dissemination is most commonly observed in a host with underlyingimmunosuppression 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 laboratoryculture and in a parasitic or tissue phase in the host.1In the saprophytic phase, the organism isdescribed as mycelia with branching septate hyphae. The aerial mycelia contain rectangularspores (ie, arthroconidia) surrounded by nonviable cells, thus creating a fragile structure. Uponfragmentation of the hyphae, the infectious arthroconidia become airborne spores (spherules)measuring 8-30 m in diameter.4These spores are inhaled by the host and reach the pulmonaryalveoli; however, they also can be introduced into skin or soft tissue by inoculation into woundsor by trauma.

Pulmonary infection can result from inhalation of a single spore in humans. Increased exposureoccurs with disruption of soil, which can occur with earthquakes, wind or dust storms, farming,construction, archeological excavations, or with drought following heavy rains. High inoculumexposures are more likely to result in symptomatic disease. Primary infection most often occursin the dry months of the summer or fall. Person-to-person transmission does not occur. Rarecases of infection from contaminated fomites (eg, contaminated plaster cast, dusty clothing) havebeen reported.5


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The incubation period of coccidioidomycosis averages 10-16 days, with a range from less than 7to 30 days.2The spores enlarge to spherules that are round double-walled structures measuringapproximately 20-100 m in diameter. The spherules undergo internal division within 48-72hours until they are filled with hundreds to thousands of offspring (ie, endospores). Rupture ofthe spherules leads to the release of endospores, which mature to form more spherules.5The

spherules and endospores are not infectious.

Most Coccidioides species infections remain confined to the lung and hilar nodes. The bodyresponds to the presence of the endospores with activation of complement and release ofchemotactic factors. An intense, primarily neutrophilic, inflammatory reaction follows; however,the recruited neutrophils and macrophages are unable to kill the organisms because the spherulesare resistant to phagocytosis. T-cell mediated immunity is important for killing and clearing ofthe organism; therefore, deficiencies in this arm of the immune system render the host of thefungus 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 ofimmune complexes, and elaboration of immunosuppressive substances by the fungi maycontribute to the impairment in cell-mediated immunity.5Eventually, immunity may recover withtreatment and control of the coccidioidomycosis.

Frequency

United States

Incidence averages approximately 150,000 cases of coccidioidomycosis per year. This estimateis greater than the 100,000 cases per year previously cited in the literature as a result ofpopulation increases in southern Arizona and central California, where the organism isendemic.6,4Coccidioides species is endemic in soil in the southwestern United States, includingCalifornia (especially the San Joaquin Valley), western Texas, New Mexico, and the deserts ofArizona. In endemic areas, the annual risk of infection is 2-4% among healthy individuals. Theorganism's habitat is characterized as the lower Sonoran life zone, with an arid-to-semiaridclimate, alkaline dry soil, hot summers, moderate-to-low rainfall of 5-20 in/y, and inability togrow 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 becausecoccidioidal infection initially is not considered in the differential.2,3,5,8Domesticated, zoo, andwild animals can also be infected with Coccidioides species.

Coccidioidal disease has a significant socioeconomic impact in the United States. An otherwisehealthy individual diagnosed with symptomatic coccidioidomycosis may miss more than 1month of school or work. Recent estimates of antifungal medication costs range from $5000-20,000 per person per year of therapy for the disease.3,9


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International

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

M

ortality/M

orbidity

Mortality is extremely uncommon with primary coccidioidomycosis. Approximately 90-95% ofinfections resolve without sequelae; however, 5-10% have severe or progressive pneumonia,including nodules or peripheral thin-walled cavities, with a smaller proportion resulting inchronic pulmonary or extrapulmonary disease. Dissemination is uncommon (approximately0.5% 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 isimmunocompromised, the risk of dissemination is much higher (up to 30-50%), and mortalitycan be as high as 70% even with appropriate therapy.2,3,5

Race

No race predilection for primary infection with Coccidioides species is observed. Disseminationis more common in Filipinos and blacks and possibly in other Asians, Hispanics, and NativeAmericans. The risk of dissemination is 175 times greater in Filipinos and 10 times greater inblacks than in non-Hispanic whites.4Some studies have suggested genetic bases to thepredisposition 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 thirdtrimester and in the peripartum period, are at higher risk for dissemination than the generalpopulation.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 ifexposed to a large respiratory inoculum.

