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Article Reference Impacts of peroxisome proliferator-activated receptor-γ activation on cigarette smoke-induced exacerbated response to bacteria.
Chronic obstructive pulmonary disease (COPD) is characterised by a state of chronic pulmonary inflammation punctuated by microbial exacerbations. Despite advances in treatment options, COPD remains difficult to manage. In this study, we investigated the potential of peroxisome proliferator-activated receptor (PPAR)γ activation as a new therapy against cigarette smoke-induced inflammation and its associated bacterial exacerbation. C57BL/6 mice were exposed to room air or cigarette smoke for either 4 days or 4 weeks and treated either prophylactically or therapeutically with rosiglitazone. The impact of rosiglitazone on cigarette smoke-induced exacerbated response to the bacterial pathogen nontypeable Haemophilus influenzae (NTHi) was studied using the therapeutic treatment protocol. We found that rosiglitazone was able to reduce cigarette smoke-induced neutrophilia both when administered prophylactically or therapeutically. Therapeutic intervention with rosiglitazone was also effective in preventing cigarette smoke-induced neutrophilia exacerbation following NTHi infection. Moreover, the anti-inflammatory effects of rosiglitazone did not lead to an increase in the pulmonary bacterial burden, unlike dexamethasone. Altogether, our data suggest that pharmacological activation of PPARγ may be an effective therapeutic approach to improve COPD management, as it is able to reduce cigarette smoke-induced inflammation and decrease the magnitude of bacterial exacerbations, without compromising the ability of the immune system to control the infection.
Article Reference Nontypeable Haemophilus influenzae and childhood pneumonia.
Nontypeable Haemophilus influenzae (NTHi) is a common microbe frequently isolated from the nasopharynx of children. Bacterial pneumonia is a major cause of morbidity and mortality in children less than 5 years of age, with the burden of disease being greatest in developing countries. Determination of the bacterial aetiology of pneumonia is difficult due to sampling constraints. However, with a combination of sampling approaches, trans-thoracic fine-needle aspiration, blood culture and screened sputum, the evidence strongly suggests that NTHi is a significant causative pathogen of pneumonia in young children. However, further studies are required. The development of a new pneumococcal conjugate vaccine containing H. influenzae protein D has the potential to be beneficial against disease caused by NTHi, including pneumonia. With the implementation of this vaccine in many regions of the world where NTHi disease is endemic, it will be critical to introduce surveillance programs wherever it is used.
Article Reference Interleukin 6, but not T helper 2 cytokines, promotes lung carcinogenesis.
Several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer compared with smokers without COPD. We have shown a causal role for COPD-like airway inflammation in lung cancer promotion in the CCSP(Cre)/LSL-K-ras(G12D) mouse model (CC-LR). In contrast, existing epidemiologic data do not suggest any definite association between allergic airway inflammation and lung cancer. To test this, CC-LR mice were sensitized to ovalbumin (OVA) and then challenged with an OVA aerosol weekly for 8 weeks. This resulted in eosinophilic lung inflammation associated with increased levels of T helper 2 cytokines and mucous metaplasia of airway epithelium, similar to what is seen in asthmatic patients. However, this type of inflammation did not result in a significant difference in lung surface tumor number (49 ± 9 in OVA vs. 52 ± 5 in control) in contrast to a 3.2-fold increase with COPD-like inflammation. Gene expression analysis of nontypeable Haemophilus influenzae (NTHi)-treated lungs showed upregulation of a different profile of inflammatory genes, including interleukin 6 (IL-6), compared with OVA-treated lungs. Therefore, to determine the causal role of cytokines that mediate COPD-like inflammation in lung carcinogenesis, we genetically ablated IL-6 in CC-LR mice. This not only inhibited intrinsic lung cancer development (1.7-fold) but also inhibited the promoting effect of extrinsic COPD-like airway inflammation (2.6-fold). We conclude that there is a clear specificity for the nature of inflammation in lung cancer promotion, and IL-6 has an essential role in lung cancer promotion.
