Coccidioidomycosis

265 (Coccidioides Species)

John N. Galgiani

SHORT VIEW SUMMARY

Definition } Alternate hyphal cells autolyze, leaving behind } A test for coccidioidal antigen is commercially
} The dimorphic fungi Coccidioides immitiss and single 3- to 5-μm cells (arthroconidia) that can available and is most frequently positive in
Coccidioides posadasiii cause a systemic fungal become airborne and are capable of being patients with extensive infection.
infection, coccidioidomycosis, also known as inhaled deep into airways. } A skin test that measures dermal
San Joaquin Valley feverr or Valley fever. } In mammalian tissue, an arthroconidium hypersensitivity in patients with prior
remodels into a spherical cell that enlarges coccidioidal infection is again commercially
Epidemiology
isotropically to form large mature spherules available.
} Coccidioidomycosis is endemic to arid regions
with scores of endospores developing within.
of the Western Hemisphere. Therapy
} Endospores, when released during spherule
} Approximately 150,3192 new US infections } Healthy patients with uncomplicated
rupture, can develop into a new spherule
occur annually, of which 50,000 produce coccidioidal pneumonia usually improve with
within host tissue or revert to mycelial growth
significant illness; of those reported to the general supportive management whether or
if removed from the infection.
Centers for Disease Control and Prevention, not antifungal drugs are used. If antifungal
} A sexual phase has not been observed, but
66% are from Arizona and 31% from treatment is initiated for such patients, it
population genetics suggest that one exists.
California. usually consists of fluconazole given orally at
Sequence analysis indicates that Coccidioides
} Infections most frequently occur during dry a dose of 400 mg/day for periods ranging from
is an ascomycete.
seasons, and the incubation period until first 3 to 6 months.
symptoms ranges from 1 to 3 weeks. Diagnosis } Patients with severe early pneumonia
} The most common illness is a } Isolation of Coccidioidess in culture from a sufficient to require intensive care
community-acquired pneumonia, lasting weeks clinical specimen is diagnostic of infection. hospitalization are often treated with
to months whether treated with antifungal } Recognizing endospore-containing spherules in intravenous amphotericin B initially until the
agents or not. Progressive pneumonia or wet mounts or histologic sections is also respiratory status stabilizes or improves.
hematogenous dissemination to other organs definitive. } When infection results in symptomatic chronic
is a serious complication that requires } Diagnosis in most patients is made fibrocavitary pneumonia or extrapulmonary
treatment. presumptively by detecting anticoccidioidal dissemination, antifungal therapy involves oral
} Patients with diabetes are more likely to suffer antibodies in serum or cerebrospinal fluconazole (400 mg daily or higher) or
pulmonary complications. fluid. itraconazole (200 mg twice or three times
} The risk of dissemination is much more } Complement-fixing anticoccidioidal antibodies daily). Treatment would normally be continued
frequent in patients with impaired cellular are quantitated by serial dilution titration. for at least 1 year. In such patients, it is not
immunity. More extensive infections are frequently infrequent for treatment to continue for
associated with higher titers, and clinical several years because relapse off treatment is
Microbiology
improvement is associated with decreasing common.
} Coccidioidess has been found in desert soil and
titers. } In some patients, surgery in addition to
associated with animal burrows but is sparsely
} Immunodiffusion techniques are routinely used antifungal drugs is essential to control
distributed, even within the most highly
to provide a qualitative mimic of the infection.
endemic regions.
complement-fixing antibody test and also to } Treatment of coccidioidal meningitis is most
} Throughout the 20th century,
detect other Coccidioidess-specific antibodies, frequently managed with oral fluconazole in
coccidioidomycosis was recognized as caused
often immunoglobulin M (IgM), which occur doses of 400 mg or more daily. This treatment
by a single fungal species, C. immitis. This
earlier.r is lifelong for all patients. Patients who
population contains two genetically and
} Proprietary enzyme immunoassay kits that develop hydrocephalus usually require the
geographically distinct clades, now recognized
measure anticoccidioidal IgM and IgG placement of an internal ventricular shunt.
as separate species: C. immitiss predominantly
antibodies are in wide use. They are
found in California and C. posadasiii in all Prevention
more sensitive in detecting early
other endemic regions. } A preventive vaccine does not exist. A vaccine
coccidioidal infections but may not be
} On most laboratory media, growth by apical candidate is under development for dogs but
as specific.
mycelial elongation is visible within a week. not yet for humans.

Although the systemic fungal infection now known as coccidioidomycosis coccidioidomycosis was thought to be a rare and nearly always fatal
has been recognized for more than a century,1 its endemic domains infection. In 1929, an accidental laboratory exposure of a medical student
continue to be expanded.2,3 A medical intern is credited with first at Stanford University resulted in only a transient respiratory infection.
identifying in 1892 a patient who had widespread disease.4 Organ- His unexpected survival stimulated a reassessment of the natural history
isms seen microscopically were mistakenly thought to be parasites, of coccidioidal infections, which soon led to the recognition that a
and only several years later was the true mycotic etiology determined common respiratory condition in the San Joaquin Valley of California
and the agent given the name Coccidioides immitis.5 For 3 decades, (Valley fever) was the more usual result of infection.6 This conclusion

3190
 3191
was corroborated with the development by Smith and colleagues of a Spherule (Parasitic) Growth
specific skin test7 and serologic assays8 for coccidioidomycosis. With In the lungs, arthroconidia remodel into spherical cells, shedding their
these tools, the clinical spectrum became well described by the mid- hydrophobic outer wall.39,40 During this phase, nuclear division and cell
1950s; an excellent monograph published by Fiese9 remains a valuable

Chapter 265 Coccidioidomycosis (Coccidioidess Species)

