Respiratory infections caused by non-typeable Haemophilus influenzae

PURPOSE OF REVIEW: This review will consider recent developments in the clinical aspects of infections due to non-typeable Haemophilus influenzae. In addition, newer developments in the areas of mechanisms of pathogenesis, host pathogen interaction, immune responses and efforts toward vaccine development will be reviewed briefly. RECENT FINDINGS: Non-typeable H. influenzae continues to be a common cause of otitis media in infants and children, sinusitis in children and adults, pneumonia in adults, and lower respiratory tract infection in adults with chronic obstructive pulmonary disease. While the rate of beta-lactamase production by isolates of H. influenzae varies geographically, most regions show a rate of 20-35% of isolates producing beta-lactamase. Recent studies have highlighted the possible role of bacterial biofilms formed by H. influenzae as a cause of otitis media. Several lines of evidence indicate that H. influenzae causes intracellular infection in the lower respiratory tract in chronic obstructive pulmonary disease and this observation has important implications in understanding the human immune response to the bacterium. Lipooligosaccharide is an important virulence factor for H. influenzae and research is generating new information on the complex role of this molecule in colonization and infection of the respiratory tract. Several surface molecules are under active evaluation as vaccine antigens. SUMMARY: Non-typeable H. influenzae is an important cause of respiratory tract infections in children and adults. Most strains are susceptible to amoxicillin/clavulanate, fluoroquinolones and the newer macrolides. Research in the next decade promises substantial progress in the challenge of developing vaccines for nontypeable H. influenzae.     

Investigation of Streptococcus pneumoniae and Haemophilus influenzae isolated from pediatric outpatients nationwide with a respiratory tract infection at the first consultation (2002-2003)--with special reference to the results of nasopharyngeal culture in pediatric patients with no previous history of antibacterial drug administration

We previously reported that penicillin-resistant Streptococcus pneumoniae (PRSP) and beta-lactamase-nonproducing ampicillin-resistant (BLNAR) were detected at a frequency of 27% and 35% in 468 strains of Streptococcus pneumoniae and 557 strains of Haemophilus influenzae isolated from pediatric patients diagnosed with respiratory infection in 20 pediatric outpatient facilities throughout Japan between November 2002 and June 2003. Here, we have added additional considerations regarding results of nasopharyngeal culture from 558 pediatric patients diagnosed with pneumonia, bronchitis, or otitis media and having no previous history of antibacterial drug administration. No significant difference was seen in the detection of S. pneumoniae or H. influenzae between nasal and oral specimens, or between patients with pneumonia, bronchitis, and otitis media. The detection of S. pneumoniae in pediatric patients 4 years old was significantly higher, however than that in pediatric patients 5 years old. The detection of H. influenzae in pediatric patients with a history of attending group childcare facilities was significantly higher than that in pediatric patients with no such history. No significant differences were seen among groups in the percentage of PSRP and BLNAR isolated among S. pneumoniae and H. influenzae strains. Nasopharyngeal culture of pediatric patients with respiratory infection yielded a higher frequency of S. pneumoniae in younger than older patients and a higher frequency of H. influenzae in pediatric patients with a history of attending group childcare facilities. The detection of resistant bacteria was considered related to other factors, such as the type of antibacterial drugs used, that are not discussed here.     

Protein D of Haemophilus influenzae: a protective nontypeable H. influenzae antigen and a carrier for pneumococcal conjugate vaccines.

Protein D (PD) is a highly conserved 42 kDa surface lipoprotein found in all Haemophilus influenzae, including nontypeable (NT) H. influenzae. PD is involved in the pathogenesis of respiratory tract infections, in the context of which it has been shown to impair ciliary function in a human nasopharyngeal tissue culture model and to augment the capacity to cause otitis media in rats. A likely mechanism indicating that PD is a virulence factor is its glycerophosphodiesterase activity, which leads to the release of phosphorylcholine from host epithelial cells. PD has been demonstrated to be a promising vaccine candidate against experimental NT H. influenzae infection. Rats vaccinated with PD cleared NT H. influenzae better after middle ear and pulmonary bacterial challenge, and chinchillas vaccinated with PD showed significant protection against NT H. influenzae-dependent acute otitis media. In a clinical trial involving children, PD was used as an antigenically active carrier protein in an 11-valent pneumococcal conjugate investigational vaccine; significant protection was achieved against acute otitis media not only caused by pneumococci but also caused by NT H. influenzae. This may have great clinical implications, because PD is the first NT H. influenzae antigen that has induced protective responses in humans.     

