Interleukin-8 Receptor 2 (IL-8R2)-Deficient Mice Are More Resistant to Pulmonary Coccidioidomycosis than Control Mice.

The pathology of human coccidioidomycosis is granulomatous inflammation with many neutrophils surrounding ruptured spherules, but the chemotactic pathways that draw neutrophils into the infected tissues are not known. We previously showed that formalin-killed spherules (FKS) stimulate mouse macrophages to secret macrophage inflammatory protein 2 (MIP-2), which suggested that CXC ELR+ chemokines might be involved in neutrophil recruitment in vivo To test that hypothesis, we intranasally infected interleukin-8R2 (IL-8R2) (Cxcr2)-deficient mice on a BALB/c background with Coccidioides immitis RS. IL-8R2-deficient mice had fewer neutrophils in infected lungs than controls, but unexpectedly the IL-8R2-deficient mice had fewer organisms in their lungs than the control mice. Infected IL-8R2-deficient mouse lungs had higher expression of genes associated with lymphocyte activation, including the Th1 and Th17-related cytokines Ifnγ and Il17a and the transcription factors Stat1 and Rorc Additionally, bronchial alveolar lavage fluid from infected IL-8R2-deficient mice contained more IL-17A and interferon-γ (IFN-γ). We postulate that neutrophils in the lung directly or indirectly interfere with the development of a protective Th1/Th17 immune response to C. immitis at the site of infection.

An Analysis of Skin Test Responses to Spherulin-Based Coccidioidin (Spherusol®) Among a Group of Subjects with Various Forms of Active Coccidioidomycosis.

BACKGROUND: A reformulated skin test for coccidioidomycosis, Spherusol®, was recently approved for use in the USA. We hypothesized that it could be useful in predicting severity of illness and outcome in various types of coccidioidomycosis. METHODS: Subjects with non-meningeal coccidioidomycosis attending a clinic in the coccidioidal endemic region were skin tested with Spherusol® and clinical data were collected at the time of testing and at follow-up. RESULTS: Twenty-seven subjects were studied, eight of whom had extrathoracic dissemination. A total of 15 subjects had positive tests, including 11 of 19 subjects with non-disseminated pulmonary disease and four with extrathoracic disseminated coccidioidomycosis. Among those with non-disseminated pulmonary disease, age ≥ 65 years, female sex, and antifungal therapy were significantly associated with a negative test on univariate but not multivariate analysis. For 23 subjects, there was a trend for those not on antifungal therapy at the time of follow-up to have a positive test but no association with coccidioidal complement-fixation titer or overall outcome. CONCLUSIONS: Not all subjects with non-disseminated pulmonary coccidioidomycosis were found to be skin test positive and half of those with extrathoracic disseminated disease manifested dermal hypersensitivity. In this small study, the results of the skin test were not clinically predictive of disease severity or outcome.

Sensitivity of Serologic Testing for Dogs Diagnosed with Coccidioidomycosis on Histology: 52 Cases (2012-2013).

Coccidioidomycosis, or Valley Fever, is a fungal infection caused by Coccidioides spp., soil-living fungi endemic to the southwest region of the United States. The infection can cause various diseases including respiratory, neurologic, cardiac, dermatologic, and ocular disease as well as osteomyelitis in dogs and many other mammals. Obtaining a definitive diagnosis can be challenging. Serology is commonly used as a screening diagnostic test for disease, but both false-negative and false-positive results have been reported. Fifty-two cases of coccidioidomycosis diagnosed via histopathology were retrospectively evaluated. The sensitivity of serology in the study population was determined to be 87% for immunoglobulin G and 46% for immunoglobulin M. The cases were evaluated for an association between negative serology results and anatomic location of disease, but these variables were found to be independent. This study reports the sensitivity of serology for canine coccidioidomycosis and highlights the importance of using multiple diagnostic tests for definitive diagnosis of infection.

Coccidioidomycosis in solid organ transplant recipients.

