Coccidioidomycosis and Histoplasmosis in Immunocompetent Individuals: A Comprehensive Review of Clinical Features, Diagnosis, and Management.

Coccidioidomycosis and histoplasmosis are endemic mycoses caused by the Coccidioides species and Histoplasma capsulatum, respectively. While these fungal infections are often associated with immunocompromised individuals, they pose significant risks to immunocompetent hosts. This review comprehensively analyzes these infections in immunocompetent individuals, focusing on clinical features, diagnostic approaches, and management strategies. The current understanding of coccidioidomycosis and histoplasmosis in immunocompetent individuals includes their clinical presentations, diagnostic methodologies, and treatment options. A literature review encompassed recent studies, clinical guidelines, and expert opinions. Data were analyzed to highlight critical aspects of the clinical manifestations, diagnostic processes, and management of these infections in immunocompetent patients. Coccidioidomycosis typically presents with pulmonary symptoms that may range from mild to severe and can include chronic and disseminated forms. Histoplasmosis also presents a spectrum of pulmonary symptoms with the potential for extrapulmonary dissemination. Diagnostic approaches for both infections involve clinical evaluation, serological tests, culture, and imaging studies. Management strategies include antifungal therapies such as fluconazole and itraconazole for coccidioidomycosis and itraconazole and amphotericin B for histoplasmosis, with treatment duration and monitoring tailored to the severity of the infection. Coccidioidomycosis and histoplasmosis can significantly affect immunocompetent individuals, with clinical presentations varying widely from mild to severe. Accurate diagnosis and appropriate management are crucial for optimal outcomes. This review underscores the importance of awareness and timely intervention in managing these endemic mycoses and highlights the need for continued research into better diagnostic and therapeutic approaches.

From soil to clinic: current advances in understanding Coccidioides and coccidioidomycosis.

SUMMARYCoccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas. While C. immitis mainly occurs in California and Washington, C. posadasii is widely distributed across North and South America. Both species induce coccidioidomycosis (San Joaquin Valley fever or, more commonly, Valley fever), with reported cases surging in the United States, notably in California and Arizona. Moreover, cases in Argentina, Brazil, and Mexico are on the rise. Climate change and environmental alterations conducive to Coccidioides spp. proliferation have been recently explored. Diagnostic challenges contribute to delayed treatment initiation, compounded by limited therapeutic options. Although antifungal drugs are often effective treatments, some patients do not respond to current therapies, underscoring the urgent need for a vaccine, particularly for vulnerable populations over 60 years old relocating to endemic areas. Despite recent progress, gaps persist in the understanding of Coccidioides ecology, host immune responses, and vaccine development. This review synthesizes recent research advancements in Coccidioides ecology, genomics, and immune responses, emphasizing ongoing efforts to develop a human vaccine.

Incidence and risk factors for invasive fungal infections in patients initiating TNF-alpha inhibitors for inflammatory bowel disease and rheumatoid arthritis.

In a commercial claims database analysis, <0.5% of patients with inflammatory bowel disease or rheumatoid arthritis developed an IFI within one year of initiating TNF-alpha therapy. Histoplasmosis was the most common IFI type. Overall IFI incidence varied based on region, underlying conditions, and use of certain immunosuppressive medications.

Coccidioidomycosis seasonality in California: a longitudinal surveillance study of the climate determinants and spatiotemporal variability of seasonal dynamics, 2000-2021.

Background: Coccidioidomycosis, an emerging fungal disease in the western USA, exhibits seasonal patterns that are poorly understood, including periods of strong cyclicity, aseasonal intervals, and variation in seasonal timing that have been minimally characterized, and unexplained as to their causal factors. Coccidioidomycosis incidence has increased markedly in recent years, and our limited understanding of intra- and inter-annual seasonality has hindered the identification of important drivers of disease transmission, including climate conditions. In this study, we aim to characterize coccidioidomycosis seasonality in endemic regions of California and to estimate the relationship between drought conditions and coccidioidomycosis seasonal periodicity and timing. Methods: We analysed data on all reported incident cases of coccidioidomycosis in California from 2000 to 2021 to characterize seasonal patterns in incidence, and conducted wavelet analyses to assess the dominant periodicity, power, and timing of incidence for 17 counties with consistently high incidence rates. We assessed associations between seasonality parameters and measures of drought in California using a distributed lag nonlinear modelling framework. Findings: All counties exhibited annual cyclicity in incidence (i.e., a dominant wavelet periodicity of 12 months), but there was considerable heterogeneity in seasonal strength and timing across regions and years. On average, 12-month periodicity was most pronounced in the Southern San Joaquin Valley and Central Coast. Further, the annual seasonal cycles in the Southern San Joaquin Valley and the Southern Inland regions occurred earlier than those in coastal and northern counties, yet the timing of annual cycles became more aligned among counties by the end of the study period. Drought conditions were associated with a strong attenuation of the annual seasonal cycle, and seasonal peaks became more pronounced in the 1-2 years after a drought ended. Interpretation: We conclude that drought conditions do not increase the risk of coccidioidomycosis onset uniformly across the year, but instead promote increased risk concentrated within a specific calendar period (September to December). The findings have important implications for public health preparedness, and for how future shifts in seasonal climate patterns and extreme events may impact spatial and temporal coccidioidomycosis risk. Funding: National Institutes of Health.

