coccidioidomicosis primaria, diagnóstico y tratamiento

Official reprint from UpToDatewww.uptodate.com ©2015 UpToDate

Author

John N Galgiani, MD

Section Editor

Carol A Kauffman, MD

Deputy Editor

Anna R Thorner, MD

Primary coccidioidal infection

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: May 06, 2015.

INTRODUCTION — Coccidioidomycosis is the infection caused by the dimorphic fungi of the genus Coccidioides (C.

immitis and C. posadasii) [1]. Most infections are caused by inhalation of spores. The clinical expression of disease

ranges from self-limited acute pneumonia (Valley Fever) to disseminated disease, especially in immunosuppressed

patients. The concentration of cases of coccidioidomycosis in the United States is in the southwestern part of the

country, where the cumulative incidence of patients requiring hospitalization in 2002 was 28.65 per 1 million persons

[2].

The clinical manifestations of uncomplicated primary infection, specific diagnostic tests, and management strategies for

primary infection will be reviewed here. Complicated infections related to coccidioidomycosis are discussed elsewhere.

(See "Management of pulmonary sequelae and complications of coccidioidomycosis" and "Coccidioidal meningitis" and

"Manifestations and treatment of extrapulmonary coccidioidomycosis" and "Coccidioidomycosis in compromised

hosts".)

EPIDEMIOLOGY — Coccidioides spp are endemic to certain lower deserts of the western hemisphere, including

southern Arizona, the southern and central valleys of California, southwestern New Mexico, and west Texas in the

United States. They are also found in parts of Mexico and Central and South America. Although these are the most

well-known regions, occasional small pockets of endemicity have been identified in more northern areas of the western

United States. For example, repeated infections have occurred at a specific American Indian archeology site in

Dinosaur National Monument in Utah [3]. Cases of coccidioidomycosis appear to have originated from eastern

Washington state [4] and C. immitis has been detected in the soil in areas that two affected individuals visited [5].

Whole genome sequencing demonstrated genetic identity between an isolate from one of the patients and four soil

isolates obtained from the area of exposure [6].

A substantial increase in the incidence of coccidioidomycosis has been observed in endemic regions of the United

States in recent years. In endemic states in which coccidioidomycosis is reportable to the United States Centers for

Disease Control and Prevention (Arizona, California, Nevada, New Mexico, and Utah), the incidence of

coccidioidomycosis increased from 5.3 cases per 100,000 population in 1998 to 42.6 cases per 100,000 population in

2011 [7]. Arizona and California account for 66 and 31 percent, respectively, of all nationally reported infections.

Inmates of two California state prisons have been disproportionately affected by coccidioidomycosis compared with

the general population, with 180 cases recognized in 2005 [8].

Several factors have been identified in Arizona, which account for much of the increase. These include a shift to more

sensitive serologic test results to define cases, year-to-year variation in precipitation, and a continued growth of the

population in endemic areas. [7,9].

Risk of infection — Estimates of the risk of endemic exposure to Coccidioides spp are approximately 3 percent per

year [10]. In addition, a telephone survey by the Arizona Department of Health Services of patients diagnosed with

Valley Fever in 2007 found that the average time of residence was 16 years [11]. Thus, even persons who have lived in

endemic regions for many years may still be susceptible to a new infection.

The risk of exposure within endemic regions is seasonal, typically being highest in dry periods following a rainy season.

As an example, periods of high incidence in Arizona range from May into July and then between October and early

December [12]. In contrast, the central California valley, which rarely receives significant summer rain, has a single

peak from late spring to late fall. The estimated number of infections per year has risen to approximately 150,000 as a

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Primary coccidioidal infection http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/primary-cocc...

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result of population increases in southern Arizona and central California [13]. Based upon population sizes within the

most highly endemic regions, it is estimated that approximately 60 percent of all United States coccidioidal infections

occur within Maricopa, Pinal, and Pima counties of Arizona and 30 percent within Kern, Tulare, and San Luis Obispo

counties of California. Cases reported to the United States Centers for Disease Control and Prevention show similar

geographic distributions.