PURPOSE OF REVIEW: The purpose of the review is an update of diagnosis and treatment of coccidioidomycosis infection in solid organ transplant (SOT) patients. Endemic fungal infections continue to be a cause of serious morbidity and mortality in transplant recipients. RECENT FINDINGS: In transplant patients there are recommendations regarding screening in areas that are endemic for coccidioidomycosis. This screening involves serologic testing and chest imaging. In endemic areas pretransplant seropositivity varies from 1.4 to 5.6%. In immunocompromised patients with elevated complement fixation titers, evaluation of cerebrospinal fluid is recommended even in the absence of symptoms. Although coccidioidomycosis can be a self-limited disease in immunocompotent patients, all SOT patients should be treated regardless of severity. This may include intravenous amphotericin B in severe cases and fluconazole therapy in milder episodes. In those SOT recipients with evidence of prior coccidioidomycosis, lifelong secondary prophylaxis with fluconazole given risk of recurrent disease. SUMMARY: Coccidioidomycosis continues to be a cause of serious morbidity and mortality in transplant recipients but with proper screening and treatment can be successfully managed.

[Clinical Features of Coccidioidomycosis:Analysis of 33 Chinese Cases].

Objective To summarize the characteristics of Chinese coccidioidomycosis cases, improve the diagnosis and treatment of this disease and prevent misdiagnosis as well as therapeutic error.Methods Search in databases including Medline,Wanfang,and CNKI using "Coccidioidomycosis" and "China" as index words yielded 23 articles that reported a total of 32 Chinese coccidioidomycosis cases.In addition,one patient with disseminated coccidioidomycos was treated in our center in April 2016.The demographic data,site of infection,clinical manifestations,past medical history,exposure history,imaging and laboratory findings,and pathological features of these 33 patients were analyzed.Results Among these 33 patients,7(21.2%)had visited an epidemic area and 6(18.2%)were immunocompromised.The disease involved the respiratory system,skin,bone,central nervous system,cornea,and stomach in 24,6,3,2,1,and 1 patients,respectively.Eight patients (24.2%) had multiple system involvement,and three of them died.The imaging findings included pulmonary nodules(n=14),mediastinal lymphadenopathy(n=5),solid shadow(n=4),cavity(n=4),pleural effusion(n=3),multiple plaques(n=2)and masses(n=2).Coccidiolys cysts were detected in the affected tissues(n=28)or in pus,exudate or pleural smear(n=3);in addition,coccidioides mycelium and spores were found in the sputum,pus,and tissue cultures in 4 cases,among whom only 2 cases were confirmed by serological examination.The treatments included triazoles(n=20),systemic or local administration of amphotericin B(n=13),surgical resection of the lesion(n=8),and intravenous gamma globulin(n=1).Five patients died,among whom three had underlying diseases that caused immunosuppression and one was an infant.The prognoses were relatively good in the remaining patients.Conclusions Early diagnosis and proper treatment can achieve good prognosis in coccidioidomycosis patients.Multi-system involvement and immunosuppression are risk factors for poor prognosis of coccidioidomycosis.For these patients,adequate and full-course medication may prevent rapid disease progression.

Coccidioidomycosis in Nonhuman Primates: Pathologic and Clinical Findings.

Coccidioidomycosis in nonhuman primates has been sporadically reported in the literature. This study describes 22 cases of coccidioidomycosis in nonhuman primates within an endemic region, and 79 cases of coccidioidomycosis from the veterinary literature are also reviewed. The 22 cases included baboons ( n = 10), macaques ( n = 9), and chimpanzees ( n = 3). The majority died or were euthanized following episodes of dyspnea, lethargy, or neurologic and locomotion abnormalities. The lungs were most frequently involved followed by the vertebral column and abdominal organs. Microscopic examination revealed granulomatous inflammation accompanied by fungal spherules variably undergoing endosporulation. Baboons represented a large number of cases presented here and had a unique presentation with lesions in bone or thoracic organs, but none had both intrathoracic and extrathoracic lesions. Although noted in 3 cases in the literature, cutaneous infections were not observed among the 22 contemporaneous cases. Similarly, subclinical infections were only rarely observed (2 cases). This case series and review of the literature illustrates that coccidioidomycosis in nonhuman primates reflects human disease with a varied spectrum of presentations from localized lesions to disseminated disease.

Coccidioidomycosis Involving Lungs and Skin: A Mimicker of Metastatic Disease.