Diagnosis of Human Endemic Mycoses Caused by Thermally Dimorphic Fungi: From Classical to Molecular Methods.

Human endemic mycoses are potentially fatal diseases caused by a diverse group of fungi that can alter their morphology in response to an increase in temperature. These thermally dimorphic fungi affect both healthy and immunocompromised hosts, causing a substantial health and economic burden. Despite this, the diagnosis of endemic mycoses is still a formidable challenge for several reasons, including similar symptomatology, limited utility of classical diagnostic methods, inaccessibility to reliable molecular approaches in most endemic areas, and a lack of clinical suspicion out of these regions. This review summarizes essential knowledge on thermally dimorphic fungi and the life-threatening diseases they cause. The principle, advantages and limitations of the methods traditionally used for their diagnosis are also described, along with the application status and future directions for the development of alternative diagnostic strategies, which could help to reduce the disease burden in endemic areas.

Coccidiomycosis septic arthritis presenting as ankle monoarthritis in a patient with presumed psoriatic arthritis.

A man in his 50s with a history of psoriasis was evaluated for acute on chronic left ankle pain. His symptoms were attributed to psoriatic arthritis, and he tried several immunosuppressive regimens without improvement. Further diagnostic workup confirmed Coccidioides immitis/posadasii septic monarthritis thought secondary to a known remote history of Valley fever while residing in Arizona and subsequent reactivation in the setting of immunosuppression. The patient ultimately required prolonged anti-fungal therapy and multiple surgical debridements.Although psoriatic arthritis can present as monarthritis, it is uncommon, with more likely differential considerations including crystal arthropathies, trauma and both typical and atypical infections. Acute monarthritis should always prompt concern for a septic joint, even in a patient with autoimmune disease. The specific history elicited from the patient, including residence in an endemic region, and known prior Coccidioides infection, increased suspicion for Coccidioides and led to the correct diagnosis and management.

A Rare Case of Simultaneous Histoplasmosis and Coccidioidomycosis.

Histoplasma and Coccidioides are fungi that can cause serious infections in immunocompromised patients. Histoplasma is primarily endemic to the central and eastern United States, while Coccidioides is primarily endemic to the southwestern United States. Here, we present a case of simultaneous histoplasmosis and coccidioidomycosis. A 69-year-old female with a past medical history of rheumatoid arthritis and polymyalgia rheumatica on immunosuppression presented to the emergency department (ED) with fevers, malaise, and confusion. She initially developed these symptoms a month prior while visiting her son in Tennessee. During this time, she lived in his basement where mold exposure was confirmed. Her symptoms gradually improved but recurred, prompting her to come to the ED. In the ED, her vital signs were as follows: temperature of 36.5˚C, heart rate of 88, respiratory rate of 16, blood pressure of 158/88, and oxygen saturation of 94% on room air. She was alert and oriented without focal neurologic deficits. Heart sounds were regular rate and rhythm, lungs were clear to auscultation bilaterally and abdomen was soft, non-tender, and non-distended. No skin rashes were observed either. Laboratory work revealed an elevated C-reactive protein (CRP), thrombocytopenia, and transaminitis. Chest X-ray showed patchy airspace disease in the left lower lobe, and she underwent a lumbar puncture which was negative for meningitis. Due to her travel to Tennessee, a urine Histoplasma antigen test was ordered which resulted positive, along with a beta-1,3-D-glucan level >500 picograms per milliliter (pg/mL), indicating disseminated histoplasmosis. Coccidioides antibodies also resulted positive, pointing to concurrent coccidioidomycosis. The patient was subsequently started on intravenous amphotericin B. Over the following days, the patient's transaminitis and thrombocytopenia improved, and she was ultimately discharged on oral itraconazole with outpatient infectious disease follow-up. Although the patient's exposure to mold was likely the source of her histoplasmosis, the source of her coccidioidomycosis is less clear given its endemicity. Even rarer is the coinciding infections, and to the best of our knowledge, this is one of the very few known cases. Immunocompromised patients who present with infectious symptoms should have a low threshold for a fungal infection workup, as prompt treatment is crucial to limiting the morbidity and mortality of these infections. Furthermore, geographic location should not narrow one's workup to endemic fungi only, as evidenced by this patient's simultaneous infections.

