Strategies to Combat Coccidioidomycosis: Are We Making Any Progress?

Coccidioidomycosis is caused by the dimorphic fungi Coccidioides immitis and Coccidioides posadasii. One of the endemic mycoses, this organism has been found solely in the semiarid to arid life zones of the southwestern United States, Mexico, and parts of Central America and South America. Clinical manifestations of disease vary greatly between patients and are largely dependent upon both the extent of exposure and the immune status of the host. The incidence of coccidioidomycosis continues to rise within the United States. Primary coccidioidal pneumonia accounts for close to 25% of all community-acquired pneumonia within endemic regions, reflecting the substantial burden of disease and health care costs associated with this infection. Although most patients with coccidioidomycosis resolve their initial infection without long-term complications, a minority of patients develop complications of disease ranging from asymptomatic pulmonary nodules to life-threatening disease such as meningitis. This review focuses on the epidemiology, clinical manifestations, spectrum of disease, and treatment options currently available for coccidioidomycosis.     

球孢子菌病的流行病学、临床表现及诊治进展

球孢子菌病是球孢子菌感染人类所致的疾病。传统认为其流行区域仅限于美洲部分地区,但随着全球人口流动,非疫区的输入性病例报道日渐增多。一些新近研究也对其传统流行病学观念提出了挑战。此外,球孢子菌病的临床表现多样,从轻微的自限性呼吸道感染到严重的全身播散性感染均可发生,给诊断带来了很大的困难。因此,尽管中国并非传统概念上的球孢子菌病疫区,国内感染病工作者仍有必要对其现状有所了解。本文针对球孢子菌病的流行现状及诊疗进展进行综述。     

An evaluation of reactivity to Coccidioides immitis skin tests in subjects with diabetes mellitus

Persons with diabetes mellitus have an increased incidence of progression and dissemination of infection with Coccidioides immitis. This increased incidence of infection suggests that diabetic subjects may have a defect in cell-mediated immunity (CMI) to coccidioidomycosis. Skin test response is also determined by CMI. A negative coccidioidin skin test is often seen with serious infections and is used as evidence that therapy should be initiated. To evaluate CMI in diabetic subjects we investigated the reactivity to coccidioidin and spherulin of 54 diabetic and 56 nondiabetic subjects. There was no difference between the two groups in the prevalence or size of positive reactions to coccidioidin. These results support the continued use of coccidioidin to evaluate the need for therapy in diabetic subjects who have coccidioidomycosis. Spherulin antigen, however, produced fewer positive reactions in the diabetic group. This decreased spherulin reactivity may be associated with the increased incidence of severe coccidioidal infection in diabetic subjects.     

The Future of Fungal Serology

The incidence of invasive fungal infections continues to grow. Early and rapid diagnosis is essential to prevent morbidity and mortality. The number of assays available for the detection of fungal antigens in human body fluids are increasing in number and becoming part of the basic diagnostic workup for many fungal infections. Detection of specific antibody has been an important component in the diagnosis of fungal infections. Complement fixation and immunodiffusion continue to be the gold standard for antibody detection but are complex to perform, require extensive expertise, and are mostly performed in reference labs. Newer assays are being developed to reduce turn-around time, but have not been fully evaluated. A challenge for improving serologic assays is to move from crude antigens and polyclonal antibodies to purified and/or recombinant antigens and monoclonal antibodies, while retaining good sensitivity and specificity. Recent developments using lateral flow methodology have provided novel point-of-care antigen assays requiring little technical expertise. Such innovative techniques will help to keep the future of fungal serology bright.     

Epidemiology of Invasive Fungal Infections in Patients with Acquired Immunodeficiency Syndrome at a Reference Hospital for Infectious Diseases in Brazil

Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20–25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres.     

Review of Epidemiology, Diagnosis, and Treatment of Invasive Mould Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Invasive mould infections are a major cause of morbidity and mortality in hematopoietic stem cell transplant recipients (HSCT). Allogeneic HSCT recipients are at substantially higher risk than autologous HSCT recipients. Although neutropenia following the conditioning regimen remains an important risk factor for opportunistic fungal infections, most cases of invasive mould infection in allogeneic HSCT recipients occur after neutrophil recovery in the setting of potent immunosuppressive therapy for graft-versus-host disease. Invasive aspergillosis is the most common mould infection. However, there has been an increased incidence of less common non-Aspergillus moulds that include zygomycetes, Fusarium sp., and Scedosporium sp. Reflecting a key need, important advances have been made in the antifungal armamentarium. Voriconazole has become a new standard of care as primary therapy for invasive aspergillosis based on superiority over amphotericin B. There is significant interest in combination therapy for invasive aspergillosis pairing voriconazole or an amphotericin B formulation with an echinocandin. There have also been advances in novel diagnostic methods that facilitate early detection of invasive fungal infections that include galactomannan and beta-glucan antigen detection and PCR using fungal specific primers. We review the epidemiology, diagnosis, and management of invasive mould infection in HSCT, with a focus on allogeneic recipients. We also discuss options for prevention and early treatment of invasive mould infections.     

