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.