Occurrence of coccidioidomycosis in a tertiary hospital in the Brazilian semi-arid region: diagnostic challenges.

Coccidioidomycosis is a systemic fungal infection that primarily affects the lungs in mammals. It is endemic to certain areas of the Americas. In Brazil, the disease occurs exclusively in the Northeast of the country, and the only etiological agent described is Coccidioides posadasii, typically found in the soil of arid regions with low rainfall. Given the scarcity of cases in Brazil, a descriptive study was conducted based on cases diagnosed with coccidioidomycosis between 2012 and 2022 at a tertiary hospital in the northeastern region of Brazil. The study analyzed medical records to identify cases of coccidioidomycosis diagnosed by clinical and/or laboratory data, discussing their clinical-epidemiological aspects. Thirteen patients were identified from seven municipalities in Ceará, all of whom were male, with a mean age of 19 years. The main risk factor was armadillo hunting, and the clinical manifestations included cough, fever, and chest pain. In this study, two patients were diagnosed by serology, one by microscopy, and ten suspected cases were diagnosed based on the clinical and epidemiological picture. Twelve patients were treated with antifungals. Clinical improvement with hospital discharge occurred in twelve patients, while one patient died. The data corroborate information from the scientific literature that the area covered by the referral hospital is endemic for coccidioidomycosis. However, local resources for diagnosing this disease were found to be deficient, with a high rate of presumptive diagnoses. This study highlights the need for actions by health surveillance systems and greater efficiency in diagnosing coccidioidomycosis in endemic areas of Brazil.

Atypical Parkinsonism: An Uncommon Presentation of Disseminated Coccidioidomycosis.

Coccidioidomycosis is endemic in the southwestern United States, Central America, and South America. Coccidioidomycosis has a variety of clinical presentations. Coccoidal meningitis is a feared form of disseminated coccidioidomycosis with high mortality and mobility rates. We reported a case of a 64-year-old man who presented with a three-week history of gait abnormalities and back pain. The patient had atypical parkinsonism, signs of cogwheeling rigidity, a masked face, intention tremor, a shuffling gait, upgazed restriction, and long track signs of left Babinski. MRI of the brain and cervical spine demonstrated scattered foci of abnormal parenchymal and leptomeningeal enhancement. The patient later developed acute cerebral infarction before a definite diagnosis of disseminated coccidioidomycosis, which was made when the result was that serum and cerebrospinal fluid coccidioidomycosis antibodies were high. The patient started lifelong antifungal treatment. We provide a natural disease process from atypical parkinsonism to cerebral infarction to hydrocephalus to enhance awareness of the myriad clinical presentations, emphasize the importance of endemic mycoses awareness, and also put forward a question of what can be done to detect coccidioidomycosis early.

Miliary coccidioidomycosis mimicking tuberculosis: Case report and review of literature.

Miliary coccidioidomycosis is a severe manifestation of diseases caused by Coccidioides immitis and Coccidioides posadasii that is endemic to the southwestern United States as well as Central and South America. While most cases of coccidioidomycosis present with pulmonary disease, certain risk factors increase the risk for disseminated disease. We present a case of miliary coccidioidomycosis in a 46-year-old patient with uncontrolled diabetes. Additionally, we review the features of thirty-seven cases of patients with miliary coccidioidomycosis.

Clinical Characteristics and Mortality Risks Among Patients With Culture-Proven Coccidioidomycosis Who Are Critically Ill: A Multicenter Study in an Endemic Region.

