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Article Reference Activation of the transforming growth factor beta pathway in bacterial otitis media.
Granulation tissue is common in otitis media (OM), yet little is known about the signaling pathways in the formation of granulation tissue in response to infections. In this study, we sought to investigate the activation of the transforming growth factor beta (TGF-beta) signaling pathway in the formation of granulation tissue in response to middle ear pathogens.
Article Reference Transcutaneous immunization as preventative and therapeutic regimens to protect against experimental otitis media due to nontypeable Haemophilus influenzae.
We have developed three nontypeable Haemophilus influenzae (NTHI) adhesin-derived immunogens that are significantly efficacious against experimental otitis media (OM) due to NTHI when delivered parenterally. We now expanded our preventative immunization strategies to include transcutaneous immunization (TCI) as a less invasive, but potentially equally efficacious, regimen to prevent OM due to NTHI. Additionally, we examined the potential of TCI as a therapeutic immunization regimen to resolve ongoing experimental OM. Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone. Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls. These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM.
Article Reference The role of DNA sensing and innate immune receptor TLR9 in otitis media.
Otitis media (OM), a common infectious disease in children, is associated with bacterial middle ear (ME) infection. Toll-like receptors (TLRs) are important mediators of innate immune responses, and TLR9 specifically recognizes the unmethylated cytidine-phosphate-guanosine (CpG) motifs in bacterial DNA. Additional sensors of foreign DNA have recently been identified. The role of DNA sensing and TLR9 was investigated in a murine model of OM induced by non-typeable Haemophilus influenzae (NTHi). Expression of genes related to DNA-sensing pathways involved in innate immunity was assessed via DNA microarray, qPCR and immunohistochemistry. Middle ear responses to NTHi were examined in wild-type and TLR9(-/-) mice by histopathology and bacterial culture. Expression of TLR9 signaling genes was modestly up-regulated during OM, as was TLR9 protein in both ME mucosal cells and infiltrating leukocytes. However, genes known to be regulated by CpG DNA were dramatically up-regulated, as were genes involved in DNA sensing by DIA, Pol-III and AIM2. Toll-like receptor 9 deletion significantly prolonged the inflammatory response induced by NTHi in the ME and delayed bacterial clearance. The results suggest that DNA sensing via TLR9 plays a role in OM pathogenesis and recovery. Alternative forms of DNA sensing may also contribute to OM.
Article Reference Divergent mechanisms for passive pneumococcal resistance to β-lactam antibiotics in the presence of Haemophilus influenzae.
Otitis media, for which antibiotic treatment failure is increasingly common, is a leading pediatric public health problem.
Article Reference Non-typeable Haemophilus influenzae and Streptococcus pneumoniae as primary causes of acute otitis media in colombian children: a prospective study.
Acute otitis media (AOM) is one of the most frequently encountered bacterial infections in children aged < 5 years; Streptococcus pneumoniae (S. pneumoniae) and non-typeable Haemophilus influenzae (NTHi) are historically identified as primary AOM causes. Nevertheless, recent data on bacterial pathogens causing AOM in Latin America are limited. This prospective study aimed to identify and characterize bacterial etiology and serotypes of AOM cases including antimicrobial susceptibility in < 5 year old Colombian children.
Article Reference Carriage of Haemophilus influenzae among Brazilian children attending day care centers in the era of widespread Hib vaccination.
Haemophilus influenzae type b vaccine was introduced into the Immunization Program of Brazil in 1999 and no study has evaluated the impact of Hib vaccination in H. influenzae carriage so far. In June 2010, Brazil introduced the 10-valent pneumococcal nontypeable H. influenzae (NTHi) conjugate vaccine (PHiD-CV). We investigated the prevalence of encapsulated H. influenzae and NTHi isolates in nasopharyngeal samples of 1192 children attending day-care centers in Goiânia, central Brazil. H. influenzae carriage rate was 32.1% and 38.4% of them carried β-lactamase TEM-1 gene. Serotype f (4.6%) was the most frequent encapsulated isolate, type b was recovered in only 0.7% and carriage rate of NTHi was 23.3%. Recurrent acute otitis media and NTHi were independently associated with colonization by β-lactamase producing H. influenzae. Changes in frequency of H. influenzae carriage isolates should be carefully monitored to assess the impact of the PHiD-CV on NTHi carriage in young children.
