Six years prior to presentation, a thirty-nine-year-old man was diagnosed
with disseminated coccidioidomycosis involving the thoracic vertebrae, skin,
and lungs. The diagnosis was made on the basis of a biopsy of lung tissue. At
the time of diagnosis, the Coccidioides complement fixation titer was 1:2048.
The patient was managed with amphotericin B (total dose, 1.5 g) and high-dose
fluconazole. Approximately eighteen months before admission, fluconazole was
discontinued when the Coccidioides titers returned to normal (<1:2).
Six months prior to presentation, the patient sustained a minor
nonpenetrating injury that resulted in pain and tenderness in the lateral
aspect of the right foot, with a recurrent nonhealing wound. The injury
initially was thought to have resolved without treatment, but two months later
another lesion recurred in the same region. Over the subsequent four months,
the patient was seen at multiple clinics and was managed with several courses
of antimicrobial medication, without healing of the wound. At that time, the
patient was noted to have osseous abnormalities on routine radiographs of the
foot and was referred to our orthopaedic clinic.
The patient had a 6 × 4-cm area of induration along the lateral and
dorsal aspects of the right foot (Fig.
1). An area of ulceration was noted over the cuboid, and there was
associated tenderness in the region of the cuboid. No drainage was noted from
the central aspect of the ulcer. Extensor tendon function was intact, and the
results of the neurovascular examination were unremarkable. The patient had no
fever, cough, or shortness of breath at the time of presentation. Radiographs
revealed osteolysis of the cuboid, the base of the fifth metatarsal, and the
lateral cuneiform (Fig. 2).
Magnetic resonance images demonstrated a large soft-tissue mass overlying the
lateral aspect of the midfoot, with inflammatory changes in the cuboid, the
lateral cuneiform, and the base of the fifth metatarsal
(Fig. 3). The patient had an
elevated serum Coccidioides complement fixation titer of 1:64, a positive
hepatitis-C antibody titer, and a negative HIV-1 antibody titer. The
erythrocyte sedimentation rate was elevated to 37 mm/hr. The complete
blood-cell count was within normal limits.
The patient underwent surgical treatment. The ulcerated area of skin and a
caseating soft-tissue mass were sharply excised. Soft, fragmented portions of
the cuboid, the base of the fifth metatarsal, and the lateral cuneiform were
débrided. The wound was irrigated and closed over a small Penrose
drain. Specimens were sent to the pathology and microbiology laboratories for
fungal, bacterial (aerobic and anaerobic), and acid-fast bacilli stains and
cultures.
Histologically, the débrided tissue demonstrated caseating
granulomatous inflammation, with spherules and endospores that were identified
with Gomori methenamine silver staining as being consistent with Coccidioides
(Fig. 4). Subsequently, fungal
and blood cultures demonstrated growth of a type of mold identified as
Coccidioides immitis on the basis of the morphological
characteristics of the hyphal elements. The specific organism was confirmed
with DNA-probe
analysis4.
The patient was given cefazolin and fluconazole perioperatively until the
diagnosis was confirmed. Thereafter, treatment was continued with 400 mg of
fluconazole, administered orally twice per day. The patient had full healing
of the soft-tissue wound at one month after surgery. The remaining portions of
the cuboid, cuneiform, and fifth metatarsal showed areas of sclerosis
radiographically. Periodic monitoring of the clinical status and liver
function tests revealed excellent tolerance of the high dose of fluconazole.
At the time of the most recent evaluation, the disease had remained quiescent
for more than four years, during which time the patient continued to take the
antifungal medication. The most recent Coccidioides antibody titer was 1:2. We
plan to continue a lifetime antifungal suppression regimen with use of
high-dose fluconazole.
Coccidioides immitis is a soil-dwelling fungus endemic to the arid
parts of the southwestern United States and regions of Central and South
America1,5.
It is a dimorphic organism, forming spores in tissue and mycelia in soil and
culture. The mycelia are formed by strands of arthroconidia that disarticulate
and become airborne or return to the soil. Infection occurs when the
arthroconidia are inhaled. In the lung, the arthroconidia become spherules
that have thick walls and contain multiple endospores. The spherules release
the endospores, which can individually initiate the formation of a new
spherule and thereby propagate in the
lung1.
Coccidioides immitis initially causes pulmonary infection by the
inoculation of airborne arthroconidia in the respiratory tract. Most people
with respiratory tract colonization remain
asymptomatic1,6.
About two-thirds of the estimated 100,000 cases of primary Coccidioides
immitis infections are subclinical and resolve without
therapy1,7.
Progressive hematogenous dissemination occurs in <1% of patients, usually
in the setting of an immunocompromised host, and the organism may involve any
organ system, most commonly the skin, meninges, and
bone6,8,9.
Non-white race is a predictor of dissemination; black patients more often have
development of disseminated bone disease, whereas Filipinos are more likely to
have development of cutaneous or central nervous system
disease10.
Bone involvement is always secondary to disseminated disease from the lung.
Previous reports have indicated that 10% to 50% of patients with disseminated
illness will have osseous
lesions9-11.
Coccidioidomycosis tends to have a predilection for osseous prominences and
the ends of long bones, resulting in previous theories that the organism is
disseminated hematologically and is possibly parasitic in the red marrow of
bones12. In its
pathological manifestations, coccidioidomycosis most closely resembles
tuberculosis. The predominant tissue reaction is granulomatous. In acute foci
purulence may predominate, and in chronic lesions fibrosis may be the main
finding13.