Article Reference Residual economic burden of Streptococcus pneumoniae- and nontypeable Haemophilus influenzae-associated disease following vaccination with PCV-7: a multicountry analysis.
This paper estimates the annual direct medical and caregiver costs of Streptococcus pneumoniae (Sp) and nontypeable Haemophilus influenzae (NTHi)-associated diseases in children younger than 10 years in Canada, Germany, Mexico, and Norway after vaccination with the 7-valent pneumococcal conjugate vaccine (PCV-7). Per-episode direct medical costs for treating Sp- and NTHi-associated diseases were summarised from the literature for three countries, and a Delphi panel was used to estimate resource use and the per-episode costs for Mexico. Per-episode or annual costs were inflated to 2008 local currency and converted to 2008 United States (US) dollars using purchasing power parities. The analysis was for 1 year; therefore, costs were not discounted. Sp- and NTHi-associated diseases resulted in current annual national costs of $179-$260 million ($5.43-$7.89 per capita) in Canada, $290-$435 million ($3.53-$5.29 per capita) in Germany, $277-$432 million ($2.59-$4.05 per capita) in Mexico, and $20-$28 million ($4.35-$6.17 per capita) in Norway. Although acute otitis media (AOM) was associated with the lowest per-case costs, it accounted for between 45% and 88% of the national direct medical costs and between 67% and 96% of caregiver costs for Sp- and NTHi-associated diseases. Sp- and NTHi-associated diseases continue to result in substantial direct medical and caregiver costs despite current PCV-7 vaccination programs.
Article Reference Invasive disease caused by Haemophilus influenzae in Sweden 1997-2009; evidence of increasing incidence and clinical burden of non-type b strains.
Introduction of a conjugated vaccine against encapsulated Haemophilus influenzae type b (Hib) has led to a dramatic reduction of invasive Hib disease. However, an increasing incidence of invasive disease by H. influenzae non-type b has recently been reported. Non-type b strains have been suggested to be opportunists in an invasive context, but information on clinical consequences and related medical conditions is scarce. In this retrospective study, all H. influenzae isolates (n = 410) from blood and cerebrospinal fluid in three metropolitan Swedish regions between 1997 and 2009 from a population of approximately 3 million individuals were identified. All available isolates were serotyped by PCR (n = 250). We observed a statistically significant increase in the incidence of invasive H. influenzae disease, ascribed to non-typeable H. influenzae (NTHi) and encapsulated strains type f (Hif) in mainly individuals >60 years of age. The medical reports from a subset of 136 cases of invasive Haemophilus disease revealed that 48% of invasive NTHi cases and 59% of invasive Hif cases, respectively, met the criteria of severe sepsis or septic shock according to the ACCP/SCCM classification of sepsis grading. One-fifth of invasive NTHi cases and more than one-third of invasive Hif cases were admitted to intensive care units. Only 37% of patients with invasive non-type b disease had evidence of immunocompromise, of which conditions related to impaired humoral immunity was the most common. The clinical burden of invasive non-type b H. influenzae disease, measured as days of hospitalization/100 000 individuals at risk and year, increased significantly throughout the study period.
Article Reference Otitis media across nine countries: disease burden and management.
To assess the perceived disease burden and management of otitis media (OM) among an international cohort of experienced physicians.
Article Reference Burden and cost of hospital admissions for vaccine-preventable paediatric pneumococcal disease and non-typable Haemophilus influenzae otitis media in New Zealand.
Streptococcus pneumoniae (Sp.) is a leading cause of paediatric bacterial meningitis, pneumonia and acute otitis media, as is non-typable Haemophilus influenzae (NTHi) for acute otitis media. In 2008, a 7-valent conjugated pneumococcal vaccine (PCV7) was included in the New Zealand (NZ) childhood immunization schedule.