Background: Coccidioidomycosis is an endemic mycosis in the southwestern United States. While most infections are mild, severe cases can be devastating. We aimed to describe the clinical characteristics and mortality risks of patients in the intensive care unit (ICU) with culture-proven coccidioidomycosis. Methods: We performed a retrospective chart review of patients in the ICU with positive Coccidioides spp culture in a large health care system in Arizona between 1 October 2017 and 1 July 2022. All data were entered into REDCap. Results: An overall 145 patients were identified and included. The median age was 51 years, with the majority male (69%) and non-Hispanic White (39%). Most patients (n = 104, 72%) had pulmonary coccidioidomycosis, and 41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement). Seventy patients (48%) died during hospitalization, and most (91%) received antifungal therapy during hospitalization. In the multivariate logistic regression model, age ≥60 years (odds ratio [OR], 7.0; 95% CI, 2.6-18.8), cirrhosis (OR, 13.1; 95% CI, 1.6-108.8), and mechanical ventilation or vasopressor support (OR, 15.4; 95% CI, 3.9-59.6) were independently associated with increased all-cause mortality, but pre-ICU antifungal use had a statistically insignificant mortality risk association (OR, 0.5; 95% CI, .2-1.2). Conclusions: In our study of patients in the ICU with coccidioidomycosis and multiple comorbidities, the mortality rate was high. Older age, cirrhosis, and mechanical ventilation or vasopressor support were significantly associated with high mortality. Future studies are recommended to evaluate those risk factors and the efficacy of rapid diagnosis and early therapy in patients at high risk.

Improving Coccidioidomycosis Testing for Emergency Department Patients With Suspect Community-Acquired Pneumonia: Analysis of Provider Attitudes and the Effect of a Targeted Intervention.

Coccidioidomycosis is a common cause of community-acquired pneumonia in endemic regions. Approximately 20 000 cases of coccidioidomycosis occur annually; however, this statistic is limited by a widespread lack of testing. Here, we analyze emergency medicine provider attitudes toward coccidioidal testing and assess the effect of an intervention to improve testing rates.

The Use of Steroids to Treat Hypercalcemia Due to Granulomatous Disease From Disseminated Coccidioidomycosis.

The clinical course and treatment of hypercalcemia from a granulomatous disease in the setting of an infectious etiology, namely disseminated coccidioidomycosis, remains incompletely understood. The mechanism and treatment of hypercalcemia have been documented in most granulomatous disorders, with sarcoidosis being the most well-understood so far. We discuss a case of a patient with a recent diagnosis of disseminated coccidioidomycosis who presented with hypercalcemia despite adequate infection control. The treatment course involved combinatorial-calcitonin, low-dose bisphosphonates, and corticosteroids, which led to a favorable outcome.

Testing for Blastomycosis, Coccidioidomycosis, and Histoplasmosis at a Major Commercial Laboratory, United States, 2019-2024.

Background: Blastomycosis, coccidioidomycosis, and histoplasmosis are environmentally acquired fungal diseases that clinically resemble bacterial and viral community-acquired pneumonia and require laboratory testing for diagnosis. Patients frequently present to primary care and experience diagnostic delays when a fungal etiology is not initially suspected. Current national-level public health surveillance for these diseases is limited and does not include laboratory data, so nationwide testing practices are unknown. Methods: We identified laboratory tests for blastomycosis, coccidioidomycosis, and histoplasmosis ordered during 1 March 2019-29 February 2024 and performed within a major national commercial laboratory system. We analyzed test results, patient and healthcare provider features, reasons for testing, and temporal trends. Results: Results included 5693 Blastomyces complement fixation tests (of those, 12% were positive), 71 858 immunodiffusion tests (0.1% positive), and 1186 serum enzyme immunoassay (EIA) tests (11% positive); 154 989 Coccidioides EIA immunoglobulin M results (5% positive) and 154 968 immunoglobulin G results (8% positive); and 46 346 Histoplasma complement fixation tests (30% positive), 49 062 immunodiffusion tests (1% positive), 35 506 serum EIA tests (4% positive), and 82 489 urine EIA tests (2% positive). Most histoplasmosis (58%-74%) and blastomycosis (42%-68%) tests were ordered from hospitals, whereas coccidioidomycosis tests were most frequently ordered by primary care providers (40%). A yearly average of 2727 positive tests were ordered by healthcare providers in states without public health surveillance for these diseases. Conclusions: Blastomycosis, coccidioidomycosis, and histoplasmosis are likely underdetected in primary care settings or by public health surveillance. Increased testing by primary care providers and expanded surveillance are needed to reduce disease burden.

[Differential diagnosis of coccidioidomycosis manifested by peripheral pulmonary lesion]. / Differentsial'naya diagnostika koktsidioidomikoza, manifestirovannogo perifericheskim obrazovaniem legkogo.

