Microbial uptake by the respiratory epithelium: outcomes for host and pathogen.

Intracellular occupancy of the respiratory epithelium is a useful pathogenic strategy facilitating microbial replication and evasion of professional phagocytes or circulating antimicrobial drugs. A less appreciated but growing body of evidence indicates that the airway epithelium also plays a crucial role in host defence against inhaled pathogens, by promoting ingestion and quelling of microorganisms, processes that become subverted to favour pathogen activities and promote respiratory disease. To achieve a deeper understanding of beneficial and deleterious activities of respiratory epithelia during antimicrobial defence, we have comprehensively surveyed all current knowledge on airway epithelial uptake of bacterial and fungal pathogens. We find that microbial uptake by airway epithelial cells (AECs) is a common feature of respiratory host-microbe interactions whose stepwise execution, and impacts upon the host, vary by pathogen. Amidst the diversity of underlying mechanisms and disease outcomes, we identify four key infection scenarios and use best-characterised host-pathogen interactions as prototypical examples of each. The emergent view is one in which effi-ciency of AEC-mediated pathogen clearance correlates directly with severity of disease outcome, therefore highlighting an important unmet need to broaden our understanding of the antimicrobial properties of respiratory epithelia and associated drivers of pathogen entry and intracellular fate.

Anti-Aspergillus Activities of the Respiratory Epithelium in Health and Disease.

Respiratory epithelia fulfil multiple roles beyond that of gaseous exchange, also acting as primary custodians of lung sterility and inflammatory homeostasis. Inhaled fungal spores pose a continual antigenic, and potentially pathogenic, challenge to lung integrity against which the human respiratory mucosa has developed various tolerance and defence strategies. However, respiratory disease and immune dysfunction frequently render the human lung susceptible to fungal diseases, the most common of which are the aspergilloses, a group of syndromes caused by inhaled spores of Aspergillus fumigatus. Inhaled Aspergillus spores enter into a multiplicity of interactions with respiratory epithelia, the mechanistic bases of which are only just becoming recognized as important drivers of disease, as well as possible therapeutic targets. In this mini-review we examine current understanding of Aspergillus-epithelial interactions and, based upon the very latest developments in the field, we explore two apparently opposing schools of thought which view epithelial uptake of Aspergillus spores as either a curative or disease-exacerbating event.

Chronic Pulmonary Aspergillosis-Where Are We? and Where Are We Going?

Chronic pulmonary aspergillosis (CPA) is estimated to affect 3 million people worldwide making it an under recognised, but significant health problem across the globe, conferring significant morbidity and mortality. With variable disease forms, high levels of associated respiratory co-morbidity, limited therapeutic options and prolonged treatment strategies, CPA is a challenging disease for both patients and healthcare professionals. CPA can mimic smear-negative tuberculosis (TB), pulmonary histoplasmosis or coccidioidomycosis. Cultures for Aspergillus are usually negative, however, the detection of Aspergillus IgG is a simple and sensitive test widely used in diagnosis. When a fungal ball/aspergilloma is visible radiologically, the diagnosis has been made late. Sometimes weight loss and fatigue are predominant symptoms; pyrexia is rare. Despite the efforts of the mycology community, and significant strides being taken in optimising the care of these patients, much remains to be learnt about this patient population, the disease itself and the best use of available therapies, with the development of new therapies being a key priority. Here, current knowledge and practices are reviewed, and areas of research priority highlighted.

Frequency, diagnosis and management of fungal respiratory infections.

PURPOSE OF REVIEW: This review highlights key recent advances in fungal respiratory infections, encompassing developments in epidemiology, diagnostics and management, focussing on Aspergillus, Pneumocystis and Cryptococcus as key pathogens. RECENT FINDINGS: Chronic pulmonary aspergillosis complicates existing lung diseases, particularly those associated with cavities or bullae, with a high global disease burden (prevalence estimate >1.1 million following tuberculosis) and significant under diagnosis (using Aspergillus IgG antibody). Several new treatment studies have been published (using caspofungin and voriconazole). Pneumocystis jirovecii demonstrates airborne transmission between infected and noninfected individuals necessitating isolation, and possibly identifying colonized patients. Early detection of serum cryptococcal antigenaemia in HIV may prevent development of meningitis, reducing morbidity and mortality, and routine testing of serum in community-acquired pneumonia cases in high endemicity areas may be helpful. Respiratory Aspergillus antigen and PCR testing is more sensitive than culture or serum testing. A new lateral flow antigen testing device may provide rapid bedside diagnosis of aspergillosis. Azole resistance to Aspergillus fumigatus is increasing across Europe. SUMMARY: The field of fungal respiratory infection continues to evolve and develop, with many recent key advances. Patients, and possibly colonized patients, with Pneumocystis require isolation in hospitals and preferably segregation in outpatients. Challenges remain in almost all areas, with further work needed to identify the true burden of Aspergillus disease and address the increasing problem of azole resistance.