Pediatrics

Coccidioidomycosis

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OVERVIEW: What every practitioner needs to know

Are you sure your patient has coccidioidomycosis? What are the typical findings for this disease?

Introduction

Coccidioidomycosis is an endemic mycosis of the Southwestern United States, Northern Mexico, and some areas of Central and South America. The primary infection is acquired by inhalation of arthroconidia (spores) of the genus Coccidioides, typically as a result of exposure to dust. Two species are identified: Coccidioides immitis in California and Coccidioides posadasii in the rest of the endemic areas. The inoculum size is small and can be as low as one spore.

The primary infection is asymptomatic in 60% of individuals. Symptoms, when present, appear 1-3 weeks after inhalation of spores that are aerosolized from soil or dust and result from wind, soil disturbance, or outdoor activities. The most common clinical presentation is pneumonia that is acute or subacute and may present as a community-acquired pneumonia or an influenza-like illness. The diagnosis is often delayed, even in endemic areas, because of lack of suspicion for this infection. The primary infection is typically limited to the lungs.

Rarely, in 0.5%-1% of infected individuals, the fungus disseminates by hematogenous spread from a pulmonary lesion to extrapulmonary sites, such as the central nervous system, bones, or skin. Such dissemination is more likely in the immunocompromised host, pregnant women, and certain ethnic groups. African Americans and Filipinos have 10 times the risk of dissemination of the general population.

A primary infection provides immunity against coccidioidal reinfection. There is no person-to-person transmission of coccidioidomycosis.

Findings

The most common manifestations of symptomatic primary infection are fatigue, cough, and shortness of breath. The fatigue may last from weeks to months. The next most common symptom is fever. Pleuritic chest pain is relatively common and is often self-limited.

Other symptoms include night sweats, chest pain, chills, arthralgias, headaches, myalgias, wheezing, skin rashes, stiff neck, sore throat, weight loss, and hemoptysis.

Disseminated disease occurs in approximately 1% of patients and consists of extrapulmonary involvement, including meningitis, osteomyelitis, lymphadenitis, and cutaneous disease. These can present singly or in different combinations. The symptoms and signs are related to the site of dissemination.

The diagnosis is suspected clinically and needs to be confirmed by culture, identification of the organism in stained body fluids or tissues, or by serologic testing.

Primary coccidioidomycosis: Cutaneous manifestations

The cutaneous manifestations of primary coccidioidomycosis are reactive in nature and consist of erythema nodosum, erythema multiforme, and toxic erythema; Sweet syndrome and reactive interstitial granulomatous dermatitis are rare manifestations of primary coccidioidomycosis.

Rarely, primary cutaneous disease can occur by direct inoculation of the fungus through a break in the skin barrier such as a cut by a piece of glass or an injury with a rock. Primary cutaneous coccidioidomycosis manifests as an ulcerated nodule at the site of inoculation, sometimes accompanied by regional lymphadenopathy.

Erythema nodosum consists of painful reddish blue subcutaneous nodules on the lower extremities that appear 1-3 weeks after the onset of symptoms and is associated with a vigorous cell-mediated immune response.

Other cutaneous manifestations of primary coccidioidomycosis include an acute generalized exanthem ("toxic erythema") that appears early after the onset of symptoms and is usually macular, papular, or morbilliform, and sometimes target-like. It is often pruritic.

Erythema multiforme can also be seen within 48 hours of onset of symptoms, with clinical and histologic features that overlap those of toxic erythema.

Rare cutaneous manifestations include Sweet syndrome manifested by tender red papules, fever, and leukocytosis, and interstitial granulomatous dermatitis with indurated cutaneous papules, nodules, or plaques appearing at the onset of symptoms.

Disseminated coccidioidal disease: Meningitis

Meningitis is often the only site of coccidioidal dissemination, although it may occur in association with other sites of dissemination. It usually becomes manifested in the first 6 months after a respiratory infection. It is typically manifested by a subacute presentation consisting of headaches. Other symptoms include sluggishness, ataxia, vomiting, or altered mental status. Nuchal rigidity is an inconsistent finding and is often absent.

Evidence of increased intracranial pressure may be present, demonstrated by the presence of papilledema. Cranial nerve palsies, typically of the third or sixth cranial nerves, may be seen at presentation. Hydrocephalus is a very common complication of coccidioidal meningitis in children and is often present at the time of diagnosis. Rarely, a severe vasculitis can lead to a sudden stroke.