We present this clinical case as a demonstration of difficulties in differential diagnosis of pulmonary coccidioidomycosis. Differential diagnostics of peripheral pulmonary lesion performed using bronchoscopy with BAL and TBCB and video-assisted thoracic surgery (VATS) biopsy. Diagnostic specimens were tested using microbiological (luminescent microscopy, culture for M. tuberculosis (BACTEC MGIT960 and Lowenstein-Jensen Medium), RT-PCR, cytological and morphological (hematoxylin-eosin, Ziehl-Neelsen, PAS, Grocott methenamine silver (GMS) stainings) examinations. A diagnosis was verified correctly In Russia the country is not endemic for coccidioidomycosis and patient was treated accordingly. Diagnostics of peripheral pulmonary lesions requires of multidisciplinary approaches. Morphological examination, based on detection of only granulomatous inflammation in lung biopsy cannot be used for finally DS and requires microbiological confirmation for TB or other infections, and dynamic monitoring of the patient with concordance their anamnesis vitae and morbi.

Evaluation of nikkomycin Z with frequent oral administration in an experimental model of central nervous system coccidioidomycosis.

We evaluated the in vivo activity of nikkomycin Z against central nervous system coccidioidomycosis. Mice were inoculated intracranially with arthroconidia of Coccidoides immitis, and treatment with nikkomycin Z (50, 100, or 300 mg/kg orally TID) or fluconazole (25 mg/kg orally BID) began 2 days later. Each dose of nikkomycin Z and fluconazole significantly improved survival and reduced brain fungal burden compared with vehicle control. Further studies of nikkomycin Z against coccidioidomycosis are warranted. IMPORTANCE: Coccidioides species are endemic fungi that are capable of causing disease in patients with various comorbidities, as well as in otherwise healthy individuals. Treatment options for coccidioidomycosis are suboptimal, as azole antifungals may be limited by drug interactions and adverse effects due to interactions with enzymes found in humans and other mammals. Nikkomycin Z is an investigational agent that works against a target specific to the fungal cell wall (chitin), which is not present in the cells of humans or other mammals. In this study, we show that frequent oral administration of nikkomycin Z is effective in an experimental model of central nervous system coccidioidomycosis. Further studies of nikkomycin Z against coccidioidomycosis may be warranted.

In vitro small molecule screening to inform novel candidates for use in fluconazole combination therapy in vivo against Coccidioides.

Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate Coccidioides infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth in vitro and determined IC50 values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease. IMPORTANCE: Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways.

Lupus Erythematosus Tumidus Misdiagnosed as Erythema Nodosum from Coccidioidomycosis.

Introduction: Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis that is categorized as intermittent cutaneous lupus erythematosus. It shares clinical similarities and histopathological features with other skin disorders, such as erythema nodosum, lymphocytic infiltrate of Jessner, and reticular erythematous mucinosis, thus making diagnosis quite challenging. We present a patient with LET whose diagnosis was confirmed after seeing several doctors. Case Presentation: A 52-year-old Hispanic female presented with tender erythematous nodules on her thighs for approximately 1 month. She was suspected of having erythema nodosum secondary to coccidioidomycosis and was prescribed fluconazole 200 mg for 30 days but showed no improvement. However, histopathological and direct immunofluorescence tests later confirmed a diagnosis of LET. The patient was treated with hydroxychloroquine, and the lesions improved remarkably after 2 weeks. Conclusion: LET is a rare dermatosis that closely resembles other dermatologic conditions such as erythema nodosum, lymphocytic infiltrate of Jessner, and reticular erythematous mucinosis. Diagnosis based on clinical features alone should be avoided, and ideally, treatment should only be initiated after confirmatory histopathological testing.

Chronic paronychia associated with fluconazole use in two pediatric patients with coccidioidomycosis.

Azoles are frequently used to treat systemic mycoses but have been associated with a number of adverse effects of the skin and skin appendages. Herein we describe two cases of chronic paronychia in pediatric patients receiving fluconazole for coccidioidomycosis. Their clinical characteristics are described, and the literature reviewed.

Coccidioidomycosis in Immunocompromised at a Non-Endemic Referral Center in Mexico.

The incidence and distribution of coccidioidomycosis are increasing. Information scarcity is evident in Mexico, particularly in non-endemic zones and specific populations. We compared the treatment and outcomes for patients with isolated pulmonary infections and those with disseminated coccidioidomycosis, including mortality rates within six weeks of diagnosis. Of 31 CM cases, 71% were male and 55% were disseminated. For 42% of patients, there was no evidence of having lived in or visited an endemic region. All patients had at least one comorbidity, and 58% had pharmacologic immunosuppressants. The general mortality rate was 30%; without differences between disseminated and localized disease. In our research, we describe a CM with a high frequency of disseminated disease without specific risk factors and non-significant mortality. Exposure to endemic regions was not found in a considerable number of subjects. We consider diverse reasons for why this may be, such as climate change or migration.