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.     

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.     

Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease

Nontypeable Haemophilus influenzae colonizes the respiratory tract of adults with chronic obstructive pulmonary disease (COPD) and causes intermittent exacerbations. Isolates of H. influenzae collected monthly in a prospective study were subjected to molecular typing. During a 7-year study spanning 345 patient-months of observation, 122 episodes of negative cultures lasting 1 month or more, and that were preceded and followed by isolation of an apparently identical strain of H. influenzae, were found. Seventeen such episodes of negative cultures, lasting 6 months or more and spanning 203 patient-months, were studied in detail to test the hypothesis that these periods of negative cultures represented continuous colonization by the same strain of H. influenzae. Molecular typing by three independent methods established that the strains preceding and following the episodes of negative cultures were indeed identical. Strain-specific H. influenzae DNA was detected in some of the sputum samples that had yielded negative cultures. These results indicate that some patients with COPD are persistently colonized with H. influenzae and that sputum cultures underestimate the frequency of colonization of the respiratory tract by H. influenzae in COPD. This observation has a significant impact on understanding bacterial colonization in COPD.     

Airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease

RATIONALE: Increased bacterial concentration (load) in the lower airways and new bacterial strain acquisition have been posited as mechanisms for chronic obstructive pulmonary disease (COPD) exacerbations. Bacterial concentrations are higher during exacerbation than during stable disease; however, these studies are cross sectional and devoid of strain typing. OBJECTIVES: To determine if the increased bacterial concentrations function as a separate mechanism for exacerbation induction independent of new strain acquisition. METHODS: In a prospective, longitudinal cohort of patients with COPD, the relationship between exacerbation occurrence, sputum bacterial concentrations, and new strain acquisition was examined. MEASUREMENTS AND MAIN RESULTS: Clinical information, quantitative sputum cultures, and molecular typing of potential bacterial pathogen isolates. Over 81 months, 104 subjects completed 3,009 clinic visits, 560 (19.6%) during exacerbations and 2,449 (80.4%) during stable disease. Among preexisting strains, sputum concentrations of Nontypeable Haemophilus influenzae and Haemophilus haemolyticus were not different in exacerbation versus stable disease. Moraxella catarrhalis (stable, 10(8.38 +/- 0.13) [mean +/- SEM] vs. exacerbation, 10(7.78 +/- 0.26); p = 0.02) and Streptococcus pneumoniae (stable, 10(8.42 +/- 0.21) vs. exacerbation, 10(7.76 +/- 0.52); p = 0.07) concentrations were lower during exacerbations compared with stable periods. Concentrations of new strains of H. influenzae (stable, 10(7.28 +/- 0.15) vs. exacerbation, 10(7.76 +/- 0.17); p = 0.04) and M. catarrhalis (stable, 10(7.85 +/- 0.15) vs. exacerbation, 10(8.37 +/- 0.14); p = 0.02), were increased during exacerbations; however, the differences were small. CONCLUSIONS: Change in bacterial load is unlikely to be an important mechanism for exacerbations. Better understanding of the host-pathogen interaction, rather than enumerating bacteria in respiratory samples, is required to provide new insights into bacterial infection in COPD.     

Clonal analysis of Hemophilus influenzae isolated from children from Pakistan with lower respiratory tract infections

The clonal diversity of 105 Hemophilus isolates from the blood of children with lower respiratory tract infection in Pakistan was analyzed. Ten isolates were identified as H. parainfluenzae and 95 as H. influenzae. Of the H. influenzae isolates, 61 (64%) were serotype b and 34 (36%) were nontypable; 95% of the type b isolates were members of a single clonal group (as defined by multilocus enzyme electrophoresis, SDS-PAGE outer membrane protein profile, and biotype). This clone is rarely observed among type b strains recovered from patients with invasive type b disease in the USA or Europe. The nontypable isolates in Islamabad also were clonally restricted: 9 clonal groups were found among 34 isolates, with just 5 clonal groups accounting for most (82%) of the strains. Children infected with type b strains were hospitalized more often than those with nontypable H. influenzae disease (64% vs. 41%, P = .06), but no other clinical or demographic features distinguished children infected by type b and nontypable strains.     