Article Reference Abrogation of nontypeable Haemophilus influenzae protein D function reduces phosphorylcholine decoration, adherence to airway epithelial cells, and fitness in a chinchilla model of otitis media.
The pneumococcal polysaccharide conjugate vaccine which includes a nonacylated protein D carrier from Haemophilus influenzae has been recently licensed for use in many countries. While this vaccine is protective against nontypeable Haemophilus influenzae (NTHI)-induced acute otitis media (OM), the mechanism underlying this protective efficacy is not yet fully understood. Protein D/glycerophosphodiester phosphodiesterase (PD/GlpQ) is an outer membrane lipoprotein expressed by NTHI that has been ascribed several functions, including host cell adherence and phosphorylcholine (PCho) acquisition. We found that a pd/glpQ NTHI mutant exhibited reduced adherence to airway epithelial cells, diminished phosphorylcholine (PCho) decoration of biofilms, and compromised fitness during experimental acute OM compared to the parent strain. We also found that exposure of NTHI to antibodies directed against the vaccine formulation recapitulated the PCho decoration and NTHI adherence phenotypes exhibited by PD/GlpQ-deficient NTHI, providing at least two likely mechanisms by which the pneumococcal polysaccharide-PD/GlpQ conjugate vaccine induces protection from NTHI-induced OM.
Article Reference Serum antibody response to three non-typeable Haemophilus influenzae outer membrane proteins during acute otitis media and nasopharyngeal colonization in otitis prone and non-otitis prone children.
Non-typeable Haemophilus influenzae (NTHi) is the most common bacteria responsible for episodic acute otitis media (AOM; non-otitis prone), recurrent AOM (rAOM; otitis prone) and AOM treatment failure (AOMTF) in children. In this 3.5 years of prospective study, we measured the serum antibody response to outer membrane proteins D, P6 and OMP26 of NTHi in children with AOM (n=26), rAOM (n=32), AOMTF (n=27). The geometric mean titers (GMTs) of IgG at their acute AOM visit against Protein D in otitis prone children were significantly lower compared to AOMTF (p value<0.01) and non-otitis prone (p value<0.03) children; otitis prone children had significantly lower IgG levels to P6 compared to AOMTF children (p value<0.02); otitis prone children had significantly lower IgG levels to OMP26 compared to AOMTF children (p value<0.04). Comparing acute to convalescent titers after AOM, otitis prone and AOMTF children had no significant change in total IgG against all the three proteins, while non-otitis prone children had significant increases to Protein D. Anti-protein D, P6 and OMP26 antibody levels measured longitudinally during NP colonization between age 6 and 24 months in 10 otitis prone children and 150 non-otitis prone children showed <2-fold increases over time in otitis prone children compared to >4 fold increases in the non-otitis prone children (p value<0.001). We conclude that otitis prone children mount less of an IgG serum antibody response toward Protein D, P6 and OMP26 after AOM which may account for recurrent infections. The data on acute sera of otitis prone vs non-otitis prone children and the acute-to-convalescence response in non-otitis prone children point to a possible link of anti-PD to protection. Moreover, the data suggest that otitis prone children should be evaluated for their responses to Protein D, P6 and OMP26 vaccine antigens of NTHi.
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 Spiral ligament fibrocyte-derived MCP-1/CCL2 contributes to inner ear inflammation secondary to nontypeable H. influenzae-induced otitis media.
Otitis media (OM), one of the most common pediatric infectious diseases, causes inner ear inflammation resulting in vertigo and sensorineural hearing loss. Previously, we showed that spiral ligament fibrocytes (SLFs) recognize OM pathogens and up-regulate chemokines. Here, we aim to determine a key molecule derived from SLFs, contributing to OM-induced inner ear inflammation.
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 The multifunctional host defense peptide SPLUNC1 is critical for homeostasis of the mammalian upper airway.