Disseminated coccidioidal disease: Osteomyelitis/arthritis

Osteomyelitis presents with involvement of long bones, most commonly the tibia and femur. Unlike bacterial hematogenous osteomyelitis, it often involves the small bones of the hands and feet and cancellous bones such as the skull or vertebrae. The lesions are multifocal in half of cases. The infection is chronic and often results in the development of sinus tracts.

Vertebral osteomyelitis usually spares the disk and can lead to parameningeal infections or meningitis. Radiographs show evidence of a lytic or sclerotic lesion.

Arthritis affects large joints and usually has a waxing and waning course. It can also be the result of direct inoculation into the joint by a foreign body such as a cactus spine.

Disseminated coccidioidal disease: Cutaneous manifestations

Cutaneous manifestations of disseminated coccidioidomycosis include papules, nodules, skin ulcers, pustules, subcutaneous abscesses, sinus tracts, and verrucous lesions, which are often found around the nasolabial folds. Sometimes it can present with fungating cutaneous lesions resembling a cutaneous tumor. The lesions, which are solitary or multiple, appear a few weeks to months after a respiratory infection.

Disseminated coccidioidal disease: Lymphadenitis

Coccidioidomycosis can present with lymphadenitis, especially with supraclavicular node involvement. The nodes enlarge over a period of 2-3 weeks and may suppurate. This presentation can often be confused with that of a lymphoma or scrofula.

Coccidioidomycosis in pregnancy

Coccidioidomycosis is uncommon during pregnancy but is associated with a high rate of dissemination that often presents as meningitis or skin or bone disease. This infection had a high fatality rate in the era before antifungal agents and patient outcomes have dramatically improved since the introduction of antifungal therapy.

The risk of dissemination during pregnancy is associated with the trimester of the pregnancy, ranging from 40% in cases diagnosed before the beginning of the pregnancy, to 50% in the first trimester, 62% in the second trimester, 96% in the third trimester and 71% in the post-partum period. Susceptibility to dissemination during pregnancy is thought to result from depressed cellular immunity and from an increase in 17 beta-estradiol and progesterone levels, which allows for growth of coccidioidal spherules.

Disseminated disease in pregnancy is also more likely in persons of African American or Hispanic ethnicity.

Congenital/neonatal coccidioidomycosis

Neonatal coccidioidomycosis has been reported, often in association with maternal infection. Disseminated disease in the pregnant mother can result in placentitis, yet the fetus is typically uninfected. Neonatal infections have sometimes been severe, resulting in dissemination, and they can be fatal.

It is commonly believed that infection in the neonate, which is usually respiratory in nature, is the result of inhalation or ingestion of amniotic fluid and vaginal secretions at the time of delivery. A case report raises the possibility that congenital infection may be possible. The neonate described in this report experienced symptoms at 15 days of age and was delivered by cesarean section with intact membranes to a mother who died of disseminated coccidioidomycosis. The placenta had numerous coccidioidal spherules, and the maternal autopsy showed evidence of disseminated disease. Unfortunately, the report does not comment on the pathologic characteristics of the uterus.

Coccidioidomycosis in immunocompromised hosts

Coccidioidal disease in the immunocompromised host can result from primary infection or from reactivation of old infection. T-cell function deficiencies put the patient at risk for severe or disseminated infection. The receipt of anti-rejection medications or of tumor necrosis factor α inhibitors increases the risk of disseminated coccidioidal disease because of their effect on T-cell function.

A recent coccidioidal infection or a positive serologic test result at the time of organ transplantation is associated with a rate of dissemination of 75% and a mortality of 29% without the use of antifungal prophylaxis. Solid organ transplant recipients are at the highest risk in the first year after transplantation.

A dramatic decrease in symptomatic coccidioidomycosis has occurred in patients with AIDS with the advent of effective antiretroviral therapy. The disease, which often presented with a diffuse reticulonodular infiltrate and was associated with a high mortality, now presents in a manner similar to that in immunocompetent individuals. The severity of disease at diagnosis correlates with the CD4 counts.

What other disease/condition shares some of these symptoms?