MICROBIOLOGY — All isolates within the genus Coccidioides were formerly designated C. immitis. However, based

upon DNA sequence analysis, two species have been identified as distinct [14,15]. Isolates from one species are

geographically distributed predominantly in California and have retained the name C. immitis. The other species is

distributed in Arizona, Utah, Texas, and other endemic regions throughout the western hemisphere and is now

designated C. posadasii.

The spectrums of diseases caused by the two species are indistinguishable, and clinical laboratories are not routinely

able to determine species. For this reason, it is simplest to refer to all isolates as Coccidioides species.

Coccidioides spp grow as mold a few inches below the surface of the desert soil. With dry conditions, the mycelia

become very fragile, are easily fractured by even slight air turbulence into single-cell spores (arthroconidia)

approximately 3 to 5 microns in size, and can remain suspended for prolonged periods of time in the air.

PATHOGENESIS — Infection is virtually always acquired by inhalation of a single arthroconidium. Within the lung, an

arthroconidium changes from a barrel-shaped cell to a spherical structure and then greatly enlarges, sometimes

becoming 70 microns or more in diameter. Enlarging spherules produce internal septations, and, within each of the

resulting subcompartments, individual cells (endospores) evolve. After several days, mature spherules rupture,

releasing endospores into the infected tissue; each endospore is potentially capable of producing another spherule [1].

Leukocytes collected by bronchoalveolar lavage from patients with acute coccidioidal pneumonia demonstrate that

cellular immunity has been activated, as evidenced by increased interleukin-17, interferon-gamma, and tumor necrosis

factor-alpha levels following in vitro stimulation with coccidioidal antigens [16]. Organisms grown from patient

specimens show a reversion to mycelia on most laboratory media [17,18].

CLINICAL MANIFESTATIONS — After infection, a wide spectrum of manifestations is possible. It is estimated that

less than one-half of all infections comes to medical attention because illness is often subclinical [19,20]. The

proportion of infections that become clinically significant increases with more intensive dust exposure. It is presumed

that this represents higher arthroconidial inoculum exposure, as occurs during archeological excavations or desert

military maneuvers [21,22].

When illness is clinically significant, a subacute process known as Valley Fever with respiratory and systemic

complaints is typical, often lasting for weeks to months. In the great majority of such infections, resolution occurs

without specific antifungal therapy. Future respiratory exposure to arthroconidia rarely, if ever, results in clinical illness.

Primary infections due to Coccidioides species most frequently manifest as community-acquired pneumonia (CAP)

approximately 7 to 21 days after exposure. In a study from Pima County, Arizona, 29 percent of patients diagnosed

with CAP were serologically positive for coccidioidal infection [23]. The most common presenting symptoms are chest

pain, cough, and fever (table 1) [24-31]. Hemoptysis may occur and suggests the development of a pulmonary cavity.

Fatigue can persist for months, and the frequent complaint of arthralgias has contributed to the alternate name of

"desert rheumatism" for this illness. Cutaneous manifestations of primary coccidioidal infection include erythema

nodosum and erythema multiforme. Erythema nodosum is much more common in women than in men and often is the

symptom prompting evaluation for Valley Fever. (See "Erythema nodosum".)

Most routine laboratory findings are unremarkable [32]. A common but nonspecific abnormality is the erythrocyte

sedimentation rate, which often is one- or twofold above the upper limits of normal. The peripheral blood leukocyte

count is usually normal or only slightly elevated. However, eosinophilia (>5 percent) was found in approximately

one-quarter of patients [1]. In occasional patients, eosinophilia can be striking.

Although initial infections usually have a respiratory component, standard posteroanterior and lateral chest radiographs


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may be unremarkable in up to one-half of all patients. Common radiographic abnormalities include unilateral infiltrate

and ipsilateral hilar adenopathy (image 1). Less frequent is evidence of a parapneumonic effusion [33]. Peripheral

thin-walled pulmonary cavities or nodules are detected in 4 to 8 percent of all patients (image 2) [34]. Rare cases of

empyema have been reported [35].

