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Concept: Haemophilus influenzae

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Sustained high coverage with recommended vaccinations among children has kept many vaccine-preventable diseases at low levels in the United States (1). To assess coverage with vaccinations recommended for children by age 2 years in the United States (2), CDC analyzed data collected by the 2015 National Immunization Survey (NIS) for children aged 19-35 months (born January 2012-May 2014). Overall, coverage did not change during 2014-2015. Coverage in 2015 was highest for ≥3 doses of poliovirus vaccine (93.7%), ≥3 doses of hepatitis B vaccine (HepB) (92.6%), ≥1 dose of measles, mumps, and rubella vaccine (MMR) (91.9%), and ≥1 dose of varicella vaccine (91.8%). The data were also examined for potential vaccination coverage differences by race/ethnicity, poverty status, and urbanicity. Although disparities were noted for each of these factors, the most striking differences were seen for poverty status. Children living below the federal poverty level* had lower coverage with most of the vaccinations assessed compared with children living at or above the poverty level; the largest disparities were for rotavirus vaccine (66.8% versus 76.8%), ≥4 doses of pneumococcal conjugate vaccine (PCV) (78.9% versus 87.2%), the full series of Haemophilus influenzae type b vaccine (Hib) (78.1% versus 85.5%), and ≥4 doses of diphtheria, tetanus, and acellular pertussis vaccine (DTaP) (80.2% versus 87.1%). Although coverage was high in some groups, opportunities exist to continue to address disparities. Implementation of evidence-based interventions, including strategies to enhance access to vaccination services and systems strategies that can reduce missed opportunities, has the potential to increase vaccination coverage for children living below the poverty level and in rural areas (3).

Concepts: Pneumonia, Vaccine, Poverty in the United States, MMR vaccine, Measles, Haemophilus influenzae, Pertussis, Vaccines

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Immunization with pneumococcal vaccines is an important prophylactic strategy for children with asplenia or splenic dysfunction, who are at high risk of bacterial infections (including S. pneumoniae). This study aimed to assess immunogenicity and safety of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, GSK) in this at-risk population.

Concepts: Immune system, Microbiology, Pneumonia, Streptococcus pneumoniae, Pneumococcal conjugate vaccine, Otitis media, Haemophilus influenzae, Polysaccharide encapsulated bacteria

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In the post-Haemophilus influenzae type b (Hib) vaccine era that began in the 1980’s, H. influenzae type a (Hia) emerged as a prominent cause of invasive disease in North American Aboriginal populations. To test whether a lack of naturally acquired antibodies may underlie increased rates of invasive Hia disease, we compared serum bactericidal activity against Hia and Hib and IgG and IgM against capsular polysaccharide between Canadian Aboriginal and non-Aboriginal healthy and immunocompromised adults. Both healthy and immunocompromised Aboriginal adults exhibited significantly higher bactericidal antibody titers against Hia than did non-Aboriginal adults (p = 0.042 and 0.045 respectively), with no difference in functional antibody activity against Hib. IgM concentrations against Hia were higher than IgG in most study groups; the inverse was true for antibody concentrations against Hib. Our results indicate that Aboriginal adults possess substantial serum bactericidal activity against Hia that is mostly due to IgM antibodies. The presence of sustained IgM against Hia suggests recent Hia exposure.

Concepts: Immune system, Glycoproteins, Immunology, Antigen, Antibodies, Haemophilus influenzae, Haemophilus, Pasteurellaceae

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Otitis media is the most common reason U.S. children receive antibiotics. The requisite 7- to 10-day course of oral antibiotics can be challenging to deliver in children, entails potential systemic toxicity, and encourages selection of antimicrobial-resistant bacteria. We developed a drug delivery system that, when applied once to the tympanic membrane through the external auditory canal, delivers an entire course of antimicrobial therapy to the middle ear. A pentablock copolymer poloxamer 407-polybutylphosphoester (P407-PBP) was designed to flow easily during application and then to form a mechanically strong hydrogel on the tympanic membrane. U.S. Food and Drug Administration-approved chemical permeation enhancers within the hydrogel assisted flux of the antibiotic ciprofloxacin across the membrane. This drug delivery system completely eradicated otitis media from nontypable Haemophilus influenzae (NTHi) in 10 of 10 chinchillas, whereas only 62.5% of animals receiving 1% ciprofloxacin alone had cleared the infection by day 7. The hydrogel system was biocompatible in the ear, and ciprofloxacin was undetectable systemically (in blood), confirming local drug delivery and activity. This fast-gelling hydrogel could improve compliance, minimize side effects, and prevent systemic distribution of antibiotics in one of the most common pediatric illnesses, possibly minimizing the development of antibiotic resistance.

