Reactivation of coccidioidomycosis: a prosthetic joint infection in Spain.

A resident of Spain was found to have a prosthetic knee infection due to coccidioidomycosis. He had a history of having pneumonia which resolved while living in an area of California endemic for Coccidioides in 1957-1961. The patient left California in 1961 returned to Spain and never left Spain thereafter. In 2006, a total knee replacement was done. In 2013, a prosthetic knee infection was documented due to coccidioidomycosis. By molecular DNA analysis, Coccidioides immitis was identified from the knee tissue, a species most commonly found in California. This represents reactivation of a Coccidioides infection 56 years after leaving the endemic area.

False-positive IgM serology in coccidioidomycosis.

The clinical observation has been made that there might be an unacceptable number of false-positive enzyme immunoassay (EIA) test results for IgM among persons suspected of having coccidioidomycosis. Patients with a positive result for IgM by EIA are thought to have a diagnosis of acute coccidioidomycosis. However, this study found that 82% of patients with an IgM-positive and IgG-negative EIA result did not have coccidioidomycosis.

Treatment of Coccidioides immitis pneumonia in two horses with fluconazole.

Pulmonary coccidioidomycosis in horses can often lead to severe systemic disease and its treatment has previously been expensive and has carried a poor prognosis. This paper describes the successful treatment of two horses with pulmonary coccidioidomycosis with a fluconazole product produced by a compounding pharmacy.

Pulmonary coccidioidomycosis in a neonatal foal.

A 13-day-old foal with profound tachypnoea and respiratory distress was examined. Thoracic radiographs revealed a severe, diffuse miliary pattern, and the foal was markedly hypoxaemic. It failed to improve with empirical treatment, and was euthanased. Lesions associated with Coccidioides immitis infection were identified at postmortem examination, and were limited to the lower respiratory tract.

Serologic studies in coccidioidomycosis.

Serologic tests are valuable in the management of patients with suspected or confirmed coccidioidomycosis. Qualitative tests (immunodiffusion, enzyme immunoassay, or latex particle agglutination) permit detection in the serum of the major antibody responses-coccidioidal IgM in early coccidioidomycosis, and complement fixing (CF) IgG, which appears later and is more persistent. Quantitation of the level (titer) of coccidioidal IgG is useful in prognosis and diagnosis. The preferable antigen for these tests is coccidioidin from the hyphal phase of Coccidioides immitis. When coccidioidal disease has disseminated to an extrapulmonary site, the corresponding fluid-cerebrospinal, synovial, peritoneal (as well as pleural)-can be tested for coccidioidal antibody provided that the serum is known to be positive. Some immunocompromised patients may have a limited humoral responsiveness; therefore, it will be important to develop a practical method for the detection of coccidioidal antigen.

Assessment of the human cellular immune response to T27K, a coccidioidal antigen preparation, by flow cytometry of whole blood.

Whole blood flow cytometry was performed among donors with various clinical forms of coccidioidomycosis using T27K, a coccidioidal antigen preparation protective in mice but not previously studied in humans. The median percent of CD3+ lymphocytes (CD3+) producing intracellular interferon-gamma (IFN-gamma) among healthy immune donors was 0.43%, significantly above that for non-immune donors (0.01%) and greater than that for subjects with other forms of coccidioidomycosis, including chronic pulmonary (0.11%), disseminated (0.09%) and concomitant human immunodeficiency virus (HIV) infection (0.07%) (P < or =0.002 for all). No increase in intracellular interleukin (IL)-10 production or apoptosis was noted in samples incubated with T27K. Among 14 HIV-infected patients with concomitant coccidioidomycosis, seven of eight patients whose peripheral blood CD4 concentration was > 200 cells microl(-1) had > 0.06% of CD3+ produce intracellular IFN-gamma, compared to none of six whose peripheral blood CD4+ lymphocyte concentration was < or =200 cells microl(-1) (P = 0.005). These data indicate that there is a specific human cellular immune response to T27K as a coccidioidal antigen and that this response can be categorized based on the clinical status of the coccidioidally infected patient.

Seeking a vaccine against Coccidioides immitis and serologic studies: expectations and realities.

The studies reported in this review indicate that, whereas the expectations from the molecular approach help to excite and enlighten us, the realities suggest that even some less modern approaches may provide the necessary practical solutions to problems of serology and vaccination against coccidioidomycosis. Concurrent conduct of the two approaches should maximize the chances for success.

Comparative efficacies of terbinafine and fluconazole in treatment of experimental coccidioidal meningitis in a rabbit model.

