NTHi and chronic suppurative lung diseases
NTHi is a normal upper airway commensal, but when it becomes established in the lower airways it elicits a strong, but ineffective inflammatory response.26 As it is an important pathogen in patients with COPD, much of our understanding of the clinical implications of chronic NTHi infection is from this patient group. Indeed, in COPD it accounts for nearly half of all isolates and is responsible for over 30% of disease exacerbations. Moreover, the severity of COPD exacerbations is associated withNTHi airway colonization. However, large knowledge gaps remain to explain why NTHi only affects a subset of COPD patients and what host-pathogen and microbial (eg. bacteria-bacteria and virus-bacteria) interactions cause this susceptibility.112 There is accumulating evidence that the biofilm-phase of NTHi may be important and knowing more about the mechanisms involved may promote targeted treatment of this chronic disease. Recent studies question the ability of antibiotics to eradicate lower airway NTHi infection in COPD patients since antibiotics do not prevent reinfection, nor do they alter the disease course76. Consequently, there has been substantial interest in creating an effective NTHivaccine.
NTHi is the major pathogen in bronchiectasis and is accompanied by airway neutrophilic infiltration and inflammatory markers, such as IL-8 and neutrophil elastase. Alveolar macrophages from PBB and bronchiectasis patients have reduced capacity to phagocytose NTHiand apoptotic neutrophils, allowing the latter to become necrotic and release ROS and proteolytic enzymes into the airways.115 NETs, which in bronchiectasis are a key marker of disease severity,116 may induce IL-17 secreting lymphocytes (Th17 and NK cells) in bronchial submucosa to further drive neutrophil recruitment and mucus hypersecretion perpetuating the cycle of inflammation.117 Compared to healthy controls, peripheral blood mononuclear cells from bronchiectasis patients also have an attenuated γ-interferon response to NTHi , but not to mitogens, suggesting a specific impairment in cell mediated immunity,118 which improves after receiving the highly conserved NTHi surface protein, protein D, incorporated into the pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV).
In CF patients NTHi are most often detected in children and adolescents and can be the predominant pathogen cultured in BAL fluid from young children.14 Nevertheless, their role as pathogens has been questioned.119 However, studies from the 1990s revealed that high NTHi loads (> 105 colony-forming units) in BAL cultures were associated with significantly higher neutrophil and IL-8 levels than when no pathogens were present.120,121 A North American CF registry-based study also found that isolatingNTHi from respiratory secretions was associated with accelerated decline in lung function in the transition from adolescence to adulthood.122 Recently, NTHi isolates from CF patients inoculated into a murine lung model induced chronic neutrophilic inflammation driven by Th17 cells and IL-17 cytokines. Taken together, these studies suggest a pathogenic role for NTHiin CF patients.
In PCD, nasal nitric oxide (nNO) levels are dramatically reduced for uncertain reasons. Recent in-vitro data suggest low levels of nNO make it easier for NTHi to adhere to primary AECs from PCD patients and form biofilms, while exogenous nitric oxide with azithromycin enhanced bacterial killing in biofilms compared to azithromycin alone.
PBB and bronchiectasis are on a continuum, and in children they have similar lower airway pathogen profiles, core microbiota, neutrophilic airway inflammation and impaired cellular immune responses toNTHi .40,128-130 A recent 5-year follow-up study of 194 children with PBB reported recurrent PBB and NTHi in BAL cultures predicted a future diagnosis of bronchiectasis, emphasizing the importance of NTHi in disease progression and outcome.