FREQUENT ABSENCE OF EARLY DIAGNOSIS — Given how nonspecific the symptoms, signs, and routine

laboratory findings of primary coccidioidal infection are, many, if not most, infections are not identified because

clinicians do not consider the diagnosis. As an example, a cluster of 21 cases of a flu-like illness with rash in the

majority of patients was noted in a church group returning to Washington State after building an orphanage in Mexico

[36]. Sixteen patients were symptomatic and sought medical attention, but the diagnosis of coccidioidomycosis was

only confirmed in one case.

Although this cluster was located outside of the southwest in an area in which Valley Fever is not common, low rates of

disease recognition have also occurred in endemic areas. In Arizona, the number of cases of coccidioidomycosis

reported to the Department of Public Health from 1999 to 2001 averaged 1900 per year [12]. This number is less than

10 percent of the expected number of illnesses, as estimated by several methods [37]. In a study from two medical

centers in metropolitan Phoenix, Arizona, the number of patients with community-acquired pneumonia (CAP) tested for

Valley Fever was only 2 and 13 percent, respectively [38]. In one study, the clinician's workload, as measured by

number of clinic visits, was directly proportional to both the number of cases of CAP diagnosed and the number of

cases of coccidioidomycosis diagnosed (figure 1) [37].

A prospective observational study found that 16 of 55 cases (29 percent) of CAP in Tucson, Arizona, were caused by

Coccidioides spp [23]. In another study, 6 of 35 patients (17 percent) with CAP in Phoenix, Arizona, had evidence of

acute coccidioidomycosis [39]. A similarly high proportion may be evident in persons who develop CAP within the one-

to three-week incubation period after visiting an endemic area.

Some practitioners consider the failure to diagnose early coccidioidal infections as an insignificant problem, since many

infections resolve without specific therapy. However, identifying coccidioidal infections as early as possible has many

benefits, including [40]:

For these reasons, the standard of care for management of this disease could be improved by a greater attention to

early diagnosis. This approach is emphasized in the 2005 Infectious Diseases Society of America (IDSA) guidelines for

the treatment of coccidioidomycosis [13] and the 2007 IDSA guidelines for the treatment of community-acquired

pneumonia [41].

METHODS OF DIAGNOSIS — Considering the diagnosis of coccidioidomycosis is an essential first step for detecting

most coccidioidal infections in patients with endemic exposure, however brief. A respiratory illness of more than a

week's duration, especially if it appears to involve the lower respiratory tract (ie, community-acquired pneumonia),

should be considered suspicious for coccidioidomycosis. Other suspicious syndromes paired with endemic exposure

are new onset of diffuse, symmetrical arthralgias and the rash of either erythema nodosum or erythema multiforme.

Because exposure usually occurs within an endemic region, it is critical to obtain an accurate travel history. Even brief

exposures, such as changing planes in Phoenix, Arizona, have been sufficient to cause infection [3,36,42-44]. In most

cases, the incubation period for onset of symptoms is 7 to 21 days. However, for patients who are

immunocompromised due to AIDS, solid organ transplantation, or lymphoma, reactivation can occur after much longer

time periods [45,46].

Allaying patient anxiety by arriving at a specific diagnosis, often simultaneously dispelling the fear of cancer●

Reducing the need for additional diagnostic testing, some of which involve invasive or costly procedures●

Eliminating empiric or protracted use of antibacterial treatments●

Reducing the morbidity of less frequent but progressively destructive extrapulmonary complications, most of

which develop within the first several months following the initial infection

●


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Culture — Isolation of Coccidioides species in culture definitively establishes the diagnosis, even in patients with

relatively mild pneumonia. Although fungal cultures are usually requested only in hospitalized patients or in those with

more extensive disease, there is value to early diagnosis as noted above. Direct examination of the smear with

potassium hydroxide (KOH) preparation or calcofluor white staining is also helpful.

There are two disadvantages to culture. First, growth may take several days to weeks with subsequent delays in

diagnosis. Furthermore, the propagation of Coccidioides spp in the clinical laboratory represents a significant health

risk, since secondary cases have been reported in workers opening the plates for inspection [47,48]. Thus, laboratory

personnel should be notified when a sample with suspected Coccidioides is being sent for processing. In contrast,

specimens for culture can be safely collected by healthcare workers since coccidioidal infection is not transmitted

person to person. Coccidioides spp are listed by the United States Centers for Disease Control and Prevention (CDC)

as a select agent. Special rules govern its handling and storage. (See the National Select Agent Registry website for

further information concerning the handling of select agents.)