Article Reference Mechanisms of clearance of nontypeable Haemophilus influenzae from cigarette smoke-exposed mouse lungs.
Inflammation is prevalent in all stages of chronic obstructive pulmonary disease, and, furthermore, individuals undergo periods of exacerbation, during which pulmonary inflammation increases, often a result of bacterial infection. The present study investigates the in vivo consequences of cigarette smoke exposure on bacterial challenge with nontypeable Haemophilus influenzae (NTHi). BALB/c and C57 black 6 (C57BL/6) mice were exposed to cigarette smoke once or twice daily for a total period of 8 weeks. Exacerbated inflammation was observed in cigarette smoke-exposed compared to room-air-exposed mice following challenge with live or heat-inactivated NTHi. Accelerated clearance of live NTHi from cigarette smoke-exposed mice was independent of the establishment of chronic inflammation or direct toxic effects of cigarette smoke components on bacteria. Mechanistically, a cell-free factor in the bronchoalveolar lavage fluid contributed to accelerated clearance following passive transfer to naive mice. Further investigation demonstrated increased titres of immunoglobulin A in the bronchoalveolar lavage fluid, but not the blood, of cigarette smoke-exposed mice, including increased titres of NTHi-specific immunoglobulin A, whereas heavy chain joining element (J(H))(-/-) B-cell-deficient cigarette smoke-exposed mice did not demonstrate decreased bacterial burden following challenge. The present results demonstrate that cigarette smoke exposure results in exacerbated inflammation following challenge with NTHi, as well as increased titres of antibodies that contribute to bacterial clearance.
Article Reference Characterization of nontypeable Haemophilus influenzae collected from respiratory infections and invasive disease cases in Manitoba, Canada.
With the introduction of the Haemophilus influenzae serotype b (Hib) vaccine, invasive Hib disease has decreased substantially, but nontypeable H. influenzae (NT Hi) disease appears to be increasing. In order to understand the origin of NT Hi strains and their relationship with serotypeable strains, we analysed 125 NT Hi isolates collected from individual patients with either invasive disease (70 isolates) or respiratory tract infections (55 isolates). Serotype-specific and capsular transport genes were absent by PCR analysis, confirming their nonencapsulated status, which also suggested the NT Hi isolates were not encapsulated strains that shed their capsules. Multilocus sequence typing confirmed the NT Hi isolates did not have the same genetic background as serotypeable strains, including Hib. Despite the genetic heterogeneity found, two major genetic clusters were identified, both containing invasive and respiratory isolates. Fourteen invasive isolates and nine respiratory isolates produced beta-lactamase and were ampicillin resistant. More invasive (26.8%) than respiratory isolates (10.9%) showed decreased susceptibility towards ampicillin by a mechanism unrelated to beta-lactamase production. Besides a change in the capsule status of invasive Hi strains, the burden of invasive Hi disease, which used to be mainly a childhood disease, has now shifted to involve both adults and infants.
Article Reference Recent advances in otitis media.
Otitis media (OM) is a pervasive illness in infants and children, and many children suffer multiple episodes during the first years of life. High rates of acute otitis media (AOM) are reported in developed and emerging countries. Early onset is common in both settings. Recurrent OM is associated with several factors, including early onset of disease, having a sibling with a history of AOM and absence of breast-feeding. Early onset disease has been hypothesized to result from Eustachian tube dysfunction, immunologic naivete and immaturity, and viral upper respiratory tract infection. Nasopharyngeal colonization with bacterial otopathogens increases the likelihood of AOM and the disease is most frequent in children with viral respiratory tract infection colonized with multiple otopathogens (Streptococcus pneumoniae, nontypeable Haemophilus influenzae [NTHi], Moraxella catarrhalis), potentially as a result of inflammation resulting from competition among the bacterial species within the nasopharynx. Epidemiologic observations and studies of pathogenesis suggest that successful strategies for reducing the burden of disease will be best accomplished by targeting multiple viral and/or bacterial pathogens and preventing early onset disease. Guidelines (2004) for the treatment of AOM in children establish a clear hierarchy among the various antibacterials for the treatment of this disease. Failure to achieve early bacterial eradication during antibiotic therapy for AOM increases the clinical failure rates in AOM in young children. Most recurrent AOM episodes occurring within 1 month after successful completion of antibiotic therapy are due to new otopathogens. Failure to eradicate middle ear and/or nasopharyngeal pathogens is associated with higher rates of clinical recurrent AOM, even when the patients show clinical improvement or cure at the end of therapy for the initial episode. Optimal strategy for the prevention of AOM recurrences requires sterilization of the middle ear and eradication of nasopharyngeal carriage of otopathogens during antimicrobial therapy.