Coccidioidal pneumonia is often indistinguishable from community-acquired pneumonia, including bacterial, atypical, and viral pneumonias. The pneumonia can resemble that of other endemic mycoses such as histoplasmosis, and a travel history is therefore critical to consideration of the differential diagnosis. Coccidioidal pneumonia also resembles tuberculosis. In patients presenting with severe hilar or paratracheal adenopathy, the diagnosis can also be confused with that of a tumor of the chest especially a lymphoma. When presenting with a pleural effusion, it is often confused with a bacterial pneumonia with empyema.

What caused this disease to develop at this time?

There are no genetic, ethnic, or immunologic parameters that affect the risk of acquiring primary coccidioidomycosis. Conversely, severe or disseminated disease is seen more frequently among some ethnic groups such as Filipinos, Asian Americans or African Americans, as well as in immunosuppressed hosts. Dissemination usually occurs relatively early, in the first weeks to months after initial infection and before a good cell-mediated immune response has developed.

In endemic areas, the organism is present in the superficial layers of soil (top 20 cm). Wind storms, earthquakes, and activities that disturb the soil such as blading land, archeologic excavations, or riding dirt bikes increase the risk of exposure and provide for a large inoculum. A history of travel to an endemic area should be sought, especially in areas of the United States where the disease is not endemic.

Malnutrition, through its effect on T-cell function, is a risk factor for severe or disseminated disease. The presence of a rash in association with pulmonary symptoms is a good clue to the diagnosis of coccidioidomycosis. When present, eosinophilia is a laboratory parameter that suggests the diagnosis. The presence of hilar adenopathy on chest radiography may also be a clue to the diagnosis in the proper epidemiologic setting. Calcification of pulmonary nodules on the chest radiograph is uncommon and points to other causes such as tuberculosis. Persons with a history of coccidioidomycosis may reactivate the infection when immunosuppressed years after the initial infection.

Rarely, cutaneous lesions can result from direct inoculation through the skin such as with an injury resulting from a broken bottle. One case report describes a cutaneous infection resulting from a cat bite.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A number of laboratory tests are used for the diagnosis of coccidioidomycosis. Diagnosis needs to be confirmed by laboratory testing.

The demonstration of spherules in the sputum, in bronchoalveolar or other body fluids, or in tissue specimens establishes the diagnosis of coccidioidomycosis. A positive culture yielding Coccidioidesspecies also establishes the diagnosis.

More commonly, serologic assays are relied on to confirm a clinical suspicion of coccidioidomycosis. Assays detect the presence of IgM and IgG, and the detection of either of these antibodies is used to confirm the diagnosis in an acute infection. A negative serologic test result does not rule out the diagnosis, as in some individuals, especially immunocompromised ones, a serologic response fails to develop.

The diagnosis of meningitis is established by cerebrospinal fluid (CSF) serologic test results and less commonly by culture, as only one third of such patients have a positive CSF culture. Serologic test results (blood or CSF) may be negative at the time of presentation in 18% of patients.

Diagnostic tests for coccidioidomycosis

The organism grows in 3-5 days on standard culture media and on fungal culture media. Spores can be aerosolized from the plates and can be highly infectious to laboratory workers. Such cultures should be handled in an appropriate biologic safety cabinet, and it is essential that the laboratory be alerted of the clinical concern about coccidioidomycosis so that inadvertant laboratory exposure is avoided.

In fluids, spherules can be identified by calcofluor or potassium hydroxide smears. The former requires special technical skills and the latter is relatively insensitive. Spherules cannot be visualized on Gram stain.

In tissues, granulomas are typically seen and the spherules can be seen on Grocott methenamine, periodic acid-Schiff, Wright-Giemsa, hematoxylin-eosin, and Papanicolaou stains.

In symptomatic patients, IgM appears in 50% of patients within 1 week and in 90% within 3 weeks from the onset of symptoms. It resolves rapidly and only 10% of patients have detectable IgM antibody after 5 months. The IgG antibody is detected 2-28 weeks after onset of symptoms. It can remain for 6-8 months and is detected in 50% to 90% by 3 months; in disseminated disease, the antibody can remain detectable for many years and its magnitude correlates with disease activity or risk of dissemination.

A positive serologic test result for IgG should be followed by antibody titration for complement-fixing antibody level measurement. High titers are often associated with disseminated infections because of continued antigenic stimulation of the host. The antibody is not protective against coccidioidomycosis.