Serologic tests — Serologic testing is helpful for making the diagnosis and for monitoring patients on therapy. (See

'Patient monitoring' below.)

In patients with primary infections managed as outpatients, diagnosis usually relies upon serologic testing. Commercial

products are available to perform screening coccidioidal serologies in any general clinical laboratory. Alternatively,

reference laboratories can carry out more detailed testing. The details of the laboratory diagnosis of

coccidioidomycosis are discussed separately. (See "Laboratory diagnosis of coccidioidomycosis".)

However, regardless of the method chosen for detecting coccidioidal antibodies, three general principles guide

interpretation:

Histopathology — The diagnosis of coccidioidomycosis is occasionally made by identification of spherules in tissue

specimens. Staining with hematoxylin and eosin, periodic acid-Schiff, or methenamine silver stain will all demonstrate

the organism, although silver stain is considered the most sensitive (picture 1A-C) [1].

Polymerase chain reaction — A real-time polymerase chain reaction (PCR) assay was developed and tested in 266

respiratory specimens and demonstrated 100 percent sensitivity and 98 percent specificity for Coccidioides spp

compared with culture [50]. Sensitivity in paraffin-embedded tissue samples was found to be lower (73 percent). If

these preliminary results are validated with larger sample numbers, real-time PCR may offer a rapid and safe means

of detecting Coccidioides directly from patient specimens, including fixed tissue.

Skin testing — Most patients who become infected with Coccidioides spp develop dermal hypersensitivity to

coccidioidal antigens as manifested by induration to skin testing [51]. In 2014, a commercial skin testing preparation

was reintroduced for clinical use [52-54]. Despite this, we do not recommend using the Coccidioides immitis spherule-

derived skin test antigen to diagnose current illness because dermal hypersensitivity remains present for life and a

reactive skin test may therefore reflect past infection unrelated to the current illness. Another problem is that

occasional patients with the more extensive complications of coccidioidomycosis may be anergic; in these cases, a

negative skin test could conceivably delay the correct diagnosis. Skin testing is more useful for epidemiologic studies,

since dermal reactivity remains present for life. Skin testing patients in endemic areas is also useful as part of the

routine assessment of individuals when they are not ill to determine baseline skin test status in order to guide future

management if they do become ill. (See "Laboratory diagnosis of coccidioidomycosis", section on 'Skin testing'.)

RISK FACTORS FOR COMPLICATIONS AND DISEASE SEVERITY — After diagnosis, the presence of complications

Any positive serologic result is very likely to be clinically relevant. Most patients lose serologic reactivity within

months of an infection unless residual lesions are evident or infection is active.

●

A negative serologic result lowers the likelihood but does not exclude the diagnosis of coccidioidomycosis.

Although most tests for coccidioidal antibodies are very specific, they are relatively insensitive, especially during

the first one to two weeks after infection [1].

●

Repeating tests, if a first serologic test is negative, will improve diagnostic sensitivity [49].●


4 de 19 17/08/2015 09:31 p.m.

should be assessed with a careful history and physical examination. Risk factors for complications include:

The most significant of these risk factors is major suppression of cellular immunity, as occurs with HIV infection [55,56],

solid organ transplantation [57-59], and high-dose glucocorticoid administration [60]. Coccidioidomycosis first

developing during pregnancy (especially during the third trimester) is a significant risk factor for severe, disseminated

disease [61,62]. Diabetes mellitus has been associated with more slowly resolving pulmonary infection and residual

pulmonary cavitation [63]. Individuals of African or Philippine descent also have an increased risk of extrapulmonary

complications [31,64,65]. Although there appears to be more serious disease with increasing age [66], a comparison

of patients younger than 60 years of age versus those ≥60 years of age did not detect significant differences [67].

(See "Coccidioidomycosis in compromised hosts" and "Coccidioidal meningitis".)

To detect extrapulmonary infection, careful review of symptoms and physical examination is usually adequate.

