Coccidioidomycosis is the infection
caused by the dimorphic fungus Coccidioides immitis. The
history of the identification of this organism and the clinical
study of the infections caused by this agent have been the subject
of a number of comprehensive reviews.1-2 Although it
was initially believed that coccidioidomycosis was an invariably
lethal infection, by the mid-1930s, it was recognized that the organism was
in fact responsible for a very common, acute, and generally self-limited
disease that was known as the San Joaquin Valley fever. In regions
where coccidioidomycosis is endemic, Valley fever continues to be
an important public health problem. In addition, coccidioidomycosis
has emerged in recent years as an important cause of disease in
immunocompromised patients, particularly those with human immunodeficiency
virus (HIV) infection.
The life cycle of C immitis is complex (reviewed
in Parish and Blair4) and demonstrates 2 distinct
phases: a saprophytic (vegetative) phase and a parasitic phase.
In soil, the organism grows as a mycelium, with branching septated
hyphae. As they mature, the mycelia develop rectangular spores (arthroconidia); at this
stage, the hyphae become very fragile, and arthroconidia easily
become airborne. When inhaled, the arthroconidia begin the parasitic
phase, and spherules form. Spherules are round,
double-walled structures that reproduce by formation of spherical
internal spores, termed endospores. A single spherule
may produce thousands of endospores, and as the spherule ruptures,
each endospore may in turn develop into a new spherule, perpetuating
the parasitic phase.
In general, C immitis appears to be confined
to the Western hemisphere. The endemic areas lie in the southwestern
United States, encompassing west Texas, New Mexico, Arizona, and
California. The organism can also be found in northwestern Mexico
and a few small areas of Central and South America. These endemic
areas have arid climates, hot summers, few winter freezes, low altitude,
and alkaline soil—ecological conditions that favor C
immitis. The organism is drought resistant, and periodic
increases in cases are observed when prolonged drought is followed
by periods of heavy rain. Arthroconidia may become airborne after
windstorms or disruption of soil by farming or construction work.
Since infection requires that arthroconidia be inhaled, person-to-person
transmission does not play a role in acquisition of coccidioidomycosis.
Hospitalizations for coccidioidomycosis are common, particularly
in endemic areas. County of residence, older age, black race, male
sex, intercurrent HIV infection, and pregnancy are all risk factors
strongly associated with an increased risk for hospitalization.5
The primary portal of entry in most patients is the lung, although
the organism may enter through the skin. Accordingly, signs and symptoms
of respiratory tract infection represent the major clinical manifestations
of acute coccidioidomycosis in most patients.6 Pulmonary coccidioidomycosis
occurs in 95% of all cases. The majority of individuals
with acute coccidioidomycosis will have either asymptomatic infection
or mild upper respiratory tract symptoms. Approximately 40% of patients
with primary infection will develop a more severe systemic illness
1 to 3 weeks after exposure, characterized by cough, malaise, fever,
chills, night sweats, anorexia, and weakness. Lower respiratory
tract illness may include pneumonia and parapneumonic effusion.
Chest pain may be quite severe in some patients, and hemoptysis
is commonly encountered in adult patients, although it is rare in
children. The radiographic appearance of acute coccidioidomycosis
is nonspecific. Bronchopneumonic infiltrate associated with hilar
adenopathy is the most common presentation, although an interstitial
pattern may be encountered. Widespread intrathoracic disease (“miliary
pattern”) may be encountered with disseminated infection.
Pulmonary infection can be divided into 3 main categories: primary,
complicated, and residual pulmonary coccidioidomycosis.6 Primary
infection occurs with inhalation of airborne arthroconidia: Remarkably,
as few as 10 arthroconidia are capable of producing infection. Symptomatic
disease manifests with predominantly an influenzalike syndrome, with
accompanying pneumonia or pleural effusion. Complicated pulmonary
coccidioidomycosis includes severe and persistent pneumonia, progressive
primary coccidioidomycosis, fibrocavitary coccidioidomycosis, empyema,
and, rarely, acute respiratory distress syndrome (ARDS). Residual
disease comprises 2 entities: pulmonary nodule and fibrosis.
An important diagnostic clue in patients with primary coccidioidomycosis
is the presence of cutaneous manifestations. The most common skin
manifestation of acute coccidioidomycosis is erythema nodosum.
