Serologic evidence for Cryptococcus neoformans infection in early childhood.
TL;DR: The results suggest that the low incidence of symptomatic cryptococcal disease in children with AIDS is not a result of lack of exposure to C neoformans, and provide both indirect and direct evidence of C neo formans infection in immunocompetent children.
Abstract: Objective. Cryptococcus neoformans is an important cause of central nervous system infection in adults with acquired immunodeficiency syndrome (AIDS) but an unusual cause of disease in children with AIDS. The basis for this age-related difference in incidence is not known but may be caused by differences in exposure or immune response. The objective of this study was to determine whether the low prevalence of cryptococcal disease among children is related to a lack of exposure to C neoformans . Methods. Sera were obtained from 185 immunocompetent individuals ranging in age from 1 week to 21 years who were being evaluated in an urban emergency department. Sera were analyzed for antibodies to C neoformans and Candida albicans proteins by immunoblotting. Immunoblot patterns were compared with those obtained from sera of patients with cryptococcosis ( n = 10) and workers in a laboratory devoted to the study of C neoformans . The specificity of our results was confirmed by several approaches, including antibody absorption and blocking studies. Sera were also analyzed for the presence of cryptococcal polysaccharide by both enzyme-linked immunosorbent assay and latex agglutination assays. Results. Sera from children 1.1 to 2 years old demonstrated minimal reactivity to C neoformans proteins. In contrast, the majority of sera from children >2 years old recognized many (≥6) C neoformans proteins. For children between 2.1 and 5 years old, 56% of sera ( n = 25) reacted with many proteins, whereas for children >5 years old ( n = 120), 70% of samples reacted with many proteins. Reactivity was decreased by absorbing sera with C neoformans extracts or by preincubating blots with sera from experimentally infected but not from control rats. Reactivity to C neoformans proteins did not correlate with reactivity to C albicans proteins, which was common in sera from children between the ages of 1.1 and 2 years. Cryptococcal polysaccharide was detected at a titer of 1:16 (∼10 ng/mL) in the sera of 1 child, a 5.6-year-old boy who presented to the emergency department with vomiting. Conclusions. Our findings provide both indirect and direct evidence of C neoformans infection in immunocompetent children. Our results indicate that C neoformans infects a majority of children living in the Bronx after 2 years old. These results are consistent with several observations: the ubiquitous nature of C neoformans in the environment, including its association with pigeon excreta; the large number of pigeons in urban areas; and the increased likelihood of environmental exposure for children once they have learned to walk. The signs and symptoms associated with C neoformans infection in immunocompetent children remained to be determined. Primary pulmonary cryptococcosis may be asymptomatic or produce symptoms confused with viral infections and, therefore, not recognized as a fungal infection. Our results suggest that the low incidence of symptomatic cryptococcal disease in children with AIDS is not a result of lack of exposure to C neoformans . These findings have important implications for C neoformans pathogenesis and the development of vaccine strategies.
Citations
More filters
TL;DR: The availability of new reagents in the form of monoclonal antibodies and melanin‐binding peptides, combined with the application of various physical techniques, has provided insights into the process of melanization, a type of pathogenic strategy that is common to highly diverse pathogens.
Abstract: Summary
Melanins are enigmatic pigments that are produced by a wide variety of microorganisms including several species of pathogenic bacteria, fungi and helminthes. The study of melanin is difficult because these pigments defy complete biochemical and structural analysis. Nevertheless, the availability of new reagents in the form of monoclonal antibodies and melanin-binding peptides, combined with the application of various physical techniques, has provided insights into the process of melanization. Melanization is important in microbial pathogenesis because it has been associated with virulence in many microorganisms. Melanin appears to contribute to virulence by reducing the susceptibility of melanized microbes to host defence mechanisms. However, the interaction of melanized microbes and the host is complex and includes immune responses to melanin-related antigens. Production of melanin has also been linked to protection against environmental insults. Interference with melanization is a potential strategy for antimicrobial drug and pesticide development. The process of melanization poses fascinating problems in cell biology and provides a type of pathogenic strategy that is common to highly diverse pathogens.
566 citations
TL;DR: The unmet clinical needs of current antifungal therapy are summarized, challenges inherent to antIFungal drug discovery and development are discussed, and recent developments aimed at addressing some of these challenges are reviewed.
Abstract: Invasive, life-threatening fungal infections are an important cause of morbidity and mortality, particularly for patients with compromised immune function. The number of therapeutic options for the treatment of invasive fungal infections is quite limited when compared with those available to treat bacterial infections. Indeed, only three classes of molecules are currently used in clinical practice and only one new class of antifungal drugs has been developed in the last 30 years. Here we summarize the unmet clinical needs of current antifungal therapy, discuss challenges inherent to antifungal drug discovery and development, and review recent developments aimed at addressing some of these challenges.
402 citations
Cites background from "Serologic evidence for Cryptococcus..."