Extrapulmonary infection can be found at any site, but skin, bones and joints, and central nervous system localization

are the most common (image 3) [68-70]. Active coccidioidal lesions typically produce regional symptoms. These

include local discomfort, swelling, and/or ulceration. Any focal abnormality of this sort that has developed since the

onset of the primary infection should be a source of concern. These physical exam findings should prompt further

imaging or sampling for histology and culture.

MANAGEMENT

Uncomplicated infections — Otherwise healthy patients without evidence of extensive coccidioidal infection or risk

factors for more serious infection usually do not need antifungal therapy. However, it is important that such patients be

followed for a year or longer to monitor for the development of complications. Therapy can be considered for certain

patients on an individual basis. (See 'Whom to treat' below.)

Whom to treat — Patients with severe illness as well as those at greatly increased risk of dissemination due to

immunosuppression or pregnancy should be treated. In contrast, the value of antifungal therapy for patients with

uncomplicated early coccidioidal infection is not known because prospective randomized trials have not been

performed. While it is clear from older studies that most patients resolve their infection without therapy, it is possible

that some patients might benefit from treatment, either by shortening the course of illness or by preventing

complications.

The possible role of treatment was evaluated in an observational study of 105 patients who had primary pulmonary

coccidioidomycosis and who were seen at a university-affiliated Veterans Administration clinic [71]. Based upon

severity of illness as assessed by the attending staff, 54 patients were treated and 51 were not. Treatment was more

likely to be initiated in patients with elevated symptom scores. There was no difference between the groups with

respect to overall rates of improvement. Among the untreated patients, none were subsequently found to have

complications.

However, among 38 of the treated patients, eight had relapse or progression of their coccidioidal infection following

discontinuation of therapy; the duration of treatment among these patients ranged from 1 to 24 months. A possible

reason for these findings is that patients with more severe illness are more likely to develop relapse. These findings

provide no support for treating patients with mild symptoms of primary coccidioidomycosis but emphasize the

HIV or AIDS●

Immunosuppressive medications used in transplants patients●

Glucocorticoids (20 mg or more per day of prednisone or its equivalent)●

Lymphoma●

Anti–tumor necrosis factor therapy●

Chemotherapy for solid tumors●

Diabetes mellitus●

Pregnancy●

Preexisting cardiopulmonary conditions●


5 de 19 17/08/2015 09:31 p.m.

importance of close and prolonged follow-up for patients with severe illness requiring treatment. (See 'Patient

monitoring' below.)

Given the absence of definitive data, it is a matter of judgment as to whether an individual patient might benefit from

therapy with available oral antifungals, most frequently itraconazole or fluconazole. As noted above, patients with

severe illness should be treated. However, opinion varies about the most relevant factors to judge the severity of

illness. Commonly used indicators include:

In addition to patients with severe illness, treatment should also be given to those at increased risk of dissemination

due to immunosuppression or pregnancy [13]. (See 'Risk factors for complications and disease severity' above.)

Treatment regimens — If a decision to begin treatment is made, reasonable doses are 400 mg/day for ketoconazole,

400 mg/day for fluconazole, and 200 mg twice daily for itraconazole [13]. Of the commercially available azoles, only

ketoconazole has been approved for the treatment of coccidioidomycosis by the US Food and Drug Administration

(FDA). However, the Mycoses Study Group has published descriptions of large prospective clinical trials using either

fluconazole or itraconazole as treatment of coccidioidomycosis.

Fluconazole has fewer drug interactions, whereas itraconazole has less of a drying effect on skin and mucous

membranes. Both fluconazole and itraconazole have a lower incidence of gastrointestinal side effects compared with

ketoconazole. Ketoconazole has also been associated with decreased testosterone synthesis and gynecomastia. (See

"Pharmacology of azoles".)

There is little information available about the value of newer azoles, such as voriconazole or posaconazole, for treating

primary coccidioidal pneumonia.

An amphotericin B preparation should be considered only in the most severe cases of coccidioidal pneumonia due to

its toxicity and problems with administration.

Duration — If treatment is instituted, the duration of azole therapy for uncomplicated primary coccidioidal infection

generally ranges from three to six months [13]. However, there is no consensus regarding which factors should guide

decisions about duration of therapy.