Infection of the bone typically causes chronic osteomyelitis, often draining
to soft tissue and creating fistulae. All bones may be
involved12,14,15.
Between 45% and 64% of bone coccidioidomycosis cases present with multiple
bone
involvement8,12.
Vertebral osteomyelitis can affect any part of the vertebra, usually sparing
the disc but putting the patient at risk of
meningitis12.
Coccidioidomycosis also may affect joints, causing synovitis. The ankles and
knees are the most common joints
involved1.
Any patient who has traveled to or lived in an endemic area is at risk for
acquisition of disease, but because bone involvement is always secondary to
disseminated disease from the lung, musculoskeletal infection is most likely
to occur in a patient with risk factors for disseminated disease, such as
immunocompromised status, non-white race, steroid or anti-tumor necrosis
factor therapies, and pregnancy (Table
I). Coccidioidomycosis should be considered in the differential
diagnosis of any chronic osseous infection in a patient with risk factors for
both acquisition and dissemination of disease. Eosinophilia of 5% to 10% and
previous pulmonary infection (often demonstrated by the presence of a
thin-walled cavity on a chest radiograph) are often findings associated with
this diagnosis1.
Elevated complement fixation antibody titers are associated with disseminated
disease. Titers equal to or higher than 1:16 have been associated with
dissemination to
bone10.
The differential diagnosis should include other fungal diseases such as
blastomycosis, cryptococcosis, candidiasis, and sporotrichosis. Multiple
diverse species of mycobacteria (both tuberculous and nontuberculous) all have
been associated with chronic osteomyelitis
syndromes5. Common
bacteria such as Staphylococcus aureus should also be considered, as
should less common ones such as Brucella and Bartonella species. Therefore,
biopsy or operative specimens for suspected coccidioidomycosis should be
submitted to the pathology and microbiology laboratories for routine staining
and cultures for fungi, acid-fast bacilli, and aerobic and anaerobic bacteria
(with a special request to hold cultures for thirty days if Brucella and
Bartonella species are suspected). Coccidioides immitis grows readily
on cultures of infected bone, tissue, and joint fluid, typically appearing in
three to four days. The organism is often demonstrated on smears as well as on
routine tissue stains. Enhanced sensitivity of the pathological diagnosis may
be obtained with use of Gomori methenamine silver stains and with fluorescent
antibody
techniques5.
Although this is an infectious disease, it is not contagious in its tissue
form. When allowed to revert to its airborne (mycelial) form, such as in
laboratory culture, however, the fungus is highly infectious. The laboratory
must be fore-warned when Coccidioides immitis is the suspected
pathogen. In addition, drainage of pus into a moist environment such as the
interior of a cast can promote transformation into the mycelial form, and
highly infectious spores can be released into the air when the cast is opened.
In these rare instances, the cast should be opened in a negative-airflow
environment under airborne transmission
precautions16.
Progressive disseminated disease to bone can be very difficult to treat.
Guidelines for the treatment of extrapulmonary coccidioidomycosis infections
have been reported7;
however, no randomized, controlled trials have been performed to validate
them, to our knowledge. In the treatment of coccidioidomycosis osteomyelitis,
recent retrospective studies have indicated an increased likelihood of success
in association with a combination of surgical and medical treatment as opposed
to medical treatment
alone2,8.
These results suggest that surgical debulking has a definite role in
increasing the effectiveness of antifungal therapy. Specific antifungals (and
their usual dosages) for the treatment of coccidioidomycosis include
amphotericin B (0.5 to 0.7 mg/kg/day, administered intravenously),
ketoconazole (400 mg/day, administered orally), fluconazole (400 to 800
mg/day, administered orally or intravenously), and itraconazole (200 mg,
administered orally two times per
day)17. In patients
who are not candidates for surgery, amphotericin B remains the most effective
antifungal medication despite its many side
effects2.
Alternatively, treatment with amphotericin lipid formulations or an oral
antifungal agent may be considered because they are less toxic than
conventional amphotericin B. A recent study comparing itraconazole with
fluconazole for the treatment of nonmeningeal coccidioidomycosis showed
similar success rates, with a slight trend toward greater efficacy of
itraconazole, especially for the treatment of skeletal
infections7.
However, its variable absorption and multiple drug-drug interactions may
preclude treatment with itraconazole in certain populations. If itraconazole
is used, measurement of serum concentrations after two weeks may determine if
absorption is satisfactory. Newer antifungal agents, such as voriconazole,
have also been used
successfully18 and
soon may become the standard of care. Lifelong fungal suppression with
antifungal medication is indicated for patients with disseminated disease to
bone as studies have shown relapse rates of as high as 75% after therapy is
stopped1-3.
Obtaining complement fixation antibody titers at the beginning of treatment is
very helpful as titers parallel the course of disease and can help the
clinician to monitor therapy. Rising titers are a bad prognostic sign, and
falling titers indicate
improvement6.
In summary, the diagnosis of bone infection caused by Coccidioides
immitis can be difficult. The clinician should suspect the entity in
patients who have traveled to or lived in endemic areas and who have risk
factors for dissemination. On the basis of the available data, a combination
of surgical débridement and antifungal therapy is the recommended
treatment. The literature indicates that a patient with known disseminated
coccidioidomycosis who discontinues suppressive antifungal medication is
likely to have development of a new bone lesion. ?