Reversal of coccidioidal anergy in vitro by dendritic cells from patients with disseminated coccidioidomycosis

Coccidioides immitis is a pathogenic, dimorphic fungus found in the southwestern United States and is the causative agent of coccidioidomycosis. Extrathoracic dissemination of coccidioidomycosis is associated with a lack of cellular immunity. Dendritic cells (DCs) have been shown to initiate and modulate cellular immune responses. To determine whether DCs could modulate or initiate the immune response in this disease, monocyte-derived DCs were generated from coccidioidal Ag nonresponsive patients with disseminated coccidioidomycosis and healthy nonimmune individuals. DCs generated from both groups demonstrated phenotypes characteristic of DCs and stimulated strong allogeneic MLR. DCs from patients and healthy nonimmune individuals pulsed with the coccidioidal Ag preparation T27K induced lymphocyte proliferation. Mature DCs were much more efficient than immature DCs in these stimulations. Furthermore, restimulation of T27K-primed PBMC with Ag-pulsed DCs generated a C. immitis-specific cellular immune response in PBMC from patients with disseminated coccidioidomycosis as well as healthy nonimmune individuals. These results show that 1) DCs have the capacity to stimulate specific cellular immune responses from patients with disseminated coccidioidomycosis who are nonresponsive to coccidioidal Ag and healthy nonimmune individuals in vitro; 2) DCs can be used to screen coccidioidal Ags as candidates for human vaccine development; and 3) DC therapy may be useful in the treatment of disseminated 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。     

Review of human and animal cases of coccidioidomycosis diagnosed in Canada

The first Canadian case of coccidioidomycosis in a human was reported in 1952 and 11 more cases since then. This study provides details of other cases of coccidioidomycosis that have been diagnosed in Canada. Based on clinical details, isolation of Coccidioides immitis, detection of a specific antibody (F band) for coccidioidomycosis by macro- or microimmunodiffusion tests, concurrently used with the complement fixation procedure, and histopathological findings, 116 more cases of this disease were verified. The great majority (94%) of these cases were diagnosed in the western Canadian provinces of British Columbia, Alberta, Saskatchewan and Manitoba, and the others in Quebec, Ontario and Nova Scotia (5,1, and 1 cases, respectively). Available information indicates that the C. immitis infections were contracted during visits to endemic areas in the United States (Arizona, California and New Mexico), Mexico, and Bolivia. Pulmonary infections were the most common type of coccidioidomycosis (93%) followed by the disseminated or meningeal types C. immitis infections occurred in individuals with or without predisposing factor(s) and were more common in males than in females. The exoantigen procedure was very useful and reliable in the accurate and rapid identification of suspected C. immitis isolates. Two cases of coccidioidomycosis were reported in animals in Ontario, Canada.     

Pulmonary mycotic infections; allergic and immunologic factors

The mechanisms of immunity and allergy, at play in every infectious disease, must be comprehended before the pathogenesis of an infection can be appreciated.Immunity, allergy and serology are concerned with specific antigen-antibody reactions. In immunity the principal concern is with the final disposition of antigen (agglutination, lysis, and phagocytosis). In allergy attention is focused upon tissue damage resulting from antigen-antibody union. In serology interest is devoted to the presence of antibody as evaluated by certain visible in vitro reactions-precipitin, agglutination, opsonization and complement fixation tests. There are two types of allergic reaction-the immediate or anaphylactic type and the delayed type or the allergic disease of infection. Neither kind takes part in the mechanism of immunity. At this time the allergic antibody and the immune antibody must be considered as two different and distinct antibodies. Skin and serologic tests are important diagnostic aids in certain pulmonary mycotic infections-for example, coccidioidomycosis, blastomycosis, histoplasmosis and moniliasis. Clinical expressions of allergy may appear in coccidioidomycosis, histoplasmosis and moniliasis. Pulmonary mycoses are divided into three groups, that is, the endogenous mycoses (actinomycosis, moniliasis, geotrichosis), the endogenous-exogenous mycoses (cryptococcosis, aspergillosis, mucormycosis) and the exogenous mycoses (nocardiosis, coccidioidomycosis, histoplasmosis, North American blastomycosis). The diagnosis and treatment of the important mycotic infections that invade lung tissue are discussed.     

