Download - Bacterial Infection and the Pathogenesis of COPD* · Bacterial Infection and the Pathogenesis of COPD* Sanjay Sethi, MD Bacterial infection of the lower respiratory tract can impact

Bacterial Infection and thePathogenesis of COPD*Sanjay Sethi, MD

Bacterial infection of the lower respiratory tract canimpact on the etiology, pathogenesis, and the clinicalcourse of COPD in several ways. Several recent cohortstudies suggest that lung growth is impaired by child-hood lower respiratory tract infection, making theseindividuals more vulnerable to developing COPD onexposure to additional injurious agents. Impairment ofmucociliary clearance and local immune defense insmokers allows bacterial pathogens to gain a footholdin the lower respiratory tract. These pathogens andtheir products can cause further impairment of muco-ciliary clearance due to enhanced mucus secretion,disruption of normal ciliary activity, and airway epithe-lial injury, and thus persist in the lower respiratorytract. This chronic colonization of the lower respiratorytract by bacterial pathogens could induce a chronicinflammatory response with lung damage. Nontype-able Haemophilus influenzae, usually regarded as anextracellular mucosal pathogen, has been demon-strated to cause intracellular infections of the upperand lower respiratory tract respiratory tissue. In-creased incidence of chronic Chlamydia pneumoniaeinfection of the respiratory tract has been associatedwith COPD. These chronic infections of respiratorytissues could contribute to the pathogenesis of COPDby altering the host response to cigarette smoke or byinducing a chronic inflammatory response. Applicationof newer molecular and immunologic research tech-niques is helping us define precisely the role of bacte-rial infection in COPD.

(CHEST 2000; 117:286S–291S)

Key words: bacterial infection; COPD; Haemophilus influenzae;pathogenesis

Abbreviations: CF 5 cystic fibrosis; IL 5 interleukin; LOS 5lipo-oligosaccharide; NTHI 5 nontypeable Haemophilus influen-zae; PCR 5 polymerase chain reaction

T he precise role of bacterial infection in COPD hasbeen a source of controversy for several decades.1,2

Several putative roles of bacterial infection in the etiology,pathogenesis, and the clinical course of COPD can beidentified.1 These include the following: (1) childhoodlower respiratory tract infection impairs lung growth re-flected in a lower FEV1 in adulthood; (2) chronic coloni-zation of the lower respiratory tract by bacterial pathogensinduces a chronic inflammatory response with lung dam-age (the vicious circle hypothesis); (3) chronic infection ofrespiratory tissues by bacterial pathogens contributes to

the pathogenesis of COPD by altering the host response tocigarette smoke or by inducing a chronic inflammatoryresponse; (4) bacteria cause acute exacerbations of chronicbronchitis, which contribute significantly to the morbidityand mortality of COPD; and (5) bacterial antigens in thelower airway induce hypersensitivity that enhances airwayhyperreactivity. With the availability of newer molecularand immunologic research techniques, the role of bacte-rial infection in COPD is being reevaluated. In this article,the first three putative roles of bacterial infection in eitherpredisposing to COPD or contributing to its pathogenesisby causing a chronic infection of the lower airways will bediscussed.

Childhood Infection and Adult Lung Function

Several recent studies have reported lung function (byspirometry) in cohorts of adult patients for whom reliableinformation is available regarding the incidence of lowerrespiratory tract infection (bronchitis, pneumonia, whoop-ing cough) in childhood (, 14 years of age; Table 1).3–6 Allof these studies have shown a lower FEV1 and often alower FVC among adults who experienced childhoodlower respiratory tract infection.3–6 This association is seenafter controlling for confounding factors such as tobaccoexposure. The magnitude of this defect in FEV1 has variedamong the studies and is greater in older cohorts. Thedefect in lung function is not obstructive with preservationof the FEV1/FVC ratio, but is consistent with “smallerlungs,” suggesting impaired lung growth. The extent ofdecrease in FEV1 is unlikely to cause symptomatic pulmo-nary disease on its own, but could make the individualsusceptible to the effects of additional injurious agentssuch as tobacco smoke.