multiplication occur, and septa extend from the internal surface of the
contemporary reference on the disease. wall to transect the growing spherule into scores of subcompartments,
The growing impact of coccidioidomycosis on public health can be each containing viable daughter cells or endospores. In tissue, spherules
attributed to changes in demography and in contemporary medicine.10 can become 75 μm in diameter (Fig. 265.1). Spherules grown in vitro
First, the populations at risk of exposure are greatly expanded. Regions demonstrate nuclear division throughout maturation, although their
in which Coccidioides spp. are endemic, which previously were sparsely size is smaller and the number of endospores is fewer.41 As a spherule
populated, now encompass major metropolitan centers such as Phoenix, matures, its outer wall thins and eventually ruptures. Early in the course
Arizona. Many of those relocating to the Southwest are retirees, and of experimental infections, this rupture occurs in approximately 4 days,42
case rates in older persons are higher than in young adults.11–13 With and with the release of endospores, the number of viable fungal units
this population growth has come greatly increased tourism and is amplified by approximately 100-fold, each of which may continue to
commerce-related movement of people into and out of endemic areas. propagate in tissue or revert to mycelial growth if removed from the
As a result, increased numbers of people are acquiring coccidioidal site of an infection.
infections both within and beyond endemic regions.14,15 Second, a major
segment of the population has emerged with compromised cellular EPIDEMIOLOGY
immunity because of either underlying diseases or immunosuppressive Geographic Range
Rang
therapies to control other diseases.16–24 These patients are unusually Coccidioides spp. are endemic to the soils of certain regions of only the
susceptible to serious coccidioidal infections, and as a result, the severity Western Hemisphere, nearly all of which are within the north and south
of coccidioidal infections as a public health problem has increased. 40-degree latitudes. Well-described transport of arthroconidia, either
Third, advances in prevention and treatment of fungal infections offer in soil on fomites43–45 or as the result of unusually severe dust storms,46
new opportunities for management. These trends have made coccidi- has produced infections in persons without endemic exposure, but this
oidomycosis more relevant to physicians everywhere.25 Finally, the generally has not led to the establishment of new areas of endemicity.
emergence of Coccidioides spp. as potential agents of bioterrorism was Regions of the United States in which Coccidioides spp. are endemic
identified by the Centers for Disease Control and Prevention (CDC) are shown in Fig. 265.2. Noncontiguous foci of endemicity also exist,
in 1997.26,27 Although Coccidioides spp. have since been removed from such as those studied at Dinosaur National Monument, Utah47 and in
the CDC list of select agents, awareness of their potential remains in eastern Washington.2 These regions generally have the characteristics
light of continued technical advances in genetic transformation.28 of the “lower Sonoran life zone,” which include an arid climate, yearly
rainfall of 5 to 20 inches, hot summers, winters with little freezing
MYCOLOGY weather, and alkaline soil. Other areas where Coccidioides spp. have
Coccidioides spp. aare dimorphic fungi that exist either as mycelia or as been identified include Mexico (adjacent to the US border; western
unique structures known as spherules.29 Both forms of growth are asexual, portions of the states of Sonora, Nayarit, Jalisco, and Michoacan; central
and it is not possible to classify Coccidioides spp. in relation to other regions, including the states of Coahuila, Durango, and San Luis Potosi);
fungi by classic taxonomy. By molecular analysis, however, Coccidioides Central America (Guatemala, Honduras, Nicaragua); and South America
spp. appear related most to other ascomycetes, most closely to the (Argentina, Paraguay, Venezuela, Colombia, Brazil).10 An archeological
medically important organisms Blastomyces dermatitidiss and Histoplasma investigation has provided evidence that Coccidioides spp. infected bison
capsulatum.30 Although a sexual phase has not been found, population 8500 years ago in what is now Nebraska, far beyond the current endemic
genetics studies suggest that one does exist.31,32 Two genetically distinct regions.48 This raises the possibility that climatic change could potentially
populations have been identified among the etiologic agents of coc- affect the geographic distribution of Coccidioides spp.49
cidioidomycosis. The occurrence of two populations was correlated Within the endemic regions, the likelihood of finding Coccidioides
with separate endemic regions where patients resided. This finding spp. in soil samples varies considerably among different locations32,50,51
prompted classification of the previously known single species, C. immitis, and different seasons. The fungus is recovered most easily toward the
into two species: C. immitis and Coccidioides posadasii. Most of the C. end of winter rains.52 This is opposite to the seasonal relationship for
immitiss isolates have been obtained from California, whereas C. posadasii acquisition of new infections, which in California and Arizona occur
isolates have been obtained from patients in other states and from most frequently during the summer months, after the soil has become
countries other than the United States.33,34 DNA sequence analysis of dry. In Arizona, there is a second peak of new clinical infections from
C. posadasii strains enabled investigators to deduce the approximate October until the winter rains, which corresponds to a similar dry
geographic origin of some infections.34,35 The two species have shown period after the late summer rains in that region.53
few phenotypic differences; the clinical manifestations resulting from
infection with either species appear the same, and in vitro susceptibility
to antifungals is similar.36,37 Molecular identification methods for dif-f
ferentiation of C. immitis from C. posadasii have been described38 but
are not yet routinely employed. Thus references in the literature to C.
immitis may actually be referring to either species. Isolates for which
the species has not been determined are best designated as simply
Coccidioides spp., which is the convention followed in this chapter.

Mycelial (Saprobic) Growth

On routine microbiologic nutrient agar media and presumably in the
soil, Coccidioides spp. grow as mycelia by apical extension, and true
septa form along their course. Maturation within 1 week of growth
results in alternating mycelial cells undergoing a process of autolysis
and thinning of the cell walls. The remaining intact cells become barrel-
shaped arthroconidia approximately 5 μm in length, develop a hydro-
phobic outer layer, and are capable of remaining viable for years. Because
the attachments of arthroconidia to adjacent cell remnants are fragile,
they are prone to separation by physical disruption or mild air turbulence.
As a result, arthroconidia readily become airborne in a form capable FIG. 265.1 Photomicrograph of a spherule in a tissue. Hematoxylin
of deposition in the lungs if inhaled. and eosin staining. (Courtesy Richard Sobonya, MD, University of Arizona.)
 3192
Part III Infectious Diseases and Their Etiologic Agents

Pacific
Ocean

Gulf of
Mexico
Percent reactors
<5%
5%-10% Mexico
10%-30%
30%-50%
50%-70%
Unexplored
FIG. 265.2 Dermal hypersensitivity mapping of the endemic intensity of coccidioidomycosis. (From Nguyen C, Barker BM, Hoover S, et al.
Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol
Rev. 2013;26:505–525.)

20,000

18,000 Arizona California

16,000

14,000
Reported cases

12,000

10,000

8,000

6,000

4,000

2,000

0
95
96
97
98
99
00
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
ion 7
90
91
92
93
94

al
vis 201
20
19
19
19
19
19
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
19
19
19
19
19

pro

FIG. 265.3 New cases of coccidioidomycosis reported to the Arizona and California Departments of Public Health. (Data source: Centers for
Disease Control and Prevention.)

Rates of Coccidioidal Infection of the large influx of new residents to the endemic regions from non-
Prevalence surveys in the 1950s of skin test reactivity to coccidioidal endemic locales (in the 2010 census, estimated to total >7 million persons
antigens in school-age children of California’s Central Valley suggested for southern Arizona and south central California), the proportion of
that the annual risk of infection was approximately 15%.54 Smith and persons within the endemic region with prior infection is approximately
colleagues55 showed that in 25% to 50% of military personnel in the 30%. Based upon these estimates, the expected number of infections
San Joaquin Valley, skin test results converted to positive during a single is on the order of 150,000 annually, resulting in approximately 50,000
year. More contemporary estimates from the same areas in California persons sick enough to seek medical attention.
and from Tucson, Arizona, indicate that the risk has declined to The numbers of infections reported to state departments of public
approximately 3% per year.54,56 Because of these lower rates and because health differ significantly from year to year (Fig. 265.3). Some variation
 3193
has been associated with total winter rainfall; more cases occur in the Coccidioides spp. can be shown in vitro by human neutrophils and
summers after wetter winters.53 On occasion, epidemics also have been mononuclear cells from persons with or without prior coccidioidal
associated with disruption of infected soil by human intent, such as with infection as judged by skin test reactivity to coccidioidal antigens.89

