Epidemiological, clinical, and genomic landscape of coccidioidomycosis in northeastern Brazil.

Coccidioidomycosis, listed as a priority mycosis by the WHO, is endemic in the United States but often overlooked in Central and South America. Employing a multi-institutional approach, we investigate how disease characteristics, pathogen genetic variation, and environmental factors impact coccidioidomycosis epidemiology and outcomes in South America. We identified 292 cases (1978-2021) and 42 outbreaks in Piauí and Maranhão states, Brazil, the largest series outside the US/Mexico epidemic zone. The male-to-female ratio was 57.4:1 and the most common activity was armadillo hunting (91.1%) 4 to 30 days before symptom onset. Most patients (92.8%) exhibited typical acute pulmonary disease, with cough (93%), fever (90%), and chest pain (77%) as predominant symptoms. The case fatality rate was 8%. Our negative binomial regression model indicates that reduced precipitation levels in the current (p = 0.015) and preceding year (p = 0.001) predict heightened incidence. Unlike other hotspots, acidic soil characterizes this region. Brazilian strains differ genomically from other C. posadasii lineages. Northeastern Brazil presents a distinctive coccidioidomycosis profile, with armadillo hunters facing elevated risks. Low annual rainfall emerges as a key factor in increasing cases. A unique C. posadasii lineage in Brazil suggests potential differences in environmental, virulence, and/or pathogenesis traits compared to other Coccidioides genotypes.

Surveillance for Coccidioidomycosis, Histoplasmosis, and Blastomycosis During the COVID-19 Pandemic - United States, 2019-2021.

Coccidioidomycosis, histoplasmosis, and blastomycosis are lower respiratory tract fungal infections whose signs and symptoms can resemble those of other respiratory illnesses, including pneumonia caused by bacterial or viral etiologies; this overlap in clinical presentation might lead to missed or delayed diagnoses. The causative fungi live in the environment, often in soil or plant matter. To describe the epidemiologic characteristics of cases of coccidioidomycosis, histoplasmosis, and blastomycosis during the COVID-19 pandemic, CDC analyzed case surveillance data for 2019-2021. During this period, a total of 59,655 coccidioidomycosis cases, 3,595 histoplasmosis cases, and 719 blastomycosis cases were reported to CDC. In 2020, fewer cases of each disease occurred in spring compared with other seasons, and most cases occurred in fall; national seasonality is not typically observed, and cases were seasonally distributed more evenly in 2019 and 2021. Fewer cases coinciding with the start of the COVID-19 pandemic, along with an unusually high blastomycosis case fatality rate in 2021 (17% compared with more typical rates of 8%-10%), suggest that the pandemic might have affected patients' health care-seeking behavior, public health reporting practices, or clinical management of these diseases. Increased awareness and education are needed to encourage health care providers to consider fungal diseases and to identify pneumonia of fungal etiology. Standardized diagnostic guidance and informational resources for fungal testing could be incorporated into broader respiratory disease awareness and preparedness efforts to improve early diagnosis of coccidioidomycosis, histoplasmosis, and blastomycosis.

Safety of fluconazole in kidney transplant recipients for prevention of coccidioidomycosis.

Coccidioides is an endemic fungus that causes infections ranging from mild respiratory illness to life-threatening disease, and immunocompromised hosts such as solid organ transplant recipients are at higher risk for disseminated infection and mortality. Our center administers fluconazole prophylaxis to kidney transplant recipients residing in geographic areas with higher incidences of coccidioidomycosis. However, because drug-drug interactions occur between triazoles and immunosuppressants used in transplant medicine, we undertook a study to ascertain whether fluconazole prophylaxis was associated with any important safety outcomes in kidney transplant recipients. This retrospective study evaluated patients who had undergone kidney transplantation between 2016 and 2019. Data on patient demographics, transplant-related clinical information, use of fluconazole prophylaxis (200 mg daily for 6-12 months post-transplant), and patient outcomes were obtained. The primary outcome was mean estimated glomerular filtration rate (eGFR) at 12 months, comparing those who received fluconazole prophylaxis to those who did not. Secondary outcomes included mean eGFR at 3 months, 6 months, and 9 months post-transplant, patient survival, biopsy-proven graft rejection, graft loss, or a new requirement for post-transplant dialysis, all within 12 months post-transplant. The mean eGFR at 12 months was similar between both groups, with 66.4 ml/min/1.73 m² in the fluconazole prophylaxis group vs. 64.3 ml/min/1.73 m² in the non-fluconazole prophylaxis group (P = 0.55). Secondary outcomes were similar across both groups. Multivariable linear regression found no significant association between fluconazole use and graft function. Fluconazole prophylaxis for prevention of coccidioidomycosis was not associated with adverse graft outcomes in kidney transplant recipients.