Serologic Detection of Coccidioidomycosis Antibodies in Northeast Brazil

Coccidioidomycosis is a systemic infection caused by Coccidioides spp. The disease is endemic in Brazil but its incidence is underreported as it is not a notifiable disease. This article presents the results of a serologic survey carried out with 229 volunteers in northeast Brazil by the immunodiffusion (ID) test with commercial Coccidioides spp. antigens. The commercial ID test detected 15 individuals without clinical diagnosis of the disease and two individuals in treatment for coccidioidomycosis. Regarding the epidemiological data, most of the positive individuals were male, between 18 and 65 years of age and were engaged in armadillo hunting. Three women who had never participated in armadillo hunts also displayed positive results for coccidioidal antibodies. Besides armadillo hunts, exposure to environmental dust in endemic areas may account for the serologic response detected in the study. The data from this study suggest the importance of performing epidemiological surveys for coccidioidomycosis in order to understand the prevalence of this disease in Brazil.     

Measurement of Cellular Immunity in Human Coccidioidomycosis

Measurement of cellular immune response in human coccidioidomycosis, a disease of the Western Hemisphere caused by the soil-dwelling fungus Coccidioides, began more than 75 years ago. Numerous studies have shown that measurement of coccidioidal cellular immunity is a useful epidemiologic and clinical tool. The first widely used coccidioidal skin-test reagent, coccidioidin, was derived from a filtrate of cultured mycelia of Coccidioides by Smith and colleagues in the 1940's. It remained the standard until the 1970's, when spherulin, obtained from the spherule form of the fungus, was found to be more sensitive. Both reagents are specific indicators of coccidioidal cellular immunity. Since then, other coccidioidal antigens have been identified and in vitro tests of cellular immunity have been shown to yield comparable results to skin testing. In vitro assays have also begun to open a window on the specific immunologic events of coccidioidal cellular immunity. Persistent expression of coccidioidal cellular immune response appears to augur an improved clinical outcome. Despite this, a study of a coccidioidal vaccine failed to demonstrate efficacy. Current and future studies are focused on modulating the coccidioidal immune response in vitro and in vivo and on developing an improved vaccine.     

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.     

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.     

Coccidioidomycosis

Coccidioidomycosis is an endemic fungal infection whose incidence and impact have been increasing in the southwestern United States. Advances in understanding its epidemiology and mycology are continuing. New diagnostic tests have been developed and experience with newer therapeutic agents continues to accumulate, but numerous clinical questions remain. Timely recognition and diagnosis of coccidioidomycosis are still problematic. With the rise in incidence, changing demographics, an aging population, and the increase in immunocompromised patients, coccidioidomycosis continues to be a fungal infection worthy of further study. This review summarizes the pathogenesis of coccidioidomycosis; the epidemiologic, diagnostic, and therapeutic approaches for coccidioidal infections; and the management challenges of select at-risk populations.     

Disseminated coccidioidomycosis in a heart transplant recipient

A cardiac transplant patient developed disseminated coccidioidomycosis shortly after transplantation and institution of immunosuppressive therapy. The patient was maintained on intravenous and intrathecal amphotericin B for 19 months, but when therapy was discontinued, the disease relapsed and he died. At autopsy the cardiac allograft was without signs of rejection, but the patient had coccidioidomycotic lesions in multiple organs. There is an increasing number of reports of disseminated coccidioidomycosis in immunocompromised patients, especially those who receive steroids or immunosuppressive therapy. Coccidioidomycosis may represent a severe complication in the transplant patient.     

Prevention of secondary cases of meningococcal disease in household contacts by vaccination.

Household contacts of patients with group A meningococcal infection were vaccinated with either meningococcal vaccine or tetanus toxoid. Five of the 523 subjects who received tetanus toxoid developed meningococcal meningitis and another four probably had meningococcal disease. Only one possible case of meningococcal infection occurred among 520 contacts vaccinated with meningococcal vaccine. Vaccination had no effect on nasopharyngeal carriage of meningococci. Vaccination of household contacts of patients with group A meningococcal infections is an effective way of using limited supplies of meningococcal vaccine, though its value would be limited in an epidemic. Secondary cases of meningococcal infection often occur within a few days of the index case, and, although vaccine alone seemed to provide adequate prophylaxis in these Nigerian subjects, additional chemoprophylaxis may be needed to cover this critical period.     

