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The unique complications of coccidioidomycosis of the spine: a detailed time line of disease progression and suppression.

STUDY DESIGN: A case report is presented. OBJECTIVE: We report a detailed time-line of disease progression and suppression in a patient with disseminated Coccidioidomycosis of the spine. The importance of consistent and thorough treatment to prevent disease recurrence is underscored. SUMMARY OF BACKGROUND DATA: Coccidioides immitis is a dimorphic fungus that lives as a saprophyte in arid, alkaline soils and as a parasite in the tissues of its host. Endemic to the arid soil of the American Southwest and Central and South America, its disease prevalence is increasing. There are 100,000 new infections diagnosed each year, of which 34% are symptomatic. Of the symptomatic individuals 5-10% will develop a serious pulmonary infection and of those that have a serious infection less than 1% will develop chronic pulmonary disease and/or extrapulmonary dissemination. METHODS: A 36-year-old black woman with a 3-year history of recent migration to the desert Southwest and a family history of sarcoidosis presented to her primary care physician with shortness of breath and a cough of 2 months' duration. An anterior-posterior radiograph revealed bilateral hilar lymphadenopathy and sarcoidosis was diagnosed. The patient was placed on oral prednisone and progressively worsened. She was referred to the Orthopedic Clinic with a complaint of severe back pain. RESULTS: Plain radiographs of the lumbar spine revealed lytic erosion of the sacral promontory. Computed tomography confirmed the sacral lesion in addition to revealing involvement of the fifth lumbar vertebral body. Over the ensuing years the patient underwent a course of operative and chemotherapeutic therapies. She endured numerous complications of the disease, one of which is being reported for the first time. Control of her disease has been accomplished through radical surgical debridement, spinal stabilization with concomitant local and systemic chemotherapy. CONCLUSIONS: The prevalence and distribution of Coccidioidomycosis is increasing as is the likelihood of seeing its often unique and bizarre clinical manifestations and complications. If included in the differential diagnosis, the disease can be recognized earlier and the likelihood of numerous complications can be avoided. Once bony involvement is diagnosed a regimen of aggressive surgical debridement as well as consistent chemotherapy must be employed if remission and/or eradication of the illness are sought.

Adult↗

Aspergillosis and lung defenses.

Aspergillosis refers to any of the illnesses caused by fungi that are members of the genus Aspergillus. The diseases range from allergic responses that occur in the absence of fungal growth (asthma, hypersensitivity pneumonitis), to colonization with or without an allergic component (allergic bronchopulmonary aspergillosis, aspergilloma, saprophytic involvement of infarcted tissue), to invasion and destruction of lung parenchyma (invasive aspergillosis, chronic necrotizing pulmonary aspergillosis). The development of lung infection and/or disease depends on interaction among three factors: the characteristics of the fungus (virulence factors), the status of host defense mechanisms, and the type of exposure. The purpose of this article is to review these factors and their relationship to the clinical syndromes of aspergillosis.

Alveolitis, Extrinsic Allergic↗

Cryptic speciation and recombination in the fungus Paracoccidioides brasiliensis as revealed by gene genealogies.

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.

Base Sequence↗

Surgical management of symptomatic pulmonary aspergilloma.

Pulmonary aspergilloma is a potentially life-threatening disease resulting from the colonization of lung cavities by the ubiquitous fungus Aspergillus fumigatus. Complex aspergilloma, characterized by thick-walled cavities with surrounding parenchymal inflammation, is a risk factor for increased morbidity and mortality. Fifteen patients with symptomatic aspergilloma underwent major thoracic procedures at North Carolina Memorial Hospital between January 1, 1972, and December 31, 1983. Twelve of the patients had hemoptysis; in 7 it was recurrent and in 5, life threatening. Tuberculosis and sarcoidosis were the most common underlying causes of lung disease, and more than half of the patients had other coexistent serious medical illness. Eleven of the 15 patients were seen with complex aspergilloma; all of the 4 major complications and the 2 deaths occurred in these patients. Bronchopleural fistula with persistent air space was the most common serious complication, and required thoracoplasty in 3 patients. Nine patients, including 5 with complex aspergilloma, had no postoperative complications, and there were no recurrent symptoms in any of the 13 operative survivors over a mean follow-up of five years. It is concluded that aggressive pulmonary resection can provide effective long-term palliation in critically ill patients with symptomatic pulmonary aspergilloma.

Adult↗

Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans.

Iron overload is known to exacerbate many infectious diseases, and conversely, iron withholding is an important defense strategy for mammalian hosts. Iron is a critical cue for Cryptococcus neoformans because the fungus senses iron to regulate elaboration of the polysaccharide capsule that is the major virulence factor during infection. Excess iron exacerbates experimental cryptococcosis and the prevalence of this disease in Sub-Saharan Africa has been associated with nutritional and genetic aspects of iron loading in the background of the HIV/AIDS epidemic. We demonstrate that the iron-responsive transcription factor Cir1 in Cr. neoformans controls the regulon of genes for iron acquisition such that cir1 mutants are "blind" to changes in external iron levels. Cir1 also controls the known major virulence factors of the pathogen including the capsule, the formation of the anti-oxidant melanin in the cell wall, and the ability to grow at host body temperature. Thus, the fungus is remarkably tuned to perceive iron as part of the disease process, as confirmed by the avirulence of the cir1 mutant; this characteristic of the pathogen may provide opportunities for antifungal treatment.

