Infect Dis Clin N Am 17 (2003) 4157

Coccidioidomycosis
Tom M. Chiller, MDa,b, John N. Galgiani, MDc,d,
David A. Stevens, MDa,b,*
a

Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center,
751 South Bascom Avenue, San Jose, CA 95128-2699, USA
b
Stanford University School of Medicine, Stanford, CA 94305, USA
c
Division of Infectious Diseases, Department of Medicine, University of Arizona, AZ, USA
d
Southern Arizona Veterans Aairs Health Care Center, Tucson, AZ, USA

The rst case of coccidioidomycosis was described in an Argentine soldier

in 1892 who presented with skin lesions resembling mycosis fungoides, but
was found to have rounded organisms within the lesions [1]. First thought to
be a protozoan, it was given the name Coccidioides because it resembled a
coccidian. In another case with similar skin lesions on an immigrant to
California, the organism was isolated and further named immitis (not mild)
to indicate its virulence and the current name Coccidioides immitis was
coined [2]. The fact that these rounded organisms were not protozoan was
established 8 years later when Ophuls and Mott [3] determined the organism was a fungus and described its life cycle.
The entity of valley fever, a self-limiting common illness of the California
San Joaquin Valley [4], was rst linked to coccidioidomycosis 35 years later
with the discovery of their common etiology. Shortly thereafter, Smith et al
[5] developed a skin test and serologic antigen (coccidioidin) and conducted
large surveys that were the rst to determine the epidemiology of the disease
in the San Joaquin Valley. These studies led to the realization that coccidioidomycosis was a public health problem, and today it is estimated that more
than 100,000 new infections occur annually in the United States.
Endemic areas
Coccidioidomycosis is endemic to specic parts of the Western Hemisphere. C immitis is particularly associated with the Lower Sonoran Life
Zone, which is characterized by hot summer months, few winter freezes,
* Corresponding author. Division of Infectious Diseases, Department of Medicine, Santa
Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128-2699.
0891-5520/03/$ - see front matter 2003, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 1 - 5 5 2 0 ( 0 2 ) 0 0 0 4 0 - 5

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rainfall between 5 and 20 inches a year, and alkaline soil. In the United
States, this is found in the southwest, primarily in parts of California,
Arizona, Nevada, New Mexico, and Texas. The southern San Joaquin
Valley of California and southern Arizona have the highest endemicity.
There are also endemic areas throughout northern Mexico and scattered
areas of Central and South America [6].

Prevalence and incidence

As mentioned, it is estimated that 100,000 infections occur annually in
the United States. Infection is the result of inhaling the arthroconidia or the
airborne spores and can infect people of any age. Owing to its habitat, the
incidence is higher in those individuals who are exposed to dust and soil
more than others. Clusters of disease are seen in archeologists [7].
The incidence and prevalence are aected by seasonal changes and natural events, such as earthquakes, droughts, and windstorms, which disturb
the soil and allow the fungus to become airborne. Some endemic areas are
in the midst of massive population growth and travel and tourism, and
hence the number of people at risk is rising. In earlier studies assessing skin
test prevalence in a population of California school children in 1939, however, 55% of elementary school and 68% of high school children were positive. Repeat surveillance done 25 years later showed only 8% and 24%,
respectively, were positive [8]. Similar trends have been found in other
endemic areas [9], demonstrating downward trends in prevalence and pointing toward complex changes in exposure that seem to occur within endemic
areas, despite population growth. This may be related to the eects of
urbanization on dusty soil reduction.

At-risk populations
Certain groups of patients are at higher risk for the development of extrapulmonary dissemination from an initial primary pulmonary infection.
Healthy males are at a higher risk than females. Those patients with compromise of their cellular immune systems are more susceptible to infection. These
groups consist of patients with AIDS and those receiving immunosuppressive
treatment, such as corticosteroids and chemotherapy for transplants and
malignancies. Another condition that has demonstrated a higher risk of dissemination is pregnancy, especially when acquired in, or the disease reactivates in, the second and third trimesters [10]. Observations from
obstetricians practicing in endemic areas, however, have not found the high
frequency of infection among pregnant women as predicted by the prior studies [11]. Together, these reports suggest that although infection occurs infrequently in pregnancies, when present there are often serious complications.