Clinical

History

In patients with suspected coccidioidomycosis, a history of travel or residence in an endemicarea is very important in establishing the risk of exposure. The exposure may be as limited asdriving through an endemic area.1,2,3,4,5,15,16

y Patients with primary pulmonary coccidioidal infection may have the following:


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o Fevero Localized adventitious breath soundso Mild respiratory distresso Arthritis and rash (classic rash is erythema multiforme [EM] or erythema nodosum [EN])

y In general, a patient with disseminated coccidioidomycosis may have signs of the following:o Chronic illnesso Weight losso Fevero Lymphadenopathy: The physical examination depends on the site of involvement and is

relatively nonspecific.

Physical

In most patients with coccidioidal infection, the primary infection is in the lungs. In 60-65% ofindividuals affected with coccidioidomycosis, primary pulmonary infection is asymptomatic.Extrapulmonary primary infections can occur with trauma causing a puncture wound from acontaminated object. Laboratory workers and children are especially at risk for cutaneous or softtissue lesions, including chancres, with regional lymphadenitis.1,2,3,4,5,15,16

y Pulmonary coccidioidomycosis15o 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 coccidioidalinfection is not imperative unless the patient is immunocompromised or has signs of

severe progressive disease or dissemination.

y Primary coccidioidomycosis3,4o 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 withprimary 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 themother can result in placental involvement, coccidioidal endometritis, and aspiration of


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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% ofprimary 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. Inaddition, chronic pulmonary infection can occur, particularly in hosts who are

immunocompromised or those with underlying diabetes. Children rarely develop

chronic pulmonary lesions.

y Disseminated coccidioidomycosis17o 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 asfrom windstorms, digging, farming, and construction.

o Approximately 0.5-1% of individuals with coccidioidomycosis develop disseminateddisease. 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. Thepresence 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-celldysfunction in patients with H

IV18

, solid organ transplantation

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, 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 ofextrapulmonary 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.21In most types ofdisseminated 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 commonjoints 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


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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

o Approximately 50% of patients with disseminated coccidioidomycosis acquireCNSdisease. 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.23Coccidioidal 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.

o Although the skin, lungs, joints, soft tissue, and meninges are the most common sites forcoccidioidal dissemination

17, 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 hasbeen reported to result in a thyroid abscess and thyrotoxicosis.

Ocular coccidioidomycosis can present as a lacrimal gland fossa mass or witheye pain, photophobia, and other symptoms of chorioretinitis or iridocyclitis.

Hepatic infection is usually asymptomatic but can be part of a hepatic-pulmonary syndrome with a brief hepatitis-like illness, hepatic granulomas, and

eosinophilia.

Coccidioidal infection of the biliary tree is uncommon but has been reported topresent 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 orgranulomas, abscesses, or fistulae in the kidney, ureter, bladder, prostate,epididymis, or testes.

Differential Diagnoses

Actinomycosis Lymphadenopathy

Acute Lymphoblastic Leukemia Lymphoproliferative Disorders

Acute Myelocytic Leukemia Meningitis, Aseptic

Aspergillosis Meningitis, Bacterial

Atypical Mycobacterial InfectionMycoplasma Infections

Blastomycosis Nocardiosis

Brucellosis Osteomyelitis

Catscratch Disease Parainfluenza Virus Infections


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Chronic Granulomatous DiseasePneumococcal Infections

FeverWithout a Focus Respiratory Syncytial Virus Infection

Histiocytosis Sarcoidosis

Histoplasmosis Toxoplasmosis

Influenza Tuberculosis

Legionella Infection Wegener Granulomatosis

Workup

Laboratory Studies

The following studies may be indicated in coccidioidomycosis:

y Nonspecific laboratory testso 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 witha 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.