Respiratory tract infections caused by Branhamella catarrhalis in outpatients with pneumoconiosis

To investigate the occurrence of Branhamella catarrhalis respiratory tract infections in 109 outpatients with pneumoconiosis, clinical and bacteriological studies were performed during a 4-year period from April 1984 to March 1988. B. catarrhalis was isolated in 26 patients; only three of these received continuous corticosteroid treatment. The incidence of B. catarrhalis respiratory tract infections increased gradually during the years 1984-1986, but decreased for the first time in 1987 compared with the previous year. There was a seasonal variation in isolations with a peak incidence during the winter, a pattern in contrast to Haemophilus influenzae. Almost all isolates produced beta-lactamase. B. catarrhalis found in mixed culture was usually in association with H. influenzae or Streptococcus pneumoniae. The isolation rates for B. catarrhalis in sputum of patients with pneumoconiosis followed those of H. influenzae and S. pneumoniae, and almost all strains were positive for beta-lactamase, so B. catarrhalis should be admitted that it is a primary pathogen.     

Coxiella burnetii and acute exacerbations/infections in patients with chronic lung disease

The aim of the present study was to determine the incidence of Q fever in patients with an acute exacerbation of a chronic lower respiratory tract infection. Eighty patients treated for acute exacerbation of chronic lower respiratory tract infections during a 30-month period were studied. Q fever was diagnosed by ELISA. Two elderly woman with pre-existing bronchiectasis (2.5%) were diagnosed as having an acute infection by Coxiella burnetii. The acute illness was considered to be a result of mixed infection with Pseudomonas aeruginosa and Haemophilus influenzae with C. burnetii. Co-infection with C. burnetii can occur during a bacterial exacerbation of a chronic lower respiratory tract infection.     

Strain-specific immune response to Haemophilus influenzae in chronic obstructive pulmonary disease

Previous studies of immune response to Haemophilus influenzae after exacerbations of chronic obstructive pulmonary disease (COPD) have yielded contradictory results. Using homologous (infecting) strains and immunoassays to surface-exposed epitopes, we tested the hypothesis that adults with COPD make new antibodies to strain-specific, surface-exposed epitopes on H. influenzae after exacerbations. We collected clinical information, sputum, and serum monthly and during exacerbations from 81 patients with COPD over 56 months. Serum antibodies to H. influenzae after exacerbations associated with H. influenzae in sputum were detected with whole bacterial cell ELISA and bactericidal assays. An immune response to homologous H. influenzae occurred after 22 of 36 (61.1%) exacerbations with newly acquired strains compared with 7 of 33 (21.2%) exacerbations with preexisting strains (odds ratio [OR] = 4.4; 95%, 1.8 to 10.8; p = 0.001). An absence of an immune response was strongly associated with complement sensitivity (OR = 0.03; 95% confidence interval, 0.003 to 0.22; p = 0.001). New bactericidal antibodies developed after exacerbations were highly strain specific, showing bactericidal activity for only 11 of 90 (12.2%) heterologous strains. Development of an immune response to H. influenzae supports its role in causing exacerbations. The strain specificity of the immune response likely represents a mechanism of recurrent exacerbations.     