Chapter 265 Coccidioidomycosis (Coccidioidess Species)

excavation; after natural events, such as severe dust storms or earthquakes; Although neutrophils do not seem to be fungicidal against Coccidioides
or during military maneuvers.57–59 Some fluctuations in rates of infections spp., mononuclear cells or natural killer cells have been shown to reduce
are not explained, however. Such is the case for an exceptionally large fungal viability.90,91 These innate cellular inhibitory effects are most
epidemic in California’s Central Valley in the period from 1992 to 1995, evident against arthroconidia or endospores and are lost as spherules
in which the incidence of infection at times was more than 10 times increase in size and mature.92 These in vitro observations can be
that normally reported, and in 2010 to 2011, in which the total number extrapolated to indicate that innate defenses may serve primarily to
of reported cases was the highest since coccidioidomycosis was made slow fungal proliferation after infection, transforming what otherwise
a reportable disease.11,60 An analysis of death certificates indicated that might be a more fulminant infection to a more subacute or chronic
approximately 160 persons die each year from coccidioidomycosis,61 process.
although these statistics may be an underestimate.62 Coccidioidal infections engender a variety of humoral responses to
several different antigens in patients, and, as discussed subsequently,
PATHOGENESIS AND CONTROL several are diagnostically useful. Coccidioides-infected B-cell–deficient
Nearly all infections are the result of inhaling arthroconidia.
arth Cutaneous mice are not as protected by vaccination as are normal mice.93 However,
inoculations have been reported, producing lymphatic extension to a specific defensive role for immunoglobulins has thus far not been
regional lymph nodes and resolving without treatment. These occurrences defined.
are exceedingly rare, however.63
A single arthroconidium may be sufficient to produce a naturally CLINICAL MANIFESTATIONS
acquired respiratory infection. This is the case for experimental infections At least one-half to two-thirds of all infectio
infections caused by Coccidioides
in mice,64 and air sampling within coccidioidal endemic regions suggests spp. are either inapparent or sufficiently mild not to prompt medical
that the ambient density of arthroconidia in the air is low.65,66 The size evaluation.55 Of those that do become medically significant, a large
of the arthroconidium would allow its deposition within the terminal majority result in a respiratory illness that is indistinguishable without
bronchiole but probably not as deeply as the alveolar space. With spherule specific testing from community-acquired pneumonia caused by other
rupture, inflammation ensues,67,68 forming a local pulmonary lesion. entities.94–96 In two observational studies in southern Arizona, coccidi-
Extracts of Coccidioides spp. have been shown to react with complement, oidomycosis was estimated to be responsible for approximately one-quarter
releasing mediators of chemotaxis for neutrophils.69 In some infections, to one-third of all cases of community-acquired pneumonia in that
Coccidioides spp. leave the lungs to establish disseminated lesions in endemic area.95,96 Nonetheless, misunderstandings of the manifestations
other parts of the body. In this sequence of events, fungal elements of coccidioidomycosis or the perceived unimportance of diagnosis of
must move from the distal bronchiole into the lung parenchyma, gain early infections have led to significant delays in diagnosis96a,96b and gross
entry into the vascular space, and leave the vascular space to create disparities between the numbers of expected and reported coccidioidal
extrapulmonary sites of infection. It is possible that endospores within infections.97–99 For example, the number of coccidioidal infections reported
macrophages travel through lymphatic vessels to the bloodstream, as to Arizona’s Department of Health Services (see Fig. 265.3) represent
has been described for dissemination of tuberculosis and histoplasmosis. only a fraction of the expected 30,000 new illnesses. Underdiagnosis
This possibility is also compatible with the common finding of infected may be even more likely for patients with coccidioidomycosis evaluated
hilar, peritracheal, supraclavicular, and cervical lymph nodes in patients outside the endemic region.57,100 Most coccidioidal infections, whether
with extrapulmonary coccidioidal infections.67 detected or not, follow a self-limited course; only a few produce residual
sequelae or chronic progressive infections. Although complications of
Histopathology untreated coccidioidal infections are typically manifested within weeks,
Microscopic examination of tissue infected with Coccidioides spp. shows months, or rarely up to 2 years after the original infection, the severity
elements of acute and chronic inflammation. Acute inflammation, of the initial respiratory infection is not correlated with the likelihood
including neutrophils and eosinophils, is associated with active infections of complications. In this context, the identification of even mild primary
and rupturing spherules.67,68 Granulomatous lesions that include lym- infections takes on added significance and clinical relevance.
phocytes, histiocytes, and multinucleated giant cells are associated with
chronic or arrested infections and with mature unruptured spherules.70 Early Respiratory Infection
In patients with widespread infections, it is common to find both The first symptoms of the primary infection usually appear 7 to 21 days
inflammatory responses represented concurrently at different anatomic after exposure. Most infections seem to develop as a result of exposure
sites. to one or a small numbers of arthroconidia. However, when exposure
is unusually intense, symptoms are more likely to appear early.101 In an
Host Defenses epidemic of coccidioidomycosis that occurred in the San Joaquin Valley
Control of coccidioidomycosis depends on T lymphocytes. This conclu- of California between 1991 and 1994,102 the findings in 536 patients
sion is supported by studies of experimentally produced infections in with new infections included cough (73%), chest pain (44%), shortness
mice71–75 and by the increased severity of naturally acquired infections of breath (32%), fever (76%), and fatigue (39%). These findings are
in T-cell–deficient patients.21,23,76–79 Peripheral mononuclear blood cells typical of earlier reports. Although the infection is often subacute in
from patients with active disseminated coccidioidomycosis have virtually development, patients occasionally report abrupt onset of symptoms,
no interferon-γγ response to coccidioidal antigens.80 This is in contrast especially that of pleurisy. Weight loss is also a common sign, and
to the brisk stimulation of similar leukocyte preparations from patients headache has been noted in 21% of patients in the absence of meningeal
in whom coccidioidal infections are competently controlled and who infection.103 Skin manifestations develop as part of the primary illness.
have delayed-type dermal hypersensitivity to coccidioidal skin-testing Most frequent and easily missed is a nonpruritic fine papular rash that
antigens.81 These findings are consistent with an absent type 1 helper occurs early and transiently during the illness. More striking are erythema
T cell (Th1) response described in some experimental animals82,83 and nodosum and erythema multiforme, which occur predominantly in
human infectious diseases, in which cellular immunity plays a role. In women. Migratory arthralgias are also common complaints, and the
humans, however, despite the observed depression of interferon-γγ levels, triad of fever, erythema nodosum, and arthralgias (especially sym-
interleukin-4 and interleukin-10 levels were not reciprocally elevated,81 metrically of the knees and ankles) has been termed desert rheumatism.
which would be indicative of a type 2 helper T cell (Th2) response. Routine laboratory findings, including serum procalcitonin levels,104
Recently, specific mutations in Th1 pathway genes have been associated are usually normal except for slightly increased peripheral blood leu-
with disseminated infection.84–86 kocytosis and an increase in the erythrocyte sedimentation rate.
In addition to T-cell–mediated control of infection, innate cellular Peripheral blood eosinophilia may be present, occasionally accounting
responses may contribute to host defense.87,88 Inhibition of growth of for two-thirds of the circulating leukocytes. Chest radiograph results
 3194
Part III Infectious Diseases and Their Etiologic Agents

A B
FIG. 265.4 Cavitation of a coccidioidal nodule. (A) A 1.8-cm nodule can be seen. (B) Eight months later, this lesion has become a thin-walled cavity.

