Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response

RATIONALE: Moraxella catarrhalis is frequently present in the sputum of adults with chronic obstructive pulmonary disease (COPD). Little is known about the role of M. catarrhalis in this common disease. OBJECTIVE: To elucidate the burden of disease, the dynamics of carriage, and immune responses to M. catarrhalis in COPD. METHODS: Prospective cohort study of 104 adults with COPD in an outpatient clinic at the Buffalo Veterans Affairs Medical Center. MEASUREMENTS: Clinical information, sputum cultures, molecular typing of isolates, and immunoassays to measure antibodies to M. catarrhalis. MAIN RESULTS: Over 81 months, 104 patients made 3,009 clinic visits, 560 during exacerbations. Molecular typing identified 120 episodes of acquisition and clearance of M. catarrhalis in 50 patients; 57 (47.5%) of the acquisitions were associated with clinical exacerbations. No instances of simultaneous acquisition of a new strain of another pathogen were observed. The duration of carriage of M. catarrhalis was shorter with exacerbations compared with asymptomatic colonization (median, 31.0 vs. 40.4 days; p = 0.01). Reacquisition of the same strain was rare. The intensity of the serum IgG response was greater after exacerbations than asymptomatic colonization (p = 0.009). Asymptomatic colonization was associated with a greater frequency of a sputum IgA response than exacerbation (p = 0.009). CONCLUSIONS: M. catarrhalis likely causes approximately 10% of exacerbations of COPD, accounting for approximately 2 to 4 million episodes annually. The organism is cleared efficiently after a short duration of carriage. Patients develop strain-specific protection after clearance of M. catarrhalis from the respiratory tract.     

Simultaneous respiratory tract colonization by multiple strains of nontypeable haemophilus influenzae in chronic obstructive pulmonary disease: implications for antibiotic therapy.

Nontypeable Haemophilus influenzae often causes exacerbations of chronic obstructive pulmonary disease (COPD), and these exacerbations are frequently treated with oral antibiotics. The goals of this study were to determine the frequency of the simultaneous presence of multiple strains of H. influenzae in sputum and to measure the MICs of antibiotics for the isolates. In a prospective study, adults with COPD were seen monthly. Sputum cultures were obtained, and individual colonies were subjected to genomic DNA typing and MIC determinations. Multiple strains of H. influenzae were present simultaneously in the sputum of 26.3% of adults with COPD. In 64.5% of these, MICs of >/=1 antibiotic varied by >/=4-fold among the strains. Therefore, multiple strains of H. influenzae are frequently present simultaneously in the sputum of adults with COPD, and the antimicrobial susceptibility of different strains in the same sputum sometimes differs.     

Identification of strains on recurrent Haemophilus influenzae infections in patients with chronic respiratory tract infections]

Nontypable Haemophilus influenzae is one of the most important pathogenic bacteria in respiratory tract infections. H. influenzae is most frequently associated with recurrent infections in chronic respiratory tract infections (CRTIs). It is known that H. influenzae often reemerges after the antibiotic treatment has been stopped. We analyzed serotype, biotype, and the OMP patterns of H. influenzae isolates from sputum of CRTIs patients to determine whether an exacerbation is caused by an identical H. influenzae strain, or by a new H. influenzae strain. One hundred eighty nine strains of H. influenzae were obtained from 124 exacerbation from 24 patients. The first and second isolates were identical in 23 out of 33 exacerbations (< or = 15-days interval between each exacerbation) and also in 22 out of 34 exacerbations (15 < days but < or = 30-days interval between each exacerbation). This is called early recurrence. In contrast, the first and second isolates were different in 28 out of 34 exacerbations (> 30-days interval between each exacerbation). This is called late recurrence. These results suggest that early recurrence and late recurrence of recurrent H. influenzae infections occur in a different mechanism.     