Serodiagnosis is generally performed by an enzyme immunoassay (EIA) or immunodiffusion (ID) test. EIA is more rapid and more sensitive than ID methodology. There is controversy regarding the rate of false-positive IgM results when only the IgM test result is positive. It is likely that most such test results are true positives. Correlation with the patient's clinical picture is needed.

EIA assays are not quantitative. Quantitation of IgG antibody is done by ID or complement fixation (CF) assay. Positive IgG tests should be quantified and are useful in assessing the risk of dissemination and in following disease activity. Generally, titers of 1:32 or higher are correlated with a high risk of dissemination.

Only the ID and CF serologic tests are standardized for detection and quantitation of antibody in the cerebrospinal fluid. Serologic assays are not standardized for use in fluids such as pleural or synovial fluid. Polymerase chain reaction has not been validated yet for the diagnosis of coccidioidomycosis.

Would imaging studies be helpful? If so, which ones?

A chest radiograph is helpful in the diagnosis of primary pulmonary coccidioidomycosis. The demonstration of pneumonic infiltrates, especially in the presence of hilar adenopathy, should raise the possibility of coccidioidomycosis in the appropriate host.

Other radiologic manifestations include thin-walled cavities, subpleural nodules, and mild to moderate effusions. Large effusions are uncommon in coccidioidomycosis. In chronic coccidioidomycosis, fibrocystic pulmonary changes may be demonstrated. Less commonly, a pyopneumothorax may be present and is more likely in those with diabetes who have poor glucose control. Bilateral reticulonodular or miliary infiltrates suggest either fungemic spread in an immunocompromised host or a very large inoculum of inhaled spores.

In patients with meningitis, computed tomography (CT) of the head is helpful in assessing and following ventricular size, which is often increased as a result of decreased CSF reabsorption or of basilar scarring leading to hydrocephalus, a common complication of coccidioidal meningitis in children. Magnetic resonance imaging (MRI) can demonstrate basilar enhancement suggesting a granulomatous meningitis, but the sensitivity is only 50%. In patients with focal neurologic deficits, it helps demonstrate evidence of cerebral vasculitis, which can be acute in onset and sometimes lead to cerebrovascular accidents..

A bone scan can be helpful in assessing the extent of osteomyelitis, when multifocal symptoms are present. Bone MRI is helpful in assessing the extent and nature of focal lesions and in mapping a possible surgical approach to suspected lesions.

In a patient with coccidioidal meningitis, CT or MRI is indicated for recurrent persistent headaches, gait disturbances, a change in mental status, or nausea and vomiting to assess for hydrocephalus or failure of a shunt apparatus.

If you are able to confirm that the patient has coccidioidomycosis, what treatment should be initiated?

Primary coccidioidal infection is generally asymptomatic or minimally symptomatic and does not require antifungal therapy. Stable pulmonary lesions can also be observed.

Chemotherapy with an azole, typically fluconazole, is used for complicated or severe pneumonias. Rapidly progressive disease, pneumonia leading to respiratory failure, and disease in pregnancy are treated with amphotericin B.

Disseminated disease is usually treated with an azole for a prolonged duration, usually more than a year. Meningitis requires lifelong therapy.

Antifungal therapy for secondary prophylaxis is indicated for severely immunosuppressed patients who are seropositive or who have a history of coccidioidomycosis. This includes patients such as solid or bone marrow transplant recipients, immunodeficient patients, or recipients of TNF inhibitor therapy.

If you are able to confirm that the patient has coccidioidomycosis, what treatment should be initiated ? - continued:

Primary coccidioidomycosis is generally asymptomatic or is associated with relatively mild symptoms. Most children with primary coccidioidomycosis do not require any antifungal therapy. They require supportive care, pain control if they have pleuritic chest pain, and attention to their nutritional status.

Stable pulmonary nodules do not require treatment.

An asymptomatic pulmonary cavity should be observed. Surgical resection should be considered if nodules show progressive enlargement, are subpleural in location, or persist for more than 2 years.

Symptomatic cavities that result in local discomfort, superinfection, or hemoptysis should be treated with oral azoles. Alternatively, surgical resection of a localized cavity can be considered.

Otherwise healthy patients with a ruptured cavity resulting in a pyopneumothorax should have the lesion resected. Antifungal therapy (Table I) is recommended for those with delay in diagnosis or those with coexisting conditions such as diabetes. Antifungal therapy may be used before surgery or along with chest tube drainage.