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43

There is also evidence to suggest that certain racial groups are at higher
risk of having disseminated disease. Early data demonstrated that persons of
Filipino ancestry accounted for a large proportion of the cases of disseminated disease [12]. Some studies have also shown that African Americans,
native Americans, Hispanics, and Asians, in descending order, are at greater
risk than whites for extrapulmonary disease. The specic genetic dierences
that may make these populations at higher risk have not been identied.
Epidemics
Epidemics associated with coccidioidomycosis have aorded an opportunity to study environmental factors that contribute to infection and help
identify high-risk groups further. In 1977, a dust storm in the San Joaquin
Valley of California gave rise to an epidemic that included the coastal and
northern regions of the state. The most recent epidemic occurred over multiple years from 1990 to 1994, also in the San Joaquin Valley. There were
nearly 15 times the reported cases compared with nonepidemic years. In
Kern County alone there were 1700 new cases in a 3-month period in
1992 [13]. This sudden increase may have been caused by environmental
conditions that had been created by several years of drought followed by
heavy rainfall in March of 1991 [14].

Pathogenesis and host defense

Mycology
Coccidioides immitis is a dimorphic fungus. The mycelial or mold form
represents the saprobic (environmental) phase and grows in soil of endemic
areas. It forms branching, septate hyphae, from which conidia (spores),
called arthroconidia, develop along its length. As the arthroconidia mature,
they become stable and easily airborne. After inhalation by animals or
humans, the fungus converts to its parasitic (tissue) phase in the host. Once
in a bronchiole, the arthroconidium transforms itself into a multinucleated
spherical structure, known as a spherule. The spherule then begins a process
of internal division producing up to hundreds of uninucleated endospores.
When the spherule reaches maturity, the endospores are released and, if they
remain in tissue, each forms new spherules. If they are released into the environment they develop into the mycelial form. Occasionally, hyphae have
been found in tissue, as in the inside of a pulmonary cavity or associated
with plastic shunt devices [15].
Primary infection
Studies in mice have demonstrated the ability of only a few arthroconidia
given intranasally to cause infection [16]. Given the size of the arthroconidia

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(<10 lm), they are easily able to escape the rst-line defenses of the respiratory tract (ltration, mucocilliary transport, and mucoid chemical inhibitors) and reach the terminal bronchus. The initial host response targets the
arthroconidia and is characterized by an inux of polymorphonuclear leukocytes [17], which seem to be responding to chemotaxins generated in
response to complement activation [18]. Within the rst 72 hours, arthroconidia convert to spherules and the inammatory response changes to a
mononuclear cell inltration, which persists throughout infection and where
the formation of granulomata may occur. Subsequent release of endospores
from spherules produces a transient polymorphonuclear leukocytes
response, presumably triggered by substances released from the rupturing
spherule. The ability of spherules to resist host defenses has been noted
by the inability of polymorphonuclear leukocytes to kill mature spherules
in vitro.
During the early stages of infection, the hosts specic immune response
helps to determine the ultimate outcome and severity of the infection. It is
clear that a cellular or TH1-type immune response is associated with control
of infection. Studies have shown that the TH1 cytokine, interferon-c, has
been associated with protective immunity in experimental murine infection
[19]. On the other hand, a limited cellular response characterized by a
TH2-type immune response with elevated levels of antibody and IgE have
been associated with worsening disease and dissemination. Studies support
these ndings, where the TH2 cytokine interleukin-4 is associated with an
impaired immune response in mice [19]. In patients, conditions where there
are defective cellular immune responses, such as AIDS, late stages of
pregnancy, or during cytotoxic chemotherapy, have been associated with
a higher risk of developing disseminated disease.
The mechanisms by which virulence is conferred on C immitis are still
not well understood. Endospore products, such as urease and serine proteinases, probably play a role in the pathogenesis of the infection. Proteases
may serve to digest antibodies and other opsonins. An enzyme with elastase
activity seems to aid in breaking down the connective tissue matrix in the
lung and helps spread the organism and destroy pulmonary parenchyma
[20]. This process also leads to increased cellular inammation and possible
further parenchymal destruction.
Clinical manifestations
Primary infection
Approximately 60% of individuals who are infected with C immitis
remain asymptomatic. The other 40% usually present with a mild to moderate inuenza-like illness, including symptoms of cough, fever with drenching
night sweats, or pleuritic chest pain. Arthralgias and myalgias may be prominent and are the reason for the synonym of desert rheumatism. Rashes