The study on bacterial infection in chronic lower respiratory tract infection--from the viewpoints of acute and chronic infection]

Using mainly changes in the amount of sputum as an index of the infectious course of chronic lower respiratory tract infection associated with purulent sputum over years, the disease was divided into stable and acute exacerbated phases and a bacteriological investigation using transtracheal aspiration (TTA) conducted. TTA was performed 107 and 45 episodes during stable phases and acute exacerbated phases respectively. Monomicrobial and polymicrobial infection were detected most frequently during the stable and acute exacerbated phases respectively (p less than 0.01). During the stable phases, the single organisms detected most frequently were H. influenzae (26 episodes) and P. aeruginosa (20 episodes), while in the cases in which multiple organisms were detected during stable phases, combination including H. influenzae were most common (19 episodes). H. influenzae was the most frequently detected organism in cases showing single organisms during acute exacerbated phases (7 episodes). In the cases in which multiple organisms were detected as well, H. influenzae was the most commonly detected organism assumed to predispose to exacerbation (7 episodes), while P. aeruginosa was not found. These results suggest that in chronic lower respiratory tract infection. H. influenzae and P. aeruginosa are important as persistent infective organisms, while H. influenzae are important in acute exacerbation.     

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.     

Changes in outer membrane proteins of nontypable Haemophilus influenzae in patients with chronic obstructive pulmonary disease

Five individual colonies of Haemophilus influenzae were isolated from each of one to three cultures of sputum collected from 18 patients with chronic obstructive pulmonary disease (COPD). The isolates were studied to investigate whether the major outer membrane proteins (MOMPs) changed during persistence. The relationship between isolates was analyzed by fingerprinting their chromosomal DNA. The fingerprints of eight strains (isolated from eight patients) with various MOMP compositions were different, whereas fingerprints of isolates with identical MOMP compositions were indistinguishable. In 12 patients, two or more strains with different MOMP compositions were found; one strain was isolated from the sputum samples of each of the six remaining patients. In seven of the 12 patients, strains with different MOMPs but with indistinguishable fingerprints were found. The differences were found in proteins b,c (five patients) and d (five patients). In patients with COPD, the MOMPs of H. influenzae are subject to changes that may enable this bacterium to escape immunological defense mechanisms.     

Counterimmunoelectrophoresis of sputum and blood for the diagnosis of chest infections caused by pneumococci or Haemophilus influenzae.

In 107 patients with lower respiratory tract infections, counterimmunoelectrophoresis (CIE) of blood and sputum, bacterial cultures of blood, sputum and nasopharyngeal secretion, and enzyme-linked immunosorbent assay (ELISA) for antibody determination were performed, with special reference to pneumococci and Haemophilus influenzae. For pneumococci CIE of sputum was superior to culture especially in antibiotic-treated patients. The clinical significance of a positive CIE of sputum was supported by close correlation to significant antibody increase. The usefulness of CIE regarding H. influenzae was more difficult to evaluate.     

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.     

The association of bacteremic Haemophilus influenzae pneumonia in adults with typable strains

Seven cases of Haemophilus influenzae pneumonia in adults are presented, and twenty-two cases recorded in the literature are reviewed. Because the relevance of H. influenzae recovered from sputum culture is uncertain, patients qualified for the series by meeting the diagnostic criteria of roentgenographic evidence of pneumonia together with recovery of the organism from the blood, pleural fluid and/or lung tissue. Consequently, this report studies essentially the bacteremic form of H. influenzae pneumonia. Analysis of the data accumulated indicates that bacteremic H. influenzae pneumonia is almost invariably (twenty-five of twenty-six cases) associated with typable strains (mainly type B) and with lobular or segmental lung involvement, especially on the right side. The role of unencapsulated and hence nontypable strains in pneumonia remains uncertain but, if they are a source of pneumonia, it is suggested that they are rarely invasive. The study also suggests that the routine typing of haemophili recovered from blood and sputum in conjunction with the x-ray findings may be of value in determining whether one is dealing with colonization or actual respiratory infection.     

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.     

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.     