...Furthermore, serological evidence of infection with Cryptococcus neoformans is common over the age of 2 yr (Goldman et al. 2001), but this organism almost never causes clinically significant disease unless the patient develops deficits in cell-mediated immunity....
[...]
TL;DR: Application of recent insights into the life cycle of C. neoformans and its different ways of engaging in sexual reproduction under laboratory conditions has just begun to affect research on the ecology and epidemiology of this human pathogenic fungus.
Abstract: Cryptococcus neoformans is a major cause of fungal meningoencephalitis in immunocompromised patients. Despite recent advances in the genetics and molecular biology of C. neoformans, and improved techniques for molecular epidemiology, aspects of the ecology, population structure, and mode of reproduction of this environmental pathogen remain to be established. Application of recent insights into the life cycle of C. neoformans and its different ways of engaging in sexual reproduction under laboratory conditions has just begun to affect research on the ecology and epidemiology of this human pathogenic fungus. The melding of these disparate disciplines should yield rich dividends in our understanding of the evolution of microbial pathogens, providing insights relevant to diagnosis, treatment, and prevention.
392 citations
TL;DR: Topics focused on in this article include species description, pathogenesis, life cycle, capsule, and stress response, which serve to highlight the specializations in virulence that have occurred in this unique encapsulated melanin-forming yeast that causes global deaths estimated at more than 600,000 annually.
Abstract: Cryptococcus neoformans and Cryptococcus gattii are the two etiologic agents of cryptococcosis. They belong to the phylum Basidiomycota and can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity, which all function as virulence determinants. Infection proceeds via inhalation and subsequent dissemination to the central nervous system to cause meningoencephalitis. The most common risk for cryptococcosis caused by C. neoformans is AIDS, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised. There have been many chapters, reviews, and books written on C. neoformans. The topics we focus on in this article include species description, pathogenesis, life cycle, capsule, and stress response, which serve to highlight the specializations in virulence that have occurred in this unique encapsulated melanin-forming yeast that causes global deaths estimated at more than 600,000 annually.
368 citations
Cites background from "Serologic evidence for Cryptococcus..."
...Serologic evidence indicates that cryptococcal infection in humans is prevalent (Goldman et al. 2001) but disease is rare....
[...]
TL;DR: Hypotheses based on data found that C. neoformans infection was documented in 2.8% of organ transplant recipients and the type of primary immunosuppressive agent used in transplantation influenced the predominant clinical manifestation of cryptococcosis are suggested.
Abstract: Unique clinical characteristics and other variables influencing the outcome of Cryptococcus neoformans infection in organ transplant recipients have not been well defined. From a review of published reports, we found that C. neoformans infection was documented in 2.8% of organ transplant recipients (overall death rate 42%). The type of primary immunosuppressive agent used in transplantation influenced the predominant clinical manifestation of cryptococcosis. Patients receiving tacrolimus were significantly less likely to have central nervous system involvement (78% versus 11%, p =0.001) and more likely to have skin, soft-tissue, and osteoarticular involvement (66% versus 21%, p = 0.006) than patients receiving nontacrolimus- based immunosuppression. Renal failure at admission was the only independently significant predictor of death in these patients (odds ratio 16.4, 95% CI 1.9-143, p = 0.004). Hypotheses based on these data may elucidate the pathogenesis and may ultimately guide the management of C. neoformans infection in organ transplant recipients.
347 citations
References
More filters
TL;DR: Results of the present study suggest that natural immunity to meningococcal disease is initiated, reinforced, and broadened by intermittent carriage of different strains ofMeningococci throughout life.
Abstract: Results of the present study suggest that natural immunity to meningococcal disease is initiated, reinforced, and broadened by intermittent carriage of different strains of meningococci throughout life. In young adults, carriage of meningococci in the nasopharynx is an efficient process of immune sensitization. 92% of carriers of serogroup B, C, or Bo meningococci were found to develop increased titers of serum bactericidal activity to their own meningococcal isolate, and 87% developed bactericidal activity to heterologous strains of pathogenic meningococci. The rise in bactericidal titer occurred within 2 wk of onset of the carrier state, and was accompanied by an increase in titer of specific IgG, IgM, and IgA antibodies to meningococci. In early childhood, when few children have antibodies to pathogenic meningococci, active immunization seems to occur as a result of carriage of atypical, nonpathogenic strains. Immunity to systemic meningococcal infection among infants in the neonatal period is associated with the passive transfer of IgG antibodies from mother to fetus. The antigenic determinants which initiate the immune response to meningococci include the group-specific C polysaccharide, cross-reactive antigens, and type-specific antigens.
1,028 citations
TL;DR: It is concluded that the patients diagnosed with cryptococcosis in France had acquired the C. neoformans infectious strain long before their clinical diagnoses were made.