Solid organ transplant recipients can be highly immune suppressed, and infection with Coccidioides (valley fever) after transplant can lead to severe infections in these patients. Our study showed that fluconazole was safe and effective for preventing Coccidioides in kidney transplant recipients.

Understanding the exposure risk of aerosolized Coccidioides in a Valley fever endemic metropolis.

Coccidioides is the fungal causative agent of Valley fever, a primarily pulmonary disease caused by inhalation of fungal arthroconidia, or spores. Although Coccidioides has been an established pathogen for 120 years and is responsible for hundreds of thousands of infections per year, little is known about when and where infectious Coccidioides arthroconidia are present within the ambient air in endemic regions. Long-term air sampling programs provide a means to investigate these characteristics across space and time. Here we present data from > 18 months of collections from 11 air sampling sites across the Phoenix, Arizona, metropolitan area. Overall, prevalence was highly variable across space and time with no obvious spatial or temporal correlations. Several high prevalence periods were identified at select sites, with no obvious spatial or temporal associations. Comparing these data with weather and environmental factor data, wind gusts and temperature were positively associated with Coccidioides detection, while soil moisture was negatively associated with Coccidioides detection. These results provide critical insights into the frequency and distribution of airborne arthroconidia and the associated risk of inhalation and potential disease that is present across space and time in a highly endemic locale.

A microbial risk assessor's guide to Valley Fever (Coccidioides spp.): Case study and review of risk factors.

Valley Fever is a respiratory disease caused by inhalation of arthroconidia, a type of spore produced by fungi within the genus Coccidioides spp. which are found in dry, hot ecosystems of the Western Hemisphere. A quantitative microbial risk assessment (QMRA) for the disease has not yet been performed due to a lack of dose-response models and a scarcity of quantitative occurrence data from environmental samples. A literature review was performed to gather data on experimental animal dosing studies, environmental occurrence, human disease outbreaks, and meteorological associations. As a result, a risk framework is presented with information for parameterizing QMRA models for Coccidioides spp., with eight new dose-response models proposed. A probabilistic QMRA was conducted for a Southwestern US agricultural case study, evaluating eight scenarios related to farming occupational exposures. Median daily workday risks for developing severe Valley Fever ranged from 2.53 × 10-7 (planting by hand while wearing an N95 facemask) to 1.33 × 10-3 (machine harvesting while not wearing a facemask). The literature review and QMRA synthesis confirmed that exposure to aerosolized arthroconidia has the potential to result in high attack rates but highlighted that the mechanistic relationships between environmental conditions and disease remain poorly understood. Recommendations for Valley Fever risk assessment research needs in order to reduce disease risks are discussed, including interventions for farmers.

Donor-derived endemic mycoses after solid organ transplantation: A review of reported cases.