Murine models of blastomycosis,coccidioidomycosis, and histoplasmosis

Animal models have contributed much to the knowledge of fungal infections and their corresponding therapeutic treatments. This is true for animal models of the primary fungal pathogens, Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum. This review gives a brief background of human diseases associated with these organisms and describes the development, details, and utility of murine models of blastomycosis, as well as coccidioidomycosis and histoplasmosis. This revised version was published online in June 2006 with corrections to the Cover Date.     

Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts

Serologic studies are an important diagnostic tool in the clinical evaluation and follow-up of persons with coccidioidomycosis. Numerous types of serologic tests are available, including immunodiffusion, enzyme immunoassay, and complement fixation. We conducted a retrospective review of the results of 1,797 serologic tests spanning 12 months from the onset of coccidioidomycosis in 298 immunocompetent and 62 immunosuppressed persons with symptomatic infection. Using the onset of symptoms as a reference point, we plotted the positive or negative serologic results over time for both groups. Compared with the immunocompetent group, immunosuppressed persons had lower rates of seropositivity for every type of test during the first year after onset of symptoms for coccidioidomycosis, although many results did not achieve statistical significance. Combining the results of these tests increased the sensitivity of the serologic evaluation in immunocompromised patients. Immunosuppressed persons have the ability to mount a serologic response to coccidioidomycosis, but in some circumstances, multiple methods may be required to improve detection.     

Inflammatory and Anti-inflammatory Responses Co-exist Inside Lung Granuloma of Fatal Cases of Coccidioidomycosis: A Pilot Report

Coccidioidomycosis is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. These fungi are endemic in the southern USA and northern Mexico. Immunocompromised patients are susceptible to develop severe forms of this fungal infection. Cytokines play an important role in controlling the fungal infection, but little is known about the predominant immunological environment in human lung tissue from fatal cases. Our aim was to analyze the pro-inflammatory and anti-inflammatory cytokines and monocyte/macrophages markers (CD14 and CD206) in the granulomas of six fatal cases of coccidioidomycosis. Cytokines and surface markers were higher in coccidioidomycosis cases when compared to control (P?<?0.05). CD14 positive cells were increased inside the coccidioidal granuloma when compared to the outside (P?<?0.05). No differences were found in the number of CD206+ cells inside the granuloma when compared to the outer population (P?>?0.05). Interestingly, an analysis of stain intensity signals showed an increased signaling of CD14, CD206, IL-10 and TNFα inside the granuloma when compared to the outside (P?<?0.05). iNOS and IL-12 gene expression were not detected in coccidioidomycosis cases, while IL-10, IL-6 and TGFβ gene expression were detected, but the differences when compared to healthy lungs were not significant (P?>?0.05). TNFα gene expression was lower in coccidioidomycosis cases when compared to healthy lung (P?=?0.05). In conclusion, pro- and anti-inflammatory responses co-exist inside of the granulomas of fatal cases of coccidioidomycosis and the absent of iNOS and IL-12 gene expression may be related with patient’s outcome.     

Candidiasis: Predisposing Factors,Prevention, Diagnosis and Alternative Treatment

Candidiasis is the most common opportunistic yeast infection. Candida species and other microorganisms are involved in this complicated fungal infection, but Candida albicans continues to be the most prevalent. In the past two decades, it has been observed an abnormal overgrowth in the gastrointestinal, urinary and respiratory tracts, not only in immunocompromised patients, but also related to nosocomial infections and even in healthy individuals. There is a widely variety of causal factors that contribute to yeast infection which means that candidiasis is a good example of a multifactorial syndrome. Due to rapid increase in the incidence in these infections, this is the subject of numerous studies. Recently, the focus of attention is the treatment and, above all, the prevention of those complications. The diagnosis of candidiasis could become quite complicated. Prevention is the most effective “treatment,” much more than eradication of the yeast with antifungal agents. There are several aspects to consider in the daily routine that can provide a strength protection. However, a therapeutic approach is necessary when the infection is established, and therefore, other alternatives should be explored. This review provides an overview on predisposition factors, prevention and diagnosis of candidiasis, highlighting alternative approaches for candidiasis treatment.     