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y Serology1,2,3,4,5,25,26o 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 infectionand 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). TheCF 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 monitorthe effect of treatment on disease and predict relapses.

y Culture


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o Culture ofCoccidioides species from infected tissue or fluids often is possible within 3-4days 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 theinfectious 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 chemiluminescentDNA probe can identify theorganism.

y Susceptibility testing ofCoccidioides species in one report revealed uniform susceptibility tomost antifungal agents.

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Imaging Studies

y Radiography1,2,3,4,5,15,16,17,21,22o 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 calcificationsdepicted 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 resolvespontaneously, albeit slowly.

o In patients with osteomyelitis, bone radiographs may show lytic lesions, periostealelevation, and bony destruction.

o

Coccidioidal osteomyelitis of the right elbow. Plain film radiograph. Photograph

by Preeyacha Pacham, MD.

CT/MRI

y The high-resolution CT scan can further delineate extent of pulmonary and lymph nodeinvolvement.

y


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Pulmonary nodule from infection with Coccidioides species. CTscan of the chest.

Photograph by Preeyacha Pacham, MD.

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Pulmonary nodule from infection with Coccidioides species. CTscan of the chest.

Photograph by Preeyacha Pacham, MD.

y 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.

y CT or MRI of the brain in patients with CNS involvement may demonstrate meningealenhancement, 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 ofSylvius.

Other Tests

y Skin tests5


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o Skin testing is not helpful in making the diagnosis of coccidioidomycosis because itcannot distinguish between past and acute infection; however, skin tests can be useful

as epidemiologic or research tools.

o A positive skin test is 5 mm or more of induration observed 48 hours after intradermalapplication. The skin test becomes positive 10-45 days after infection or 2-21 days after

symptom onset.

o Anergy is common in patients with disseminated disease, even without underlyingimmunosuppression. In addition, a low level of cross-reactivity with blastomycosis and

histoplasmosis occurs.

Procedures

y Perform lumbar puncture in patients with fever, headache, nuchal rigidity, meningismus, mentalstatus changes, or ataxia.

16,17

y Bronchoscopy with bronchoalveolar lavage, needle aspiration, and/or lung biopsy may beindicated with persistent or progressive infections, especially in hosts who are

immunocompromised.

y Synovial biopsy may be needed to document coccidioidal dissemination to a joint.Histologic Findings

y Histopathologic specimens of affected tissues may reveal the pathognomonic spherules onhematoxylin-eosin or silver stains.

y

Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine

silver (GMS) stain. Photograph by Joseph Rabban, MD.

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Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine

silver (GMS) stain. Photograph by Joseph Rabban, MD.

y Spherules may be observed in tracheal aspirates; purulent material; biopsies of lymph nodes,skin, or organs; joint fluid; urine; and, less commonly, cerebrospinal fluid.

y Tissue lesions consist of granulomas with abundant giant cells and histiocytes, with or withoutacute inflammation.

y Caseous necrosis, fibrous changes, and rare calcification can also be found.Treatment

Medical Care

Antifungal therapy is not usually necessary for uncomplicated acute primarycoccidioidomycosis. For many patients, management of uncomplicated acute primarycoccidioidal pneumonia mainly relies on periodic reassessment of symptoms and resolution ofany radiographic findings. However, some experts propose treatment of all symptomaticpatients; 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 severeprogressive pulmonary disease or with concurrent risk factors fordissemination.10,1,2,3,4,5,15,16,17,18,21,22,23

y Indicators of severity of illness for which to consider therapy of acute primary pulmonaryinfection include the following:

3

o Continuous fever for longer than 1 montho Night sweats for longer than 3 weekso Weight loss greater than 10%o Prominent or persistent hilar adenopathy


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o Large (>50% of one lung) or bilateral pulmonary infiltrateso Complement fixation (CF) titers greater than or equal to 1:16o Persistent symptoms for longer than 2 monthso Inability to worko Age older than 55 years

y Risk factors for dissemination for which treatment should be initiated include the following:o Primary infection during infancyo Primary infection during pregnancy, especially in the third trimester, or immediately

postpartum

o Immunosuppressiono Chronic debilitation or underlying disease, including diabetes mellitus or preexisting

cardiopulmonary disease

o High inoculum exposureso Certain ethnicities, such as Filipino or black

y Typical antifungal therapy of acute primary pulmonary coccidioidomycosis in these high-riskgroups 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.y 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.