A rabbit model of coccidioidal meningitis was used to compare the therapeutic efficacies of terbinafine (TBF) and fluconazole (FCZ). Hydrocortisone acetate-treated New Zealand White male rabbits were infected intracisternally with either 2.2 x 10(4) or 6.4 x 10(4) Coccidioides immitis arthroconidia. Oral treatment with polyethylene glycol 200 (PEG) twice daily (n = 8), TBF twice daily (n = 9; 200 mg/kg of body weight/day), or FCZ once daily (n = 8; 80 mg/kg/day) began on day 5 and continued for 21 days. Mean survival times were 20, 24, and 32 days for rabbits treated with PEG, TBF, and FCZ, respectively. All of the FCZ-treated animals (100%; P = 0.003), 56% of the TBF-treated animals (P = 0.4), and 25% of the PEG-treated animals survived the length of the study. Both FCZ and TBF were effective at reducing the incidence of paresis. Only FCZ was effective at reducing most neurological and systemic signs. FCZ treatments resulted in lower cerebrospinal fluid (CSF) protein concentrations and leukocyte counts and faster clearing of CSF fungal cultures compared with those for PEG-treated controls, but TBF treatments had no significant effect on these parameters. Neither drug affected CSF glucose levels. Mean serum TBF levels by bioassay were within the range of 3.5 to 6.2 microgram/ml at 1, 2, and 4 h postdosing and 0.35 to 7.0 microgram/ml at 14 h postdosing. No TBF was detected in CSF. Mean FCZ levels (24 to 25.5 h postdosing) by bioassay were 16.4 to 19.2 and 13.5 to 19.2 microgram/ml in serum and CSF, respectively. The reduction in the numbers of CFU in the spinal cord and brain was over 100-fold (P = 0.0005) in FCZ-treated animals and 2-fold (P

Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis.

Coccidioidal meningitis is a devastating disease that requires long-term therapy with little hope of cure. A rabbit model of coccidioidal meningitis was used to compare the therapeutic efficacies of fluconazole (FCZ) and itraconazole (ITZ). Hydrocortisone-treated male New Zealand white rabbits were infected intracisternally with 5.0x10(4) to 5.4x10(4) arthroconidia of Coccidioides immitis. Oral treatment with polyethylene glycol 200 (PEG) (n = 9), FCZ (n = 8; 80 mg/kg of body weight/day), or ITZ (n = 8; 80 mg/kg/day) began 5 days after infection and continued for 28 consecutive days. Both FCZ and ITZ reduced the number of CFU of C. immitis organisms in the spinal cord and brain compared with the number in PEG-treated animals (P< or =0.003), but the results for FCZ and ITZ were not different from each other. Histopathologic severity (semiquantitative scoring system by an observer blinded to treatment) was equally reduced in both FCZ and ITZ treatment groups compared with that in controls (P< or =0.0004). Both treatments resulted in lower cerebrospinal fluid (CSF) protein concentrations and leukocyte counts and faster clearing of C. immitis from CSF compared with the results for PEG-treated controls. Neither drug affected CSF glucose levels. Both compounds were effective at reducing neurological and systemic signs and extending survival (P< or =0.014). FCZ was more effective at reducing head and body shakes, posture changes, and incontinence; ITZ was more effective at reducing continuous fever. Mean levels of FCZ and ITZ in the serum and CSF were determined by bioassay; at 17 to 26 h postdosing, levels were 28.1 to 40.0 and 22.4 to 29.9 microg/ml, respectively, for FCZ and 0.77 to 2.51 and 0 microg/ml, respectively, for ITZ. The sera of most animals developed antibody to C. immitis, but azole treatment attenuated antibody development in CSF and its titer. In conclusion, both FCZ and ITZ were efficacious, but neither was curative in a rabbit model of coccidioidal meningitis.

Identification and cloning of an aspartyl proteinase from Coccidioides immitis.

A 45 kDa protein was isolated from a soluble vaccine prepared from formaldehyde-killed spherules of Coccidioides immitis. From the N-terminal amino acid sequence, the protein yielded a 17-amino-acid peptide that was homologous to sequences of other fungal aspartyl proteinases. The coccidioidal cDNA encoding the proteinase was amplified using oligonucleotide primers designed from the 45 kDa N-terminal amino acid sequence and a fungal aspartyl proteinase consensus amino acid sequence. The PCR product was cloned and sequenced, and the remaining 5' upstream and 3' downstream cDNA was amplified, cloned, and sequenced. The cDNA encoding the coccidioidal aspartyl proteinase open reading frame was cloned and the fusion protein containing a C-terminal His-tag expressed in E. coli. The recombinant aspartyl proteinase was purified by immobilized metal affinity chromatography. This recombinant protein will be used for further studies to evaluate its antigenicity, including protective immunogenicity.