Can fungal biomarkers be used to improve antifungal therapy in the intensive care unit?

Invasive fungal infections have an increasing incidence worldwide, and patients in intensive care settings are particularly vulnerable to them. Candidemia is the third most common bloodstream pathogen in intensive care units (ICUs) in the United States, and a number of reports have recently been published regarding the increasing incidence of invasive aspergillosis in ICUs throughout the world. Because research has shown that early antifungal therapy is associated with better outcomes, clinicians are starting to explore new diagnostic fungal markers, which are more sensitive and faster than the traditional diagnostic standards of culture and histopathology.     

Phenotypic and molecular identification of Coccidioides posadasii in a patient evaluated for bilateral lung transplantation

BackgroundCoccidioidomycosis is an endemic fungal infection caused by Coccidioides immitis and Coccidioides posadasii. It can be particularly severe in transplant recipients that have a current or a previous coccidioidal infection. Fatal case of coccidioidomycosis has been described in this group of patients.AimsWe report a severe case of pneumonia caused by C. posadassi in a 29 year-old white woman that had been admitted to hospital as part of the evaluation for bilateral lung transplantation. The patient was a native and resident of Catamarca, Argentina. Molecular methodologies contributed to the species identification.MethodsClinical, laboratory records and microbiological tests were carried out to diagnose the infection and to identify C. posadasii.ResultsA fungus was isolated from BAL culture. Phenotypic characterization, specific PCR and experimental animal inoculation demonstrated the presence of C. posadasii. The patient responded well to amphotericin B deoxycholate. Lung transplantation was postponed.ConclusionsSpecific PCR can be an important alternative for the correct identification of C. immitis or C. posadasii in laboratories with implemented molecular biology tools. This case emphasizes the need for a systematic assessment in organ transplant units of patients inhabiting endemic areas of coccidioidomycosis.     

Investigating the Relationship Between Climate and Valley Fever (Coccidioidomycosis)

Valley fever (coccidioidomycosis) is a disease caused by inhalation of spores from the soil-dwelling Coccidioides fungal species. The disease is endemic to semiarid areas in the western USA and parts of Central and South America. The region of interest for this study, Kern County, California, accounts for approximately 14% of the reported valley fever cases in the USA each year. It is hypothesized that the weather conditions that foster the growth and dispersal of the fungus influence the number of cases in the endemic area. This study uses regression-based analysis to model and assess the seasonal relationships between valley fever incidence and climatic variables including concurrent and lagged precipitation, temperature, Palmer Drought Severity Index, wind speed, and PM₁₀ using data from 2000 to 2015. We find statistically significant links between disease incidence and climate conditions in Kern County, California. The best performing seasonal model explains up to 76% of the variability in fall valley fever incidence based on concurrent and antecedent climate conditions. Findings are consistent with previous studies, suggesting that antecedent precipitation is an important predictor of disease. The significant relationships found support the “grow and blow” hypothesis for climate-related coccidioidomycosis incidence risk that was originally developed for Arizona.     

Laboratory diagnostics of invasive fungal infections: an overview with emphasis on molecular approach

Although invasive fungal diseases (IFDs) are relatively rare, they have become an increasingly common life-threatening complication in a variety of critically ill patients. Due to changes in treatment strategies, patterns of IFDs have changed substantially as well. Yeast infections have shifted toward a higher proportion of non-albicans Candida species, but their overall incidence has remained stable. In contrast, IFDs caused by molds, including particularly various species of Aspergillus, Fusarium, and Mucorales, have increased in number. In view of the growing incidence and the high mortality rates of IFDs, accurate diagnostic techniques permitting timely onset of adequate antifungal treatment are of paramount importance. Although conventional approaches such as microscopy, cultivation, histopathological examination, and imaging methods still represent the gold standard, the diagnosis remains difficult because of limited sensitivity and specificity. Noninvasive and culture-independent diagnostic techniques, including fungal antigen detection, and different molecular-based techniques are becoming increasingly important. Of the fungal surrogate markers such as cell wall components, galactomannan and (1,3)-β-d-glucan by commercially available diagnostic kits have become widely used, but the results are still controversial. A plethora of PCR-based diagnostic methods targeting different gene regions and exploiting a variety of amplicon detection tools have been published. Molecular assays have the capacity to overcome the limitations of other diagnostic approaches, but the current lack of methodological standardization and validation, together with not always clear interpretation of the results, has prevented broad application in the clinical setting.     