are abnormal in more than half of patients. This partially accounts for
different estimates in two Arizona studies of coccidioidomycosis as a
cause of community-acquired pneumonia. A case definition that required
an abnormal chest radiograph in one study96 was lower than one that
did not.95 Common radiographic findings include unilateral infiltrates,
hilar adenopathy, and peripneumonic pleural effusions. Persistent hilar
or peritracheal adenopathy may be associated with extrathoracic spread
of infection.105 Lung cavities are present initially in approximately 8%
of infections recognized in adults but are less frequent in children.106
Uncommonly, coccidioidal pneumonia manifests as a diffuse process
leading to respiratory failure, either because of high-inoculum expo-
sure107,108 or because of fungi in the bloodstream that seed the lung in
many sites.22,109 The manifestation is often fulminant, mimicking that
of septic shock or a bacterial infection, and despite treatment, the rate
of mortality is high. Approximately one-third of human immunodefi-
ciency virus (HIV)–infected patients with clinically acquired immu-
nodeficiency syndrome (AIDS) exhibit this radiographic appearance.
Although fungemia associated with diffuse pulmonary infiltrates may
occur in immunologically intact patients,110 it is nearly always attributable
to a recognizable cellular immunodeficiency state.111 In HIV-infected
patients with fungemia, the CD4+ counts are typically less than 100
cells/mm3 and the viral load is high.112
Although some of the presenting signs, symptoms, and routine
laboratory studies are statistically more likely to occur with coccidioidal
infections than with respiratory illness of other causes, the overlap of
clinical syndromes is substantial.94–96 For most patients, specific testing
is necessary to secure a definitive diagnosis of coccidioidomycosis.
Most coccidioidal respiratory infections resolve without complications
but often take several weeks to many months to do so. When resolution
of the self-limited illness is protracted, the symptom of fatigue is fre-
quently the last to resolve. This fatigue syndrome, disproportionate to
other evidence of infection syndrome, may strikingly interfere with FIG. 265.5 Fungus ball in the right lung of a coccidioidal cavity.
normal daily activities or the ability to return to work, and it can be a Bronchoscopy specimens yielded Coccidioides spp. in culture. (From Winn
source of considerable distress. A recent small study of such subjects RE, Johnson R, Galgiani JN, et al. Cavitary
r coccidioidomycosis with fungus
demonstrated a striking oxygen utilization deficit,113 but further studies ball formation. Chest. 1994;105:412–416.)
will be needed to determine how extensively this mechanism accounts
for this very common complaint. A few patients with infections develop examination.114–116 On occasion, nodules liquefy and drain into a bronchus
various pulmonary sequelae, and even fewer patients manifest dis- to form a cavity (Fig. 265.4).
seminated infection outside the lungs. Despite their relative infrequency, Pulmonary cavities may be present initially or in the later stages of
these complications pose significant difficulties in diagnosis and manage- the primary infection. They are usually peripheral and solitary, and
ment (discussed later). with time, most develop a distinctive thin wall.106 Cavities may not
cause any symptoms, and half close within 2 years. Others are associated
Pulmonary Nodules and Cavities with local symptoms of pleuritic pain, cough, or hemoptysis. A fungus
Approximately 4% of pulmonary infections result in a nodule, ranging ball may develop within cavities, either from mycelia of Coccidioides
up to 5 cm in diameter. A nodule typically causes no symptoms but spp.117,118 or with other species of fungi (Fig. 265.5). Another infrequent
may be indistinguishable from a neoplasm without histologic but well-recognized complication is rupture of a peripheral coccidioidal
 3195
cavity into the pleural space and its manifestation as a pneumothorax. systemic symptoms, such as night sweats and weight loss, and local
Ruptures commonly occur in athletic young men and are not associated symptoms. Recently, two patients with a mutation of STAT1 have been
with underlying immunodeficiency. Because the fungal walls of Coc- described with a chronic consumptive coccidioidal pneumonia, which

Chapter 265 Coccidioidomycosis (Coccidioidess Species)

cidioides spp. are inflammatory, ruptured coccidioidal cavities often is strikingly devoid of cavitation in contrast to what occurs more
produce fluid in the pleural space, and the presence of an air-fluid level commonly.86
within the pleural space is a clue that the process is not a spontaneous
pneumothorax or a ruptured pulmonary bleb (Fig. 265.6). If the cavity Extrapulmonary Dissemination
is diagnosed early, surgical resection of the cavity and closure of the Coccidioides spp. spread beyond the lungs in approximately 0.5% of all
pulmonary leak is the preferred treatment.119,120 Less commonly, pleural infections in the general population. Several factors dramatically increase
disease can occur without rupture of a cavity. In a study of pleural the risk of dissemination, however: immunodeficiency conditions, such
coccidioidomycosis, 10 of 36 (28%) patients had pleural-predominant as the later stages of HIV infection112 and Hodgkin lymphoma23; and
disease without cavity or cavity rupture.121 therapies that suppress immune function, such as therapy to prevent
solid-organ rejection,124 high-dose corticosteroid therapy (equivalent
Chronic Fibrocavitary Pneumonia to long-term prednisone doses >20 mg/day),78 and therapeutic inhibitors
In contrast to thin-walled coccidioidal cavities, a chronic fibrotic of tumor necrosis factor.18,125 In two-thirds of renal-transplant recipients
pneumonic process that develops in some patients is characterized by who developed coccidioidal infection, the infection progressed to
pulmonary infiltrates and pulmonary cavitation (Figs. 265.7 and 265.8).122 dissemination.76 With transplantation, the risk is heightened mostly by
This form of infection is not common among patients with T-cell either newly acquired disease or reactivation of prior infection. Transmis-
deficiencies but seems to be associated with diabetes or preexisting sion by the engrafted organ has also been reported.126–128 Dissemination
pulmonary fibrosis related to smoking or other causes.123 Involvement is more likely to develop in men than in women.129–131 Dissemination
of more than one lobe is more common, and these lesions may cause is also more likely, however, if infection is diagnosed during pregnancy,
especially during the third trimester or in the immediate postpartum
period.132 The risk of dissemination also appears to be increased among
persons of African or Filipino ancestry, although the exact magnitude
of the risk is controversial.129,133,134 Extrapulmonary dissemination is
not associated often with pulmonary complications. Many patients with
disseminated coccidioidal infection have entirely normal chest
radiographs.
The most common site of dissemination is the skin. The range of
lesions includes superficial maculopapular lesions, keratotic and verrucose
ulcers, and subcutaneous fluctuant abscesses. There is a predilection
for lesions at the nasolabial fold (Fig. 265.9). Although most extrapul-
monary dissemination is the result of hematogenous spread, supracla-
vicular and cervical lymphadenopathy is also a frequent manifestation
and probably represents lymphatic drainage from the primary pulmonary
infection. A rare manifestation is peritoneal coccidioidomycosis, which
clinically resembles tuberculous peritonitis.135
Joints and bones are common sites of dissemination. Joint infections
differ from the self-limited joint complaints of desert rheumatism in
that infections are typically asymmetrically distributed and are associated
with a prominent synovitis and effusion. Although any joint can become
infected, the knee is involved most frequently; other common locations
include the joints of the hands and wrists, feet and ankles, vertebrae,
FIG. 265.6 Chest computed tomography scan of ruptured coccidi- and pelvis.136–140 Infection may be limited to the synovium or may erode
oidal cavity with pneumothorax. White star points to air in the pleural to involve the underlying bone. Alternatively, bones may be involved
space. first with secondary extension into the joint.141,142 Although long bones