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(erythema multiforme or erythema nodosum) may be seen. Systemic symptoms of fatigue, weakness, and anorexia are also common. Abnormal chest
radiographic ndings are seen in up to half of symptomatic patients. Typically, inltrates are associated with ipsilateral hilar adenopathy, although
many other patterns are possible. Peripneumonic pleural eusions also may
occur, and occasionally are very large. Most symptoms generally clear within 2 to 3 weeks. Some patients may take many weeks to months before all
their symptoms, especially fatigue, resolve. Approximately 5% of patients
develop residual pulmonary lesions or complications and less than 1% develops extrapulmonary disease. Although this is a small portion of the total
patients infected, these patients are overrepresented in clinical practice, especially outside the endemic areas.
Pulmonary nodule
Approximately 5% of patients who develop pneumonia during the primary infection then develop pulmonary nodules. They are usually solitary
and patients are mostly asymptomatic. If the nodules do not progress, they
pose no serious further problems. The major diculty arises in evaluating a
patient with a pulmonary nodule in an endemic area who was not known to
have prior coccidioidomycosis [21]. Fine-needle aspiration of these lesions
may oer a less invasive method to aid in diagnosis. One hundred (29%)
of 348 patients aspirated were smear or culture positive for C immitis [22].
Pulmonary cavity
Cavities also develop in approximately 5% of patients after the acute
pneumonia. They are typically solitary, near the pleura, and thin-walled.
Patients are generally asymptomatic and approximately half regress after
2 years. Cavities are frequently asymptomatic but may produce cough, chest
pain, and hemoptysis. Occasionally a mycetoma or fungus ball may develop
inside the cavity. Infrequently, peripheral cavitary lesions may rupture into
the pleural space.
Although a ruptured coccidioidal cavity produces symptoms quite similar
to those of a spontaneous pneumothorax, a useful distinguishing dierence
is the development of evident uid and air within the pleural space. This
results in an air-uid level evident on upright chest radiographs, a nding
that is uncommon with spontaneous pneumothorax.

Diuse pneumonia
Coccidioidomycosis can diusely involve the lungs in both primary and
late disease. In primary infection, diuse pulmonary involvement can represent multiple sites of infection. This is most often caused by inhalation of
large amounts of arthroconidia rather than immunosuppression. Diuse

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pneumonia can also represent the result of hematogenous spread of the fungus. This is a rapidly progressive pulmonary disease that may result in respiratory failure and is particularly seen in immunocompromised hosts. On
chest radiography this appears as a diuse reticulonodular pattern throughout the lung. Rarely, C immitis produces a chronic form of diuse pneumonia. This is a slowly progressive brocavitary process. Patients may have
years of pulmonary symptoms plus weight loss and fever. The lungs characteristically have biapical bronodular lesions with retraction and cavitation,
making the chest radiographs distinct from those of acute disease.
Extrapulmonary or disseminated
The extrapulmonary manifestations of coccidioidomycosis are almost
always caused by dissemination due to hematogenous spread of the fungus.
There does seem to be asymptomatic dissemination as demonstrated by the
recovery of C immitis from the urine of patients with isolated pulmonary
disease [23]. Patients usually manifest symptoms of extrapulmonary disease
a few months after the primary infection. These are widely diverse, depending on the site of dissemination, and may involve multiple sites. In the discussion to follow, extrapulmonary diseases are separated into nonmeningeal
and meningeal, because the latter is the most devastating complication and
deserves special attention.
Nonmeningeal
Skin
The skin is the most common site of disseminated disease. There are a
variety of skin manifestations; most often these are papules and verrucous
lesions. Plaques, supercial abscesses, pustules, and granulomatous lesions
can also be seen [24]. Symptoms are usually minor with minimal evidence
of acute inammation. It is important to note that skin lesions may represent only part of the picture and they should prompt a detailed investigation
of other possible sites of dissemination. The presence of an ulcerating lesion
should make the physician consider the possibility of a sinus tract. Skin
biopsy of lesions often demonstrates spherules microscopically. Fungal cultures should also be obtained because they are even more helpful for making
the diagnosis than microscopic examination.
Bone
Osteomyelitis is also a common manifestation of disseminated disease.
The vertebral column is one of the most common sites; other sites are the
tibia, skull, metacarpals, metatarsals, femur, and the ribs [25]. In vertebral
disease, paraspinal masses with sinus tract formation are common, but vertebral disks are usually unaected. All sites may develop into cold lesions
and manifest abscesses and sinus tracts. Radiography generally demon-