Haemophilus haemolyticus: a human respiratory tract commensal to be distinguished from Haemophilus influenzae

BACKGROUND: Haemophilus influenzae is a common pathogen in adults with chronic obstructive pulmonary disease (COPD). In a prospective study, selected isolates of apparent H. influenzae had an altered phenotype. We tested the hypothesis that these variant strains were genetically different from typical H. influenzae. METHODS: A prospective study of adults with COPD was conducted. Strains of apparent H. influenzae obtained from a range of clinical sources were evaluated by ribosomal DNA sequence analysis, multilocus sequence analysis, DNA-DNA hybridization, and sequencing of the conserved P6 gene. RESULTS: Variant strains were determined to be Haemophilus haemolyticus by means of 4 independent methods. Analysis of 490 apparent H. influenzae strains, identified by standard methods, revealed that 39.5% of sputum isolates and 27.3% of nasopharyngeal isolates were H. haemolyticus. Isolates obtained from normally sterile sites were all H. influenzae. In a prospective study, acquisitions of new strains of H. haemolyticus were not associated with exacerbations of COPD, whereas 45% of acquisitions of new strains of H. influenzae were associated with exacerbations. CONCLUSIONS: Standard methods do not reliably distinguish H. haemolyticus from H. influenzae. H. haemolyticus is a respiratory tract commensal. The recognition that some strains of apparent H. influenzae are H. haemolyticus substantially strengthens the association of true H. influenzae with clinical infection.     

Acute respiratory infections in day care

A 16-year, longitudinal study of acute respiratory infections was conducted in a day care center. The incidence of infections peaked in the second six months of life (10 per child per year) and declined thereafter. Fewer than 10% of infections involved the lower respiratory tract. The isolation of respiratory viruses was associated closely with illnesses, and viruses appeared to be the most important causes of respiratory infections. Haemophilus influenzae type b was isolated infrequently and caused no invasive disease. Nontypable H. influenzae and Streptococcus pneumoniae were isolated frequently but were not associated epidemiologically with illnesses. Group A streptococci were isolated with moderate frequency but were not a major problem. Although the data presented are an inadequate basis for firm conclusions, they suggest that the incidence of acute respiratory infections during the first year of life is higher among children in day care centers than among those cared for at home but that the incidence in later years is perhaps lower for children who enter day care as infants and remain in day care through the preschool years.     

Role of Antimicrobial Agents in the Management of Exacerbations of COPD

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a common occurrence and characterize the natural history of the disease. Over the past decade, new knowledge has substantially enhanced our understanding of the pathogenesis, outcome and natural history of AECOPD. The exacerbations not only greatly reduce the quality of life of these patients, but also result in hospitalization, respiratory failure, and death. The exacerbations are the major cost drivers in consumption of healthcare resources by COPD patients. Although bacterial infections are the most common etiologic agents, the role of viruses in COPD exacerbations is being increasingly recognized. The efficacy of antimicrobial therapy in acute exacerbations has established a causative role for bacterial infections. Recent molecular typing of sputum isolates further supports the role of bacteria in AECOPD. Isolation of a new strain of Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae was associated with a considerable risk of an exacerbation. Lower airway bacterial colonization in stable patients with COPD instigates airway inflammation, which leads to a protracted self-perpetuating vicious circle of progressive lung damage and disease progression. A significant proportion of patients treated for COPD exacerbation demonstrate incomplete recovery, and frequent exacerbations contribute to decline in lung function. The predictors of poor outcome include advanced age, significant impairment of lung function, poor performance status, comorbid conditions and history of previous frequent exacerbations requiring antibacterials or systemic corticosteroids. These high-risk patients, who are likely to harbor organisms resistant to commonly used antimicrobials, should be identified and treated with antimicrobials with a low potential for failure. An aggressive management approach in complicated exacerbations may reduce costs by reducing healthcare utilization and hospitalization.     

Influenza vaccination in patients with asthma: effect on the frequency of upper respiratory tract infections and exacerbations.