Nontypable Haemophilus influenzae: a review of clinical aspects, surface antigens, and the human immune response to infection

Nontypable Haemophilus influenzae has now become well established as an important pathogen in both adults and children. Recent work has identified clear distinctions between nontypable and type b strains of H. influenzae. These organisms affect different patient populations, cause different infections, present different surface antigens to the host, and are genetically different. The commonest clinical manifestation of infection due to nontypable H. influenzae in adults is lower respiratory tract infection, particularly in the elderly and in those with chronic bronchitis. The bacterium is a frequent cause of acute otitis media in children. The surface of nontypable H. influenzae is composed of outer-membrane proteins and lipooligosaccharide, and both of these demonstrate substantial antigenic heterogeneity, which can be used to serotype isolates. Some respiratory tract isolates are fimbriated, but the role of fimbriae in pathogenesis is unclear. Antibodies to outer-membrane proteins and lipooligosaccharide are present in human serum. Investigation of human immunity to infection is focusing on identification of those antigens to which protective antibody is directed.     

流感嗜血杆菌血清分型及其产酶率的初步研究

目的 了解上海地区流感嗜血杆菌感染株，携带株的血清型及主要血清型的β内酰胺酶产生率。方法 收集急性上，下呼吸道感染患的痰及咽拭子等标本５３４份及无呼吸道感染对照组咽拭子标本２５５份，应用改良哥伦比亚巧克力培养基进行分离培养；应用玻片凝集法及反向间接血凝法对分离出的Ｈｉ进行血清分型，并检测Ｈｉｂ和不可分型株产β内酰胺酶情况。     

Therapy of chronic recurrent respiratory tract infections

In 1987, the most frequently identified pathogens in chronic respiratory tract infections in our clinic were Haemophilus influenzae, Pseudomonas aeruginosa, Branhamella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae. Recurrent infection is a common phenomenon in patients with chronic respiratory tract infections, including chronic bronchitis, chronic bronchiolitis and bronchiectasis. H. influenzae is the most common pathogen in such patients. Macrolides, tetracyclines and new quinolones were effective to protect against recurrent infection of H. influenzae and these finding suggested that L-forms of H. influenzae may be significant in the recurrence of infection in patients with chronic respiratory tract infection. Bacterial colonization of the oropharynx is the initial event in most lower respiratory tract infections. Gargling protects against bacteria colonization of the oropharynx and occurrence of acute exacerbation.     

Comparative efficacies of different antibiotic treatments to eradicate nontypeable <Emphasis Type="Italic">Haemophilus influenzae</Emphasis>infection

Background  

Nonencapsulated and nontypeable Haemophilus influenzae (NTHi) is a major cause of human respiratory tract infections. Some strains of NTHi can cause invasive diseases such as septicemia and meningitis, even if H. influenzae is not generally considered to be an intracellular pathogen. There have been very few reports about the therapeutic efficacy of antibiotics against respiratory tract infection caused by NTHi in mice because it is difficult for H. influenzae to infect mice. Therefore, we evaluated the efficacy of antibiotics against NTHi in both a cell culture model and a mouse model of infection.     

Vaccine prevention of acute otitis media

The incidence of acute otitis media (AOM) in infants and young children has increased dramatically in recent years in the United States. AOM often follows upper respiratory tract infections due to pathogens such as respiratory syncytial virus (RSV), influenza virus, and parainfluenza virus (PIV). These viruses cause eustachian tube dysfunction that is critical to the pathogenesis of AOM. Vaccines against these viruses would likely reduce the incidence of AOM. In three previous studies, influenza virus vaccines reduced the incidence of AOM by 30% to 36%. Vaccines to prevent infections with RSV and PIV type 3 are undergoing clinical testing at this time. Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis are the three most common AOM pathogens. Heptavalent pneumococcal conjugate vaccine is effective in preventing invasive disease and AOM caused by serotypes contained in the vaccine. Vaccine candidates for NTHi and M. catarrhalis are under development.     