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47

strates well-demarcated lytic lesions in larger bones; smaller bones may

appear more irregular and moth-eaten. It is important to work-up any sign
or symptom that could be attributed to a possible bony dissemination.
A bone scan is a useful screening test if bony involvement is suspected.
Joints
Infection of the synovium accounts for approximately 20% of patients
with hematogenous dissemination. The knee is the most common joint and
may present with an isolated synovitis without bony involvement. A single
joint is involved in 90% of cases. All joints have been found to be aected,
with the lower extremities being more common than the upper extremities
[25]. Synovial uid is exudative and yields a positive culture in only about
half the cases.
Other sites
Coccidioidomycosis has been found in almost every organ. Reports of
infection involving the eye, larynx, thyroid, and peritoneum have been
reviewed in the literature. There are also cases of genitourinary disease of
the prostate, kidney, and uterus. Infections involving prosthetic grafts and
peritoneal shunts have also been reported.
Meningitis
The spread of C immitis to the central nervous system is the most lethal
form of the infection. This occurs in approximately 200 patients per year in
the United States. The most common form presents as chronic granulomatous meningitis, usually involving the basilar meninges. Cerebral and cerebellar abscesses may also be found [26]. The most common symptoms are
headache, nausea, vomiting, and altered mental status. Other symptoms and
signs have included nuchal rigidity, diplopia, and other cranial neuropathies
[27]. Onset of symptoms is usually subacute, but may occur during the primary illness. Although headache is reported as a symptom by approximately
20% of patients with self-limited (nonmeningeal) coccidioidomycosis, physicians should have a low threshold to examine the cerebrospinal uid (CSF)
of patients whose headache is severe, persists, or is associated with other
ndings referable to the central nervous system. Initial CSF ndings show
a mononuclear cell pleocytosis, with a low glucose and elevated protein concentrations. Up to 70% of patients may have eosinophils in their CSF [28].
Ventricular uid usually shows much less inammation than lumbar or cisternal uid. The occurrence of hydrocephalus is a common complication of
coccidioidal meningitis. The ability to use CT scans to identify dilated ventricles, and MRI scanning to identify patency of the aqueduct of Sylvius
more specically, are important in the management of hydrocephalus.
Whether communicating or noncommunicating, ventriculoperitoneal shunting commonly is used.