y Persons with asymptomatic pulmonary nodules or cavities often do not warrant antifungaltherapy in the absence of immunosuppression.

y 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.

y Antifungal therapy, often in conjunction with surgical treatment, is recommended for patientswith ruptured coccidioidal cavities.

y Individuals with chronic progressive fibrocavitary pneumonia may be treated with prolongedazole 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.

y 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 amphotericinB. 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 400-

2000 mg/d for fluconazole, and up to 800 mg/d for itraconazole.

y In patients who warrant amphotericin B therapy but have drug-related toxicities, lipidamphotericin B formulations can be considered and have been effective in animal models,


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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.

y The preferred regimen for individuals with meningeal disease is administration of oralfluconazole, 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.

y Lifelong antifungal therapy must be continued in patients with CNS involvement23withCoccidioides species because of high relapse rates (ie, up to 75%) with oral azoles.

y CNS vasculitis is a life-threatening complication of coccidioidal meningitis. Short-term treatmentwith high-dose IV corticosteroids has been reported with varying results in regards to benefit.

Surgical Care

y 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.

y In patients with chronic osteomyelitis, drainage of sequestrum in bones and debridement ofadjacent 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.

y The benefit of irrigation and local instillation of amphotericin B to joints, cavities, or abscessesaffected by coccidioidomycosis is controversial, and no clear data supporting this practice are

available.

y Hydrocephalus from CNS involvement often requires shunt placement for management.Medication

Historically, amphotericin B has been the drug of choice to treat disseminatedcoccidioidomycosis. More recently, oral azoles have provided a desirable alternative for bothinitial therapy and completion of courses after amphotericin therapy. The benefits of azolesinclude oral formulations and fewer adverse effects. Large, multicenter, nonrandomized clinicaltrials have studied the response of chronic pulmonary and disseminated coccidioidal infections tooral azoles (eg, fluconazole, itraconazole, ketoconazole) and have found adequate treatmentefficacy 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 toimprove 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


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Polyene antifungal

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

Amphotericin B (Fungizone, AmBisome,Abelcet)

Polyene antibiotic produced by a strain ofStreptomyces nodosus; can be fungistatic orfungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellularcomponents to leak with subsequent fungal cell death.DOC for rapidly progressing coccidioidal infection and disease nonresponsive to PO azoletherapy. Liposomal amphotericin should be used when significant nephrotoxicity is a risk withconventional amphotericin B therapy. Intrathecal amphotericin B has been used for coccidioidalmeningitis.

y DosingAdult

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

Pediatric

Administer as in adults

y InteractionsAntineoplastic agents may enhance potential of amphotericinB for renal toxicity,

bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate

hypokalemia; risk of renal toxicity is increased with cyclosporine

y ContraindicationsDocumented hypersensitivity

y PrecautionsPregnancy

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


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Precautions

Severe renal dysfunction can result; administer NS bolus or PO sodium chloride before eachdose; monitor serum electrolytes (eg, magnesium, potassium), liver function, CBC count, andhemoglobin 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 patientsreceiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocytetransfusion); IT administration may cause pain with administration, headache, paresthesias,nerve palsies, and arachnoiditisPremedication with acetaminophen and/or diphenhydramine may reduce infusion-relatedsymptoms and may be repeated at appropriate dosing interval if infusion is prolonged;hydrocortisone (mixed with amphotericin solution) has also been used to reduce infusion-relatedsymptoms

Azole antifungals

Oral azoles have been used in the treatment of disseminated coccidioidomycosis and primarypulmonary infections in high-risk groups. Overall, the initial response rate is 50-60% with azoletherapy, although relapse rates may be as high as 50%. A preliminary report from the MycosesStudy Group found no statistically significant difference in efficacy between fluconazole anditraconazole. 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 toergosterol, thereby disrupting cellular membranes.Used in treatment of primary pulmonary infections in high-risk groups and of disseminatedcoccidioidomycosis. Preferred over ketoconazole because of better response rates and less GIand endocrine adverse effects. Available in PO susp.