Table I.

Antifungal Agents for the Therapy of Coccidioidomycosis
Drug Dose Advantages Disadvantages
0.5-1.5 mg/kg/d Faster effect Toxicity (fever, chills, decreased renal function, electrolyte abnormalities, especially hypokalemia)Limited CNS penetration
3-5 mg/kg/d Faster effectLess toxicity than deoxycholate preparations Toxicity (see above)Limited CNS penetration
12-20 mg/kg/d Well toleratedOral administration (excellent bioavailability)Once-daily doseCost Rare hepatotoxicityRashesHair lossTeratogen
10 mg/kg/d More effective than fluconazole in osteomyelitis Erratic absorption of capsulesNeed to monitor drug levelsPossible teratogen
7 mg/kg/d ? Limited dataCostVisual disturbancesPhotodermatitisPossible teratogen
? ? Available in liquid onlyTake with full meal, TID or QIDDrug interactionsCostLimited dataPossible teratogen

Children with severe pneumonia, those with chronic or disseminated disease, immunocompromised hosts (especially organ transplant recipients), those on high-dose steroids, recipients of TNF inhibitor, and patients with AIDS should receive antifungal therapy. Patients with diabetes and those with chronic pulmonary disease do not control the disease well and are candidates for antifungal therapy, typically with oral fluconazole.

Fluconazole has excellent bioavailability, and intravenous administration should be reserved for patients who cannot be fed until enteral feedings can be restored. The usual pediatric dose is 12-15 mg/kg/d given once a day, preferably with food. The dose can be split initially into a twice-daily dose if the patient has abdominal discomfort. In adults, the usual dose is 400 mg/d, but some experts use higher doses of fluconazole such as 800-1200 mg/d in severely ill patients such as those with meningitis.

Amphotericin B is the drug of choice in individuals with respiratory failure, those with rapidly progressive disease, and pregnant women. Amphotericin B deoxycholate (1 mg/kg/d), amphotericin B lipid complex or liposomal amphotericin B at doses of 3-5 mg/kg once daily are used. Once the patient improves, therapy can be changed to the azoles, except in pregnant women because of the potential teratogenic effects of the azoles.

Patients with disseminated disease are usually treated with an azole.

Patients with meningitis are typically treated with fluconazole. Itraconazole is an alternative drug. The patient should be evaluated for the presence of hydrocephalus, which requires the insertion of a ventriculoperitoneal shunt.

Osteomyelitic lesions should be curetted if possible. The preferred azole for osteomyelitis is itraconazole. Absorption of the pills is erratic and itraconazole levels should be monitored. The liquid and intravenous formulations contain cyclodextrin and have more reliable absorption.

The treatment of uncomplicated pulmonary disease, when indicated, is recommended for a period of 3-6 months.

Patients with miliary infiltrates should be treated for at least 1 year.

Immunocompromised patients should be treated for at least 1 year. If they have continued severe immunosuppression, they should receive secondary prophylaxis with an azole.

Therapy for disseminated coccidioidomycosis is given for at least a year, and in some cases, such as with coccidioidal meningitis, for a lifetime because of the high rate of relapse when the azoles are stopped. Some experts treat meningitis with intrathecal amphotericin B, a therapy that is associated with a high rate of side effects but that has been successful in some patients with severe meningitis.

Patients with severe chronic osteomyelitis that cannot be surgically debrided may require prolonged therapy, sometimes for a lifetime, for suppression of the infection.

Therapy for immunocompromised patients need to be continued as long as severe immunosuppression persists.

Seropositive patients or patients with a history of coccidioidomycosis who are severely immunosuppressed, such as bone marrow or solid organ transplant recipients, should be treated prophylactically throughout the period of severe immunosuppression.

Recipients of tumor necrosis factor (TNF) antagonists (etanercept and infliximab) are at increased risk of severe disease and should have their immunosuppression reduced and should be treated with fluconazole for a prolonged period.

Therapy for coccidioidomycosis is now generally limited to azoles. The use of amphotericin B–based products is declining and is generally reserved for the most severe cases in which the fastest response to therapy is sought. Table I gives a list of antifungal agents for the therapy of coccidioidomycosis.

What are the adverse effects associated with each treatment option?