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Diagnosis
Biopsy and culture
The denitive diagnosis is established if the organism is isolated from a
clinical specimen. The fungus grows on most culture media and may appear
after incubation at most temperatures. It may grow relatively rapidly and be
seen as early as 2 days after inoculation into media, although more often 5
days or longer is required. It is important to notify the clinical laboratory if
infection caused by C immitis is suspected, to minimize the risk of inadvertent accidental exposure of laboratory personnel to infection. In the mycelial
form, denitive identication by colonial structure is not possible and it
must be identied by other means. Specialized laboratories can convert it
to the parasitic form in animals where it can be readily identied. A
DNA-specic probe is now available in a commercial kit, making identication possible on the day growth is noted [29].
Tissue specimens oer the potential for rapid diagnosis, because stains of
mature spherules with endospores from clinical specimens are pathognomonic for infection. This type of direct examination is also useful for cytologic specimens, as with bronchoalveolar lavage uid and sputum. Although
faster, direct examination is still not as sensitive as culture and both methods
should be used simultaneously when attempting to establish the diagnosis.
Antibody detection
Serologic testing plays an important role in the diagnosis and management of patients with coccidioidomycosis. There are two major antigens
used. They consist of the tube precipitin-reacting antigen and the complement-xing (CF) antigen, named for the specic assays originally used to
identify antibodies. In primary infection, IgM antibodies against tube precipitin-reacting antigen appear in serum earlier than antibodies against
CF antigen. They can be detected in up to 75% of primary disease. Tube precipitin-reacting antibodies disappear and are not found in chronic infections, whereas IgG antibodies to CF antigen are found in chronic
infections and persist in relation to the extent of disease [28]. False-positive
CF tests are rare. If the infection resolves, CF antibodies usually disappear,
whereas continued infection gives persistent titers. Furthermore, changes in
the antibody titer generally reect the course of the disease and are helpful in
determining if the disease is improving or worsening. CF antibodies can also
be detected in the CSF of patients with meningitis and similarly can be used
to monitor disease. There are several dierent kits being used in clinical laboratories and it is important that an experienced laboratory conrm any
positive test. Such laboratories should be able to relate the height of the
patients titer to their data base of titers seen previously in patients with
localized primary versus disseminated disease. The serologic assay may thus
give important information about the progression of the infection.

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Antigen and DNA detection

The ability to detect circulating antigen and the presence of specic DNA
sequences of coccidioidomycosis could provide additional tools to aid in
diagnosis. These methods oer an alternative to the reliance on the consistent humoral immune response of patients. Research laboratories have demonstrated the ability to detect antigen in both acute and chronic disease and
the clinical use of these tests continues to be evaluated [30]. Similarly, specic DNA testing for use in diagnosis is not commercially available for coccidioidomycosis. There is some early evidence that both polymerase chain
reaction amplication and hybridization techniques targeting C immitis
ribosomal RNA may be useful, but further clinical evaluation is needed [31].
Treatment
Recently, the Infectious Disease Society of America published a set of
practice guidelines for the major systemic mycoses, including coccidioidomycosis [32]. These are available online (http://www.IDSociety.org). Optimal treatment for the many forms of this disease still generates debate. In
the following sections, specic treatment recommendations are outlined.
This is based on supportive evidence where available, but to a large extent
on personal experience in treating these complicated patients.
In general, most infections that require therapy can be treated with one of
three available agents. Amphotericin B deoxycholate (AmB) is usually
reserved for severe infections, where disease is rapidly progressing. Doses
given in the range of 0.5 mg/kg to 0.7 mg/kg intravenously are used. The lipid formulations of AmB have not been extensively studied in coccidioidal
infection, but may oer a means of giving more drug with less toxicity
[33,34]. Fluconazole is probably the most frequently used medicine given its
tolerability, although high relapse rates have been reported in some studies
[35]. Usually doses of 400 mg/d are given, but it has been used in doses as
high as 1200 mg/d without complications. Itraconazole in both capsules and
solution has also been shown to be eective. Doses range from 400 to 600
mg/d. Relapse rates may be lower than with uconazole [36,37]. A recent
study comparing uconazole with itraconazole in the treatment of nonmeningeal coccidioidomycosis showed a trend toward better ecacy with itraconazole in skeletal forms of disseminated infection but did not show
signicant dierences between the two drugs after 8 months, the planned
duration of observation. The advantage of itraconazole, however, became
statistically demonstrable 12 months after therapy started [36].
Pulmonary disease
Primary pneumonia
Most primary coccidioidal infections resolve without treatment. There is
continued disagreement among experts in endemic areas whether these