PATIENT MONITORING — Regardless of whether treatment is instituted, immediately following diagnosis, patients

are seen in follow-up every two to four weeks. During the weeks to months following presentation, respiratory

symptoms (eg, cough and pleurisy) and systemic signs (eg, weight loss, night sweats, and fever) typically markedly

diminish or resolve. Once such improvement has occurred, intervals between clinic visits are usually extended to every

three to six months for up to two years (especially in those who are treated with antifungals [71]) to document

radiographic resolution and identify any evidence of pulmonary or extrapulmonary complications [13].

Fatigue and lethargy associated with coccidioidal pneumonia may persist for many weeks or months, far beyond the

resolution of all other symptoms and laboratory abnormalities. The protracted duration of these symptoms resulting

from the disease itself is compounded by the resulting deconditioning from reduced physical activity. Developing a

structured physical rehabilitation program and referral to a physical therapist for reconditioning training is often helpful.

Serial serologic testing for complement fixing–type anti-coccidioidal antibodies should be repeated at least once

several weeks after the initial diagnosis, since a rise in antibody concentrations may be associated with progressive

disease [72]. Although the original descriptions of this test noted that titers greater than 1:16 were often found in

Greater than 10 percent loss of body weight●

Night sweats persisting greater than three weeks●

Infiltrates involving more than half of one lung or portions of both lungs●

Prominent or persistent hilar adenopathy●

Anti-coccidioidal complement fixing antibody concentrations in excess of 1:16●

Inability to work●

Persisting symptoms for more than two months●


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patients with disseminated infection, this correlation is now less reliable due to differences in commercial assays.

Serologic studies may also be compromised in patients with altered immunity (transplant patients or HIV-infected

patients) [1].

In patients who have a positive Coccidioides antigen test, which sometimes occurs in those with extensive disease, we

typically repeat this test every one to two months until it becomes negative. We use it to confirm that the burden of

disease is being reduced by treatment. It should not be used to determine timing of discontinuation of therapy since

patients require continued therapy even after this test has become negative.

Radiographic abnormalities should be rechecked to determine if they resolve or leave a residual nodule or cavity.

Determining whether pulmonary lesions evolve into residual nodules is also useful because it obviates the need to

investigate the etiology of this radiographic finding in the future. (See "Management of pulmonary sequelae and

complications of coccidioidomycosis".)

An evaluation for disseminated disease should begin if a patient develops any suspicious skin lesions, severe or

persistent headaches, or new joint effusions. (See 'Risk factors for complications and disease severity' above.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and

“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading

level, and they answer the four or five key questions a patient might have about a given condition. These articles are

best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics

patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to

12 grade reading level and are best for patients who want in-depth information and are comfortable with some

medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics

to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info”

and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

Epidemiology

Clinical manifestations

th th

th

th

Basics topic (see "Patient information: Valley Fever (coccidioidomycosis) (The Basics)")●

Coccidioidomycosis is the infection caused by the dimorphic fungi of the genus Coccidioides (C. immitis and C.

posadasii). Most infections are caused by inhalation of spores. The clinical expression of disease ranges from

self-limited acute pneumonia (Valley Fever) to disseminated disease, especially in immunosuppressed patients.

(See 'Introduction' above.)

●

Coccidioides spp are endemic to certain lower deserts of the western hemisphere including southern Arizona, the

southern and central valleys of California, southwestern New Mexico, and west Texas in the United States. They

are also found in parts of Mexico and Central and South America. (See 'Epidemiology' above.)

●

After infection, a wide spectrum of manifestations is possible. It is estimated that less than one-half of all

infections come to medical attention because illness is often subclinical. (See 'Clinical manifestations' above.)

●

When illness is clinically significant, a subacute process known as Valley Fever with respiratory and systemic

complaints is typical, often lasting for weeks to months. In the great majority of such infections, resolution occurs

without specific antifungal therapy. (See 'Clinical manifestations' above.)

●

Primary infections due to Coccidioides species most frequently manifest as community-acquired pneumonia

approximately 7 to 21 days after exposure. (See 'Clinical manifestations' above.)