AIDS-Related Opportunistic Infections↗

[Relationship between the genetic background of donor KIR recipient HLA and the outcomes in HLA-identical sibling HSCT].

OBJECTIVE: To explore the relationship between the genetic background of donor KIR/recipient HLA and the outcomes in HLA-identical sibling HSCT. METHODS: HLA genotype was determined by polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) and/or PCR-sequence-specific primer (PCR-SSP). Donor KIR genotype was determined by PCR-SSP. A retrospective study was carried out to analyze the outcomes of 59 patients with various hematologic malignancies received non T-cell-depleted transplant from HLA-identical sibling donors. RESULTS: Incidence of grade II-IV acute graft-versus-host disease (aGVHD) was significantly lower in patients of KIR/HLA matched group than in KIR/HLA mismatched group (32% vs 78%, P = 0.026). The incidence of grade II-IV aGVHD (24% vs 61%, P = 0.018) and fungus infection (14% vs 44%, P = 0.028) were significantly lower in Bw4 matched group than in Bw4 mismatched group. In myeloid diseases, Bw4 matched patients had much lower incidence of fungus infection (12% vs 80%, P = 0.002) compared with Bw4 mismatched patients, and C2 matched patients had higher overall survival (OS) compared with C2 mismatched patients (P = 0.01). CONCLUSIONS: Donor KIR/recipient HLA genetic background is correlated with the outcomes of HLA-identical sibling HSCT in incidences of grade II-IV aGVHD, fungus infection and OS. KIR/HLA matched patients may have lower incidence of aGVHD. Bw4 matched patients may have lower incidences of aGVHD and fungus infection. C2 matched patients may have longer OS.

Female↗

Stachybotrys chartarum: cause of human disease or media darling?

This is a review of the literature of associations of the saprotrophic fungus Stachybotrys chartarum sensu lato with human and animal illnesses. This fungus grows on very wet cellulose-based building materials. S. chartarum has been the subject of considerable media attention because of temporal associations of exposure with unexpected and dramatic outcomes such as infant pulmonary hemosiderosis and neurocognitive damage. It is generally accepted that living or working in mouldy environments is associated with building related asthma, exacerbating asthma in mould-sensitive asthmatics and increased rates of upper respiratory disease. However, such relationships are with building-associated moulds, comprising many species that colonize wet or damp building materials, and are not specific to S. chartarum. There is limited evidence that severe lung damage can occur from building exposure to S. chartarum but possibly only under conditions of exposure that approach those associated with handling contaminated straw. There is no positive evidence in the literature to account for putative neurological damage resulting from exposure to this mould.

Allergens↗

Comparative pathogenicity of Fusarium graminearum isolates from China revealed by wheat coleoptile and floret inoculations.

Fusarium head blight (FHB) or scab caused by Fusarium species is an economically important disease on small grain cereal crops worldwide. Accurate assessments of the pathogenicity of fungal isolates is a key obstacle toward a better understanding of the Fusarium-wheat scab system. In this study, a new laboratory method for inoculation of wheat coleoptiles was developed, which consists of cutting off the coleoptile apex, covering the cut apex with a piece of filter paper soaked in conidial suspension, and measuring the lengths of brown lesions 7 days post inoculation. After coleoptile inoculation, distinct brown lesions in the diseased stems were observed, in which the presence of the fungus was verified by PCR amplification with F. graminearum Schwable-specific primers. Coleoptile inoculation of six wheat varieties indicated that a highly susceptible wheat variety was more suitable as a differentiating host for the pathogenicity assay. Analysis of the coleoptiles inoculated with a set of 58 different isolates of F. graminearum showed a significant difference in the lengths of the lesions, forming the basis by which pathogenicity of the isolates was assessed. Field inoculation of florets of three wheat varieties over 2 years revealed significant differences in pathogenicity among the 58 isolates, and that the highly resistant and highly susceptible wheat varieties were more appropriate and stable for pathogenicity assessment in field trials. Comparative analyses of eight inoculation experiments of wheat with 58 F. graminearum isolates showed significant direct linear correlations (P<0.001) between coleoptile and floret inoculations. These results indicate that the wheat coleoptile inoculation is a simple, rapid and reliable method for pathogenicity studies of F. graminearum in wheat.

China↗

A Ras protein from a phytopathogenic fungus causes defects in hyphal growth polarity, and induces tumors in mice.