FIG. 265.7 Pulmonary cavity in the right upper lobe with sur-
r FIG. 265.8 Computed tomography scan of the fibrocavitary process
rounding fibrosis. shown in Fig. 265.7.
 3196
Coccidioidal meningitis is the most serious form of disseminated
infection. Untreated, it is nearly always fatal within 2 years of diagno-
sis.145,146 Like most other complications of coccidioidomycosis, meningitis
Part III Infectious Diseases and Their Etiologic Agents

usually develops relatively soon after the initial infection. In one study
of 22 patients who developed meningitis after a large dust storm, central
nervous system symptoms developed on average after 5.4 weeks of
illness.147 Similarly, a review of cases from the Department of Veterans
Affairs and military records showed that, of 25 patients who developed
meningitis, 20 did so within 6 months of their first symptoms of infec-
tion.146 Common presenting symptoms are headache, vomiting, and
altered mental status.148–150 In addition to cerebrospinal fluid (CSF)
findings of an elevated white blood cell count, elevated protein levels,
and a depressed glucose level, CSF eosinophils are occasionally promi-
nent.151 The main areas of involvement are the basilar meninges.
Hydrocephalus is a common complication, especially early in children.152
Attention has been drawn to vasculitis and focal intracerebral coccidioidal
abscesses as less frequent complications.153–155
FIG. 265.9 Ulcerative lesion of disseminated coccidioidal infection.
(From Galgiani JN. Coccidioidomycosis. West J Med. 1993;159:153–171.) DIAGNOSIS
The manifestation
manifestations of most early coccidioidal infections overlap sub-
stantially with those of other respiratory infections.94–96 Specific laboratory
testing is usually necessary to establish a diagnosis of coccidioidomycosis.
In regions where Coccidioides spp. are endemic, this testing is com-
monplace. In most of the rest of the United States, the possibility of
coccidioidomycosis is unlikely to be considered unless a geographic
exposure is elicited in the patient’s history. Because the incubation period
is usually 1 to 3 weeks, endemic exposure within this period should
raise the possibility of coccidioidomycosis to account for a respiratory
condition of new onset. Exposure need not be extensive. Infections
have occurred in patients whose only exposure occurred while changing
airplanes at the Phoenix airport or during a single drive across California’s
Central Valley.
Complications of the initial infection, such as chronic pneumonia
or extrathoracic dissemination, may take longer to become apparent
but nearly always emerge within 2 years after exposure. One exception
to this rule is the detection of a pulmonary nodule or a solitary pulmonary
cavity, which may persist without symptoms for many years after the
original infection. Another special case is the setting of waning immunity,
such as after the development of AIDS or with immunosuppressive
therapy associated with solid-organ transplantation. In such circum-
stances, exposure to Coccidioidess spp. in the distant past may be sufficient
to account for the current clinical illness.156
When the possibility of coccidioidomycosis has been raised, diagnosis
is usually established in two ways: (1) identifying spherules in, or
recovering Coccidioides spp. from, a clinical specimen; or (2) detecting
specific anticoccidioidal antibodies in serum, CSF, or other body fluid.

Direct Examination and Culture

Isolating Coccidioides organisms from a patient is definitive evidence
of a coccidioidal infection, and this diagnostic approach is used most
frequently for patients with complicated pulmonary or disseminated
syndromes. Sputum or other clinical specimens can be collected at no
risk to personnel because the infection is not transmitted from the
primary specimen. Direct microscopic examination of secretions can
be performed immediately or after the addition of potassium hydroxide.
FIG. 265.10 Sagittal magnetic resonance imaging shows an anterior Calcofluor staining of the cell wall in a wet mount may also help to
paraspinous abscess extending from the base of the skull to the distinguish spherules from leukocytes. Coccidioides spp. cannot be
midthoracic vertebrae. Arrow 1 points to an abscess that originated in detected on Gram stains. Spherules also can be detected by cytology
a cervical vertebra and dissected anteriorly. Arrow 2 identifies a normal stains (e.g., in bronchoscopy specimens)157; hematoxylin and eosin stains;
spinal cord. The arrowheads indicate abscesses anterior to the thoracic and other specialized procedures, such as silver or periodic acid–Schiff
vertebrae. Multiple surgical procedures were necessary to control this staining. Hematoxylin and eosin staining of spherules produces a distinc-
infection. tive autofluorescence that may help to identify a few organisms in
tissues.158 Using species-specific probes, researchers found that in situ
hybridization was not as sensitive as silver staining but was more
specific.159 Although culture results are more sensitive, identification
may be affected, vertebral infection is much more common. Involvement of spherules by direct examination is more rapid and may speed diagnosis.
of multiple vertebrae is typical.143 These may coalesce to produce anterior Direct detection of Coccidioides in sputum by polymerase chain reaction
or posterior paraspinous soft tissue abscesses or an epidural abscess has been reported and may become clinically available soon.38,160–162
(Fig. 265.10). Magnetic resonance imaging (MRI) is often helpful in Coccidioidess spp. grow well on most mycologic or bacteriologic media
defining the exact location of these lesions.144 after 5 or 7 days of incubation. Aerobic conditions are required. When
 3197
growth occurs, it is typically as a white (nonpigmented) mold. There however, end point results for the same serum samples may vary considerably
are many exceptions to this general appearance, however, and the on testing by different laboratories. More useful are serial determinations
morphologic appearance is not reliable in determining whether the of complement-fixing antibody concentrations performed by the same
fungus is Coccidioidess spp.163 When growth is evident on culture medium,

Chapter 265 Coccidioidomycosis (Coccidioidess Species)