Article Reference Otitis media: viruses, bacteria, biofilms and vaccines.
Otitis media typically presents as either acute otitis media (AOM), with symptoms including fever, otalgia, otorrhoea or irritability and short duration; or as otitis media with effusion (OME), which is often asymptomatic and characterised by accumulation of fluid in the middle ear. Diagnostic certainty of otitis media is challenging, given the young age of patients and variability of symptoms. Otitis media predominantly occurs as coincident to viral upper respiratory tract infections and/or bacterial infections. Common viruses that cause upper respiratory tract infection are frequently associated with AOM and new-onset OME. These include respiratory syncytial virus, rhinovirus, adenovirus, parainfluenza and coronavirus. Predominant bacteria that cause otitis media are Streptococcus pneumoniae, Moraxella catarrhalis, and non-typeable Haemophilus influenzae. Antibiotic therapy does not significantly benefit most patients with AOM, but long-term prophylactic antibiotic therapy can reduce the risk of otitis media recurrence among children at high risk. In Australia, 84% of AOM is treated with antibiotic therapy, which contributes to development of antibiotic resistance. Vaccine development is a key future direction for reducing the world burden of otitis media, but requires polymicrobial formulation and ongoing monitoring and modification to ensure sustained reduction in disease burden.
Article Reference 10-valent pneumococcal nontypeable Haemophilus influenzae PD conjugate vaccine: Synflorix.
The global burden of disease due to Streptococcus pneumoniae remains high. The licensed 7-valent pneumococcal conjugate vaccine (7vCRM, Prevenar/Prevnar) has successfully reduced invasive disease in the USA, but serotype coverage is incomplete and some evidence suggests that serotype replacement has occurred. Recently, a new 10-valent pneumococcal nontypeable Haemophilus influenzae (NTHi) protein D (PD) conjugate vaccine (PHiD-CV, Synflorix) has been licensed in more than 40 countries, including Europe, for the prevention of invasive disease and acute otitis media (AOM) due to pneumococcus in infants and children. PHiD-CV is immunogenic in infants when administered as a three-dose primary vaccination in a range of schedules and has a safety profile comparable to that of 7vCRM. Additional serotypes in PHiD-CV (1, 5 and 7F) increase overall serotype coverage and improve coverage in specific age groups and against specific disease syndromes. The use of the PD carrier, which provided protection against AOM caused by NTHi in a large efficacy trial testing a prototype of the final vaccine formulation, suggests that PHiD-CV will also provide some protection against AOM due to NTHi.
Article Reference Prevention of otitis media: now a reality?