●

Given how nonspecific the symptoms, signs, and routine laboratory findings of primary coccidioidal infection are,●


7 de 19 17/08/2015 09:31 p.m.

Diagnosis

Management

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 2460 Version 14.0

many, if not most, infections are not identified because clinicians do not consider the diagnosis. (See 'Frequent

absence of early diagnosis' above.)

Considering the diagnosis of coccidioidomycosis is an essential first step for detecting most coccidioidal

infections. Because exposure nearly always occurs within an endemic region, it is critical to obtain an accurate

travel history. (See 'Methods of diagnosis' above.)

●

Isolation of Coccidioides species in culture definitively establishes the diagnosis, even in patients with relatively

mild pneumonia. Direct examination of the smear with potassium hydroxide (KOH) preparation or calcofluor white

staining is also helpful. (See 'Culture' above.)

●

In patients with primary infections managed as outpatients, diagnosis usually relies upon serologic testing.

Commercial products are available to perform screening coccidioidal serologies in any general clinical laboratory.

Alternatively, reference laboratories can carry out more detailed testing. (See 'Serologic tests' above and

"Laboratory diagnosis of coccidioidomycosis".)

●

After diagnosis, the presence of complications should be assessed with a careful history and physical

examination. The most significant risk factor is major suppression of cellular immunity, as occurs in with HIV

infection, solid organ transplantation, and high-dose glucocorticoid administration. (See 'Risk factors for

complications and disease severity' above.)

●

Otherwise healthy patients without evidence of extensive coccidioidal infection or risk factors for more serious

infection usually do not need antifungal therapy. However, it is important that such patients be followed for a year

or longer to monitor for the development of complications. (See 'Uncomplicated infections' above.)

●

Patients with severe illness as well as those at greatly increased risk of dissemination due to immunosuppression

or pregnancy should be treated. These would be considered complicated situations. (See 'Whom to treat'

above.)

●

If a decision to begin treatment is made, reasonable doses are 400 mg/day for ketoconazole, 400 mg/day for

fluconazole, and 200 mg twice daily for itraconazole. Fluconazole has fewer drug interactions, whereas

itraconazole has less of a drying effect on skin and mucous membranes. Both fluconazole and itraconazole have

a lower incidence of gastrointestinal and other side effects compared with ketoconazole. (See 'Treatment

regimens' above.)

●

The duration of azole therapy for uncomplicated primary coccidioidal infection generally ranges from three to six

months. (See 'Duration' above.)

●


8 de 19 17/08/2015 09:31 p.m.

GRAPHICS

Initial symptoms and signs of coccidioidal pneumonia

Complaint Median percentage (range)

Constitutional

Fever 61 (30 to 99)

Fatigue 59 (32 to 83)

Pulmonary

Chest pain 73 (52 to 95)

Cough 64 (44 to 89)

Dyspnea 21 (12 to 63)

Hemoptysis 5 (3 to 21)

Other

Headache 27 (17 to 74)

Sore throat 24 (14 to 41)

Arthralgia 23 (8 to 52)

Erythema nodosum 9 (3 to 23)

Graphic 69260 Version 3.0


9 de 19 17/08/2015 09:31 p.m.

Pulmonary coccidioidomycosis

(A) Chest radiograph shows consolidation in right lower lung zone

(arrow) and right hilar enlargement (arrowhead).

(B) Mediastinal window of contrast-enhanced computed tomography

(CT) (5 mm collimation) scan obtained at the level of bronchus

intermedius shows enlarged right hilar (arrowhead), subcarinal, and

paraesophageal lymph nodes (arrows).

(C) CT scan obtained at the level of the right middle lobe bronchus

shows parenchymal consolidation in the right middle lobe and enlarged

subcarinal lymph nodes (arrows).

(D) Photomicrograph of the surgical biopsy specimen shows

granulomatous inflammation and fibrosis with infiltration of

multinucleated giant cells, eosinophils, and lymphocytes (hematoxylin

and eosin stain, x100).

(E) Photomicrograph shows a yeast form developing a spherule of

Coccidioides immitis (arrow), which is engulfed by a multinucleated

giant cell (arrowheads). The periodic acid-Schiff stain highlights its thick

yeast wall (periodic acid-Schiff stain, x400). The patient was a


10 de 19 17/08/2015 09:31 p.m.