Concepts: Medicine, Bacteria, Auditory system, Otitis media, Ear, Penicillin, Clostridium difficile, Haemophilus influenzae

52

Otitis media (OM) is the most common childhood bacterial infection, and leading cause of conductive hearing loss. Nontypeable Haemophilus influenzae (NTHi) is a major bacterial pathogen for OM. OM characterized by the presence of overactive inflammatory responses is due to the aberrant production of inflammatory mediators including C-X-C motif chemokine ligand 5 (CXCL5). The molecular mechanism underlying induction of CXCL5 by NTHi is unknown. Here we show that NTHi up-regulates CXCL5 expression by activating IKKβ-IκBα and p38 MAPK pathways via NF-κB nuclear translocation-dependent and -independent mechanism in middle ear epithelial cells. Current therapies for OM are ineffective due to the emergence of antibiotic-resistant NTHi strains and risk of side effects with prolonged use of immunosuppressant drugs. In this study, we show that curcumin, derived from Curcuma longa plant, long known for its medicinal properties, inhibited NTHi-induced CXCL5 expression in vitro and in vivo. Curcumin suppressed CXCL5 expression by direct inhibition of IKKβ phosphorylation, and inhibition of p38 MAPK via induction of negative regulator MKP-1. Thus, identification of curcumin as a potential therapeutic for treating OM is of particular translational significance due to the attractiveness of targeting overactive inflammation without significant adverse effects.

Concepts: Immune system, Inflammation, Bacteria, Infection, Chemokine, Otitis media, Haemophilus influenzae, Turmeric

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Vaccination is the most effective intervention to reduce morbidity and mortality from vaccine-preventable diseases in young children (1). Data from the 2016 National Immunization Survey-Child (NIS-Child) were used to assess coverage with recommended vaccines (2) among children aged 19-35 months in the United States. Coverage remained ≥90% for ≥3 doses of poliovirus vaccine (91.9%), ≥1 dose of measles, mumps, and rubella vaccine (MMR) (91.1%), ≥1 dose of varicella vaccine (90.6%), and ≥3 doses of hepatitis B vaccine (HepB) (90.5%). Coverage in 2016 was approximately 1-2 percentage points lower than in 2015 for ≥3 doses of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), ≥3 doses of poliovirus vaccine, the primary Haemophilus influenzae type b (Hib) series, ≥3 HepB doses, and ≥3 and ≥4 doses of pneumococcal conjugate vaccine (PCV), with no changes for other vaccines. More direct evaluation of trends by month and year of birth (3) found no change in coverage by age 2 years among children included in combined data from the 2015 and 2016 NIS-Child (born January 2012 through January 2015). The observed decreases in annual estimates might result from random differences in vaccination coverage by age 19 months between children sampled in 2016 and those sampled in 2015, among those birth cohorts eligible to be sampled in both survey years. For most vaccines, 2016 coverage was lower among non-Hispanic black* (black) children than among non-Hispanic white (white) children, and for children living below the federal poverty level(†) compared with those living at or above the poverty level. Vaccination coverage was generally lower among children insured by Medicaid (2.5-12.0 percentage points), and was much lower among uninsured children (12.4-24.9 percentage points), than among children with private insurance. The Vaccines for Children(§) (VFC) program was designed to increase access to vaccines among children who might not otherwise be vaccinated because of inability to pay. Greater awareness and facilitating use of VFC might be helpful in reducing these disparities. Efforts should also be focused on minimizing breaks in continuity of health insurance and eliminating missed opportunities to vaccinate children during visits to health care providers. Despite the observed disparities and small changes in coverage from 2015, vaccination coverage among children aged 19-35 months remained high and stable in 2016.

Concepts: Pneumonia, Vaccine, Vaccination, Vaccination schedule, Measles, Haemophilus influenzae, Pertussis, Vaccines

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BACKGROUND: The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the effectiveness of a pneumococcal vaccine containing ten serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins (PHiD-CV10) against invasive pneumococcal disease. METHODS: In this cluster-randomised, double-blind trial, children aged younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants aged younger than 7 months at the first vaccination received either a 3+1 or a 2+1 vaccination schedule, children aged 7-11 months received a 2+1 schedule, and those 12-18 months of age received a two-dose schedule. The primary and secondary objectives were to assess vaccine effectiveness against culture-confirmed invasive pneumococcal disease due to any of the ten vaccine serotypes for the 3+1 and 2+1 schedules, respectively, in children who received at least one PHiD-CV10 dose before 7 months of age. Masked follow-up of pneumococcal disease lasted from the first vaccination (from February, 2009, to October, 2010) to January 31, 2012. Invasive disease data were retrieved from data accumulated in the national infectious diseases register. This trial and the nested acute otitis media trial are registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254, respectively. FINDINGS: 47 369 children were enrolled from February, 2009, to October, 2010. 30 528 participants were assessed for the primary objective. 13 culture-confirmed vaccine-type cases of invasive pneumococcal disease were detected: none in the PHiD-CV10 3+1 group, one in the PHiD-CV10 2+1 group, and 12 in the control groups. The estimates for vaccine effectiveness were 100% (95% CI 83-100) for PHiD-CV10 3+1 and 92% (58-100) for PHiD-CV10 2+1 groups. Two cases of any culture-confirmed invasive disease irrespective of serotype were detected in combined PHiD-CV10 infant cohorts compared with 14 in the corresponding control cohorts (vaccine effectiveness 93%, 75-99). In catch-up cohorts, seven cases of invasive disease were reported, all in the control group: two cases in the children enrolled at 7-11 months of age; and five cases in children enrolled at 12-18 months of age (vaccine effectiveness 100%, 79-100). Non-fatal serious adverse events suspected to be vaccine-related were reported via routine post-immunisation safety surveillance in 18 children. INTERPRETATION: This nationwide trial showed high PHiD-CV10 effectiveness against invasive pneumococcal disease when given in different schedules. For the first time, effectiveness of a 2+1 schedule in infants was confirmed in a clinical trial. FUNDING: GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare, Finland.

