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Robert L Clancy,1 Allan W Cripps2 1School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia; 2School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast Campus, Gold Coast, QLD, AustraliaCorrespondence: Allan W CrippsSchool of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast Campus, Gold Coast, QLD 4222, AustraliaTel +61 7 56780321Email allan.cripps@griffith.edu.auAbstract: In subjects with chronic bronchitis, protection against acute bronchitis following oral administration of a whole-cell killed nontypeable Haemophilus influenzae (NTHi) preparation was demonstrated in the mid-1980s. Subsequently, studies aiming to validate clinical efficacy of this oral treatment were complicated by a number of factors, including the modification of clinical definitions, the implications of which were not recognized at that time. The objective of this review is to integrate our pre-clinical and clinical research in this field conducted over the past 30 years to demonstrate the evolution of the idea of communication between mucosal surfaces through the common mucosal immune system and the development of an effective oral NTHi immunotherapy. Our earliest studies recruited subjects with chronic sputum production and high levels of culture-positive sputum for Gram-negative bacteria but by 2000, the clinical diagnostic focus had switched from “chronic bronchitis” to “chronic obstructive pulmonary disease” (COPD), which was functionally defined using spirometry. This change led to variable clinical trial results, confirming the importance of chronic sputum production and culture-positive sputum. Additional conditioning factors such as patient age and gender were influential in study populations with low culture-positive sputum production. Through this period, studies in human and in rodent models provided new insights into airway protection mechanisms and the pathogenesis of airway inflammation. Key findings were the importance of a dysbiosis within the airway microbiome, and the critical role of an interdependence between the bronchus and the gut, with a Peyer’s patch-dependent extra-bronchus “loop” controlling the composition of the bronchus microbiome. Within this context, intercurrent virus infections initiate a microbiome-dependant hypersensitivity reaction involving Peyer’s patch-derived Th17 cells. We conclude that whole-cell killed NTHi immunotherapy has consistent and significant benefits when examined in the context of changing clinical disease definitions, age and gender, and has the potential to change the natural history of chronic airway disease.Keywords: lung infection, airway inflammation, oral immunotherapy, lung immunity, nontypeable Haemophilus influenzae, COPD, chronic obstructive pulmonary disease

Diana C Otczyk1, Robert L Clancy2, Allan W Cripps11School of Medicine, Griffith Health Institute, Griffith Health, Griffith University, Gold Coast, Queensland, Australia; 2Immunology Unit, Hunter Area Pathology Service and University of Newcastle, Newcastle, New South Wales, AustraliaBackground: Intralumenal bacteria play a critical role in the pathogenesis of acute infective episodes and airway inflammation. Antigens from colonizing bacteria such as nontypeable Haemophilus influenzae (NTHi) may contribute to chronic lung disease through an immediate hypersensitivity response. The objective of this study was to determine the presence of specific NTHi-IgE antibodies in subjects with chronic bronchitis (CB) and COPD who had smoked.Methods: Serum, sputum, and saliva samples were collected from subjects with CB and moderate–severe COPD and healthy aged-matched controls. Total IgE and specific NTHi IgE were measured by enzyme linked immmunosorbent assay. Throat swabs were examined for the presence of NTHi.Results: The results demonstrate that: i) specific NTHi IgE antibodies occur at a low level in healthy subjects; ii) those with both CB and moderate–severe COPD have elevated specific NTHi IgE antibody compared with healthy controls, with higher levels in those with most severe disease; iii) IgE levels are greater in those with moderate–severe COPD than in those with CB. They demonstrate specific NTHi IgE antibody is regularly found at higher than normal levels in COPD.Conclusion: The detection of IgE antibody to colonizing bacteria in all subjects with CB or moderate–severe COPD identifies a possible mechanism of bronchospasm in these subjects amenable to specific intervention therapy.Keywords: nontypeable Haemophilus influenza, chronic bronchitis, chronic obstructive pulmonary disease, IgE, smoking