Otitis media (OM) is a highly prevalent pediatric disease caused by normal flora of the nasopharynx that ascend the Eustachian tube and enter the middle ear. As OM is a disease of opportunity, it is critical to gain an increased understanding of immune system components that are operational in the upper airway and aid in prevention of this disease. SPLUNC1 is an antimicrobial host defense peptide that is hypothesized to contribute to the health of the airway both through bactericidal and non-bactericidal mechanisms. We used small interfering RNA (siRNA) technology to knock down expression of the chinchilla ortholog of human SPLUNC1 (cSPLUNC1) to begin to determine the role that this protein played in prevention of OM. We showed that knock down of cSPLUNC1 expression did not impact survival of nontypeable Haemophilus influenzae, a predominant causative agent of OM, in the chinchilla middle ear under the conditions tested. In contrast, expression of cSPLUNC1 was essential for maintenance of middle ear pressure and efficient mucociliary clearance, key defense mechanisms of the tubotympanum. Collectively, our data have provided the first in vivo evidence that cSPLUNC1 functions to maintain homeostasis of the upper airway and, thereby, is critical for protection of the middle ear.
Article Reference Serum intercellular adhesion molecule 1 variations in young children with acute otitis media.
Acute otitis media (AOM) is an inflammatory reaction in the middle ear, most often occurring in young children. Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis are the most common bacteria isolated. Intercellular adhesion molecule 1 (ICAM-1) is involved in the innate immune response to infection by microorganisms, in effective antigen presentation, and in subsequent T-cell activation. Here we prospectively studied levels of serum soluble ICAM-1 (sICAM-1) before, at the time of, and after antimicrobial treatment of AOM in a group of 138 children ages 6 to 30 months. Middle ear fluids were collected by tympanocentesis to identify otopathogens. We found that (i) serum levels of sICAM-1 were significantly higher in S. pneumoniae-, nontypeable H. influenzae-, and M. catarrhalis-infected children than in well children (P < 0.001), confirming that a systemic inflammatory response occurs during AOM; (ii) sICAM-1 levels varied from no elevation (110 ng/ml) to elevation to high levels (maximum, 1,470 ng/ml) among children with AOM; (iii) in paired samples, sICAM-1 levels increased 4- to 20-fold when children developed AOM compared to their sICAM-1 levels before infection; and (iv) the level of sICAM-1 returned to the pre-AOM level at the convalescent stage of AOM after successful antimicrobial therapy. We conclude that AOM often causes a systemic inflammatory reaction, as measured by elevation of the serum sICAM-1 level, and that a high variability in sICAM-1 responses occurs with the presence of otopathogens during AOM.
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 Antibody response to Haemophilus influenzae outer membrane protein D, P6, and OMP26 after nasopharyngeal colonization and acute otitis media in children.
Development of natural antibodies to 3 nontypeable Haemophilus influenzae (NTHi) outer membrane proteins (D, P6 and OMP26) was prospectively studied in 130 children 6-30 months of age during NP colonization and acute otitis media (AOM). IgG antibody to protein D, P6 and OMP26 increased with age (p<0.001). Serum IgG responses to NP colonization were different for the 3 proteins: protein D responses occurred at a later age than P6, and OMP26 responses were minimal. For all 3 proteins serum antibody levels in the convalescent phase of AOM infection were not as high as after NP colonization. Antibodies to protein D and P6 but not OMP26 were bactericidal.
Article Reference Coinfection with Haemophilus influenzae promotes pneumococcal biofilm formation during experimental otitis media and impedes the progression of pneumococcal disease.
Otitis media is an extremely common pediatric infection and is mostly caused by bacteria that are carried within the nasopharyngeal microbiota. It is clear that most otitis media cases involve simultaneous infection with multiple agents.
Article Reference Appropriate treatment of acute otitis media in the era of antibiotic resistance.
The outcome of treatment for acute otitis media (AOM) differs between various antibiotic drugs. Outcome depends upon the drugs' pharmacokinetics, but in the case of infectious diseases also on the susceptibility of the organism and the interaction between the drug and the organisms at the specific site of infection (pharmacodynamics). In the era of antibiotic resistance, it is thus important to understand the pharmacokinetics/pharmacodynamics of the various available drugs in the context of AOM and its main two pathogens, Streptococcus pneumoniae and non-typeable Haemophilus influenzae. In terms of clinical outcome, it is also important to realize that AOM is a self-limiting disease in most cases, so that response to treatment is always compared with the expected background response when not treated. A favourable clinical outcome (cure/improvement) at the end of the treatment period is expected for those in whom the pathogens are eradicated within 3-5 days, thus clinical failure rates are several fold lower in children with early eradication (within 3-5 days) compared with those in whom no early eradication takes place. Because of the higher spontaneous bacterial elimination this might not always be appreciated. In this review, the relationship between antibiotic resistance, the various antibiotic drugs and their pharmacokinetic/pharmacodynamic patterns, the bacteriological outcome and clinical outcomes are addressed. This review is meant to assist the clinician in both a better understanding of the current recommendations for the treatment of AOM and the steps to be taken to follow AOM patients.