y DosingAdult

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

y Interactions


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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

y ContraindicationsDocumented hypersensitivity, pregnancy, concurrent QT-prolonging drugs, congenital long QT

pts or conditions that incur QT prolongation risk


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

Precautions

Monitor closely if rashes develop and discontinue drug if lesions progress; may cause clinicalhepatitis, cholestasis, and fulminant hepatic failure (including death) in patients with underlyingmedical conditions (eg, AIDS, malignancy) and in those taking multiple concomitantmedications; not recommended for mothers who are breastfeeding

Itraconazole (Sporanox)

Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth byinhibiting CYP450-dependent synthesis of ergosterol, a vital component of fungal cellmembranes.Used to treat primary pulmonary infections in high-risk groups and disseminatedcoccidioidomycosis. Preferred over ketoconazole because of better response rates and less GIand endocrine adverse effects. IV form available, but long-term usage is not established. Alsoavailable in PO solution. The PO solution provides better, more consistent absorption than thecapsule. Take capsules with full meal to improve absorption, but take oral solution on emptystomach, if possible.

y DosingAdult

400 mg/day PO

Pediatric

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


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y InteractionsStrong 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)

y ContraindicationsDocumented hypersensitivity; pregnancy; concurrent QT-prolonging drugs or congenital long QT



Precautions

BlackBox WarningsCongestive heart failure (CHF): Negative inotropic effects reported with IV administration;reassess therapy if signs or symptoms of CHF occur during administrationContraindicated drug interactions: Potent CYP450 3A4 inhibitor; serious cardiovascular events,including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/orsudden death reported when administered with drugs metabolized by this isoenzyme system,including cisapride, pimozide, quinidine, dofetilide, or levomethadyl acetateOther precautionsCaution in hepatic insufficiencies; level can be checked after 2 wk of therapy to documentadequate 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 arepreferred because of low response rates (


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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 InteractionsStrong 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 ContraindicationsD

ocumented hypersensitivity

y Precautions

Pregnancy


Precautions

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

Follow-up

Further Outpatient Care

y Treatment of patients with primary pulmonary coccidioidomycosis relies on periodic monitoringof symptoms and radiographic studies to assess residual disease (eg, nodules, cavities) and

identify signs of early dissemination.

y Continue follow-up care for at least 1-2 years or until resolution of all coccidioidal diseaseoccurs. The identification of progressive pulmonary disease or dissemination warrants initiationof antifungal therapy as outlined in Medication.

y Follow-up care of patients with disseminated coccidioidomycosis includes periodic monitoring ofthe complement fixation (CF) titer until it is less than 1:8. Also, monitor other abnormal

laboratory or radiographic studies at regular intervals.

y Initially, monitor CF titers at monthly intervals until a consistent decrease has beendocumented. Relapses of coccidioidomycosis can be predicted by recurrence of symptoms,


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physical findings, and increases in the CF titer. Cerebrospinal fluid (CSF) abnormalities and CF

titers may persist for months despite therapy.

y Development of hydrocephalus in a patient with coccidioidal meningitis who is otherwise stableand improving does not imply failure of antifungal therapy.

y Monitor routine health maintenance as well as reviews of all medications for potential druginteractions with the prescribed antifungal therapy. Periodically evaluate adverse effects of

antifungal medications by history and laboratory testing.

Deterrence/Prevention

y Infection with Coccidioides species can be minimized with dust control measures at constructionor archaeological sites and in areas with large amounts of soil disruption.

y Within the hospital, isolation precautions are not necessary because person-to-persontransmission 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

y 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.

y No vaccines to prevent coccidioidomycosis currently are used in humans. A killed spherule-derived 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, recombinantDNA

techniques to develop vaccines using the proline-rich31

and other antigens from the Coccidioides

spherule appear promising.

Miscellaneous

MedicolegalPitfalls

y Delay in diagnosis of disseminated coccidioidomycosis may occur, given the insidious nature ofthe 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 previousauthors Michele M Cheung, MD and Peggy Weintrub, MD to the development and writing ofthis article.


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Documents

Pediatric Coccidioidomycosis