Coccidioidomycosis is the major systemic mycoses, considered to be 1 of the most infectious fungal diseases. In symptomatic patients, the most common manifestation is pulmonary disease, but many other organs can be affected. Disseminated disease occurs in 1%-5% of all patients affected by coccidioidomycosis and can affect any organ, with the skin, central nervous system, and musculoskeletal system being reported as the most prevalent. Here, we report a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats. He was treated with various antibiotics for possible upper respiratory tract infection without symptomatic improvement. Computed tomography of the chest revealed numerous subcentimeter noncalcified pulmonary nodules scattered throughout both lungs with extensive mediastinal and bilateral hilar lymphadenopathy. The patient was referred to our hospital for further evaluation of suspected metastatic lung disease. Physical examination revealed an erythematous 1.2 cm nodule on his left medial eyebrow. Skin biopsy of the lesion revealed prominent squamous epithelial hyperplasia with basal keratinocytic atypia and associated mixed inflammatory infiltrate and scattered large thick-walled spherules containing variable-sized endospores, predominantly within the multinucleated giant cells. Special stain Periodic acid-Schiff tissue culture studies confirmed these to be Coccidioides immitis. After appropriate treatment with antifungal therapy for 5.5 months, his symptoms have improved with complete disappearance of lung nodules and a partially cavitated (1.1 × 1.1 cm) lesion in the left upper lung confirmed by follow-up chest computed tomography. With this report, the authors highlight disseminated coccidioidomycosis, a great mimicker of metastatic lung disease, which was diagnosed by skin biopsy, to ensure its prompt recognition and appropriate antifungal therapy.

Coccidioidomycosis.

A 23-year-old man presented with new-onset pruritic and painful urticarial lesions and targetoid erythematous plaques on both palms, the trunk, and the upper and lower extremities (Figure 1). Additionally, small pustules were discovered on the neck (Figure 2), and there with edematous erythematous vermillion lips with splaying onto the cutaneous lips without ulceration. The patient stated he had had a fever before the eruption, fatigue, chills, myalgias, and sore throat. A chest x-ray was obtained and showed bilateral infiltrates. Two 4-mm punch biopsies were performed on the left forearm and left side of the neck; a resulting section from the left forearm is shown in Figure 3.

Total and Lectin-Binding Proteome of Spherulin from Coccidioides posadasii.

Coccidioides is a virulent dimorphic fungus that causes coccidioidomycosis (valley fever) in mammals, including humans. Although the genome has been sequenced, a proteomic analysis does not exist. To address this gap in proteomic knowledge, we generated the proteome of spherulin (a well-studied lysate of fungal spherules) and identified 1390 proteins. Some of the proteins included glycosylation enzymes, which led us to hypothesize that fungal glycosylation patterns may be different from those of mammals and could be exploited to detect Coccidioides in tissues. We performed lectin-based immunohistochemistry on formalin-fixed paraffin-embedded human patients' lung tissues. GSL-II (Griffonia simplificonia lectin II) and sWGA (succinylated wheat germ agglutinin) lectins bound specifically to endospores and spherules in infected lungs. To identify lectin-binding glycoproteins in spherulin, we performed lectin-affinity chromatography, followed by LC-MS/MS. A total of 195 glycoproteins from spherulin bound to GSL-II, 224 glycoproteins bound to sWGA, and 145 glycoproteins bound to both lectins. This is the first report of the specific reactivity of GSL-II and sWGA lectins to Coccidioides endospores and spherules in infected human tissues and the first listing of the Coccidioidal proteome from spherulin using sequences present in three Coccidioides databases: RefSeq, SwissProt, and The Broad Institute's Coccidioides Genome project.

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.

Uphill both ways: Fatigue and quality of life in valley fever.

Primary pulmonary coccidioidomycosis is characterized by prolonged respiratory and systemic symptoms and fatigue. We prospectively administered the fatigue severity scale (FSS) and Short Form-36 Health Status Questionnaire (SF-36) to patients with proven or probable primary pulmonary coccidioidomycosis to quantify disease effect on quality of life (QOL). The 24-week observational study did not specify whether antifungal treatment would be provided; the treating physician made treatment decisions. FSS and SF-36 were completed at 4-week intervals. Thirty-six patients participated, of whom 20 received antifungal treatment. At onset of coccidioidal illness, mean FSS score was higher (ie, more fatigue) in the treatment group. However, in early illness, both groups had higher fatigue levels than reference populations with other diseases (eg, multiple sclerosis). FSS scores gradually improved, and scores in each group were below the severe fatigue level at week 12 and week 16 in the nontreatment and treatment groups, respectively. By week 24, mean FSS score of the nontreatment group equaled the general population. SF-36 component and profile scores were lower (with more symptoms) in the treatment group at each time point than the nontreatment group; both groups showed similar improvement. Mental and emotional health SF-36 scores were not as severely affected as physical scores. Most patients reached a physical functioning level similar to the general population at week 12. Pulmonary coccidioidomycosis causes severe fatigue and substantially affects physical abilities. Fatigue was found to be prolonged, with gradual improvement in QOL, regardless of antifungal administration.

