These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
This review summarizes knowledge on various aspects of paracoccidioidomycosis. Mycelial propagules, chlamydospores, and arthroconidia exhibit thermal dimorphism; arthroconidia are infectious in animals and, by electron microscopy, appear well provided for survival. The mycelial-to-yeast-phase transformation requires a strict control of glucan synthesis probably mediated by membrane enzymes. Hormonal influences on the transformation of the fungus (mycelium or conidium to yeast phase) have been demonstrated. Estrogen-binding proteins have been detected in the fungal cytosol, and during the transformation novel proteins are produced as a result of estradiol incorporation. Clinical forms have been better defined on the basis of better experimental models. Emphasis has been placed on the lungs as the portal of entry and on the existence of silent pulmonary infections. A specific Paracoccidioides brasiliensis antigen, the 43-kDa glycoprotein (Gp43), has been identified, characterized, and cloned. This has led to improved reproducibility and specificity of serologic tests. The depression of cell-mediated immune responses has been associated with severe disease in humans and in the experimental host. T-cell subsets in patients' tissues were characterized by means of monoclonal antibodies, and a reduced CD4/CD8 ratio was demonstrated. This has been related to alterations in lymphokine and tumor necrosis factor production, production of antigen-antibody complexes, etc. Amphotericin B has provided effective therapy. Azole derivatives have also improved prognosis and facilitated therapy. Itraconazole is presently the drug of choice, yet incapacitating sequelae (mainly pulmonary fibrosis) still constitute major problems.
Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis, a disease confined to Latin America and of marked importance in the endemic areas due to its frequency and severity. This species is considered to be clonal according to mycological criteria and has been shown to vary in virulence. To characterize natural genetic variation and reproductive mode in this fungus, we analyzed P. brasiliensis phylogenetically in search of cryptic species and possible recombination using concordance and nondiscordance of gene genealogies with respect to phylogenies of eight regions in five nuclear loci. Our data indicate that this fungus consists of at least three distinct, previously unrecognized species: S1 (species 1 with 38 isolates), PS2 (phylogenetic species 2 with six isolates), and PS3 (phylogenetic species 3 with 21 isolates). Genealogies of four of the regions studied strongly supported the PS2 clade, composed of five Brazilian and one Venezuelan isolate. The second clade, PS3, composed solely of 21 Colombian isolates, was strongly supported by the alpha-tubulin genealogy. The remaining 38 individuals formed S1. Two of the three lineages of P. brasiliensis, S1 and PS2, are sympatric across their range, suggesting barriers to gene flow other than geographic isolation. Our study provides the first evidence for possible sexual reproduction in P. brasiliensis S1, but does not rule it out in the other two species.
Until recently, Histoplasma capsulatum was believed to harbour three varieties, var. capsulatum (chiefly a New World human pathogen), var. duboisii (an African human pathogen) and var. farciminosum (an Old World horse pathogen), which varied in clinical manifestations and geographical distribution. We analysed the phylogenetic relationships of 137 individuals representing the three varieties from six continents using DNA sequence variation in four independent protein-coding genes. At least eight clades were idengified: (i) North American class 1 clade; (ii) North American class 2 clade; (iii) Latin American group A clade; (iv) Latin American group B clade; (v) Australian clade; (vi) Netherlands (Indonesian?) clade; (vii) Eurasian clade and (viii) African clade. Seven of eight clades represented genetically isolated groups that may be recognized as phylogenetic species. The sole exception was the Eurasian clade which originated from within the Latin American group A clade. The phylogenetic relationships among the clades made a star phylogeny. Histoplasma capsulatum var. capsulatum individuals were found in all eight clades. The African clade included all of the H. capsulatum var. duboisii individuals as well as individuals of the other two varieties. The 13 individuals of var. farciminosum were distributed among three phylogenetic species. These findings suggest that the three varieties of Histoplasma are phylogenetically meaningless. Instead we have to recognize the existence of genetically distinct geographical populations or phylogenetic species. Combining DNA substitution rates of protein-coding genes with the phylogeny suggests that the radiation of Histoplasma started between 3 and 13 million years ago in Latin America.
Although endemic mycoses are a frequent health problem in Latin American countries, clinical and epidemiological data remain scarce and fragmentary. These mycoses have a significant impact on public health, and early diagnosis and appropriate treatment remain important. The target population for endemic disease in Latin America is mostly represented by low-income rural workers with limited access to a public or private health system. Unfortunately, diagnostic tools are not widely available in medical centers in Latin America; consequently, by the time patients are diagnosed with fungal infection, many are already severely ill. Among immunocompromised patients, endemic mycoses usually behave as opportunistic infections causing disseminated rather than localized disease. This paper reviews the epidemiology of the most clinically significant endemic mycoses in Latin America: paracoccidioidomycosis, histoplasmosis, and coccidioidomycosis. The burdens of disease, typically affected populations, and clinical outcomes also are discussed.
This review discusses the epidemiology of the most clinically relevant opportunistic fungal infections in Latin America, including candidiasis, cryptococcosis, trichosporonosis, aspergillosis, and fusariosis. The epidemiologic features, including incidence, of some of these mycoses are markedly different in Latin America than they are in other parts of the world. The most consistent epidemiologic data are available for candidemia, with a large prospective study in Brazil reporting an incidence that is 3- to 15-fold higher than that reported in studies from North America and Europe. Species distribution also differs: in Latin America, the most common Candida species (other than Candida albicans) causing bloodstream infections are Candida parapsilosis or Candida tropicalis, rather than Candida glabrata.
Adult BALB/c mice of both sexes were infected intranasally with 106 viable P. brasiliensis conidia. Animals were sacrificed at intervals up to 6 months and studied by histopathology and organ cultures. At the time of challenge lung sections showed that instilled conidia had reached the alveoli; at 12 h such conidia were transforming into yeast cells, with multiple buds appearing by 18 h. Initially, the cellular infiltrate was composed of polymorphonuclear leukocytes; 6 days later, lymphocytes, plasmocytes and macrophages predominated. Multinucleated giant cells appeared only after 6 weeks. The rate of pulmonary infection as determined by organ culture was high (82 of the 83 mice studied). The experimental infection was progressive as indicated by increasing numbers of viable fungi with time. The results of this study demonstrate that the conidia produced by P. brasiliensis mycelial form are infectious, producing active disease in healthy animals.
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