laboratory. In general, higher titers reflect more extensive coccidioidal
care should be taken not to open the culture container except in an infection, increasing complement-fixing antibody concentrations are
appropriate biocontainment cabinet. Cultures at this stage are highly associated with worsening disease, and decreasing titers are useful in
infectious, and infections have occurred in laboratory personnel when monitoring response to therapy. These are general relationships that are
cultures have not been handled properly.164 occasionally not borne out by the course of individual patients.175a
The mycelial form of growth is not specific for Coccidioides spp.,
and further testing is required for species identification. The most Immunodiffusion Tests
common way for microbiologists to test this is to detect a specific Antibodies that were detected by the original tube precipitin or
ribosomal RNA sequence using a commercially available DNA probe complement-fixing tests can be detected by alternative procedures known
(Accuprobe, Hologic, San Diego).165 At present, molecular methods to as the immunodiffusion tube precipitin and immunodiffusion complement-
differentiate between C. immitis and C. posadasii are available only at fixingg tests. Although these tests are conducted similarly, different antigens
a limited number of reference laboratories. Genus identification can are used to measure different types of antibodies. As with the original
also be done by detection of an exoantigen in an extract of fungal tests, the immunodiffusion tube precipitin test result is reported by
growth.166,167 Until December of 2012, fungal isolates identified as some laboratories as the IgM test result, and the immunodiffusion
Coccidioides spp. were subject to strict federal security regulations complement-fixing result is reported as the IgG test result. Both tests
developed for all select agents of bioterrorism. However, Coccidioides have been found to be at least as sensitive as their original counter-
spp. have been delisted, and CDC oversight is no longer in effect. parts.176,177 The quantitative immunodiffusion procedure closely correlates
with the quantitative complement-fixing antibody test.178 Immunodif- f
Serologic Testing fusion tests are more amenable to being manufactured and distributed
Serologic testing is the most frequent means of diagnosing primary in commercially prepared kits, which allow them to be performed in
coccidioidal infections because the patients may not be able to produce laboratories not fully dedicated to a mycology specialty.
a sputum specimen, and fungal cultures often are not practical in an
ambulatory setting. It may also be indispensable in establishing the Enzyme-Linked Immunoassays
cause of chronic meningitis because cultures of CSF are commonly Enzyme immunoassays for coccidioidal antibodies are available com-
negative in coccidioidal meningitis. Of the variety of tests available, mercially (Meridian Bioscience, Inc., Cincinnati, OH; IMMY, Norman
most are highly specific for an active infection.168,169 Minimally reactive OK; Mira Vista Diagnostics, Indianapolis, IN). The test kits allow the
test results are often diagnostically important and should not be dismissed specific detection of IgM or IgG antibodies; however, these results are
as insignificant. A negative serologic test result never excludes the not interchangeable with the complement fixation or immunodiffusion
presence of a coccidioidal infection, however. Performing one or more test results. Positive results with this commercial kit are highly sensitive
repeated serologic tests over the course of 2 months increases the sensitiv- for coccidioidal infection. On occasion, false-positive results are noted,
ity of serologic diagnosis, especially for recently acquired infections. especially with the IgM enzyme immunoassay.179–181 At present, enzyme
immunoassay results should ordinarily be confirmed with immunodif- f
Tube Precipitin Antibodies fusion tube precipitin, immunodiffusion complement-fixing, or com-
Tube precipitin antibodies stimulated by a coccidioidal infection were plement-fixing test results. When the more established tests fail to
originally detected by the presence of a precipitin button that formed corroborate the enzyme immunoassay, a coccidioidal infection may in
at the bottom of a test tube after overnight incubation of the patient’s fact exist, but the diagnosis is less firmly established.182–184
serum mixed with coccidioidal antigen.7 Because immunoglobulin M
(IgM) is most avid at forming immune precipitins, and because these Latex Tests
reactions were detected early after the onset of infection, this test is Latex tests for coccidioidal antibodies are also available commercially.
sometimes referred to as the IgM test. The antigen responsible for this They are attractive to clinical laboratories because they are easy to use,
reaction is a polysaccharide from the fungal cell wall. At some time and results are obtained rapidly. There are significant numbers of false-
within the first 3 weeks of symptoms, tube precipitin antibodies are positive reactions, however, and the latex test is not as reliable as the
detected in 90% of patients; this prevalence declines to less than 5% other tests described in this section.168
more than 7 months after the onset of a self-limited illness.
Skin Testing
Complement-Fixing Antibodies Dermal delayed-type hypersensitivity to coccidioidal antigens is highly
When the patient’s serum is mixed with coccidioidal antigen, an immune specific for coccidioidal infection.185 In clinical practice, especially within
complex forms that consumes complement.170 This event is detected by the endemic regions for coccidioidomycosis, perhaps the best use of coc-
subsequent addition of sensitized red blood cells, which normally lyse in cidioidal skin testing in patients when they are not ill is to determine
the presence of complement but remain intact if the complement is depleted. if they are immune from future disease as a result of past infection.
Because immunoglobulin G (IgG) is the immunoglobulin class usually Because skin test results remain positive after infection in most people
involved in these immune complexes, this test is sometimes referred to as for life, however, a result may not be related to the current illness. In
the IgG test. Although this test originally was developed through the use of addition, some of the most serious infections may be associated with
various complex extracts of Coccidioides spp., it is now known that the selective anergy, and the skin test may not reveal reactivity. As useful
antigen involved in this reaction is a chitinase.171–173 Subsequent work as skin test results are for epidemiologic studies, the tests have important
demonstrated that a recombinant truncation of amino acids 20 to 310 limitations as screening procedures for recent infection. For patients
eliminated serologic cross-reactivity with antibodies stimulated during in whom coccidioidomycosis has been diagnosed by other means, skin
histoplasmosis,174 and that all of the coccidioidal antibody reactivity was testing may have prognostic significance.186 Coccidioidal skin testing
located from amino acids 111 to 310.175 In early coccidioidal infections, reagents ceased being available commercially in the 1990s. However, a
complement-fixing antibodies are detected later and for longer periods reformulation of the spherule-derived skin test antigen was reintroduced
than are tube precipitin antibodies.8 Complement-fixing antibodies can be in 2015 as Spherusol (Nielsen BioSciences, Inc., San Diego, CA), and
detected in other body fluids, and their detection in CSF is an especially is approved to test for immune responsiveness in patients previously
important aid to the diagnosis of coccidioidal meningitis. Complement- diagnosed with coccidioidomycosis.187–189
fixing antibody concentration is expressed as a titer, such as 1 : 4 or 1 : 64,
indicating the greatest dilution of serum at which complement consumption Coccidioidal Antigen Detection
is still detected. Traditionally, a titer of 1 : 16 or greater has been associated Antigenemia may occur with either early or chronic coccidioidal infec-
frequently with extrathoracic dissemination. Because of technical factors, tions and could be the basis of a diagnostic test.190–193 A commercial
 3198
test is available (MiraVista Diagnostics, Indianapolis, IN) for detecting improved.209 In a report of 3 patients with coccidioidal meningitis, 2
coccidioidal antigens.194 This test, applied to CSF specimens, may be improved with posaconazole.210 For voriconazole, there is less published
particularly useful for diagnosing meningitis.195,196 literature, but case reports suggest that it may also be effective.211–214
Part III Infectious Diseases and Their Etiologic Agents