Article Reference Nasopharyngeal carriage of Haemophilus haemolyticus in otitis-prone and healthy children.
Haemophilus haemolyticus is often incorrectly categorized as nontypeable Haemophilus influenzae (NTHI) upon culture. PCR analyses of 266 NTHI-like nasopharyngeal isolates from children with and without recurrent acute otitis media (rAOM) revealed that 11.7% were H. haemolyticus and 9.4% gave equivocal results. Children with rAOM were more likely to carry H. haemolyticus.
Article Reference CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/- mice.
Innate immune mechanisms are crucial in defense against bacterial illnesses in humans, as evidenced by abnormal antibacterial responses due to defects in TLR signaling, seen in children with MyD88 or IL-1R-associated kinase 4 deficiency. Otitis media (OM) is the most common disease of childhood, and the role of innate immune molecules in this disorder remains unclear. In a murine model of OM, we show that, in the absence of TNF, a key effector of innate immunity, this disease is prolonged after middle ear infection with nontypeable Haemophilus influenzae (NTHi). In the absence of TNF, mice fail to upregulate both TLRs and downstream genes and proteins, such as CCL3, resulting in defects in both inflammatory cell recruitment and macrophage function. Peritoneal macrophages of mice lacking TNF have a diminished ability to phagocytose and kill NTHi, and this defect is partially corrected in vitro by exogenous rTNF. Addition of rCCL3 alone or in combination with rTNF restores phagocytosis and killing by TNF-deficient macrophages to that of unstimulated wild-type macrophages. In vivo administration of rCCL3 to animals deficient in TNF fully restores the ability to control OM due to NTHi, whereas a CCL3-blocking Ab impaired the ability of wild-type mice to recover from OM. Thus, CCL3 is a potent downstream effector of TNF-mediated inflammation in vitro and in vivo. Manipulation of CCL3 and/or TNF may prove to be effective therapeutic approaches in OM or other conditions associated with defective TNF generation.
Article Reference Current management of pediatric acute otitis media.
Acute otitis media (AOM) is the most common childhood bacterial infection for which antibiotics are prescribed worldwide. The most common pathogens causing AOM in children are Streptococcus pneumoniae, nontypeable Haemophilus influenzae, Moraxella catarrhalis and Group A streptococcus. Antibiotic resistance is increasing among the bacterial pathogens causing AOM, with percentages of penicillin- and macrolide-resistant S. pneumoniae strains estimated to be between 30 and 70%, and of beta-lactamase-producing H. influenzae ranging between 20 and 40%. The introduction of the seven-valent pneumococcal conjugated vaccine had a major role in decreasing the number of vaccine-related S. pneumoniae AOM episodes, recurrent AOM cases and cases requiring the insertion of ventilation tubes. In parallel, it caused a rapid shift in the microbiology of AOM, characterized by an increase in the number of non-vaccine S. pneumoniae serotypes and H. influenzae isolates. The management of AOM in childhood has evolved considerably during recent years as a result of the new insights provided by the publication of the American Academy of Pediatrics and American Academy of Family Physicians guidelines for the treatment of AOM. The new treatment guidelines establish a clear hierarchy among various antibacterials used in the treatment of AOM and also the use of an age-stratified approach to AOM by recommending an observation strategy ('watchful waiting') without the use of antibacterials for some groups of AOM patients. Adherence to such a policy in patients with uncertain/questionable AOM diagnosis and/or mild-to-moderate symptoms, in addition to its implementation in patients over 2 years of age, could substantially reduce the use of antibacterials for the treatment of AOM and play a major role in the strategy of decreasing antibacterial resistance.