Complications and Yield of Computed Tomography-Guided Transthoracic Core Needle Biopsy of Lung Nodules at a High-Volume Academic Center in an Endemic Coccidioidomycosis Area.

PURPOSE: Previous studies with small sample sizes have shown a wide range of complication rates and no study has investigated the yield of computed tomography-guided transthoracic core needle biopsies (CTTCB) for coccidioidomycosis. To better assess the safety, accuracy, and risk factors for complications of CTTCB of pulmonary nodules, we conducted a retrospective study at a high-volume academic center in an endemic coccidioidomycosis area. METHODS: We conducted a retrospective study of 203 patients who underwent CTTCB of pulmonary nodules between December 2010 and May 2013. We collected demographics, clinical, and radiographic data. Each case was reviewed for complications. Diagnostic accuracy was assessed by comparing CTTCB with final diagnoses. RESULTS: The overall complication rate was 25 %. Pneumothorax accounted for 24 % of complications with 7 % of pneumothoraces requiring chest tube. 1.5 % were complicated by hemoptysis but none required blood transfusions. There was an association between complications and age, presence of emphysema on CT, traversed lung length, and lesion depth. The overall sensitivity of the CTTCB for all types of lung cancer was 93 %, and specificity of 100 %. The positive predictive value of CTTCB for lung cancer was 100 %. The sensitivity and specificity of CTTCB for a coccidiomycosis lung nodule was 83 % with a specificity of 100 % with a PPV of 100 %. CONCLUSION: Our study demonstrates that CTTCB is a relatively safe method for evaluating lung nodules and highly accurate in evaluating lung nodules due to coccidioidomycosis in an endemic area. The primary risk factors for complications from CTTCB are the presence of emphysema on CT scan, lesion depth, and traversed lung length.

Calcinospherules: A Unique Morphology of Dystrophic Calcification That Mimics Deep Fungal Infection.

Dystrophic calcification may occur in association with cutaneous neoplasms. We report the case of a 50-year-old woman with unusual appearing dystrophic calcification that was mistaken for coccidiomycosis during Mohs micrographic surgery for an invasive squamous cell carcinoma on the lower lip. The term "calcinospherule" is suggested as a term to describe the round calcified bodies found within the lesion that mimicked spherules with endospores characteristic of Coccidioides imitis infection. Both the dermatopathologist and Mohs micrographic surgeon should be aware of this entity as well as other calcified bodies that may be encountered in Mohs micrographic surgery frozen sections. Literature regarding these calcified bodies is briefly reviewed.

Coccidioidomycosis in Biopsies with Presumptive Diagnosis of Malignancy in Dogs: Report of Three Cases and Comparative Discussion of Published Reports.

Coccidioidomycosis is a respiratory fungal infection with occasional systemic dissemination. The disseminated coccidioidomycosis is considered a multifaceted disease. In medicine, disseminated coccidioidomycosis is included within a group of infectious diseases that have been referred as the great imitators. In many cases, malignancies are included in the presumptive diagnosis. In veterinary medicine, disseminated coccidioidomycosis is common in dogs. Nonetheless, despite of being a diagnostic dilemma, disseminated coccidioidomycosis is underestimated and frequently not included into differentials, even in endemic zones. Herein, we describe three cases of granulomatous inflammation caused by Coccidioides spp. which were masquerading malignancies in dogs (0.39 %). The presumptive diagnoses in these cases were osteosarcoma, lymphoma and neurofibroma, respectively. A PCR assay employing tissues in paraffin blocks resulted positive for C. posadasii in one of these cases. A comparative discussion on the ambiguous clinic-pathological presentation of disseminated coccidioidomycosis in dogs and humans is included.

Retrospective analysis of cutaneous lesions in 23 canine and 17 feline cases of coccidioidomycosis seen in Arizona, USA (2009-2015).