The appearance of these lesions, known in California as the “valley bumps,” correlates
with the development of cell-mediated immunity and is associated
with a lower risk of dissemination. These painful, tender lesions
are distributed on the anterior tibial surface. Although not specific
for coccidioidomycosis, the finding of erythema nodosum in a child
residing in an endemic area strongly suggests recent acute coccidioidomycosis.
Less commonly, erythema multiforme may be present, and, like erythema
nodosum, this rash is also assumed to be immunologically mediated.
Interstitial granulomatous dermatitis and Sweet syndrome have recently
been recognized as additional reactive signs of the infection.7 Primary
cutaneous infection with C immitis is rare, with
most cases being attributed to laboratory accidents. The skin may
also be a target organ in the setting of disseminated infection
(see next section).
Other Coccidioidomycosis Disease
Approximately 0.5% of patients with acute coccidioidomycosis
will develop disseminated infection. Dissemination
is more common in men, pregnant women (discussed in this section),
and in certain ethnic groups (individuals of African, Mexican, or
Filipino ancestry). Major disseminated disease sites include bones,
joints, visceral organs, and the central nervous system.
Local pain is the usual hallmark of musculoskeletal coccidioidomycosis,
with warmth and swelling accompanying the systemic symptoms of infection.
Over one third of cases of disseminated coccidioidomycosis are complicated
by osteomyelitis, which is unifocal in most cases. Any bone can
become infected, but the most commonly involved sites are skull,
metacarpals, metatarsals, spine, and tibia. Bone scans are more
sensitive than plain radiographs in making the diagnosis. When present,
vertebral lesions tend to be multiple and pose a high risk for central
nervous system spread. Tendinitis, synovitis, or frank arthritis may
result from bloodstream dissemination. Swelling and tenderness are
present, most commonly involving the ankle and knee. Fungus can
usually be cultured from the affected synovial fluid, and synovial
biopsy is indicated in suspect cases.
Coccidioidomycosis meningitis is an important
and serious complication of disseminated infection.8 It
typically presents within the first 6 months following primary infection.
Importantly, the signs of meningeal irritation common in bacterial meningitis
are generally absent. Headache is the most common symptom. Fever,
weakness, vomiting, focal neurologic deficits, and meningismus may
occur, but many patients are asymptomatic; therefore, any patient
with disseminated coccidioidomycosis should probably undergo lumbar
puncture regardless of symptoms. Cerebrospinal fluid analysis typically
shows a mononuclear pleocytosis, with decreased glucose and elevated
protein levels. Meningitis may be associated with parenchymal involvement evident
on magnetic resonance imaging. The course of coccidioidomycosis
meningitis is often chronic. Hydrocephalus is a common complication. C
immitis is rarely recovered from cerebrospinal fluid, but complement-fixing
antibodies for coccidioidin are present in almost all cases.
Other manifestations of disseminated coccidioidomycosis may include
seeding of visceral organs, genitourinary tract infection, ophthalmic
complications (chorioretinitis), and cutaneous infection. Muscle
involvement may occur in disseminated cases, with occasional development
of abscesses or draining sinus tracts. Of particular interest to
pediatricians is the issue of coccidioidomycosis in pregnancy.
Pregnant women are at high risk of dissemination of coccidioidomycosis,
presumably due to the physiological reduction in type 1 T-helper-cell
cytokine responses that occurs during pregnancy.9,10 Historically,
untreated disseminated coccidioidomycosis during pregnancy was thought
to be associated with extensive maternal and fetal mortality and
was a leading cause of maternal death in endemic areas of endemicity,
demonstrating a dramatically increased risk of dissemination in
African American women.11 As recently as 1995,
therapeutic abortions and early deliveries were advocated in certain
contexts, although more recent reports suggest that the risk of
transplacental infection and fetal complications may have been overstated.12 Infection
in the newborn may also be acquired via the birth canal. The mortality
of disseminated disease is higher in neonates than in older children
in Immunocompromised Patients
In recent years C immitis has emerged as a major
pathogen in immunocompromised patients, particularly those with
HIV infection.13C immitis also
has an enhanced pathogenic potential in other immunosuppressed patients,
such as organ transplant recipients, children with congenital immunodeficiencies,
and patients on immunosuppressive therapies, including tumor necrosis
factor antagonists such as infliximab.14-16 Coccidioidomycosis
in immunocompromised patients represents a mix of new and reactivated
infections. Diffuse pulmonary disease is common, and lung biopsy
is often required to make the diagnosis. Extrapulmonary disease
may be difficult to eradicate, necessitating chronic suppressive
therapy (see section “Therapy”). Even a remote
history of residence or travel to an endemic area should be sought, since
the major problem in making the diagnosis is a lack of suspicion
of the possibility of coccidioidomycosis.