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patients should be treated and, if so, which ones and for how long. Before
the azole antifungals were developed, the only available therapy was AmB
and there was little enthusiasm to use amphotericin in primary infection
given its toxicities. Currently, the presence and tolerability of oral azoles
provide therapy that can be given easily in an outpatient setting. This has
lowered the threshold for deciding to treat primary infection, and some
clinicians treat all primary infections.
In assessing this issue, it is important to consider the reasons for treating
a primary self-limiting infection. These include the ability to lessen the morbidity associated with the acute infection and the possible ability to reduce
the development of more serious complications. In coccidioidomycosis,
there is currently no evidence that treatment of the primary infection with
any therapy accomplishes either of these goals. It is known that relapses are
common with azole therapy in chronic disease, even after 6 to 24 months of
treatment. This suggests that azoles do not eradicate the infection and treatment of primary disease might only delay the onset of complications rather
than prevent them. There is also the concern that early treatment could
blunt an appropriate immune response and make one more susceptible to
later infection. Finally, there is the issue of treatment cost. Considering the
cost of uconazole alone, if 20,000 patients with acute infection each year
are treated for a period of 3 months at a cost of $500 per month, the total
cost each year is approximately $3,000,000.
Given these considerations, the authors believe that therapy for most primary infection is not advisable. The patients should be followed carefully
for signs or symptoms of complications and therapy initiated if they develop. CF antibody titers are recommended and, if elevated, may suggest
more extensive disease.
There are, however, some patients in whom the authors advocate therapy during the initial infection, even though data from controlled trials
are lacking. Factors that inuence this decision include a high inoculum
of fungus (as in a laboratory accident); elevated antibody titers; extensive
pneumonia; and the presence of risk factors for the development of
extrapulmonary disease. Patients in whom T-cell immunity is decient,
as in patients with AIDS or patients on immunosuppressive medicines
after transplantation, should receive therapy during primary infection.
Similarly, patients presenting with an extensive pneumonia may progress
to respiratory failure and should also receive therapy. Primary infection
during pregnancy also warrants therapy given the devastating complications that can occur. Specic treatment recommendations for these conditions are discussed later.
In immunologically intact patients who are given treatment, primary
therapy consists of either oral uconazole or itraconazole. The dose is usually 400 mg/d. It is probably sucient to treat for 4 to 6 weeks after active
infection has resolved, although many physicians treat for periods of 3
months or longer.

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Nodule
Generally, pulmonary nodules do not require specic therapy and often
disappear in the rst 2 years after infection. Therapy is recommended during
this period, however, if the patient is or becomes immunosuppressed. In that
case, uconazole or itraconazole can be used and should be maintained for
the duration of immunosuppressive therapy. Patients who have undergone
resection do not require further antifungal therapy if the lesion is completely
resected.
Cavity
Many patients with cavities are asymptomatic and, although the cavities
harbor fungus, do not require specic antifungal therapy. They often resolve
within several years, but require continued observation, because some do
not resolve. Cavities are considered to be candidates for resection if they are
visible for longer than 2 years in association with symptoms, adjacent to the
pleura, or increasing in size. Patients who develop symptoms from cavities,
such as pain and hemoptysis, may have concurrent fungal or bacterial superinfection. These patients should be given a trial of oral azole therapy or antibiotics. Some may have improvement, but often their symptoms recur and
when feasible they should have the cavity resected.
The most pronounced complication of cavitary lesions is rupture into the
pleural space, because coccidioidal empyema is commonly refractory to
treatment. Surgery (resection plus attempted closure of any bronchopleural
stulae) plus chemotherapy is the preferred form of treatment.
Diuse pneumonia
Diuse primary pneumonia in normal hosts usually consists of multiple
sites of infection caused by a large inoculum of arthroconidia. This infection
should be treated to lessen the fungal burden so that the immune system can
respond appropriately. Azole therapy is preferred, unless the patient is very
ill, in which case AmB should be used. Therapy should continue for at least
3 months with close follow-up. Acute diuse pneumonia in immunocompromised patients warrants aggressive antifungal therapy, because it can progress to respiratory failure. Amphotericin is the initial therapy of choice until
the infection is under control; then patients can be changed to oral azole
therapy. They need to continue therapy until the immune status has reconstituted, which may mean that some patients continue indenite therapy.
In chronic brocavitary pneumonia, initial therapy with an azole may be
preferred, because progression of the disease is often slow and the drugs are
less toxic and orally available. If the patient is worsening rapidly, then
amphotericin is indicated because it has a more rapid onset of antifungal
activity. Treatment with amphotericin is generally continued until the
patient is stable, then changed to oral azole therapy. Some have suggested
a total dose between 1 and 2 g of amphotericin should be given; however,
this is arbitrary and it is more important to base the decision to change