COCCIDIOIDOMYCOSIS AS A COMPLICATION OF PREGNANCY

Records of 33 cases of coccidioidomycosis occurring during pregnancy were reviewed. In this group the incidence of dissemination of the disease was considerably greater than the reported incidence of dissemination in all cases of coccidioidomycosis.The incidence of dissemination was higher in the patients who contracted coccidioidomycosis late in pregnancy than it was in those in whom onset of the disease occurred earlier in gestation; but dissemination occurred in all Negro patients in the group, regardless of the time of onset during pregnancy.The chief complicating effect when onset was in the first trimester of pregnancy was a tendency to abortion. In cases in which onset was in the third trimester, the incidence of premature labor was extremely high.There was no evidence of congenital infection in any of the babies, but in one case invasion of the placenta by coccidioidal spherules was observed.     

Aspergillus-specific antibodies – Targets and applications

Aspergillus is a fungal genus comprising several hundred species, many of which can damage the health of plants, animals and humans by direct infection and/or due to the production of toxic secondary metabolites known as mycotoxins. Aspergillus-specific antibodies have been generated against polypeptides, polysaccharides and secondary metabolites found in the cell wall or secretions, and these can be used to detect and monitor infections or to quantify mycotoxin contamination in food and feed. However, most Aspergillus-specific antibodies are generated against heterogeneous antigen preparations and the specific target remains unknown. Target identification is important because this can help to characterize fungal morphology, confirm host penetration by opportunistic pathogens, detect specific disease-related biomarkers, identify new candidate targets for antifungal drug design, and qualify antibodies for diagnostic and therapeutic applications. In this review, we discuss how antibodies are raised against heterogeneous Aspergillus antigen preparations and how they can be characterized, focusing on strategies to identify their specific antigens and epitopes. We also discuss the therapeutic, diagnostic and biotechnological applications of Aspergillus-specific antibodies.     

Large-Scale Land Development,Fugitive Dust,and Increased Coccidioidomycosis Incidence in the Antelope Valley of California, 1999–2014

Ongoing large-scale land development for renewable energy projects in the Antelope Valley, located in the Western Mojave Desert, has been blamed for increased fugitive dust emissions and coccidioidomycosis incidence among the general public in recent years. Soil samples were collected at six sites that were destined for solar farm construction and were analyzed for the presence of the soil-borne fungal pathogen Coccidioides immitis which is endemic to many areas of central and southern California. We used a modified culture-independent nested PCR approach to identify the pathogen in all soil samples and also compared the sampling sites in regard to soil physical and chemical parameters, degree of disturbance, and vegetation. Our results indicated the presence of C. immitis at four of the six sites, predominantly in non-disturbed soils of the Pond-Oban complex, which are characterized by an elevated pH and salt bush communities, but also in grassland characterized by different soil parameters and covered with native and non-native annuals. Overall, we were able to detect the pathogen in 40% of the soil samples (n = 42). Incidence of coccidioidomycosis in the Antelope Valley was positively correlated with land use and particulate matter in the air (PM10) (Pearson correlation coefficient >0.5). With the predicted population growth and ongoing large-scale disturbance of soil in the Antelope Valley in coming years, incidence of coccidioidomycosis will likely further increase if policy makers and land developers continue to ignore the risk of grading land without implementing long-term dust mitigation plans in Environmental Impact Reports.     

Current Diagnosis and Management of Mucormycoses

Due to the rising incidence of diabetes mellitus, the increasing populations of immunocompromised individuals of varied etiologies, and the progresses that have been made in the management of the critically ill, the incidence of invasive fungal infections, in particular those caused by the Mucorales, is increasing. Currently available diagnostics frequently miss this infection. Knowledge of the factors placing individuals at risk for and the varied clinical presentations of mucormycosis should alert clinicians of the possible presence of this infection. Survival of individuals with mucormycosis is dependant on prompt diagnosis and aggressive therapy with antifungal agents; surgical debridement; and, if possible, reversal of the risk factors predisposing the individual to this infection. It is hoped that improved diagnostic testing, improvements in pharmacotherapy, and adjunctive therapies will improve the morbidity and mortality of mucormycosis.     

艾滋病合并真菌感染研究概述

真菌感染是艾滋病患者最常见、比重最大的机会性感染,是最重要致死原因之一。常见的机会性真菌感染包括：念珠菌病、卡氏肺孢子菌病、隐球菌病、马尔尼菲蓝状菌感染、组织胞浆菌病、球孢子菌病。本文介绍了机体的CD4⁺T淋巴细胞与机会性真菌感染关系以及常见的真菌感染的流行病学、发病机制、临床表现、诊断、治疗、预防等方面研究进展。提高临床医生对这类真菌感染系统全面的认识,有助于做到早期诊断、早期治疗,合理选择抗真菌药物,从而提高患者生存质量,延长生存时间。