Acute otitis media (AOM), one of the most common childhood diseases, is associated with a substantial medical, social and economic burden. Non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae are the two main causes of bacterial OM. The 7-valent pneumococcal CRM(197)-conjugate vaccine (7vCRM, Prevnar/Prevenar, Wyeth) demonstrated efficacy against AOM caused by vaccine pneumococcal serotypes. Protection against overall AOM was also observed with an 11-valent pneumococcal protein D-conjugate vaccine (11Pn-PD) in the Pneumococcal Otitis Efficacy Trial (POET). Following POET, an optimized 10-valent pneumococcal non-typeable H. influenzae protein D-conjugate vaccine (PHiD-CV; Synflorix, GlaxoSmithKline Biologicals) was developed. This vaccine includes serotypes 1, 5, and 7F, in addition to those already included in 7vCRM, and was recently licensed in Europe for active immunization against invasive disease and AOM caused by S. pneumoniae in infants and children from 6 weeks up to 2 years of age. The use of protein D as carrier protein permits avoidance of possible interferences known to occur with some conjugate vaccines, and has the added potential benefit of providing protection against NTHi. This review seeks to highlight the recent advances in the field of OM vaccination, with a focus on data regarding the recently licensed PHiD-CV.
Article Reference Otitis media: prospects for prevention.
Alternatives to vaccination for preventing the considerable morbidity of otitis media (OM) are limited. Non-typable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae together account for approximately 80% of OM cases worldwide, so vaccines against these most serious pathogens should materially reduce the burden of OM. Early trial data for a vaccine prototype including NTHi and 11 pneumococcal serotypes, interpreted carefully in relation to other trials, suggest that OM can now be considered a vaccine-preventable disease. Despite differences of scenario according to healthcare and bacteriology circumstances of different countries, a provisional analysis of health-economic precedents and policy considerations favours vaccination.
Article Reference Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model.
Lung cancer is the leading cause of cancer deaths in the United States. In addition to genetic abnormalities induced by cigarette smoke, several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lungs, have an increased risk of lung cancer (1.3- to 4.9-fold) compared to smokers without COPD. This suggests a link between chronic airway inflammation and lung carcinogenesis, independent of tobacco smoke exposure. We studied this association by assaying the inflammatory impact of products of nontypeable Haemophilus influenzae, which colonizes the airways of patients with COPD, on lung cancer promotion in mice with an activated K-ras mutation in their airway epithelium. Two new mouse models of lung cancer were generated by crossing mice harboring the LSL-K-ras(G12D) allele with mice containing Cre recombinase inserted into the Clara cell secretory protein (CCSP) locus, with or without the neomycin cassette excised (CCSP(Cre) and CCSP(Cre-Neo), respectively). Lung lesions in CCSP(Cre-Neo)/LSL-K-ras(G12D) and CCSP(Cre)/LSL-K-ras(G12D) mice appeared at 4 and 1 month of age, respectively, and were classified as epithelial hyperplasia of the bronchioles, adenoma, and adenocarcinoma. Weekly exposure of CCSP(Cre)/LSL-K-ras(G12D) mice to aerosolized nontypeable Haemophilus influenzae lysate from age 6-14 weeks resulted in neutrophil/macrophage/CD8 T-cell-associated COPD-like airway inflammation, a 3.2-fold increase in lung surface tumor number (156 +/- 9 versus 45 +/- 7), and an increase in total lung tumor burden. We conclude that COPD-like airway inflammation promotes lung carcinogenesis in a background of a G12D-activated K-ras allele in airway secretory cells.
Article Reference Multiple consecutive lavage samplings reveal greater burden of disease and provide direct access to the nontypeable Haemophilus influenzae biofilm in experimental otitis media.
