Lung eosinophil recruitment in response to Aspergillus fumigatus is correlated with fungal cell wall composition and requires γδ T cells.

The differential recognition of fungal cell wall polysaccharides that program innate and adaptive immunity to the human opportunistic fungal pathogen Aspergillus fumigatus has been a focus of considerable interest. In a mouse model of fungal conidia aspiration, decreased relative levels of cell wall core carbohydrates ß-1,3-glucan to chitin in A. fumigatus isolates and mutant strains were correlated with increased airway eosinophil recruitment. In addition, an increase in fungal surface chitin exposure induced by the ß-1,3-glucan synthesis-targeting drug caspofungin was associated with increased murine airway eosinophil recruitment after a single challenge of conidia. The response to increased A. fumigatus chitin was associated with increased transcription of IL-17A after a single aspiration, although this cytokine was not required for eosinophil recruitment. Rather, both RAG1 and γδ T cells were required, suggesting that this subset of innate-like lymphocytes may be an important regulator of potentially detrimental type 2 immune responses to fungal inhalation and infection.

The Quality of Cost-Utility Analyses in Orthopedic Trauma.

As health care in the United States transitions toward a value-based model, there is increasing interest in applying cost-effectiveness analysis within orthopedic surgery. Orthopedic trauma care has traditionally underemphasized economic analysis. The goals of this review were to identify US-based cost-utility analysis in orthopedic trauma, to assess the quality of the available evidence, and to identify cost-effective strategies within orthopedic trauma. Based on a review of 971 abstracts, 8 US-based cost-utility analyses evaluating operative strategies in orthopedic trauma were identified. Study findings were recorded, and the Quality of Health Economic Studies (QHES) instrument was used to grade the overall quality. Of the 8 studies included in this review, 4 studies evaluated hip and femur fractures, 3 studies analyzed upper extremity fractures, and 1 study assessed open tibial fracture management. Cost-effective interventions identified in this review include total hip arthroplasty (over hemiarthroplasty) for femoral neck fractures in the active elderly, open reduction and internal fixation (over nonoperative management) for distal radius and scaphoid fractures, limb salvage (over amputation) for complex open tibial fractures, and systems-based interventions to prevent delay in hip fracture surgery. The mean QHES score of the studies was 79.25 (range, 67-89). Overall, there is a paucity of cost-utility analyses in orthopedic trauma; however, the available evidence suggests that certain operative interventions can be cost-effective. The quality of these studies, however, is fair, based on QHES grading. More attention should be paid to evaluating the cost-effectiveness of operative intervention in orthopedic trauma.

Isolate-dependent growth, virulence, and cell wall composition in the human pathogen Aspergillus fumigatus.

The ubiquitous fungal pathogen Aspergillus fumigatus is a mediator of allergic sensitization and invasive disease in susceptible individuals. The significant genetic and phenotypic variability between and among clinical and environmental isolates are important considerations in host-pathogen studies of A. fumigatus-mediated disease. We observed decreased radial growth, rate of germination, and ability to establish colony growth in a single environmental isolate of A. fumigatus, Af5517, when compared to other clinical and environmental isolates. Af5517 also exhibited increased hyphal diameter and cell wall ß-glucan and chitin content, with chitin most significantly increased. Morbidity, mortality, lung fungal burden, and tissue pathology were decreased in neutropenic Af5517-infected mice when compared to the clinical isolate Af293. Our results support previous findings that suggest a correlation between in vitro growth rates and in vivo virulence, and we propose that changes in cell wall composition may contribute to this phenotype.

Eosinophils are recruited in response to chitin exposure and enhance Th2-mediated immune pathology in Aspergillus fumigatus infection.

In patients infected with the fungus Aspergillus fumigatus, Th1 responses are considered protective, while Th2 responses are associated with increased morbidity and mortality. How host-pathogen interactions influence the development of these protective or detrimental immune responses is not clear. We compared lung immune responses to conidia from two fungal isolates that expressed different levels of the fungal cell wall component chitin. We observed that repeated aspirations of the high-chitin-expressing isolate Af5517 induced increased airway eosinophilia in the lungs of recipient mice compared to the level of eosinophilia induced by isolate Af293. CD4(+) T cells in the bronchoalveolar lavage fluid (BALF) of Af5517-aspirated mice displayed decreased gamma interferon secretion and increased interleukin-4 transcription. In addition, repeated aspirations of Af5517 induced lung transcription of the Th2-associated chemokines CCL11 (eotaxin-1) and CCL22 (macrophage-derived chemokine). Eosinophil recruitment in response to conidial aspiration was correlated with the level of chitin exposure during germination and was decreased by constitutive lung chitinase expression. Moreover, eosinophil-deficient mice subjected to multiple aspirations of Af5517 prior to neutrophil depletion and infection exhibited decreased morbidity and fungal burden compared to the levels of morbidity and fungal burden found in wild-type mice. These results suggest that exposure of chitin in germinating conidia promotes eosinophil recruitment and ultimately induces Th2-skewed immune responses after repeated aspiration. Furthermore, our results suggest that eosinophils should be examined as a potential therapeutic target in patients that mount poorly protective Th2 responses to A. fumigatus infection.