58-year-old man with a one-month history of dyspnea and fever.

Reproduced with permission from: Fungal and parasitic infections. In:

Imaging of pulmonary infections. Muller NL, Franquet T, Kyung SL (Eds),

Lippincott Williams & Wilkins, Philadelphia 2007. Copyright © 2007 Lippincott

Williams & Wilkins. www.lww.com.



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Chest computed tomograph of a patient with

coccidioidomycosis

High-resolution computed tomography (CT) image (1.5-mm collimation)

shows thin-walled cavity in right upper lobe. The diagnosis of

coccidioidomycosis was made at surgical resection. The patient was a

44-year-old man who developed coccidioidomycosis following travel to

an endemic area.

Reproduced with permission from: Fungal and parasitic infections. In:

Imaging of pulmonary infections. Muller NL, Franquet T, Kyung SL (Eds),

Lippincott Williams & Wilkins, Philadelphia 2007. Copyright © 2007 Lippincott

Williams & Wilkins. www.lww.com.



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Physician-specific diagnosis of Valley Fever in

relation to workload and diagnosis of community-

acquired pneumonia (CAP)

Size of yellow circles is proportional to diagnoses of Valley Fever (1 to 10

patients). Red circles indicate physicians who have not diagnosed Valley

Fever. The black arrow points to a physician who had not diagnosed this

infection despite making the diagnosis of CAP 98 times.

Reproduced with permission from: Campion JM, Gardner M, Galgiani JN.

Coccidiodomycosis (Valley Fever) in older adults: An increasing problem. Arizona

Geriatrics Society Journal 2003; 8:3. Copyright © Arizona Geriatrics Society.



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Coccidioides spp in lung tissue

Spherules of Coccidioides spp in a transbronchial biopsy specimen

stained with hematoxylin and eosin.

Courtesy of Jeffrey Houck, MD.



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Methenamine silver stain of a pleural biopsy specimen, showing small

spherules (white arrow), clumps of endospores (blue arrow), and hyphal

forms (black arrows; original magnification, x400).

Reproduced with permission from: Nicolasora N, Cinti SK, Riddell IV J,

Kauffman CA. Photo quiz. A 53-year-old man with a large air bubble in his

chest. Clin Infect Dis 2008; 47:823. Copyright © 2008 University of Chicago

Press.



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Spherules of Coccidioides spp in a transbronchial biopsy specimen

stained with periodic acid-Schiff (PAS).

Courtesy of Jeffrey Houck, MD.



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MRI of patient with disseminated

coccidioidomycosis

42-year-old woman with paranoid schizophrenia who presented with

weight loss, fever, and malaise. Patient had previously been evaluated at

another hospital for multiple vertebral lesions and right breast mass that

was eroding through right anterior chest wall.

(A) Sagittal T2-weighted magnetic resonance image (MRI) of cervical

spine shows large paraspinal fluid collection (arrowheads) with

contiguous vertebral body involvement from C5 to T3 with relative

sparing of intervertebral disks.

(B) Sagittal T2-weighted MRI of thoracic spine shows T7 to T8 discitis

and osteomyelitis with anterior epidural extension (arrow) and resultant

spinal cord compression and edema (arrowhead).

From: Wilde GE, Emery C, Lally JF. Radiological reasoning: Miliary disease,

vertebral osteomyelitis, and soft-tissue abscess. AJR Am J Roentgenol 2008;

190:S11-7. Reprinted with permission from the American Journal of

Roentgenology.


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Disclosures: John N Galgiani, MD Grant/Research/Clinical Trial Support: Viamet [anti-fungal drugs (VT-1161)]. Consultant/Advisory Boards:Viamet [anti-fungal drugs (various, pre-clinical)]; Nielsen Biosciences [Coccidioidomycosis (spherusol)]. Employment: Valley Fever Solutions(nikkomycin z). Equity Ownership/Stock Options: Valley Fever Solutions (nikkomycin z). Carol A Kauffman, MD Nothing to disclose. Anna RThorner, MD Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.

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Disclosures


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coccidioidomicosis primaria, diagnóstico y tratamiento

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