BACKGROUND: Donor-derived endemic mycoses are infrequently reported. We summarized the clinical characteristics and outcomes of these infections to provide guidance to transplant clinicians. METHODS: Multiple databases were reviewed from inception through May 31, 2023 using endemic fungi as key words (e.g., Coccidioides, histoplasma, blastomyces, talaromyces, paracoccidioides). Only donor-derived infections (DDI) were included. RESULTS: Twenty-four cases of DDI were identified from 18 published reports; these included 16 coccidioidomycosis, seven histoplasmosis, and one talaromycosis. No cases of blastomycosis and paracoccidiodomycosis were published. The majority were male (17/24,70.8%). Half of the cases were probable (12/24, 50%), seven were possible (29.2%), and only five were proven DDI (20.8%). Donor-derived coccidioidomycosis were observed in kidney (n = 11), lung (n = 6), liver (n = 3), heart (n = 2) and combined SOT recipients (1 KP, 1 KL) at a median time of .9 (range .2-35) months after transplantation. For histoplasmosis, the majority were kidney recipients (6 of 7 cases) at a median onset of 8 (range .4-48) months after transplantation. The single reported possible donor-derived talaromycosis occurred in a man whose organ donor had at-risk travel to Southeast Asia. Collectively, the majority of donors had high-risk exposure to Coccidioides (9/11) or Histoplasma sp. (6/6). Most donor-derived endemic mycoses were disseminated (18/24, 75%), and mortality was reported in almost half of recipients (11/24, 45.8%). CONCLUSION: Donor-derived endemic mycoses are often disseminated and are associated with high mortality. A detailed evaluation of donors for the potential of an undiagnosed fungal infection prior to organ donation is essential to mitigate the risk of these devastating infections.

The dog as a sentinel and animal model for coccidioidomycosis.

Coccidioidomycosis is a potentially fatal fungal disease of humans and animals that follows inhalation of Coccidioides spp. arthroconidia in the environment. The disease in dogs resembles that in people, and because dogs may be at increased risk of exposure due to their proximity to the ground and digging behavior, they are valuable models for the disease in humans. Dogs have been sentinels for identification of new regions of endemicity in Washington and Texas. Canine serosurveillance has also been used to predict variables associated with environmental presence of Coccidioides spp. Expansion of the endemic region of coccidioidomycosis with climate change-along with predicted population increases and increased development in the southwest United States-may result in 45.4 million additional people at risk of infection by 2090. Here we provide an overview of the value of dogs as sentinels for the disease and encourage the routine reporting of coccidioidomycosis cases in dogs to public health agencies. We also highlight the value of dogs as naturally occurring models for studying novel treatment options and preventatives, such as a novel live avirulent coccidioidomycosis vaccine.

Coccidioides spp. exposure among military working dogs in endemic regions of the United States.

Coccidioidomycosis is a fungal disease in arid regions of the United States that is predicted to expand with climate change. Cases in military personnel and military working dogs (MWDs) impact personnel readiness and result in healthcare costs. To examine Coccidioides exposure among MWDs, 276 banked serum samples were retrieved from dogs housed in California, Texas, Arizona, New Mexico, Nevada, and Utah. Using gel immunodiffusion, six (2.1%) specimens were IgG-positive and three (1.1%) were equivocally IgM-positive. The IgG-positive samples were from Arizona (2 [prevalence 8.0%]) and California (4 [3.7%]). These data will guide future efforts to study MWDs as sentinels for human coccidioidomycosis.

This study aimed to determine the prevalence of exposure to coccidioidomycosis, the cause of Valley Fever in both humans and animals, among military working dogs (MWDs)located in endemic regions of the United States. The data will be used to guide efforts to study MWDs as sentinels for human disease.

Diagnostic delays in cutaneous coccidioidomycosis: A report from Central California.

Cutaneous Coccidioidomycosis (CC) infection can present with a wide variety of clinical presentations and is well known as a 'great imitator'. We performed a retrospective analysis of patients with CC in a large referral center in Central Valley, California, from 2010 to 2022 using the ICD9 and ICD10 codes for coccidioidomycosis and CC. We identified 40 patients with CC during the study period. The mean age of the study population was 43 years (with standard deviation of 14.08). Among these, 60% were men and 40% women. The appearance of the lesions varied from ulcers, plaques, nodules, blisters, cellulitis, and abscesses. The most common site of CC lesions was in the lower extremities (42.5%), followed by upper extremities (30%), chest and abdomen, head and neck (25% each). Only 22.5% of the 40 cases were diagnosed as CC and 15% were diagnosed as erythema nodosum. Rest were diagnosed initially as bacterial cellulitis in 37.5%, tinea in 7.5%, and others in 12.5%. There was resolution of the cutaneous lesions in all patients with antifungal treatment. The mean time of diagnosis from onset of symptoms on an average was 12 weeks (8-16 weeks) in our study with 75% cases initially misdiagnosed. Comprehensive knowledge about the manifestations and evaluation of CC among primary care providers and emergency room physicians is essential to prevent delays in diagnosis and treatment.