Outbreak of coccidioidomycosis in Washington state residents returning from Mexico.

In July 1996 the Washington State Department of Health (Seattle) was notified of a cluster of a flulike, rash-associated illness in a 126-member church group, many of whom were adolescents. The group had recently returned from Tecate, Mexico, where members had assisted with construction projects at an orphanage. After 1 member was diagnosed with coccidioidomycosis, we initiated a study to identify further cases. We identified 21 serologically confirmed cases of coccidioidomycosis (minimum attack rate, 17%). Twenty cases (95%) occurred in adolescents, and 13 patients (62%) had rash. Sixteen symptomatic patients saw 19 health care providers; 1 health care provider correctly diagnosed coccidioidomycosis. Coccidioides immitis was isolated from soil samples from Tecate by use of the intraperitoneal mouse inoculation method. Trip organizers were unaware of the potential for C. immitis infection. Travelers visiting regions where C. immitis is endemic should be made aware of the risk of acquiring coccidioidomycosis, and health care providers should be familiar with coccidioidomycosis and its diagnosis.

New aspects of some endemic mycoses.

The treatment of mycetomas varies according to their etiological agents and the clinical state of the patient. For the treatment of eumycetomas, the azole derivatives are the drugs of choice, with itraconazole rendering better results than ketoconazole and presenting better tolerance. Actinomycetomas are treated according to different therapeutic schemes: dapsone plus sulfamethoxazol-trimethoprim (SMT), and streptomycin or amikacin or amoxicillin plus clavulanic acid. The first therapeutic scheme is very useful in the treatment of Nocardia mycetoma, while the association of amikacin plus SMT is the best treatment for those cases produced by Actinomadura madurae. Ciprofloxacin is a very useful drug for the treatment of actinomycotic mycetomas with bone lesions. Although there are several criteria for evaluating clinical outcome there is no accepted criterion of cure. During the 1990s, there was a remarkable increase in the incidence of coccidioidomycosis in California, USA. An almost ten-fold increase in the number of cases was registered during 1992 and 1993 over the usual incidence. A gradual reduction in coccidioidomycosis cases was observed in the late 1990s. This particular coccidioidomycosis outbreak took place in areas of low endemicity, as well as in those of usual high endemicity. Among the factors believed to have influenced this phenomenon were a drought followed by abundant winter/spring rainfall, increased immigration of susceptible individuals, increase in excavation/construction work and a better diagnosis of the infection, particularly in the last part of the decade. The majority of patients presented the usual clinical manifestations of symptomatic primary infection but an unusual number of cases with acute respiratory failure were observed.

Evaluation of the susceptibility of Coccidioides immitis to lufenuron, a chitin synthase inhibitor.

The activity of the chitin synthase inhibitor lufenuron was evaluated in vitro using the spherule-endospore (SE) phase of Coccidioides immitis. The lufenuron was also used to treat mice infected with C. immitis by the respiratory route. In vitro, lufenuron had no effect upon fungal cell growth. Two formulations of lufenuron were evaluated in vivo. Neither the oral nor the injectable lufenuron extended the survival of mice infected with C. immitis when compared with placebo-treated mice.

Mammary candidosis in lactating women.

Though perceived to be a growing problem by lactation professionals, fungal infection of the breast (mammary candidosis) is largely unstudied. Candida albicans, a commensal organism encountered frequently in the vagina and gastrointestinal tract of humans, has been reported to be responsible for both superficial (cutaneous) and localized (ductal) infection of the mammary gland in lactating women, though the latter association is not universally accepted. Severe pain is considered to be characteristic of yeast infection of the breast and may be a cause of premature weaning among lactating mothers. Given that pain is often the complaint that prompts mothers to consult lactation professionals, it is important that healthcare providers working with lactating women be knowledgeable about this disease. In this article, current research regarding yeast infection of the breast is summarized, including morphology and pathology, diagnosis, risk factors, and common treatment options.

A model of coccidioidal meningoencephalitis and cerebrospinal vasculitis in the rabbit.

Coccidiodal meningitis is a devastating complication of disseminated coccidioidomycosis. An animal model of this infection could enhance understanding of the pathogenesis of the disease and lead to improvements in therapy. A rabbit model of central nervous system infection simulating human disease was established using a blind cisternal tap technique to inoculate 4 x 10(3)-1 x 10(6) arthroconidia of Coccidioides immitis into the cisterna magna. Systemic, neurologic, and histopathologic findings of meningitis were observed in all rabbits, but an inoculum of 2 x 10(4) arthroconidia produced a chronic illness in which meningeal endarteritis obliterans was consistently observed. Serial sampling of cerebrospinal fluid demonstrated an inflammatory response. Growth of C. immitis was demonstrated by quantitative fungal culture from brains and proximal spinal cords.