Colonization and transmission of Haemophilus influenzae type b (Hib)

Haemophilus influenzae type b (Hib) remains the leading cause of invasive bacterial infection in Japanese children. More than 110 countries that have included Hib conjugate vaccines in their routine vaccination programs have seen dramatical decrease in the incidence of Hib infections. In Japan, the vaccine has been introduced for voluntary immunization since December 2008 and has been provided free of charge only since January 2011. This review reports the prevalence of Hib and its clones among healthy children and pediatric patients diagnosed with invasive or non-invasive Hib infections in Sado Island, Japan. Of 25 Hib isolates collected in this surveillance, 4 genotypic patterns (ST54-gBLPACR-III, ST54-gBLNAR-I/II, ST190-gBLNAS, and ST95-gBLPACR-I/II) were detected. These STs were double or triple-locus variants of each other. Under the same antimicrobial selective pressure, high prevalence of gBLPACR strain (76.0%) was confirmed in Hib isolates, while gBLPACR prevalence in nontypeable H. influenzae was very low (5.2%). These data suggested that each ST strain may be brought into Sado Island by different routes. We note that surveillance of healthy subjects to identify Hib carriers is important to understand their role in transmission of Hib.     

Update on the development and use of viral and bacterial vaccines for the prevention of acute otitis media.

Acute otitis media (AOM) is the most frequent diagnosis in physician offices among children 1-4 years of age. Viruses that cause upper respiratory tract infections (i.e., respiratory syncytial virus [RSV], influenza virus, parainfluenza virus [PIV], and others) play an important role in the development of AOM. Prevention of infections with these viral pathogens likely would reduce the incidence of AOM. In three previous studies, influenza virus vaccines showed 30-36% efficacy against the development of AOM. Vaccines to prevent infections with RSV and PIV type 3 are undergoing clinical testing at this time. The three major bacterial pathogens causing AOM are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis. Pneumococcal conjugate vaccine, licensed in the United States in 2000, was shown in two pivotal trials to reduce the incidence of all causes of AOM by 6%, pneumococcal AOM by 34%, and pneumococcal AOM caused by serotypes contained in the vaccine by 57%. Currently, vaccines against NTHi and M. catarrhalis are under development.     

Pneumococcal vaccines: do they prevent infection and how?

PURPOSE OF REVIEW: The purpose of this review is to update and summarize information concerning the epidemiology of infections due to Streptococcus pneumoniae and the early results of effectiveness studies of the heptavalent pneumococcal conjugate vaccine. This vaccine was licensed in the US in 2000, and has been used increasingly since that time. RECENT FINDINGS: Several studies have documented a dramatic decline in the rate of invasive infections due to S. pneumoniae in children under 5 years of age. There has been a simultaneous decrease in serious infections in persons over 20 years of age, presumably because of a decrease in transmission of S. pneumoniae to unvaccinated individuals. Three different studies have shown a modest reduction in the overall number of cases of acute otitis media in children who have received the vaccine. Although the overall number of cases has decreased there has been an increase in the number of cases of acute otitis media caused by serotypes of S. pneumoniae not contained in the vaccine. Worldwide, many studies have appeared that examine the prevalence of different pneumococcal serotypes/serogroups as a cause of invasive and respiratory disease, to assess the likelihood that the vaccine will be effective in particular geographic areas. SUMMARY: Use of the heptavalent pneumococcal conjugate vaccine has led to a major decline in the prevalence of invasive pneumococcal disease (bacteremia, meningitis) and a more modest decrease in respiratory tract infections (acute otitis media, pneumonia). Continued surveillance is essential to document future trends in the occurrence of pneumococcal infections and the enduring protectiveness of the heptavalent pneumococcal conjugate vaccine.     

The frequency of non-typeable Haemophilus influenzae systemic disease in children

95 strains of Haemophilus influenzae (H. influenzae) isolated from blood of the patients with systemic infections were serotyped by staphylococcal coagglutination during the ten years from 1992 through 2001. As a result, 92 (96.8%) cases were caused by type b strains and 3 (3.2%) cases were caused by non-typeable strains. Three cases with systemic infection due to non-typeable H. influenzae were reported. One patient was a premature neonate with sepsis and respiratory failure who had a fulminant course and died. The other two patients were a 3-year-old girl and a 1-month-old boy both with pneumonia. About their underlying conditions, one received intravenous steroid therapy and the other suffered from respiratory syncytial virus infection. They were treated with appropriate antibiotics and their clinical courses were satisfactory and uncomplicated. Non-typeable H. influenzae was isolated from not only blood but also the lower respiratory tract in all three cases. Systemic infection due to non-typeable strain is rare. But, it should be recognized as a substantial proportion of the serious infections caused by H. influenzae.     