The typically recovered quantity of nontypeable Haemophilus influenzae (NTHi) bacteria in an ex vivo middle ear (ME) aspirate from the chinchilla model of experimental otitis media is insufficient for direct analysis of gene expression by microarray or of lipopolysaccharide glycoforms by mass spectrometry. This prompted us to investigate a strategy of multiple consecutive lavage samplings to increase ex vivo bacterial recovery. As multiple consecutive lavage samples significantly increased the total number of bacterial CFU collected during nasopharyngeal colonization or ME infection, this led us to evaluate whether bacteria sequentially acquired from consecutive lavages were similar. Comparative observation of complete ex vivo sample series by microscopy initially revealed ME inflammatory fluid consisting solely of planktonic-phase NTHi. In contrast, subsequent lavage samplings of the same infected ear revealed the existence of bacteria in two additional growth states, filamentous and biofilm encased. Gene expression analysis of such ex vivo samples was in accord with different bacterial growth phases in sequential lavage specimens. The existence of morphologically distinct NTHi subpopulations with varying levels of gene expression indicates that the pooling of specimens requires caution until methods for their separation are developed. This study based on multiple consecutive lavages is consistent with prior reports that NTHi forms a biofilm in vivo, describes the means to directly acquire ex vivo biofilm samples without sacrificing the animal, and has broad applicability for a study of mucosal infections. Moreover, this approach revealed that the actual burden of bacteria in experimental otitis media is significantly greater than was previously reported. Such findings may have direct implications for antibiotic treatment and vaccine development against NTHi.
Article Reference Prospects for a vaccine against otitis media.
Otitis media is a major cause of morbidity in 80% of all children less than 3 years of age and often goes undiagnosed in the general population. There is evidence to suggest that the incidence of otitis media is increasing. The major cause of otitis media is infection of the middle ear with microbes from the nasopharynx. The anatomical orientation of the eustachian tube, in association with a number of risk factors, predisposes infants and young children to the infection. Bacteria are responsible for approximately 70% of cases of acute otitis media, with Streptococcus pneumoniae, nontypeable Haemophilus influenzae and Moraxella catarrhalis predominating as the causative agents. The respiratory viruses, respiratory syncytial virus, rhinovirus, parainfluenza and influenza, account for 30% of acute otitis media cases. Over the past decade, there has been a profound increase in the reported resistance to antibiotics, which, with increased disease burden, has focussed attention on vaccine development for otitis media. A polymicrobial formulation containing antigens from all major pathogens would have the greatest potential to deliver a sustained reduction in the disease burden globally. The disappointing outcomes for otitis media seen with the polysaccharide pneumococcal conjugate vaccine have raised major challenges for the vaccination strategy. Clearly, more knowledge is required concerning immune mechanisms in the middle ear, as well as vaccine formulations containing antigens that are more representative of the polymicrobial nature of the disease. Antigens that have been extensively tested in animal models are now available for testing in human subjects.
Article Reference Bacterial otitis media: a vaccine preventable disease?
Otitis media (OM) is the most common childhood illness for which medical advice is sought. Whilst the disease rarely results in death, there is a significant level of morbidity and economic burden on the community. Although the causes of OM are multifactoral, bacterial and viral infections are the single most important cause. Bacteria responsible for infections of the middle ear are predominantly, nontypeable Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Antibiotics have been widely used to treat children who present to a medical clinic with OM. However, given the high prevalence of this disease and the increasing incidence of microbial resistance to antibiotics, there is a need to develop alternative therapeutic strategies such as vaccination. Pneumococcal polysaccharide vaccination has produced disappointing results for effectiveness in preventing OM and there is evidence of an increased incidence of disease due to non-vaccine serotypes. An efficacious vaccine for bacterial OM would require combining protective protein antigens from all three causative bacteria. A combined bacterial-viral vaccine formulation would produce the most profound and sustained impact on reducing the global incidence of OM.
Article Reference Human neutrophil elastase degrades SPLUNC1 and impairs airway epithelial defense against bacteria.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a significant cause of mortality of COPD patients, and pose a huge burden on healthcare. One of the major causes of AECOPD is airway bacterial (e.g. nontypeable Haemophilus influenzae [NTHi]) infection. However, the mechanisms underlying bacterial infections during AECOPD remain poorly understood. As neutrophilic inflammation including increased release of human neutrophil elastase (HNE) is a salient feature of AECOPD, we hypothesized that HNE impairs airway epithelial defense against NTHi by degrading airway epithelial host defense proteins such as short palate, lung, and nasal epithelium clone 1 (SPLUNC1).
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