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.     

FUNGUS DISEASE IN NORTHERN CALIFORNIA

A systematic search for disease caused by fungi was made in a group of patients from northern California.Superficial mycotic infection was diagnosed frequently. Systemic fungus infection was found in approximately 0.6 per cent of an unselected group observed at Stanford University clinics—coccidioidomycosis or actinomycosis in almost all cases.Clinically unsuspected fungus infection was rare. Various species of Candida were frequently recovered, particularly from debilitated patients who had received antimicrobial therapy. Only rarely could these organisms be conclusively demonstrated to have caused serious disease.     

mRNA vaccines against COVID-19: a showcase for the importance of microbial biotechnology

Pfizer-BioNTech and Moderna developed in record time mRNA vaccines against COVID-19 of high efficacy. The modest protection achieved with a similarly designed mRNA from CureVac underlines the importance of biotechnological details in formulation such as replacement of uridine by pseudouridine in the mRNA encoding the SARS-CoV-2 spike protein or the lipid composition of the nanoparticle coating the mRNA. Phase 3 vaccine trials and vaccine studies in special subject groups as well observational studies in whole populations confirmed the real-world vaccine efficacy against symptomatic disease, particularly against severe COVID-19 cases and to a lesser extent against mild SARS-CoV-2 infections. mRNA vaccine protection extended also to the alpha and beta variant viruses. The surge of delta variants led to an increase of infections and cases even in populations which achieved high vaccine coverage. This efficacy decline resulted to a lesser extent from a weaker neutralization of the delta variant but mostly from a waning vaccine protection over time. Data from Israel documented the efficacy of a third ‘booster’ injection 5 months after the second injection in older segments of the population. Adverse reactions consisted of transient injection site pain, headache, muscle pain, fatigue, fever and chills. Extensive surveillance studies documented a good safety profile revealing only a non-significant increase in transient facial nerve paralysis and a significant, but modest increase in myocarditis in vaccinated young males that was lower than the myocarditis risk induced by SARS-CoV-2 infection.     

COCCIDIOIDOMYCOSIS—Treatment with Isonicotinic Acid Hydrazide

Since coccidioidal granulomas are histologically indistinguishable from tuberculous granulomas, a long course of isonicotinic acid hydrazide therapy was tried experimentally in three cases of coccidioidomycosis, with good results. In two cases the disease was far advanced and prognosis poor before INH therapy was begun. In one case the disease was mild and symptoms abated after a short course of small doses of INH. It recurred when INH therapy was discontinued, and again resolved when larger doses of INH were given over a longer period.INH seemed to have an effect on appetite also, although the patients were taking B-complex vitamins both before and during INH treatment. The three patients ill with coccidioidomycosis averaged a weight gain of four and a half pounds a month during the period of INH therapy. Six well persons who were underweight and lacked appetite were given INH without other drugs, and they then had an increase in appetite and in weight.     

Coccidioidomycosis; treatment with isonicotinic acid hydrazide

Since coccidioidal granulomas are histologically indistinguishable from tuberculous granulomas, a long course of isonicotinic acid hydrazide therapy was tried experimentally in three cases of coccidioidomycosis, with good results. In two cases the disease was far advanced and prognosis poor before INH therapy was begun. In one case the disease was mild and symptoms abated after a short course of small doses of INH. It recurred when INH therapy was discontinued, and again resolved when larger doses of INH were given over a longer period.INH seemed to have an effect on appetite also, although the patients were taking B-complex vitamins both before and during INH treatment. The three patients ill with coccidioidomycosis averaged a weight gain of four and a half pounds a month during the period of INH therapy. Six well persons who were underweight and lacked appetite were given INH without other drugs, and they then had an increase in appetite and in weight.     

Pneumococcal conjugate vaccines - implications for community antibiotic prescribing

Infections caused by Streptococcus pneumoniae are a major cause of morbidity and mortality in the pediatric population worldwide. Development of increasing resistance to multiple classes of antibiotics is making treatment of infections caused by this organism much more difficult. In order to prevent disease, a 23-valent pneumococal polysaccharide vaccine is available. However, this vaccine is poorly immunogenic in infants and young children. The development and licensing of pneumococcal conjugate vaccines that are safe and effective in the pediatric population is an important step in our ability to decrease the prevalence of pneumococcal disease seen.     