Cutaneous Coccidioidomycosis (CC) is defined as a fungal infection of the skin and/or subcutaneous tissues caused by the Coccidioides fungus. CC has been classified into primary CC which is caused by direct inoculation of the fungal organism into the skin, reactive CC defined as delayed hypersensitivity reaction, and disseminated CC which involves multiple organs infection. CC infection can present with a wide variety of clinical presentations and is well known as a 'great imitator'. Untreated CC can lead to worsening of local infection and the risk of dissemination to other organs. Coccidioidomycosis may be incorrectly diagnosed, and patients are more likely to receive unnecessary antibacterial drugs, laboratory tests, imaging, and invasive procedures, all of which could contribute to unnecessary costs and additional adverse health consequences. We performed a retrospective analysis of patients with CC in a large referral center in Central Valley, California, from 2010 to 2022. The mean time of diagnosis from onset of symptoms on an average was 12 weeks (8­16 weeks) in our study with 75% cases initially misdiagnosed. There is a need for collaboration between doctors and researchers across multiple counties within the Central Valley of California to develop strategies for diagnosing and treating CC and raising awareness in the community about the elevated risk of this infection for prevention and early detection.

Coccidioides species antifungal susceptibility testing: Experience from a large healthcare system in the endemic region.

The clinical utility of Coccidioides species antifungal susceptibility testing (AST) remains unclear. This study describes the clinical course of eight patients with severe or chronic coccidioidomycosis and subsequent Coccidioides AST. We present the clinical manifestations, antifungal treatment regimens, and clinical outcomes for these patients.

The role of antifungal susceptibility in the management of coccidioidomycosis remains unknown. This report presents cases of complex coccidioidomycosis where clinicians elected to conduct antifungal susceptibility testing as part of the treatment approach.

Endemic mycoses - are we making progress in management?

PURPOSE OF REVIEW: The endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes. RECENT FINDINGS: Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis. SUMMARY: The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.

Multicentric Case Series and Literature Review of Coccidioidal Otomastoiditis.

Coccidioidomycosis involving the ear, mastoid bone, or both is uncommon. We describe 5 new cases from the United States and review 4 cases reported in the literature of otomycosis and mastoiditis caused by Coccidioides. Of the 9 cases, 8 were linked to residence in or travel to California. Two patients had poorly controlled diabetes mellitus, 7 had otomastoiditis, 1 had otitis externa without mastoid involvement, and 1 had mastoiditis without otic involvement. Four patients had concurrent or prior pulmonary coccidioidomycosis. Ipsilateral facial nerve palsies developed in 2 patients. All patients received antifungal treatment for varying durations, and 8 of the 9 patients underwent surgical debridement. Clinicians should consider coccidioidomycosis as a differential diagnosis for otomastoiditis in patients with geographic risks.

Endemic Systemic Mycoses in Italy: A Systematic Review of Literature and a Practical Update.

Endemic systemic mycoses such as blastomycosis, coccidioidomycosis, histoplasmosis, talaromycosis, paracoccidioidomycosis are emerging as an important cause of morbidity and mortality worldwide. We conducted a systematic review on endemic systemic mycoses reported in Italy from 1914 to nowadays. We found out: 105 cases of histoplasmosis, 15 of paracoccidioidomycosis, 10 of coccidioidomycosis, 10 of blastomycosis and 3 of talaromycosis. Most cases have been reported in returning travelers and expatriates or immigrants. Thirtytwo patients did not have a story of traveling to an endemic area. Fortysix subjects had HIV/AIDS. Immunosuppression was the major risk factor for getting these infections and for severe outcomes. We provided an overview on microbiological characteristics and clinical management principles of systemic endemic mycoses with a focus on the cases reported in Italy.