Demonstration of the organism by examination and culture of clinical
specimens, with confirmation of positive cultures utilizing nucleic
acid hybridization methods, remain the definitive diagnostic approaches
to establishing the diagnosis of coccidioidomycosis.17 Sputum,
joint fluid, bronchoalveolar lavage fluid, soft tissue aspirates,
and deep tissue surgical specimens offer the best yield by culture.
Spinal fluid culture is positive by culture only about one third
of the time, and when the diagnosis of meningitis is being considered,
multiple lumbar punctures may increase the diagnostic yield. It
is important to remember that cultures of C immitis represent
a potentially severe biologic hazard, and laboratory personnel should
be alerted to the possibility of the diagnosis prior to processing
of specimens. Microscopic examination of clinical specimens may
be useful, to search for the presence of endospore-containing spherules.
Fine-needle aspiration of suspect lesions in soft tissue or bone,
synovial biopsies, and skin biopsies all provide suitable specimens
for histopathological evaluation.
Nonculture techniques, such as fungal DNA detection by polymerase
chain reaction, colorimetric and antibody-based assays to detect
cell wall or capsular polysaccharides, and serology, are also helpful
in making the diagnosis of coccidioidomycosis.18 The mycelial
phase antigen, coccidioidin, is the most important target of antibody
response. Serum IgM antibodies, called precipitins, can be detected
1 to 3 weeks after onset of symptoms in most cases and are readily identifiable
by a variety of immunodiffusion, latex agglutination, or enzyme
immunoassay methods. Complement-fixing serum IgG antibodies (CFA)
appear later in the course of infection, and usually decline 6 to 8
months following primary infection, although antibody may continue
to be detectable for years. The CFA titer is a useful marker of
disease activity. Sera should be run in paired fashion (acute and
convalescent) for titer comparison. Rising titers are a bad prognostic
sign, whereas falling titers suggest improvement. In the majority
of patients with meningitis, CFA is present in cerebrospinal fluid,
and titers parallel the course of meningeal disease.
Skin tests may also be used in the diagnostic approach to coccidioidomycosis,
although interpretations of these tests can be problematic. Most
patients with symptomatic primary infections will have a positive
test (> 5 mm induration) within 1 month of disease onset. Patients
with erythema nodosum may have a severe response to skin tests because
of their particularly intense delayed-type hypersensitivity response
to coccidioidin antigen. Cutaneous anergy is common in individuals
with disseminated coccidioidomycosis, and a negative skin test in
such patients does not exclude the diagnosis.
The decision to initiate antifungal therapy in the setting of
coccidioidomycosis depends on the extent of disease and the risk
factors a patient may have for complicated or disseminated disease.
Although most patients with symptomatic primary infection recover
spontaneously, treatment is mandated in several clinical settings.
Once disease has spread outside the lung (bone, joint, and soft
tissue infections, genitourinary tract infections, and central nervous
system involvement), antifungal therapy is almost always warranted.
In certain circumstances, individuals with symptomatic primary infection
should also be treated, even if disease appears to be limited to
the lungs, since the risk of dissemination is high. These patients
include pregnant women, young infants, the immunocompromised, and individuals
with chronic or debilitating illnesses. The magnitude of the CFA
titer at time of diagnosis is also of value in making decisions
regarding therapy. Disseminated disease is virtually never seen
if the CFA titer is 1:32 or less. Therefore, titers of more than
1:32 may represent an indication for therapy in symptomatic primary
infection, irrespective of other clinical findings.
Historically, amphotericin B and its lipid congeners have been
regarded as the gold standards of therapy for severe pulmonary and disseminated
coccidioidomycosis. The availability of azoles and, more recently,
triazoles have relegated the amphotericins to use only in severe
or widely disseminated disease, azole intolerance, or when contraindications to
azoles exist, such as during pregnancy. The extended-spectrum azoles,
such as posaconazole and voriconazole, may prove to be more efficacious
in the treatment of coccidioidomycosis than prior azoles, including
fluconazole and itraconazole.
C immitis meningitis represents a special circumstance
regarding treatment. In meningitis, the intrathecal use of amphotericin
B is still frequently recommended, alone or in combination with
a triazole. Because of the extremely high risk of relapse, therapy,
typically a triazole, appears to need to be given for life.19