Ras is a low-molecular-weight guanine nucleotide (GDP/GTP)-binding protein that transduces signals for growth and differentiation in eukaryotes. In mammals, the importance of Ras in regulating growth is underscored by the observation that activating mutations in ras genes are found in many animal tumors. Colletorichum trifolii is a filamentous fungal pathogen of alfalfa which causes anthracnose disease. To investigate signaling pathways that regulate growth and development in this fungus, a gene encoding a Ras homolog (CT-Ras) was cloned from C. trifolii. CT-Ras exhibited extensive amino acid similarity to Ras proteins from higher and lower eukaryotes. A single amino acid change resulting in mutationally activated CT-Ras induced cellular transformation of mouse (NIH 3T3) fibroblasts and tumor formation in nu/nu mice. In Colletotrichum, mutationally activated CT-Ras induced abnormal hyphal proliferation and defects in polarized growth, and significantly reduced differentiation in a nutrient-dependent manner. These results show that C. trifolii Ras is a functional growth regulator in both mammals and fungi, and demonstrate that proper regulation of Ras is required for normal fungal growth and development.

3T3 Cells↗

Multifocal osteomyelitis caused by Paecilomyces varioti in a patient with chronic granulomatous disease.

This report describes an 18-year-old male patient with chronic granulomatous disease who developed cutaneous nodules and multifocal osteomyelitis with the saprophytic fungus Paecilomyces varioti. After several biopsies the organism was identified. Anti-fungal susceptibility testing was performed. Combination therapy with amphotericin B and gamma-interferon followed by long-term therapy with itraconazole and gamma-interferon resulted in a clinical response.

Adolescent↗

Inheritance of partial resistance against Colletotrichum lindemuthianum in Phaseolus vulgaris and co-localization of quantitative trait loci with genes involved in specific resistance.

Anthracnose, one of the most important diseases of common bean (Phaseolus vulgaris), is caused by the fungus Colletotrichum lindemuthianum. A "candidate gene" approach was used to map anthracnose resistance quantitative trait loci (QTL). Candidate genes included genes for both pathogen recognition (resistance genes and resistance gene analogs [RGAs]) and general plant defense (defense response genes). Two strains of C. lindemuthianum, identified in a world collection of 177 strains, displayed a reproducible and differential aggressiveness toward BAT93 and JaloEEP558, two parental lines of P. vulgaris representing the two major gene pools of this crop. A reliable test was developed to score partial resistance in aerial organs of the plant (stem, leaf, petiole) under controlled growth chamber conditions. BAT93 was more resistant than JaloEEP558 regardless of the organ or strain tested. With a recombinant inbred line (RIL) population derived from a cross between these two parental lines, 10 QTL were located on a genetic map harboring 143 markers, including known defense response genes, anthracnose-specific resistance genes, and RGAs. Eight of the QTL displayed isolate specificity. Two were co-localized with known defense genes (phenylalanine ammonia-lyase and hydroxyproline-rich glycoprotein) and three with anthracnose-specific resistance genes and/or RGAs. Interestingly, two QTL, with different allelic contribution, mapped on linkage group B4 in a 5.0 cM interval containing Andean and Mesoamerican specific resistance genes against C. lindemuthianum and 11 polymorphic fragments revealed with a RGA probe. The possible relationship between genes underlying specific and partial resistance is discussed.

Chromosome Mapping↗

Antibody-dependent leukocyte killing of Cryptococcus neoformans.

Cryptococcus neoformans is an encapsulated, yeast-like fungus which is pathogenic for man. The role of various facets of the immune response which prevent disseminated disease in most normal hosts is unclear. A chromium-release assay was developed using radiolabeled cryptococci to reexamine antibody-dependent cell-mediated killing of this fungus. For a small capsule strain this assay served as a qualitative measure of effector cell function and was correlated with an assay of lethal injury to the organism. Polymorphonuclear leukocytes rather than mononuclear cells were the most active effector cells, causing significant chromium release from the fungus at effector-to-target ratios as low as 3:1. Polymorphonuclear leukocytes and mononuclear cells from a patient with chronic granulomatous disease showed minimal antibody-dependent cell-mediated chromium release suggesting that the final fungicidal pathway may be similar in antibody-dependent and antibody-independent leukocyte killing of this organism.

Animals↗

Green fluorescent protein (GFP) as a new vital marker in the phytopathogenic fungus Ustilago maydis.

Pathogenic development of Ustilago maydis, the causative agent of corn smut disease, is a multistep process. Compatible yeast-like cells fuse and this generates the infectious dikaryon which grows filamentously. Having entered the plant the dikaryon induces tumors in its host in which massive proliferation of fungal material, karyogamy and spore formation occur. In order to follow fungal development from the initial steps to the final stage we have expressed the green fluorescent protein (GFP) from Aequorea victoria as a vital marker in U. maydis and demonstrate that GFP-tagged strains can be used to study host-pathogen interactions in vivo.

Gene Expression Regulation, Fungal↗