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on the individual status of each patient. Antifungal therapy should continue

for 6 or more months after the disease is considered inactive, but may be
required for several years.
Extrapulmonary or disseminated disease
Nonmeningeal
For the most part, extrapulmonary disease is treated with azoles. The rst
randomized prospective trial comparing uconazole and itraconazole in
nonmeningeal disseminated coccidioidomycosis was recently published and
has been previously mentioned. It showed cure rates of 50% and 63%,
respectively, after 8 months of treatment [36]. These were not signicantly
dierent, although itraconazole demonstrated a trend toward better ecacy,
especially in subgroup analysis in the treatment of skeletal infections. Shortterm relapse rates were 18% for itraconazole and 28% for uconazole, not
signicantly dierent. Given these results, itraconazole may have a role as
initial azole therapy, especially in bone and joint disease. This must be considered carefully, however, given the problems with drug absorption and the
numerous drug interactions associated with its use. Furthermore, this study
compared the use of a single daily dose of 400 mg of uconazole, which may
be lower than needed, given the fact that higher doses have been used eectively in meningitis and nonmeningitis therapy [38]. The authors believe that
either drug could be considered for the treatment of disseminated disease.
Skeletal disease may warrant itraconazole use. Serum drug levels may need
to be checked to ensure adequate absorption.
Disseminated infections that seem to be worsening rapidly should be
initially treated with amphotericin. Some clinicians believe that there are
sucient azole failures at sites, such as the vertebral column, to warrant
amphotericin therapy for such disease. Dosing and duration of therapy are
similar to that described for diuse pneumonias. Patients who do not
respond to oral azole therapy may also benet from switching therapy to
AmB. Often, however, failure may be related to lesions that require surgery.
It is clear that some coccidioidal lesions are only controlled with debridement or drainage in conjunction with antifungal therapy; some examples are
when there are pus collections, nonviable tissue, and sequestrae.
Treatment courses for extrapulmonary disease vary depending on the
rapidity of the response to therapy. At least 6 months of therapy after disease becomes inactive is recommended, but this often extends to several
years.
Meningitis
Before the availability of amphotericin, the mortality of coccidioidal
meningitis was 90% at 1 year and nearly 100% by 2 years [39]. Intravenous
amphotericin is not eective against the disease, however, and must be given
directly into the cerebrospinal space to be eective. The traditional method

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of treating patients with meningitis requires repeated delivery of AmB into

the intrathecal space, most often by lumbar, cisternal, or ventricular injections. Administration of AmB through subcutaneous reservoirs with a catheter is often used to alleviate the need for repeated CSF taps. Before
initiating therapy, it is important to evaluate the ow of CSF to determine
the appropriate injection site, because abnormalities are common and loculation of uid may occur.
Administration of AmB into the lumbar space is preferred for its comparative ease and ability to reach the base of the brain. Multiple sites of CSF
injection may be required if ow is obstructed by infection or brosis. Therapy by the cisternal route is favored by some clinicians, and it does place the
drug close to the usual epicenter of the disease, the basal meninges. Lumbar
intrathecal therapy is performed by mixing the drug into a hyperbaric solution of 10% dextrose in water and, after injection, placing the patient in
Trendelenburgs position for 30 minutes. To help avoid toxicities like back
pain, neuropathy, and fever, the initial dose is low (eg, 0.01 to 0.05 mg) and
increased gradually each day until a maximum tolerated dose, usually 0.5 to
1 mg, is reached. The frequency of therapy is tapered slowly and total duration depends on patient response, but is usually at least 6 months. Signs and
symptoms of clinical improvement, CSF leukocyte count, and CF antibody
levels are monitored. Complications of intrathecal therapy include pain,
headaches, paresthesias, and nerve palsies, which are most likely caused
by arachnoiditis or direct neurotoxic eects of AmB. These side eects are
almost always transient, but therapy should be stopped while they subside,
because they can be permanent.
The use of oral azoles to treat meningitis has been examined for longer
than a decade. Fluconazole and itraconazole at doses of 400 mg/d have had
response rates ranging from 67% to 88%, without signicant toxicity. These
high rates have been seen in primary infection and patients who were failing
therapy with amphotericin [27]. The response is somewhat slower than traditional intrathecal therapy. This has led the authors to begin with higher
doses of uconazole or itraconazole (800 mg/d) in some patients and even
higher doses in cases not responding appropriately. Cure with azole therapy
is dicult if not impossible to attain, however, with relapse rates as high as
75% after only 1 year of stopping therapy [40]. Azole therapy must be continued lifelong. Whether the high-dose therapy can be reduced if a patient
responds is not clear. Taken together, these facts have led some clinicians
back to a renewed interest in intrathecal therapy combined with oral azole
therapy. This approach oers the chance for a more rapid response and possibly a cure, with the benets of a shorter duration of intrathecal therapy
and fewer side eects.
Recently, the development of a rabbit model for coccidioidal meningitis
has helped evaluate possible new treatment strategies. Some rabbits were
cured of infection when treated with high doses of intravenous liposomal
amphotericin (AmBisome), which seems to attain high concentrations in the