Update on the Epidemiology of Coccidioidomycosis

Coccidioidomycosis is an illness caused by the soil-dwelling, dimorphic fungi, Coccidioides immitis and Coccidioides posadasii, which are found primarily in niche ecological zones of the Western Hemisphere. The bulk of infections due to Coccidioides are found within the endemic areas of Arizona, California, Mexico, and Central America. Outcomes run the gamut from asymptomatic to a self-limited or even chronic pulmonary process, up to severe disseminated, and life-threatening disease. Patients at particular risk include the elderly, pregnant women, and members of certain ethnicities. Recent changes in the epidemiology and our overall understanding of coccidioidomycosis that pose a particular challenge to healthcare professionals include the rising incidence of disease, identification of infections thought to be acquired outside the previously described zones of endemicity, and the risks posed to the immunosuppressed population due to the increasing use of immunomodulatory pharmaceutical agents.     

Dendritic cell‐targeting DNA‐based nasal adjuvants for protective mucosal immunity to Streptococcus pneumoniae

To develop safe vaccines for inducing mucosal immunity to major pulmonary bacterial infections, appropriate vaccine antigens (Ags), delivery systems and nontoxic molecular adjuvants must be considered. Such vaccine constructs can induce Ag‐specific immune responses that protect against mucosal infections. In particular, it has been shown that simply mixing the adjuvant with the bacterial Ag is a relatively easy means of constructing adjuvant‐based mucosal vaccine preparations; the resulting vaccines can elicit protective immunity. DNA‐based nasal adjuvants targeting mucosal DCs have been studied in order to induce Ag‐specific mucosal and systemic immune responses that provide essential protection against microbial pathogens that invade mucosal surfaces. In this review, initially a plasmid encoding the cDNA of Flt3 ligand (pFL), a molecule that is a growth factor for DCs, as an effective adjuvant for mucosal immunity to pneumococcal infections, is introduced. Next, the potential of adding unmethylated CpG oligodeoxynucleotide and pFL together with a pneumococcal Ag to induce protection from pneumococcal infections is discussed. Pneumococcal surface protein A has been used as vaccine for restoring mucosal immunity in older persons. Further, our nasal pFL adjuvant system with phosphorylcholine‐keyhole limpet hemocyanin (PC‐KLH) has also been used in pneumococcal vaccine development to induce complete protection from nasal carriage by Streptococcus pneumoniae . Finally, the possibility that anti‐PC antibodies induced by nasal delivery of pFL plus PC‐KLH may play a protective role in prevention of atherogenesis and thus block subsequent development of cardiovascular disease is discussed.

     

Pneumococcal Virulence Factors: Structure and Function

The overall goal for this review is to summarize the current body of knowledge about the structure and function of major known antigens of Streptococcus pneumoniae, a major gram-positive bacterial pathogen of humans. This information is then related to the role of these proteins in pneumococcal pathogenesis and in the development of new vaccines and/or other antimicrobial agents. S. pneumoniae is the most common cause of fatal community-acquired pneumonia in the elderly and is also one of the most common causes of middle ear infections and meningitis in children. The present vaccine for the pneumococcus consists of a mixture of 23 different capsular polysaccharides. While this vaccine is very effective in young adults, who are normally at low risk of serious disease, it is only about 60% effective in the elderly. In children younger than 2 years the vaccine is ineffective and is not recommended due to the inability of this age group to mount an antibody response to the pneumococcal polysaccharides. Antimicrobial drugs such as penicillin have diminished the risk from pneumococcal disease. Several pneumococcal proteins including pneumococcal surface proteins A and C, hyaluronate lyase, pneumolysin, autolysin, pneumococcal surface antigen A, choline binding protein A, and two neuraminidase enzymes are being investigated as potential vaccine or drug targets. Essentially all of these antigens have been or are being investigated on a structural level in addition to being characterized biochemically. Recently, three-dimensional structures for hyaluronate lyase and pneumococcal surface antigen A became available from X-ray crystallography determinations. Also, modeling studies based on biophysical measurements provided more information about the structures of pneumolysin and pneumococcal surface protein A. Structural and biochemical studies of these pneumococcal virulence factors have facilitated the development of novel antibiotics or protein antigen-based vaccines as an alternative to polysaccharide-based vaccines for the treatment of pneumococcal disease.