Abstract: To date, the time of acquisition of a Cryptococcus neoformans infectious strain has never been studied. We selected a primer, (GACA)(4), and a probe, CNRE-1, that by randomly amplified polymorphic DNA (RAPD) analysis and restriction fragment length polymorphism (RFLP), respectively, regrouped strains from control samples of C. neoformans var. grubii environmental isolates according to their geographical origins. The two typing techniques were then used to analyze 103 isolates from 29 patients diagnosed with cryptococcosis in France. Nine of the 29 patients lived in Africa a median of 110 months prior to moving to France; 17 of the patients originated from Europe. Results showed a statistically significant clustering of isolate subtypes from patients originating from Africa compared to those from Europe. We conclude that the patients had acquired the C. neoformans infectious strain long before their clinical diagnoses were made.
318 citations
TL;DR: To determine the incidence of cryptococcosis and its risk factors among human immunodeficiency virus (HIV)-infected persons, population-based active surveillance was conducted in four US areas during 1992-1994 and a case-control study was done.
Abstract: To determine the incidence of cryptococcosis and its risk factors among human immunodeficiency virus (HIV)-infected persons, population-based active surveillance was conducted in four US areas (population, 12.5 million) during 1992-1994, and a case-control study was done. Of 1083 cases, 931 (86%) occurred in HIV-infected persons. The annual incidence of cryptococcosis per 1000 among persons living with AIDS ranged from 17 (San Francisco, 1994) to 66 (Atlanta, 1992) and decreased significantly in these cities during 1992-1994. Among non-HIV-infected persons, the annual incidence of cryptococcosis ranged from 0.2 to 0.9/ 100,000. Multivariate analysis of the case-control study (158 cases and 423 controls) revealed smoking and outdoor occupations to be significantly associated with an increased risk of cryptococcosis; receiving fluconazole within 3 months before enrollment was associated with a decreased risk for cryptococcosis. Further studies are needed to better describe persons with AIDS currently developing cryptococcosis in the era of highly active antiretroviral therapy.
242 citations
TL;DR: The prevalence of cryptococcal disease in New York City in 1991 among human immunodeficiency virus (HIV)-infected patients who were at risk of developing cryptococcosis is estimated to be 6.1%-8.5%.
Abstract: Cryptococcal infections are not reportable illnesses, and there have been limited attempts to estimate their incidence or prevalence. This study estimates the prevalence of cryptococcal disease in New York City in 1991 among human immunodeficiency virus (HIV)-infected patients who were at risk. Numerator data were generated by surveying all hospitals in New York City to determine the number of patients with cultures positive for Cryptococcus neoformans as well as the number of patients with positive cryptococcal latex agglutination tests in 1991; 517 culture-positive patients were identified, and 1,277 patients were estimated to have a positive cryptococcal latex antigen test. Of these cases, 96% were estimated to be related to infection with HIV. Denominator data were generated via an active surveillance program of the New York City Department of Health. The annual prevalence of cryptococcosis among HIV-infected patients at risk in New York City is estimated to be 6.1%-8.5%.
236 citations
TL;DR: The present study demonstrates that C. neoformans penetrates the lung parenchyma shortly after infection, immunocompetent rats control pulmonary cryptococcosis efficiently, with minimal extrapulmonary dissemination and low levels of serum GXM; and macrophage activation is likely to play a crucial role in limiting C. Neoformans infection in the rat lung.
Abstract: The pathogenesis of Cryptococcus neoformans pulmonary infection in the rat was studied after intratracheal inoculation. Lungs were examined at various times following infection for histopathology in conjunction with macrophage markers, proliferating cell nuclear antigen (PCNA), and capsular glucuronoxylomannan (GXM) antigen. Serum GXM, immunoglobulin M (IgM) and IgG titers and organ fungal burden were compared with pathological findings. C. neoformans organisms were in the lung parenchyma 2 h postinoculation, and GXM antigen was present in surrounding tissues shortly thereafter. Extrapulmonary dissemination occurred early in infection. Two phases of host cellular inflammatory response were discernible: early local macrophage recruitment at 2 to 4 days followed by granulomatous inflammation, which reached maximum intensity 14 days after infection. The granulomatous phase was preceded by lymphocyte influx with macrophage proliferation and maturation into epithelioid histiocytes; this was paralleled by a shift of yeasts from extracellular to intracellular spaces. Tissue IgG deposits, serum IgG to GXM, and localization of tissue GXM immunoreactivity to epithelioid cells were noted at 2 to 4 weeks. A 10-fold decrease in lung fungal burden occurred 25 days postinfection and was associated with resolving granulomas, fewer proliferating cells, and decreased tissue GXM. The present study demonstrates that (i) C. neoformans penetrates the lung parenchyma shortly after infection; (ii) immunocompetent rats control pulmonary cryptococcosis efficiently, with minimal extrapulmonary dissemination and low levels of serum GXM; and (iii) macrophage activation is likely to play a crucial role in limiting C. neoformans infection in the rat lung.
165 citations