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T.M. Chiller et al / Infect Dis Clin N Am 17 (2003) 4157

central nervous system [41]. This remains to be studied in humans, but could
oer an alternative to intrathecal therapy.
Special considerations
HIV
Patients should be treated with amphotericin initially if disease is severe
and then may be changed to oral azole therapy. Those with AIDS or disseminated infection should be given lifelong therapy with azoles. Consideration should be given before using itraconazole in these patients because
they may have diculty absorbing the capsules due to hypochlorhydria.
Pregnancy
Therapy for patients who present with primary infection during the second and third trimesters of pregnancy should be strongly considered. These
patients have been found to be at high risk for complications. Unfortunately, the oral azoles are not considered safe for use during pregnancy.
Amphotericin is the treatment of choice.
Transplant recipients
Clinicians are beginning to get more experience in managing these
patients, but controlled studies are lacking. Patients who present with active
disease should be managed with aggressive antifungal therapy, because they
are immunosuppressed. Patients who have had a history of a coccidioidal
illness in the past, or if antibodies are detected, should receive antifungal
therapy after transplantation is performed. The specic duration of therapy
is unknown, but they may require lifelong treatment.

Immunotherapy
To control the infection successfully, an appropriate T-cell response or
TH1 response is needed. Both interferon-c and interleukin-12 seem to be
important mediators in the establishment of this type of response. These
cytokines have been found to be important in immunity against coccidioidal
infections in animal models [19,42]. Using these cytokines as adjunctive
therapy in patients who are very ill and immunodecient is certainly a consideration and warrants clinical study.

New and investigational antifungals

There are several new drugs in dierent stages of development that are
worth briey mentioning. A new triazole, posaconazole, from Schering

T.M. Chiller et al / Infect Dis Clin N Am 17 (2003) 4157

55

Plough has been shown to be very potent in animal models [43] and data
from a clinical trial are being analyzed. The chitin synthase inhibitor, nikkomycin Z, has been an eective treatment in murine models. The newest antifungal just approved by the Food and Drug Administration for Aspergillus
infections, caspofungin, is a member of a class of antifungals known as echinocandins. This drug has also shown activity against C immitis in animals.
Echinocandins are only available in the intravenous form, but may oer
additional treatment options in the future for dicult cases.

Prevention and vaccine development

That so many persons control their infections with the development of
competent cellular immunity has stimulated several decades of research to
discover a vaccine to prevent coccidioidomycosis. A whole-spherule vaccine
was studied in a human eld trial and the power of the study was insucient
to demonstrate if ecacy was present [44]. More recent studies have focused
on specic proteins as the basis for a recombinant vaccine. Several laboratories are currently collaborating in this eort, which has now resulted in
several promising leads. At the present rate of progress, it is hoped that
human safety trials with a combination of these recombinant antigens in a
polyvalent vaccine candidate will be possible by 2005.

Acknowledgments
The authors thank Neil M. Ampel, University of Arizona and Southern
Arizona Veterans Aairs Health Care Center, Tucson, Arizona, for careful
review of the manuscript and many helpful suggestions.

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