Coccidioides undetected in soils from agricultural land and uncorrelated with time or the greater soil fungal community on undeveloped land.

Coccidioidomycosis is a typically respiratory fungal disease that, in the United States, occurs primarily in Arizona and California. In California, most coccidioidomycosis cases occur in the San Joaquin Valley, a primarily agricultural region where the disease poses a risk for outdoor workers. We collected 710 soil samples and 265 settled dust samples from nine sites in the San Joaquin Valley and examined how Coccidioides detection varied by month, site, and the presence and abundance of other fungal species. We detected Coccidioides in 89 of 238 (37.4%) rodent burrow soil samples at five undeveloped sites and were unable to detect Coccidioides in any of 472 surface and subsurface soil samples at four agricultural sites. In what is the largest sampling effort undertaken on agricultural land, our results provide no evidence that agricultural soils in the San Joaquin Valley harbor Coccidioides. We found no clear association between Coccidioides and the greater soil fungal community, but we identified 19 fungal indicator species that were significantly associated with Coccidioides detection in burrows. We also did not find a seasonal pattern in Coccidioides detection in the rodent burrow soils we sampled. These findings suggest both the presence of a spore bank and that coccidioidomycosis incidence may be more strongly associated with Coccidioides dispersal than Coccidioides growth. Finally, we were able to detect Coccidioides in only five of our 265 near-surface settled dust samples, one from agricultural land, where Coccidioides was undetected in soils, and four from undeveloped land, where Coccidioides was common in the rodent burrow soils we sampled. Our ability to detect Coccidioides in few settled dust samples indicates that improved methods are likely needed moving forward, though raises questions regarding aerial dispersal in Coccidioides, whose key transmission event likely occurs over short distances in rodent burrows from soil to naïve rodent lungs.

Pulmonary Coccidioidomycosis Complicated by Nontuberculous Mycobacterial Pulmonary Diseases with a Literature Review.

Following an endobronchial examination, a young mine supervisor was treated with antibiotics for a pulmonary nontuberculous mycobacterial infection for approximately one year. However, a review of the radiological findings revealed a different possibility. Accordingly, pulmonary resection was performed, and histopathological analysis revealed numerous yeast-like fungi. Since the patient had stayed in the southwestern United States for two months in 2009, eight years previously, coccidioidomycosis was strongly suspected. The diagnosis of coccidioidomycosis was subsequently confirmed by serology and polymerase chain reaction testing of the excised specimen. Here, we report an educational case that emphasizes the importance of meticulous medical history-taking and awareness of endemic mycoses in other countries in the context of globalization.

Pediatric Laryngeal Coccidioidomycosis: A Case Series in an Endemic Region.

BACKGROUND: Laryngeal coccidioidomycosis is a rare but life-threatening manifestation of coccidioidomycosis. Data in children are sparse and limited to case reports. We conducted this study to review the characteristics of laryngeal coccidioidomycosis in children. METHODS: We performed a retrospective review of patients ≤21 years of age with laryngeal coccidioidomycosis who were treated from January 2010 to December 2017. We collected demographic data, clinical and laboratory studies and patient outcomes. RESULTS: Five cases of pediatric laryngeal coccidioidomycosis were reviewed. All children were Hispanic and 3 were female. The median age was 1.8 years and the median duration of symptoms before diagnosis was 24 days. The most common symptoms included fever (100%), stridor (60%), cough (100%) and vocal changes (40%). Airway obstruction requiring tracheostomy and/or intubation for airway management was present in 80%. The most frequent location of lesions was the subglottic area. Coccidioidomycosis complement fixation titers were frequently low and culture/histopathology of laryngeal tissue was necessary to make a definitive diagnosis. All patients required surgical debridement and were treated with antifungal agents. None of the patients had recurrence during the follow-up period. CONCLUSIONS: This study suggests that laryngeal coccidioidomycosis in children presents with refractory stridor or dysphonia and severe airway obstruction. Favorable outcomes can be achieved with a comprehensive diagnostic work-up and aggressive surgical and medical management. With the rise in cases of coccidioidomycosis, physicians should have a heightened awareness regarding the possibility of laryngeal coccidioidomycosis when encountering children who have visited or reside in endemic areas with stridor or dysphonia.