Immunization with Haemophilus influenzae Hap adhesin protects against nasopharyngeal colonization in experimental mice

Nontypeable Haemophilus influenzae is a common cause of respiratory tract disease and initiates infection by colonizing the nasopharynx. The H. influenzae Hap adhesin is an autotransporter protein that was discovered because it promotes intimate interaction with human epithelial cells. Hap contains an extracellular domain called Hap(s) that has adhesive and protease activity and an outer membrane domain called Hap(beta) that serves to present Hap(s) on the surface of the cell. Hap(s) purified from nontypeable H. influenzae strain P860295 was used to immunize BALB/c mice intranasally. Immunization stimulated significant mucosal and serum anti-Hap(s) antibody titers, which were augmented by the addition of mutant cholera toxin (CT-E29H) as an adjuvant. Immunization was associated with a marked reduction in the density of nasopharyngeal colonization when mice were challenged with a heterologous strain of nontypeable H. influenzae. These results suggest that intranasal immunization with Hap formulated with CT-E29H may be a valuable vaccine strategy for the prevention of nontypeable H. influenzae disease.     

Demonstration of non-capsulated Haemophilus influenzae in the tissues of the respiratory tract in atopic and non-atopic subjects by means of an immunofluroescence technique.

The use of an immunofluorescence method for demonstration of non-capsulated H. influenzae colonization and penetration in the tissues of the respiratory tract seems to be a useful and convenient laboratory method. However, in in the tissues of the lower respiratory tract H. influenzae in our materials could not be demonstrated.     

High-molecular-weight proteins of nontypable Haemophilus influenzae mediate attachment to human epithelial cells.

Nontypable Haemophilus influenzae are Gram-negative bacilli that represent a common cause of human disease. These organisms initiate infection by colonizing the upper respiratory tract. Despite the essential role of colonization, the bacterial determinants of this process remain poorly defined. We recently identified a family of surface-exposed high-molecular-weight proteins of nontypable H. influenzae that are related to filamentous hemagglutinin, a critical adherence factor of Bordetella pertussis. The genes encoding the two such high-molecular-weight proteins (HMW-1 and HMW-2) expressed by a prototypic nontypable H. influenzae strain have now been cloned and sequenced. In this study we examined the role of the HMWs in adherence to human epithelial cells. We found that loss of expression of HMW-1 by the prototypic strain and a HMW-1-like protein in a heterologous nontypable H. influenzae strain markedly decreased the capacity to adhere. The absence of expression of both HMW-1 and HMW-2 in the prototypic strain or their homologs in the second strain was associated with a further decrease in adherence. Expression of either HMW-1 or HMW-2 in nonadherent laboratory strains of Escherichia coli resulted in acquisition of the adherence phenotype. These results indicate that both HMW-1 and HMW-2 and the homologous proteins from a second strain can mediate attachment. We speculate that these proteins and the related proteins in other nontypable H. influenzae isolates are important colonization factors.     

Clinical effects of piperacillin and tazobactam/piperacillin on Haemophilus influenzae lower respiratory tract infection in pediatric patients

OBJECTIVE: The prevalence of beta-lactamase-nonproducing ampicillin-resistant (BLNAR) Haemophilus influenzae (H. influenzae) has been increasing in recent years. Piperacillin (PIPC) is one of a few beta-lactams possessing good activity against BLNAR H. influenzae. We studied clinical efficacy of piperacillin and its beta-lactamase inhibitor, tazobactam/piperacillin (TAZ/PIPC) in children with lower respiratory tract infection caused by H. influenzae including resistance strains. METHODS: Subjects were 20 children with lower respiratory tract infection caused by H. influenzae treated with PIPC 100mg/kg/day (7 cases) or TAZ/PIPC 125mg/kg/day (13 cases). We selected cases from which resistant H. influenzae strains might be detected. Patients received prior antimicrobial therapy within two weeks before admission, or with underlying diseases. We examined patient profiles, clinical efficacy, susceptibilities for 6 beta-lactam antibiotics [PIPC, TAZ/PIPC, ampicillin (ABPC), cefotaxime (CTX), ceftriaxone (CTRX), and meropenem (MEPM)] and analyzed 6 genotype patterns of beta-lactam resistant genes by PCR. RESULTS: Efficacy was 7/7 in patients in PIPC group and 12/13 in patients in TAZ/PIPC group. Diminished efficacy was seen in only one case complicated with severe RSV infection. The susceptibility of all strains but one beta-lactamase producing, ABPC resistant (BLP) strain to PIPC and of all to TAZ/ PIPC was below 0.25 microg/mL. The genotype of the 15 strains isolated from the sputum on administration was as follows; beta-lactamase nonproducing, ABPC-susceptible (gBLNAS) strains were 4, gBLP strain was 1, beta-lactamase nonproducing, and ABPC-resistant (gLow-BLNAR) strains were 2, beta-lactamase nonproducing, ABPC resistant (gBLNAR) strains were 8. CONCLUSION: PIPC and TAZ/PIPC were useful against lower respiratory tract infection caused by H. influenzae including BLNAR in children.     