There is also very little published experience with isavuconazole.214a

MANAGEMENT Because the manifestations, locations, and severity of progressive
General Approac
Approaches forms of coccidioidomycosis vary among patients, the need for surgery
The three components of managing coccidioidal infections are (1) is determined by the nature of specific lesions on a case-by-case basis.
assessment of the need for intervention, (2) selection of antifungal agents In some patients, especially in whom skeletal involvement is extensive,
for patients who would benefit from treatment, and (3) choice of surgical débridement and drainage of infected sites may be essential to achieving
procedures for débridement and reconstruction of destructive lesions. control of the infection. Even if therapy is effective in arresting fungal
A revised practice guideline has been published25 and is available online proliferation, fungal debris already present may continue to produce
from the Infectious Diseases Society of America (IDSA; www.idsociety.org). tissue destruction until it is surgically removed. Patients with persistent
A training manual for nonspecialists is also available (vfce.arizona.edu). fever and malaise may benefit from drainage of large collections of pus.
In patients with newly diagnosed coccidioidal infections, it is crucial Also, surgery may be needed to stabilize bones that are structurally
to assess the extent of disease at present and the factors that increase unsound or when the spinal cord is at risk of compression. Advances
the risk of future complications. The current extent of disease can usually in imaging with computed tomography or MRI have aided greatly in
be assessed with a careful review of systems, physical examination, and the evaluation of specific lesions.215 Repeated use of these modalities
chest radiographs. When new focal complaints of discomfort or swelling often helps to identify lesions that are progressing despite the current
are identified, these should be evaluated further with appropriate imaging management strategy and patients who may benefit from additional
or, if necessary, biopsy. Pain referable to bones might be assessed with surgical intervention or other changes in management.
a radionuclide bone scan or an MRI.197,198 Recently, positron emission
tomography/computed tomography scans have been used to also detect Early Uncomplicated Infections
extrapulmonary disease activity, although to what extent the metabolic For patients with neither risk factors for nor evidence of extrapulmonary
activity represents areas of tissue destruction is uncertain.199,200 An spread, treatment is of unproven benefit. To date, no placebo-controlled
effusion that develops in a joint could be aspirated for cell count and trials concerning this self-limited form of infection have determined
culture, a progressively severe headache may necessitate MRI and whether treatment hastens the resolution of symptoms or prevents the
especially lumbar puncture to evaluate the possibility of meningitis, risk of complications. Experts familiar with coccidioidomycosis have
and a nonhealing skin lesion may necessitate biopsy. widely varying recommendations for management of specific patients
In the general population, pulmonary or extrapulmonary complica- in this category. Although some physicians recommend treatment for
tions are uncommon. There is a special risk of disseminated infection, all patients, others recommend treating only patients with more severe
however, with conditions that prominently suppress T-cell immunity manifestations. Even with selective therapy, its benefit is uncertain.216,217
as detailed earlier. Patients with active infection and these risk factors A nonrandomized, uncontrolled, single-site study found no statistical
nearly always should be treated with antifungal therapy even if there difference in symptom resolution in patients with primary mild-to-
is no evidence of extrapulmonary spread. Patients with diabetes mellitus moderate pulmonary infection treated or not treated with antifungals.218
are not prone to extrapulmonary dissemination. They are more likely In that study, 20 of 36 patients received therapy, 18 of whom received
to develop pulmonary cavitation or chronic pneumonia, however, and fluconazole at 400 mg daily for a median of 8.5 weeks. Evidence that
may be more likely to require treatment.123 is often considered to indicate more severe infection includes loss of
more than 10% of body weight, intense night sweats for more than 3
Therapy weeks, infiltrates involving more than half of one lung or portions of
Available antifungal agents include amphotericin B and the azole antifungal both lungs, prominent or persistent hilar or peritracheal adenopathy,
agents. Their pharmacology is described in detail in Chapters 40A to anticoccidioidal complement-fixing antibody titer greater than 1 : 16,
40D. In coccidioidomycosis, selecting between amphotericin B and azole failure to develop dermal hypersensitivity to coccidioidal antigens,
antifungals is based primarily on the degree of respiratory compromise inability to work, or symptoms that persist for more than 2 months.25
in pulmonary infections or the rate of progression of disseminated Because persons of African or Filipino descent seem to have some
infections. Amphotericin B is perceived to have a more rapid onset of increased risk of dissemination, this factor sometimes also weighs in
action; therefore despite its well-known toxic effects, it is the preferred the decision for treatment. If treatment is recommended, commonly
initial therapy for patients who have developed serious respiratory prescribed therapies include currently available oral azole antifungal
compromise or who are deteriorating rapidly. There is no evidence that agents, usually fluconazole, for courses ranging from 3 to 6 months.
a lipid formulation of amphotericin B improves on the efficacy of colloidal Although extrapulmonary dissemination usually occurs in the first
(conventional) amphotericin B, but liposomal or lipid complex ampho- several months of untreated coccidioidal infections, it is now clear that early
tericin B is often used because of less toxicity. Azole antifungals are treatment of the pulmonary syndrome does not prevent but may delay
often selected for patients with chronic processes because possible dissemination in some patients. In fact, late dissemination may not be
differences in rate of response to azole antifungals would be outweighed recognized until years after initial azole treatment is stopped.216,218 Also, it
by their ease of administration and lack of toxicity. Ketoconazole was has been noted that persons treated for early pneumonia are less likely to
the only orally available azole antifungal approved by the US Food and develop a complement-fixing antibody response.219 These considerations
Drug Administration for the treatment of coccidioidomycosis but is should be taken into account when deciding whether to treat the early
no longer the preferred drug for this disease because of hepatotoxicity. otherwise uncomplicated coccidioidal pneumonia with antifungals.
Several clinical trials have indicated that fluconazole and itraconazole
are efficacious.201–207 No studies have demonstrated general superiority Diffuse Pneumonia
of one azole antifungal over another. In a comparison of fluconazole Diffuse bilateral infiltrates represent either hematogenous infection of
(400 mg once a day) and itraconazole (200 mg twice daily), the primary the lungs or multiple foci of infection resulting from exposure to a high
analysis showed that the two drugs were within 20% of each other in inoculum of arthroconidia. In either case, even early infections are regarded
producing responses.204 In a secondary analysis of skeletal lesions, as serious and warranting therapy. Initial therapy in such cases is usually
response was obtained in twice as many subjects treated with itraconazole with amphotericin B, at least for the first several weeks and until the illness
as those treated with fluconazole. The newer azoles, voriconazole and seems to be improving. Concomitant use of a brief course of corticosteroids
posaconazole, have also been used to treat coccidioidomycosis. In one in this situation is controversial but advocated by some authorities.220 After
study, 17 of 20 patients treated with 400 mg/day of posaconazole suspen- this time, therapy is often switched to an antifungal azole agent for at least
sion improved.208 However, of 9 patients in whom treatment was dis- 1 year. Fungemia resulting in diffuse pulmonary infiltrates is often the
continued, 3 suffered relapse. In another study of 15 patients in whom consequence of severe immunodeficiency, and in such patients, treatment
previous treatments had failed, 11 treated with 800 mg/day of posaconazole may need to be continued indefinitely to prevent relapse.
 3199
Pulmonary Cavity medication in a hyperbaric glucose solution, and lateral cervical injection.
Cavitation as a sequela of coccidioidal pneumonia is often asymptomatic The technique, frequency, and dosage of intrathecal amphotericin B
and may not necessitate treatment. With the passage of time, some vary widely among practitioners.

Chapter 265 Coccidioidomycosis (Coccidioidess Species)