BACKGROUND: Coccidioidomycosis is a fungal disease caused by the dimorphic saprophytic fungus Coccidioides immitis or C. posadasii. Primary pulmonary infection can disseminate to cutaneous and subcutaneous tissues, or less commonly direct cutaneous inoculation may occur. HYPOTHESIS/OBJECTIVES: To characterize the historical, clinical, diagnostic and treatment findings in dogs and cats with cutaneous manifestation of coccidioidomycosis. ANIMALS: Twenty three dogs and seventeen cats diagnosed between 2009 and 2015 in Arizona, USA. METHODS: Retrospective review of medical records from dogs and cats from an endemic area with a confirmed diagnosis via histopathology, cytology and/or culture, and skin lesions. RESULTS: Age of affected dogs ranged from 14 weeks to 13 years (median = 7 years), whereas cats ranged from 3 to 17 years (median = 9 years). Subcutaneous nodules were the most common lesions in both species. Lesions were distributed widely and not often found over sites of bone infection. In 75% of dogs and 54.5% of cats with cutaneous lesions there were clinical signs of systemic illness, supporting the diagnosis of cutaneous disseminated disease. Four dogs and four cats had localized lesions with no systemic illness, consistent with possible primary cutaneous infection. The most common mode of diagnosis was cytology identification in both species. Fluconazole was the most commonly prescribed antifungal drug. CONCLUSIONS AND CLINICAL IMPORTANCE: Coccidioidomycosis is the most common mycosis of dogs and cats in endemic regions and cutaneous signs of the disease may be an initial presenting complaint. This study identified a variety of cutaneous manifestations of the disease in dogs and cats and should be recognized by clinicians.

Primary Cutaneous Coccidioidomycosis Presenting as a Recurrent Preauricular Cyst.

A 31-year-old Filipino active duty marine presented with a 2-year history of a waxing and waning nodule on his left cheek that had been incised and drained on multiple occasions. The patient had no significant medical history other than a positive purified protein derivative test with negative chest x-ray finding treated with a 9-month course of isoniazid in 2010. He denied cough, fever, chills, night sweats, weight loss, joint/bone pain, or prior trauma to the area. On initial examination, there was a 1×1-cm erythematous indurated nodule associated with an overlying violaceous scar on his left preauricular cheek. Since the lesion was presumed to be an inflamed epidermal cyst, it was initially treated with 0.1 cc of interlesional triamcinolone acetonide (10 mg/cc). At 1-month follow-up, the lesion was slightly less indurated, but an excisional biopsy was performed to remove the residual nodule. The biopsy showed an essentially normal epidermis with focal dermal fibrosis below which were multiple collections of histiocytes and multinucleated giant cells surrounded by a dense lymphoplasmacytic infiltrate with numerous eosinophils (Figure 1). A few multinucleated giant cells contained large thick-walled spherules, some with endospores, consistent with Coccidioides immitis (Figure 2). Serological tests showed positive serum for C immitis IgG antibodies with low levels of complement-fixing antibodies (1:2). IgM antibodies were negative. Findings from chest x-ray and bone scan failed to reveal evidence of systemic disease. Although the infectious disease physician felt that the patient most likely had primary cutaneous coccidioidomycosis (PCC), since the duration of the infection was unknown and the patient was Filipino, thereby increasing his risk of dissemination, he was placed on a daily regimen of 400 mg of oral fluconazole until his complement fixation titers became undetectable.

Coccidioidal Tenosynovitis of the Hand and Wrist: Report of 9 Cases and Review of the Literature.

BACKGROUND: Tenosynovitis is an uncommon manifestation of disseminated infection with Coccidioides fungal species. Most experts treat this infection with combined surgical debridement and antifungal medication. The aim of our study was to examine the outcomes of patients with coccidioidal tenosynovitis of the hand and wrist. METHODS: We retrospectively searched for the records of patients with coccidioidal tenosynovitis of the hand and wrist at our institution. between 1987 and 2013. We also conducted a review of the literature from 1950 to 2014 to identify additional cases. RESULTS: We identified 9 cases of coccidioidal tenosynovitis of the hand and wrist at our institution, along with 5 other cases found in a review of the literature. The relapse rate was high overall (50%) and was higher after discontinuation of antifungal therapy (71%) in both immunocompromised and immunocompetent patients. Results of serologic testing were not predictive of relapse. CONCLUSIONS: A treatment strategy for coccidioidal tenosynovitis should focus on long-term administration of antifungal agents.

Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models.

Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC50 and MIC90 values of 1 and 2 µg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo (P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment (P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.