Amphotericin therapy is associated with fever, chills, decreased renal function, and electrolyte disturbances. The azoles are generally well tolerated and are rarely hepatotoxic. Drug interactions and risk of QTc prolongation need to be assessed for each patient because of the effect of the azoles on the cytochrome P450 (CYP) enzyme system. Voriconazole is associated with transient visual disturbances in about one fifth of recipients. It also increases sensitization of the skin to sun exposure.

What are the adverse effects associated with each treatment option ? - continued:

Amphotericin B deoxycholate is associated with a high rate of side effects. Fever, chills, nausea and vomiting, and anorexia are common side effects. In addition, patients receiving amphotericin often experience electrolyte abnormalities, especially hypokalemia and hypomagnesemia, and anemia. The glomerular filtration rate is also decreased and hypertension develops in some patients.

Premedication with acetaminophen and diphenhydramine is often needed to control some of these side effects. Intrathecal amphotericin is associated with headaches and often leads to a chemical arachnoiditis. Microsomal and liposomal preparations of amphotericin B share the same side effects, although they are generally less severe than those seen with amphotericin B deoxycholate.

Fluconazole is well tolerated. Occasionally, children will have abdominal pain when the treatment is started; this is lessened by dividing the dose into a twice-daily regimen initially. Rare side effects include transaminitis and hair loss.

Itraconazole is generally well tolerated. Like the other azoles, it has significant potential drug interactions. Its most common side effects consist of gastrointestinal symptoms and rash. Absorption of the capsules is erratic, and drug levels should be monitored in serious infections.

Voriconazole is associated with visual disturbances, usually transient, in 20% of recipients. Its use often results in dermatitis and photosensitization, a problem in areas endemic for coccidioidomycosis.

Posaconazole is available only in a liquid formulation. It is a potent inhibitor of CYP3A4. It can result in hepatotoxicity and elevated levels of cyclosporine, tacrolimus, and sirolimus. Careful attention should be paid to possible drug interactions. It can result in QT segment prolongation.

What are the possible outcomes of coccidioidomycosis?

Coccidioidal pneumonia is generally a self-limited disease that resolves without sequelae, and the initial infection provides immunity against further infections. In about 5% of patients, a persistent pulmonary nodule or a thin-walled cavity can be seen. Such a cavity needs no additional therapy unless hemoptysis develops, at which time surgical resection may be in order. It is generally thought that antifungal therapy has little to no effect on the course of cavitary disease.

Fibrocystic disease can be chronic and cause scarring and secondary bacterial or fungal pulmonary infections.

Disseminated disease requires therapy of variably prolonged duration. The prognosis of meningitis depends on the extent of disease. In children, the vast majority of patients acquire hydrocephalus (communicating and noncommunicating), leading to the need for a ventriculoperitoneal shunt. A few also acquire a "trapped" fourth ventricle, requiring a separate shunt to drain the fourth ventricle.

Cranial nerve palsies can also develop and if they do not resolve with therapy, eye muscle surgery is required to correct the strabismus. These children are also at risk for significant cognitive and developmental deficits, especially when the disease develops in children younger than 5 years of age. The relapse rate of meningitis is high (84%) when azole therapy is discontinued, hence it is essential that therapy be continued for a lifetime to keep the infection suppressed. The mortality of untreated coccidioidal meningitis was 100% within 2 years before the availability of antifungal therapies.

Osteomyelitis should be treated with antifungal agents and when possible, surgical debriding of granulomatous lesions. It is often multifocal and may involve cancellous bone. Treatment is typically given for 1-2 years, but some patients, especially those with spinal lesions, may not respond well and require prolonged, sometimes lifelong, therapy.

Lymphadenitis and cutaneous disease respond well to antifungal therapy, which is given usually for about 1 year.

It is to be noted that chemotherapy is fungistatic and that normal cell-mediated immune responses are essential in controlling the disease. Hence, immunocompromised patients will need to remain on antifungal prophylaxis, typically with fluconazole, for as long as their cell-mediated immune responses are depressed. In addition, immunosuppression should be reduced whenever possible.

Therapy of coccidioidomycosis with azoles is generally well tolerated, and these drugs have a good safety profile. They can be potent inducers or inhibitors of the CYP enzyme system and therefore careful attention should be given to possible drug interactions.

No therapy is needed for mild to moderate coccidioidal pneumonia in the immunocompetent host.