cavities disappear. Cavities that do not close spontaneously over 1 to In addition to antifungal therapy to control the meningeal inflamma-
several years are sometimes resected to prevent future complications, tion, surgical interventions are required for two other manifestations.
especially if the cavity shows progressive enlargement or is immediately One is hydrocephalus, a common complication of coccidioidal meningitis.
adjacent to the pleura and may cause pneumothorax. This potential Hydrocephalus ordinarily does not respond to antifungal therapy, and a
benefit must be weighed against the risks of the surgical procedure, shunting procedure is required. Ventriculoperitoneal shunts could become
which vary according to the general health of the patient and the skill a conduit for Coccidioides spp. from the cerebrospinal space to the peri-
of the surgeon. toneum, but this usually does not result in clinically apparent abdominal
Pulmonary cavities occasionally produce symptoms, such as local complications in patients on azole treatment. Fluid from a ventriculo-
pain, superinfection, or hemoptysis. When this occurs, treatment is peritoneal shunt is unreliable for assessing therapy because the whole
usually instituted with oral antifungal azole therapy. This therapy often blood cell count, protein, and glucose measurements are less abnormal
is accompanied by a diminution of symptoms, but recurrences are during infection than is found in lumbar CSF.226 A second and uncommon
frequent if therapy is stopped. Antifungal treatment does not influence complication is intracerebral abscesses.154 These lesions may necessitate
the size or disappearance of the cavity. For these patients, resection is drainage or resection, in addition to systemic antifungal drug therapy.
a reasonable alternative to long-term suppressive medical therapy.120 Another complication of coccidioidal meningitis is vasculitis.155 In
Extrapulmonary dissemination from a solitary pulmonary cavity is very a retrospective series of 221 patients with meningitis, 18 (8.1%) had
uncommon. cerebrovascular accidents (CVAs), presumed to be a result of the infec-
tion.227 Administering corticosteroids for this complication is contro-
Chronic Fibrocavitary Pneumonia versial. In this series, 14 of the patients received dexamethasone at doses
Persistent coccidioidal pneumonia is ordinarily treated with oral azole between 8 and 40 mg/day for 10 to 21 days, with the majority of these
antifungal agents. Responses to these agents are approximately 55% to patients (9 of 14) receiving dexamethasone 10 mg intravenously once,
60% as judged by improved symptoms and radiographic appearance. followed by 4 mg four times daily. Steroid tapering ranged from 2 to 6
Treatment options for patients who do not respond include surgical weeks. One patient received hydrocortisone (50 mg every 6 hours for
resection of infection localized to a single lobe; switching to an alternative 10 days). None of these 15 patients had subsequent CVAs, whereas the
antifungal azole; for fluconazole, raising the dosage; or instituting three patient who did not receive corticosteroids all had additional
amphotericin B therapy. CVAs. These courses of steroids did not appear to interfere with the
effectiveness of the antifungal therapy.
Extrapulmonary Dissemination
For most patients with nonmeningeal dissemination, initial therapy is New Therapies
with an oral antifungal azole. Exceptional patients with rapidly progressive Because the fungal wall of Coccidioidess organisms contains (1,3)-β-d-glucan
infection or infection in critical locations, such as vertebrae, may respond and chitin,39 antifungals that interfere with synthesis of these polysaccharides
faster to initial therapy with amphotericin B, but this has not been potentially could be therapeutic for coccidioidomycosis. Caspofungin
proved. As discussed previously, surgical débridement or drainage of (Cancidas; Merck & Co., Inc., Kenilworth, NJ) has been effective in treatment
selected lesions may be an important component of controlling infec- of experimental coccidioidal infections.228,229 However, clinical experience
tion.221,222 As in chronic coccidioidal pneumonia, treatment is continued is limited to combination therapy including an azole.230,231
for at least 1 year and for 6 months past the point at which all evidence Nikkomycin Z, a chitin synthase inhibitor discovered in the 1970s,
of further improvement has ceased. Even so, relapses occur in approxi- was subsequently shown to be effective as a therapy against experimental
mately one-third of patients when therapy is stopped, and some patients murine coccidioidal infection.232–234 Clinical trials were initiated in the
may require suppressive therapy indefinitely. 1990s but were soon interrupted because the sponsoring pharmaceutical
In the management of coccidioidal meningitis, most patients now company went out of business.235 In 2005 the inactive project was
are treated initially with fluconazole. This is a major departure from transferred to the University of Arizona, which has reactivated the
therapy with intrathecal amphotericin B, which until the early 1990s clinical studies.236,237 A multidose phase I trial has been completed without
was still standard treatment.223 Although there have been no comparative identifying any safety concerns. Currently, new supplies of nikkomycin
trials of intrathecal amphotericin B and fluconazole, the response rate Z need to be manufactured to support phase II trials.
of approximately 70% with fluconazole at 400 mg/day is probably at Olorofim is an inhibitor of dihydroorotate dehydrogenase that has
least as good as that achieved with intrathecal amphotericin B, and use recently been shown to have antifungal activity.237aa Recently it has shown
of fluconazole avoids most of the toxicity associated with amphotericin activityy against an experimental central nervous system infection in
B. Higher doses of fluconazole have produced responses in some patients mice237b and is in clinical trials as treatment for other fungal infections.
who did not respond initially to 400 mg/day.150 Similar results have
been obtained in patients treated with itraconazole, although there is PREVENTION
less clinical experience with this drug than with fluconazole.202 Both Developing a vaccine as a means of preventing coccidioidomycosis has
posaconazole and voriconazole have been used as salvage therapy but been an attractive goal for many years. This strategy might be useful
offer no benefit to patients who have responded to fluconazole. The because immunity develops in most persons who are infected naturally.
effect of azole treatment is to arrest fungal proliferation within the A formalin-killed, whole-cell spherule vaccine was found to be exception-
meninges and, as a result, inflammation resolves, as indicated by ally protective against lethal intranasal infections in mice.238–243 The
normalization of spinal fluid cell count and hypoglycemia, and this whole-cell vaccine also induced a great deal of local inflammation at
may produce a complete and lifelong remission of symptoms. However, the injection site, however, and thus the dose in humans is limited to
azole therapy is not curative and dormant spherules persist, presumably 1.84 mg.244 For an average human, this is approximately 1/1000 of the
indefinitely. It is a consensus opinion that patients who respond to azole vaccine dose (milligrams per kilogram) required for protection in mice.
therapy should continue suppressive treatment for life.25 In one series When this dose of formalin-killed spherule vaccine was used in a human
in which 18 patients who had achieved an azole remission discontinued field trial, vaccination failed to result in significantly fewer symptomatic
azole therapy, 14 relapsed and 2 died.224 Moreover, it is recommended cases of coccidioidal pneumonia than were detected in placebo recipi-
to use at least 400 mg/day of fluconazole as maintenance therapy, even ents.245 One plausible explanation for the failure is that the inflammatory
in patients who are completely controlled on this dose. reactions to the whole-cell vaccine prevented use of a sufficient dose
Patients who do not respond to oral azole therapy may benefit from of the antigens responsible for protection. If this is the case, use of a
intrathecal amphotericin B.225 Routes of administration include repeated purified or recombinant antigen might circumvent this limitation.
percutaneous intracisternal injection, injection into Ommaya reservoirs Several antigens have been expressed as recombinant proteins and,
that drain to either the cistern or a ventricle, lumbar puncture with when used with Th1-based adjuvants, have evoked protection against
 3200
experimental coccidioidal infections in mice.246 Unfortunately, the costs that for the polio vaccine246 and, if available, would be cost-effective.249
of developing a formulation of these vaccine candidates have been prohibi- That said, the population that would benefit from a Valley fever vaccine
tive, and this has prevented their further evaluation. Alternative approaches is relatively small and may not support commercial incentive to develop
Part III Infectious Diseases and Their Etiologic Agents

involve the development of a live-attenuated vaccine247 or a vaccine with the product. Thus it is likely that other sources of support may be needed
a live nonpathogenic fungus that engenders cross-species protection.248 if a coccidioidal vaccine development program is to be successful.
Recently, a heterologue of a gene identified to be involved in virulence Regarding preemptive or prophylactic use of prophylactic antifungal
for a corn pathogen, Cochliobolus heterostrophus, was deleted from C. agents for visitors or residents of endemic regions, there is no evidence
posadasii.28 This mutant causes no disease either in mice without an that this would be of benefit, even for highly immunosuppressed persons.
immune system or in those infected with millions of arthroconidia. A special case exists where an accidental laboratory exposure is identified.
Moreover, when this mutant is used as a live vaccine, it is very protective.248a A detailed approach to managing such an occurrence has been pub-
This vaccine is now in active development as a candidate to prevent coc- lished.164 The recommended adult prophylactic dose of fluconazole or
cidioidomycosis in dogs. If safe and effective as a canine vaccine, this itraconazole is 400 mg daily. Drug interactions and pregnancy must be
would provide further evidence that it might also be useful for humans. taken into account. There are specific recommendations for prophylactic
The public health benefits from an effective preventive vaccine for antifungals for organ transplant recipients as outlined in the current
coccidioidomycosis for the population at risk are roughly equivalent to IDSA practice guidelines.25

115. Pasha AK, Walsh TK, Ampel NM. Dual-time-point FDG 199. Dryden JR, Starsiak MD, Johnston MJ, et al. Bone scan,
Key References PET/CT to distinguish coccidioidal pulmonary nodules PET-CT, and MRI in disseminated coccidioidomycosis.
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1. Hirschmann JV. The early history of coccidioidomycosis: 864. 200. Foerter J, Sundell J, Vroman P. PET/CT: first-line
1892-1945. Clin Infect Dis. 2007;44:1202–1207. 120. Ashfaq A, Vikram HR, Blair JE, et al. Video-assisted examination to assess disease extent of disseminated
2. Litvintseva AP, Marsden-Haug N, Hurst S, et al. Valley thoracoscopic surgery for patients with pulmonary coccidioidomycosis. J Nucl Med Technol.
fever: finding new places for an old disease: Coccidioides coccidioidomycosis. J Thorac Cardiovasc Surg. 2016;44:212–213.
immitis found in Washington State soil associated with 2014;148:1217–1223. 204. Galgiani JN, Catanzaro A, Cloud GA, et al. Comparison
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