Pseudomonal infections in patients with COPD: epidemiology and management

COPD is a common disease with increasing prevalence. The chronic course of the disease is characterized by acute exacerbations that cause significant worsening of symptoms. Bacterial infections play a dominant role in approximately half of the episodes of acute exacerbations of COPD. The importance of pseudomonal infection in patients with acute exacerbations of COPD stems from its relatively high prevalence in specific subgroups of these patients, and particularly its unique therapeutic ramifications. The colonization rate of Pseudomonas aeruginosa in patients with COPD in a stable condition is low.A review of a large number of clinical series of unselected outpatients with acute exacerbations of COPD revealed that P. aeruginosa was isolated from the patients' sputum at an average rate of 4%. This rate increased significantly in COPD patients with advanced airflow obstruction, in whom the rate of sputum isolates of P. aeruginosa reached 8-13% of all episodes of acute exacerbations of COPD. However, the great majority of bacteria isolated in these patients were not P. aeruginosa, but the three classic bacteria Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis. The subgroup of patients, with acute exacerbations of COPD, with the highest rate of P. aeruginosa infection, which approaches 18% of the episodes, is mechanically ventilated patients. However, even in this subgroup the great majority of bacteria isolated are the above-mentioned three classic pathogens. In light of these epidemiologic data and other important considerations, and in order to achieve optimal antibacterial coverage for the common infectious etiologies, empiric antibacterial therapy should be instituted as follows. Patients with acute exacerbations of COPD with advanced airflow obstruction (FEV(1) <50% of predicted under stable conditions) should receive once daily oral therapy with one of the newer fluoroquinolones, i.e. levofloxacin, moxifloxacin, gatifloxacin, or gemifloxacin for 5-10 days. Patients with severe acute exacerbations of COPD who are receiving mechanical ventilation should receive amikacin in addition to one of the intravenous preparations of the newer fluoroquinolones or monotherapy with cefepime, a carbapenem or piperacillin/tazobactam. In both subgroups it is recommended that sputum cultures be performed before initiation of therapy so that the results can guide further therapy.     

Outer membrane protein and lipooligosaccharide analysis of paired nasopharyngeal and middle ear isolates in otitis media due to nontypable Haemophilus influenzae: pathogenetic and epidemiological observations

We studied isolates of nontypable Haemophilus influenzae from cultures of nasopharynx and middle ear fluid (MEF) done simultaneously on children with otitis media. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of outer membrane protein (OMP) patterns demonstrated that in 16 of 19 pairs, the nasopharyngeal and MEF strains were identical. With four monoclonal antibodies to lipooligosaccharide (LOS) determinants, 17 of the 19 pairs were identical. Thus the pathogenesis of otitis media due to nontypable H. influenzae appears to involve spread of the bacteria from the nasopharynx to the middle ear. Analysis of middle ear isolates from four children with recurrent otitis media caused by nontypable H. influenzae indicated that the recurrent episodes were caused by reinfection with different strains rather than by persistence of the same strain. OMP and LOS analysis of strains from two sisters with concurrent otitis media suggested that person-to-person transmission of nontypable H. influenzae can occur among children.     

Major bacteria of community-acquired respiratory tract infections in Turkey

To determine the bacterial etiology of lower respiratory tract infections (LRTIs) in Turkey, quantitative cultures of sputum were carried out. The major pathogens for LTRIs were found to be Haemophilus influenzae, followed by Streptococcus pneumoniae and Moraxella catarrhalis. Only 6.1% of the H. inlfuenzae and all strains of M. catarrhalis were beta-lactamase producers. An E-test showed that 31.2% of the S. pneumoniae strains had an intermediate resistance to penicillin, and the remaining strains were susceptible; no fully resistant strains were detected.