Endemic mycoses in children in North America: a review of radiologic findings.

Clinically significant endemic mycoses (fungal infections) in the United States (U.S.) include Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides immitis/posadasii. While the majority of infections go clinically unnoticed, symptomatic disease can occur in immunocompromised or hospitalized patients, and occasionally in immune-competent individuals. Clinical manifestations vary widely and their diagnosis may require fungal culture, making the rapid diagnosis a challenge. Imaging can be helpful in making a clinical diagnosis prior to laboratory confirmation, as well as assist in characterizing disease extent and severity. In this review, we discuss the three major endemic fungal infections that occur in the U.S., including mycology, epidemiology, clinical presentations, and typical imaging features with an emphasis on the pediatric population.

Was Coccidioides a Pre-Columbian Hitchhiker to Southcentral Washington?

Coccidioides immitis, a pathogenic environmental fungus that causes Valley fever (coccidioidomycosis) primarily in the American Southwest and parts of Central and South America, has emerged over the past 12 years in the Columbia River Basin region, near the confluence with the Yakima River, in southcentral Washington state, USA. An initial autochthonous Washington human case was found in 2010, stemming from a wound derived from soil contamination during an all-terrain vehicle crash. Subsequent analysis identified multiple positive soil samples from the park where the crash occurred (near the Columbia River in Kennewick, WA), and from another riverside location several kilometers upstream from the park location. Intensified disease surveillance identified several more cases of coccidioidomycosis in the region that lacked any relevant travel history to known endemic locales. Genomic analysis of both patient and soil isolates from the Washington cases determined that all samples from the region are phylogenetically closely related. Given the genomic and the epidemiological link between case and environment, C. immitis was declared to be a newly endemic fungus in the region, spawning many questions as to the scope of its presence, the causes of its recent emergence, and what it predicts about the changing landscape of this disease. Here, we review this discovery through a paleo-epidemiological lens in the context of what is known about C. immitis biology and pathogenesis and propose a novel hypothesis for the cause of the emergence in southcentral Washington. We also try to place it in the context of our evolving understanding of this regionally specific pathogenic fungus.

Central Nervous System Coccidioidomycosis in Children: A Retrospective Case Series.

BACKGROUND: Published literature on central nervous system (CNS) coccidioidomycosis in children is limited. Here we describe a large case series of pediatric CNS coccidioidomycosis from a tertiary care center in an endemic region. METHOD: This is a retrospective case review of patients ≤21 years old with a diagnosis of CNS coccidioidomycosis from January 1, 2000, to December 31, 2018. RESULTS: Thirty patients (median age 10.8 years) were identified and most (93%) were previously healthy. Fever (90%), headache (70%), vomiting (53%), and fatigue (57%) were the most common presenting clinical manifestations, with focal neurological signs/symptoms present in 14 (47%). The initial serum Coccidioides compliment fixation (CF) titer was ≤ 1:8 in 33%. Most patients had extra-axial brain involvement (83%) and seven (23%) had associated spinal cord disease. Shunt placement was required in 70% and 62% required revision. Fluconazole was the initial treatment in 22 (73%), with treatment failure occurring in 50%. Most patients (77%) stabilized and were maintained on suppressive therapy, 4 (13%) experienced relapses and/or progressive disease, and one (3%) died, while long-term neurological complications occurred in 17%. CONCLUSIONS: CNS coccidioidomycosis is an uncommon and sometimes devastating complication of disseminated coccidioidomycosis. Many patients present with relatively low CF titers and hydrocephalus is common. Fluconazole treatment failures are common, and management remains difficult despite recent advances in therapy. Most patients do well once the disease is stabilized and require lifelong therapy. Newer therapeutic agents are needed.