Influenza epidemics of variable extent and severity occur every winter and are frequently associated with exacerbations of asthma. Accordingly, annual vaccination against influenza is recommended for patients with asthma. However, there are very limited data concerning its protective effect in this group of patients. The aim of this study was to assess the effect of influenza vaccination on the frequency of upper respiratory tract infections and also asthma-related outcomes such as exacerbation rates, hospital admissions, and rescue courses of oral corticosteroids in patients with stable asthma. Between September 15 and November 7, 2001, a total of 128 patients with asthma were randomly assigned to receive (n = 86) and not to receive vaccine (n = 42). The primary outcome measures were frequency of upper respiratory tract infections and exacerbations of asthma during the winter following vaccination. Study subjects were asked to record the presence and duration of symptoms suggestive of an upper respiratory tract infection and call their physician in the presence of conditions suggestive of an exacerbation until March 2002. Among the vaccinated group, 48% of the patients reported that they had no upper respiratory tract infection during the winter following injection, whereas 57% of nonvaccinated participants were upper respiratory symptom free during the same period (p > 0.05). The frequency of upper respiratory tract infection was also not different between the two groups in all severity forms of asthma (p > 0.05). There was no significant difference in the frequency of exacerbations of asthma between the two groups during the study period (p > 0.05). None of the vaccinated group was hospitalized due to an asthma attack; however, two patients (4.8%) in the nonvaccinated group had to be hospitalized following an exacerbation (p > 0.05). In summary, our findings do not support the protective effect of influenza vaccination for patients with asthma. However, no firm conclusions on this effect of the vaccine can be made without the data on the rate of influenza epidemic in that season and without the knowledge of the cause of upper respiratory tract infections in those patients. Therefore, we believe randomized, double-blind, placebo-controlled studies, including larger subgroups of severe asthmatics, are needed to evaluate the protective effect of influenza vaccination in asthma.     

Evaluation of Respiratory Viral Pathogens in Acute Asthma Exacerbations during Childhood

Objective. Common upper respiratory tract viruses are the most frequent and important causes of asthma exacerbations in both children and adults. Prospective epidemiologic studies report that up to 80% of childhood exacerbations are associated with viral upper respiratory tract infections. Materials and methods. The study group consisted of 104 children with asthma aged 3–17 years who received treatment for asthma exacerbations in our clinic between September 2009 and 2010. Nasopharyngeal and nasal swabs were obtained from all patients during an acute attack, and from the control group (31 subjects). These specimens were investigated for the presence of viral respiratory pathogens using a real-time multiplex PCR method. The patients were compared for the presence of respiratory pathogens and factors related to the severity of the asthma exacerbation. Results. A pathogenic respiratory virus was detected in 53.8% of patients in the acute exacerbation group. The most commonly encountered viral agent was Rhinovirus (35.6%). Patients who had an acute exacerbation with or without a detectable viral pathogen were compared according to the severity of the exacerbation, the need for systemic steroids, and hospitalization rates. No statistically significant difference was found. Conclusion. Although viral upper respiratory tract infections are the most common cause of asthma exacerbations, the severity level of the exacerbation seems to be independent of whether a respiratory virus has been detected.     

A prospective study of viral and mycoplasma infections in chronic inflammatory bowel disease

Seventy-two children with chronic inflammatory bowel disease were investigated for infections with various viruses and Mycoplasma pneumoniae, Chlamydia psittaci, and Coxiella burnetii to determine whether these pathogens are associated with acute onset exacerbations. Altogether 54 infections were identified serologically, of which 23 (42.6%) were associated with exacerbations. This corresponded to 24.2% of the recorded exacerbations during the study period. The respiratory pathogens accounted for 59.3% of the infections and 43.8% of these were associated with gastrointestinal symptoms. This is consistent with the observation that up to 40% of the exacerbations were associated with symptoms of antecedent or concurrent infection, most commonly involving the respiratory tract. Rubella virus, Epstein-Barr virus, and adenovirus were associated with acute exacerbations in 5 children. Thus, common pathogens were frequently associated with exacerbations and account for a large proportion of the commonly reported symptoms of a concurrent infection. The possible causal relationship between these pathogens and exacerbation of inflammatory bowel disease is discussed. Reactivation of latent herpesviruses was identified in 4 children with active disease and indicates that the converse relationship may also occur.     