Concepts: Streptococcus pneumoniae, Vaccine, Vaccination, Otitis media, Haemophilus influenzae

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Myeloid differentiation factor 88 (MyD88) acts as a crucial adaptor molecule for Toll-like receptors (TLRs) and interleukin (IL)-1 receptor signaling. In contrast to the well-studied positive regulation of MyD88 signaling, how MyD88 signaling is negatively regulated still remains largely unknown. Here, we demonstrate for the first time to our knowledge that MyD88 protein undergoes lysine 63 (K63)-linked polyubiquitination, which is functionally critical for mediating TLR-MyD88-dependent signaling. Deubiquitinase CYLD negatively regulates MyD88-mediated signaling by directly interacting with MyD88 and deubiquitinating nontypeable Haemophilus influenzae (NTHi)-induced K63-linked polyubiquitination of MyD88 at lysine 231. Importantly, we further confirmed this finding in the lungs of mice in vivo by using MyD88(-/-)CYLD(-/-) mice. Understanding how CYLD deubiquitinates K63-linked polyubiquitination of MyD88 may not only bring insights into the negative regulation of TLR-MyD88-dependent signaling, but may also lead to the development of a previously unidentified therapeutic strategy for uncontrolled inflammation.

Concepts: Immune system, Protein, Pneumonia, Toll-like receptor, Receptor, Haemophilus influenzae, Receptors, Regulatory agency

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The human pathogen Haemophilus influenzae causes mainly respiratory tract infections such as acute otitis media in children and exacerbations in patients with chronic obstructive pulmonary disease. We recently revealed the crystal structure of H. influenzeae protein E (PE), a multifunctional adhesin that is involved in direct interactions with lung epithelial cells and host proteins. Based upon the PE structure we here suggest a hypothetical binding pocket that is compatible in size with a hemin molecule. An H. influenzae mutant devoid of PE bound significantly less hemin in comparison to the PE-expressing wild type counterpart. In addition, E. coli expressing PE at the surface resulted in a hemin-binding phenotype. An interaction between hemin and recombinant soluble PE was also demonstrated by native-PAGE and UV-visible spectrophotometry. Surface plasmon resonance revealed an affinity (Kd) of 1.6×10(-6)M for the hemin-PE interaction. Importantly, hemin that was bound to PE at the H. influenzae surface, was donated to co-cultured luciferase-expressing H. influenzae that were starved of hemin. When hemin is bound to PE it thus may serve as a storage pool for H. influenzae. To our knowledge this is the first report showing that H. influenzae can share hemin via a surface-located outer membrane protein.

Concepts: Protein, Gene, Lung, Pneumonia, Escherichia coli, Otitis media, Surface plasmon resonance, Haemophilus influenzae

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AIM: Community-acquired pneumonia (CAP) is presumed to be bacterial in origin and empirical antibiotics are almost always given on admission. However, early detection of viral infection is also very important for hospital infection control and timely use of antiviral agents. The present study aimed to compare patients with viral and bacterial pneumonia, and identify independent predictors of viral pneumonia. METHODS: A prospective cohort study was carried out in a tertiary teaching hospital in a 1-year period. Older patients (aged ≥65 years) were recruited if they were admitted for CAP confirmed by chest radiographs. RESULTS: A cohort of 488 patients was analyzed. Infective causes were found in 137 (28.1%) patients. Bacterial, viral and mixed infections were detected in 86 (17.6%), 41 (8.4%) and 10 (2.0%) patients, respectively. Bacteriology was established mostly by sputum culture and virology by nasopharyngeal aspirate (NPA) viral culture. The commonest bacterial isolates were Haemophilus influenzae (31), Pseudomonas aeruginosa (15), Mycobacterium tuberculosis (14), Klebsiella spp. (9) and Streptococcus pneumoniae (6). Influenza A virus (28, 8 were pandemic 2009 A/H1N1 subtype) and respiratory syncytial virus (16) were the most frequent viral causes. Independent predictors of viral pneumonia included nursing home residence (RR 3.056, P = 0.009) and absence of leukocytosis (RR 0.425, P = 0.026). CONCLUSIONS: All nursing home residents hospitalized for CAP should undergo NPA viral testing because of infection control, early antiviral treatment and discharge planning. We suggest that empirical antiviral agents might be considered for nursing home residents hospitalized for CAP if outbreaks of influenza-like illness are reported in nursing homes. Geriatr Gerontol Int 2013; ●●: ●●-●●.

Concepts: Immune system, Bacteria, Microbiology, Virus, Pneumonia, Streptococcus pneumoniae, Influenza, Haemophilus influenzae