For those with severe disease, large pleural effusions, extrapulmonary disease, or immunocompromising conditions, therapy should always be given. In these patients, the azoles are tolerated much better and have an acceptable risk-benefit profile. I reserve the use of amphotericin-based products to patients with severe nonmeningeal disease in which a more rapid response is desirable, as their side effects are significant.

What causes this disease and how frequent is it?

Coccidioidomycosis is an endemic mycosis of the southwestern US deserts, northern Mexico, and some areas of Central and South America. It occurs throughout the years, with peaks during dry seasons following a rainy period. It is estimated to be responsible for about 150,000 infections in the United States each year. It affects all age groups and its incidence is about 250/100,000 population.

In the United States, 95% of reports are from California and Arizona, the latter being responsible for 60% of all reports. Sixty percent of infections are asymptomatic. Symptomatic disease is more likely in the elderly.

The risk of acquiring a primary infection is similar across ethnic groups; however, the risk of dissemination is higher in certain populations such as Filipinos and African Americans.

There has been a dramatic rise in the number of cases of coccidioidomycosis over the last 5 years in Arizona and California that is only partially explained by improved reporting. In Arizona, 11,888 cases were reported in 2010 compared with a median of 4815 cases over the preceding 5 years.

The infection is acquired by inhalation of spores that are typically aerosolized during windy dry days following a rainy season during which the fungus germinates in the soil. The inoculum size is as small as one arthrospore. The infection is not communicable from person to person.

The organism grows best in the superficial layers of the soil and is present especially around rodent burrows and old Native American ruins and burial sites. Activities that result in disturbance of the soil—such as construction, agricultural work, archeologic digs, and military field training—increase the risk of acquiring coccidioidal infections, as do natural events such as earthquakes.

Immunosuppression is a risk factor for reactivation of old infection, as well as for extrapulmonary dissemination.

The risk of dissemination of coccidioidal infections is related to genetic factors. Individuals of Filipino or African American descent are at increased risk for severe pulmonary or disseminated disease. Among Hispanics, blood type A is associated with more symptomatic disease, whereas blood group B is associated with dissemination. Certain HLA class II antigens influence susceptibility to severe disease.

How do these pathogens/genes/exposures cause the disease?

Coccidioidal infections are acquired by inhalation of arthrospores. The initial host response is neutrophilic, resulting in only partial control of the infection. Coccicioidal antigens are presented by dendritic cells and results in a Th1 response that is essential in control of the infection and that correlates with evidence of cutaneous sensitivity, lymphocyte transformation, and gamma interferon production. As the disease progresses, cell-mediated responses become defective, resulting in an ineffective response of Th2 helper cells. Disseminated disease is characterized by the formation of granulomatous lesions with abundant giant cells and histiocytes.

Some genetic mutations conferring increased susceptibility to coccidioidomycosis, such as interferon-gamma receptor 1 have recently been identified.

There are few case reports of neonatal infection that may have been spread vertically, typically in women with endometritis and infected amniotic fluid. Generally, young infants acquire their infection from heavy exposure to dust.

Rarely, cutaneous disease may result from direct inoculation of the skin rather than acquisition through the respiratory route.

Other clinical manifestations that might help with diagnosis and management

Rarely, coccidioidomycosis presents with a mediastinal mass that can mimic a lymphoma and is sometimes associated with paratracheal, or supraclavicular masses. Sometimes patients present with a pericardial effusion resulting from a focus of disease adjacent to the pericardium. Initial presentation may be associated with arthralgias or arthritis as a manifestation of hypersensitivity; rarely, the arthritis may be the result of dissemination of the infection to the articular cartilage and typically involves the large joints.

There a few reports of laryngeal involvement with coccidioidomycosis, leading to presentations of croup or epiglottitis. Respiratory tract infections may also be manifested by pleural effusions or empyemas. Soft tissue abscesses, single or multiple, may also be seen. Coccidioidomycosis can present with involvement of any organ, including the eye, prostate, liver, spleen, thyroid, breast, kidney, epididymis, or uterus. Rarely, coccidioidomycosis has presented with a picture of septic shock.

What complications might you expect from the disease or treatment of the disease?

Primary coccidioidomycosis is often asymptomatic and rarely leads to complications. The latter are more commonly associated with more severe disease or with dissemination.