Role of viruses in exacerbations of chronic obstructive pulmonary disease

Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and mortality and hospital admission. Respiratory viral infections, especially rhinoviruses, are a major cause of COPD exacerbations, with upper respiratory tract infections being associated with over 50% of COPD exacerbations. The presence of an upper respiratory tract infection leads to a more severe exacerbation and a longer symptom recovery time at exacerbation. Respiratory viral infections occurring during COPD exacerbations are more likely to lead to hospitalization. Sputum inflammatory markers were found to be higher in those patients with symptoms of a common cold or where rhinovirus was detected at exacerbation, thus suggesting that viral infections lead to greater airway inflammation and thus more severe exacerbations. COPD exacerbations are associated also with systemic inflammatory effects with increases in markers such as plasma fibrinogen and interleukin-6. Respiratory viruses have also been detected when the patients are stable, and this suggests that chronic viral infection may occur. Strategies to prevent viral infection will have a significant effect on the morbidity of COPD and will improve quality of life.     

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.     

Antibacterial resistance among children with community-acquired respiratory tract infections (PROTEKT 1999-2000)

OBJECTIVE: To determine the susceptibility of bacterial respiratory tract pathogens, isolated from children (0-12 years) as part of the global PROTEKT surveillance study (1999-2000), to a range of antibacterials, including the ketolide telithromycin. METHODS: Minimum inhibitory concentrations of the antibacterials studied were determined at a central laboratory using the NCCLS microdilution broth method. Macrolide resistance mechanisms were detected by PCR. RESULTS: Of 779 Streptococcus pneumoniae isolates worldwide, 43% were non-susceptible to penicillin (18% intermediate; 25% resistant) and 37% were resistant to erythromycin, with considerable intercountry variation. Eighteen per cent of 653 Haemophilus influenzae and >90% of 316 Moraxella catarrhalis isolates produced beta-lactamase. Of 640 Streptococcus pyogenes isolates, 10% were resistant to erythromycin, with considerable intercountry variation. All S. pneumoniae and 99.8% of H. influenzae isolates were susceptible to telithromycin using breakpoints proposed to the NCCLS (相似文献   

Haemophilus influenzae in chronic bronchitis

Colonization of the adult respiratory tract with nontypable Haemophilus influenzae is a dynamic process with new strains being acquired and replacing old strains periodically.The organism is a common cause of exacerbations of chronic bronchitis based on 3 lines of evidence: quantitative culture of the lower airways obtained by protected specimen brush, antibiotic trials, and serological studies. Nontypable H. influenzae expresses multiple adhesin molecules that mediate adherence to the respiratory tract mucosa. Recent studies have established that the bacterium penetrates the mucosal surface and survives intracellularly and in the interstitium of the submucosa. The organism shows a remarkable degree of antigenic diversity on its surface, including phase variation of lipooligosaccharide, antigenic heterogeneity of surface proteins, point mutations in genes encoding surface proteins and horizontal transfer of genes. These strategies facilitate evasion of the human immune response. Substantial progress has been made in identifying vaccine antigens to prevent infections caused by nontypable H. influenzae.     

R-factor involvement in a local outbreak of ampicillin-resistant Haemophilus influenzae infections.

In a Swedish nursery 11 of 15 children harboured non-encapsulated Haemophilus influenzae in their nasopharynx. Six children had ampicillin-resistant and beta-lactamase-producing isolates. Five of these children had otitis whereas one was healthy. In order to identify the origin of the H. influenzae isolates their O-antigen determinants were studied by an immunodiffusion technique. 18 different rabbit antisera were used. For each isolate an O-antigen pattern was recorded. Five of the 6 resistant isolates had the same O-antigen pattern, indicating that their origin was one strain. The 6th isolate was from another strain. Different isolates from the same strain were found to be either sensitive or resistant to ampicillin. In one child the H. influenzae lost its resistance during trimethoprim-sulphamethoxazole treatment. It is concluded that an R-factor may have been involved in the distribution of ampicillin resistance in the H. influenzae studied. Previous in-vitro studies have shown that beta-lactamase production can be transmitted by a plasmid among H. influenzae strains.     

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.