Coccidioidomycosis in a bottlenose dolphin.

A stranded bottlenose dolphin (Tursiops truncatus gilli) succumbed to a pulmonary infection of Coccidioides immitis. The dolphin initially presented with mild inspiratory dyspnea that rapidly worsened over 48 hr to include buoyancy abnormalities and finally death. At necropsy, caseous nodules were observed throughout the lungs and perihilar lymph nodes. On histological examination of tissues, double walled organisms containing endospores characteristic of C. immitis were observed in lung, perihilar lymph nodes, and brain. Pyogranulomatous infiltrates were observed in the lung and perihilar lymph nodes only. A DNA Gen-Probe test performed on a purified isolate confirmed infection by C. immitis. Serum was positive for antibodies to C. immitis at a titer of 1:128 and was negative for all known marine morbilliviruses. Although there have been reports of C. immitis infections in free ranging marine wildlife, including California sea lions (Zalophus californianus) and sea otters (Enhydra lutris), this is the first reported case of coccidioidomycosis in a cetacean.

Comparison of topical administration of clotrimazole through surgically placed versus nonsurgically placed catheters for treatment of nasal aspergillosis in dogs: 60 cases (1990-1996).

OBJECTIVE: To examine the clinical response to topical administration of clotrimazole in dogs with nasal aspergillosis, to compare effect of surgically placed versus nonsurgically placed catheters used for administration on outcome, and to examine whether subjective scoring of computed tomographic images can predict outcome. DESIGN: Retrospective case series. ANIMALS: 60 dogs with nasal aspergillosis. PROCEDURE: Information including signalment, history, diagnostics, treatment method, and outcome was retrieved from medical records of dogs with nasal aspergillosis treated between 1990 and 1996 at the University of California School of Veterinary Medicine or cooperating referral practices. Final outcome was determined by telephone conversations with owners and referring veterinarians. Images obtained before treatment were subjectively assessed to develop an algorithm for predicting outcome. RESULTS: Clotrimazole solution (1%) was infused during a 1-hour period via catheters surgically placed in the frontal sinus and nose (27 dogs) and via nonsurgically placed catheters in the nose (18). An additional 15 dogs received 2 to 4 infusions by either route. Topical administration of clotrimazole resulted in resolution of clinical disease in 65% of dogs after 1 treatment and 87% of dogs after one or more treatments. The scoring system correctly classified dogs with unfavorable and favorable responses 71 to 78% and 79 to 93% of the time, respectively. CLINICAL IMPLICATIONS: Topical administration of clotrimazole, using either technique, was an effective treatment for nasal aspergillosis in dogs. Use of non-invasive intranasal infusion of clotrimazole eliminated the need for surgical trephination of frontal sinuses in many dogs and was associated with fewer complications.

Protection against lethal murine coccidioidomycosis by a soluble vaccine from spherules.

The formaldehyde-killed, whole-spherule vaccine, which is protective against lethal challenge of laboratory animals with Coccidioides immitis, was fractionated. It yielded a soluble, multicomponent, subcellular fraction termed the 27K vaccine. This vaccine, when it was accompanied by adjuvant, protected mice against lethal intranasal and intravenous challenge with C. immitis.

Probable false positive coccidioidal serologic results in patients with cystic fibrosis.

Coccidioidomycosis is an acquired fungal infection that afflicts primarily the respiratory tract. Cystic fibrosis patients who are being treated with glucocorticoids and immunosuppressed organ recipients may be at risk for infection with Coccidiodes immitis or reactivation of latent infection. The diagnosis is best made by demonstration of the organism in pathologic specimens or by culture. Serologic screening is another method that is reliable in most patients. We studied 98 patients who had serologic screening for Coccidiodes immitis performed as part of their evaluation for lung transplantation. This study revealed that approximately 15% of the cystic fibrosis patients screened had putative coccidioidal IgM, in the absence of an IgG response. None of the patients studied had a positive fungal culture for the organism. None of the non-cystic fibrosis patients screened had detectable coccidioidal IgG or IgM. We hypothesize that cystic fibrosis patients may have hyperimmune sera which interferes with serologic screening tests. We would recommend repeat serologic testing and attempts to identify the organism in tissue or by culture to confirm the diagnosis in these patients.