Primary infection is often complicated by prolonged cough, pleuritic chest pain, malaise, and fatigue, which can be prolonged and debilitating. Cutaneous manifestations are often associated with coccidioidal pneumonia unlike community-acquired pneumonia.

Pulmonary disease can be accompanied by pleural effusions, which are often small but may, rarely, be large.

Persistent granulomas or thin-walled cavities persist after resolution of the pneumonia in 5% of cases.

Occasionally, the granulomas rupture into the pleural cavity, leading to a pyopneumothorax, a condition seen primarily in diabetic patients.

Meningitis is often complicated by hydrocephalus requiring the insertion of a ventriculoperitoneal or ventriculopleural shunt. In my experience, all of these children have remained dependent on the shunt. Less commonly, as the disease and scarring progress, the fourth ventricle can dilate and require separate drainage. Treatment of meningitis with intrathecal amphotericin B can lead to arachnoiditis. Meningitis can also be accompanied by a vasculitis and the development of cerebral infarcts. Other complications include arachnoiditis, developmental delays, hearing deficits, and ophthalmoplegias.

Osteomyelitis is chronic and can lead to soft tissue abscesses or pathologic fractures. Spinal osteomyelitis is especially challenging and requires a combined medical and surgical approach with a surgeon familiar with coccidioidomycosis.

Are additional laboratory studies available; even some that are not widely available?

A coccidioidal EIA antigen assay has been developed with a sensitivity of 71% in immunocompromised individuals with moderate to severe disease. The assay has good specificity but results are positive in 10% of individuals with other endemic mycoses. Its sensitivity in less severe cases or in immunocompetent individuals is not known.

How can coccidioidomycosis be prevented?

There is no effective vaccine for the prevention of coccidioidomycosis. Prevention is achieved by avoiding activities that disturb the superficial layers of the soil in endemic areas. Dust control is important especially in agricultural areas and in construction projects.

Controlling reactivation of disease in immunocompromised individuals is achieved by treating high-risk patients, such as transplant patients, prophylactically with antifungal agents, typically fluconazole.

Dust control and avoidance of high-risk activities such as archeologic digging in endemic areas are important in high-risk patients.

What is the evidence?

Guidelines for management and treatment of coccidioidomycosis and the strength of the recommendations can be found in the Infectious Diseases Society of America (IDSA) treatment guidelines for coccidoidomycosis. There are no randomized, controlled studies of antifungal therapy except for a comparative study of fluconazole and itraconazole in disseminated coccidioidomycosis that shows better results with itraconazole in the treatment of coccidioidal osteomyelitis.

Blair, JE, Currier, JT. "Significance of isolated positive IgM serologic results by enzyme immunoassay for coccidioidomycosis". Mycopathologia. vol. 166. 2008. pp. 77-82.

Crum-Cianflone, NF, Truett, AA, Teneza-Mora, N. "Unusual presentations for coccidioidomycosis. A case series and review of the literature". Medicine. vol. 85. 2006. pp. 263-77.

DiCaudo, DJ. "Coccidioidomycosis: a review and an update". J Am Acad Dermatol. vol. 55. 2006. pp. 929-42.

Galgiani, JN, Ampel, NM, Blair, JE. "Infectious Diseases Society of America. Coccidioidomycosis". Clin Infect Dis. vol. 41. 2005. pp. 1217-23.

(IDSA guidelines for the therapy of coccidioidomycosis.)

Pappagianis, D, Zimmer, BL. "Serology of coccidioidomycosis". Clin Microbiol Rev. vol. 3. 1990. pp. 247-68.

Saubolle, MA, McKellar, PP, Sussland, D. "Epidemiologic, clinical and diagnostic aspects of coccidioidomycosis". J Clin Microbiol. vol. 45. 2007. pp. 26-30.

Valdivia, L, Nix, D, Wright, M. "Coccidioidomycosis as a common cause of community-acquired pneumonia". Emerg Infect Dis. vol. 12. 2006. pp. 958-62.

Ongoing controversies regarding etiology, diagnosis, treatment

Vaccines for coccidioidomycosis remain elusive. Although the antigens tested to date result in an immune response, there is no evidence that this immune response is protective.

To date, all antifungal agents used in the therapy of coccidioidomycosis are fungistatic. Nikkomycin Z, a fungicidal agent, is being evaluated for the treatment of coccidioidomycosis.

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