Serologically indicated pneumococcal respiratory infection in children.

Streptococcus pneumoniae infection was indicated serologically in 84 (19%) of 449 children hospitalized with middle or lower respiratory tract infection. Pneumococcal antigen was detected in acute serum in 28 patients, but in acute urine in only 2. An antibody response to type-specific capsular polysaccharides of S. pneumoniae was indicated in 27 patients and to a protein antigen, pneumolysin, in 25 patients, but to C-polysaccharide in only 10 patients. The observations mentioned above suggest that each serological test for pneumococcal etiology is insensitive, and to get an optimal result, a large panel of pneumococcal antigen and antibody assays must be used. Pneumococcal infection could be indicated serologically although no focus of infection, such as pneumonia or acute otitis media, or no laboratory evidence of bacterial infection as elevated values of C-reactive protein concentration, erythrocyte sedimentation rate or white blood cell count was present. Particularly antibody responses to pneumococcal pneumolysin were present in children without pneumonia or acute otitis media. Our results point out that no nonspecific parameter can be used for the selection of patients with probable pneumococcal etiology among children with respiratory tract infection. Concomitant viral infection, in most cases RSV infection, was present in a third of the children with pneumococcal infection. It is concluded that pneumococcal etiology should be actively sought for also in patients with viral respiratory infection, especially in young children with RSV infection.     

The antimicrobial activity of fluoroquinolone agents against pathogenic organisms in respiratory tract infections and its clinical effect

The efficacy rate, minimal inhibitory concentrations (MICs), and resistance of fluoroquinolone agents against causative organisms in respiratory tract infections from January to March, 1988 were investigated. Of 333 pathogenic strains 85% consisted of 5 major causative organisms of respiratory tract infection (Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Branhamella catarrhalis, and Staphylococcus aureus). In 61 (59 cases) of these 333 strains, including 3 cases of acute pharyngitis, 5 of acute bronchitis, 3 of pneumonia, and 48 of chronic lower respiratory tract infection fluoroquinolone agents were administered. The efficacy rate was 76.3% in all cases, and 75% in cases with chronic lower respiratory tract infection. The fluoroquinolone agents were 100% effective in H. influenzae and B. catarrhalis, though the efficacy rate was 67% in S. aureus and 40% in P. aeruginosa. The susceptibility of all strains to fluoroquinolone agents were investigated. There was no resistant strain in H. influenzae and B. catarrhalis, though resistant strains to fluoroquinolone agents have increased in S. aureus and P. aeruginosa. The efficacy rate was investigated using the MIC of administered fluoroquinolone agent against causative organisms. It is surmised that the efficacy of that agent has an MIC of 1.56-3.13 micrograms/ml.     

Diagnostic tools in respiratory tract infections: use and comparison with Finnish guidelines

The objectives of this prospective epidemiological study were to describe the diagnosis and treatment of respiratory tract infections by Finnish general practitioners and to compare current practice with national evidence-based guidelines. All patients (n = 4386) seeking primary care for a respiratory tract infection for the first time in 30 health centres during 1 week in November 1998 participated in the study. The main outcome measures were the amounts and types of diagnostic tests used and antimicrobials prescribed. Tympanometry was used in 1% of patients with acute otitis media. Ultrasonography, sinus radiography or both were used in 80% of cases of sinusitis and antigen detection or culture for Streptococci in 57% of throat infections. In acute bronchitis, a chest radiograph was taken in 5% of cases and the CRP level determined in 8%. The corresponding figures for pneumonia were 49% and 39%. In pneumonia and throat infection, diagnostic testing was statistically significantly associated with the use of antimicrobials, but not in otitis, sinusitis or acute bronchitis. Diagnostic tests were underused in respiratory tract infections compared to evidence-based recommendations.     

Therapeutic Implications of Antibacterial Resistance in Community-Acquired Respiratory Tract Infections in Children

Abstract. The global spread of antibacterial resistance has important implications for the current and future management of bacterial respiratory tract infections in children. Data suggest that emerging resistance to commonly prescribed antibacterials, such as macrolides and trimethoprim-sulfamethoxazole, is beginning to impact the treatment of these infections, which include acute otitis media, tonsillitis/pharyngitis and community-acquired pneumonia. There is, therefore, a need for additional agents that are active against common respiratory tract pathogens, including resistant strains and are suitable for use in children. Infection control measures to curb the clonal spread of antibacterial resistance are also extremely important.