Although the association between childhood lower re-spiratory tract infection and impaired lung function inadulthood is now well established, there is ongoing debateas to whether this association reflects a cause-effectrelationship in which the infectious process damages avulnerable lung undergoing rapid postnatal growth andmaturation. If this was the case, then the effect of theinfection on lung function should be seen only in the first2 years of life during postnatal lung growth but not in laterchildhood (3 to 14 years). However, this has not beenobserved consistently in the studies to date.3–6 An alter-native explanation for the observed association is that anundetermined genetic factor predisposes these individualsto lower respiratory tract infections in childhood as well asa lower FEV1 in adulthood. This explanation implies thatimpaired lung growth antedates the respiratory tract in-fection.

The etiology of childhood pneumonia and bronchitiswas not established in these studies. Bacterial infection,especially by Streptococcus pneumoniae and Haemophilusinfluenzae is a common cause of severe pneumonia inchildren.7 The impact of childhood bacterial lower respi-ratory tract infection on the prevalence of COPD is likelyto be greater in developing countries where there is a highincidence and inadequate treatment of these infections.

*From the VA Western New York Healthcare System andDepartment of Medicine, Division of Pulmonary and CriticalCare, State University of New York at Buffalo, Buffalo, NY.Supported by VA Merit Review.Correspondence to: Sanjay Sethi, MD, VA Western New YorkHealthcare System (151), 3495 Bailey Ave, Buffalo, NY 14215;e-mail: [email protected]

286S Thomas L. Petty 42nd Annual Aspen Lung Conference: Mechanisms of COPD

Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21946/ on 06/27/2017

Vicious Circle Hypothesis

Tobacco smoking cannot be the sole factor responsiblefor the pathogenesis of COPD, as only a small proportion(15%) of smokers develop chronic bronchitis and an evensmaller proportion go on to develop COPD. In theabsence of underlying lung disease, the tracheobronchialtree is sterile. In patients with COPD, the tracheobron-chial tree is chronically colonized with potential respira-tory pathogens, predominantly nontypeable H influenzae(NTHI), S pneumoniae, and Moraxella (Branhamella)catarrhalis.8,9 Several years ago, we proposed a viciouscircle hypothesis to explain how chronic bacterial coloni-

zation of the lower airways in patients with COPD canperpetuate inflammation and contribute to progression ofthe disease (Fig 1).1,10 Substantial supporting evidence forthis hypothesis, both in vitro and in vivo, has nowaccumulated and is discussed below.

Vicious Circle Hypothesis Supporting Evidence

Central to the vicious circle hypothesis is the notion thatonce bacterial pathogens have gained a foothold in thelower respiratory tract from impaired mucociliary clear-ance due to tobacco smoking, they persist by furtherimpairing mucociliary clearance (Fig 1). This impairment

Figure 1. Schematic diagram of the vicious circle hypothesis of the role of bacterial colonization in theprogression of COPD.

Table 1—Association of Childhood Lower Respiratory Tract Infection With Level of Lung Function in Adults

StudyAuthors/yr n

Childhood Lower RespiratoryTract Infection

Age atFollow-up Effect on FEV1

Barker et al3/1991 639 (all male subjects) Bronchitis or pneumonia infirst yr

59–67 yr 2 200 mL

Shaheen et al4/1994 618 Pneumonia in first 2 yr 67–74 yr 2 650 mL (in male subjectswith pneumonia)Bronchitis in first 2 yr

Johnston et al5/1998 1,392 Pneumonia in first 7 yr 34–35 yr 2 102 mL (with pneumonia)Whooping cough in first 7 yr

Shaheen et al6/1998 239 Pneumonia in first 14 yr 57.6 6 4.3 yr 2 390 mL (with pneumonia infirst 2 yr)

Bronchitis in first 14 yr 2 130 mL (with bronchitis infirst 2 yr)

CHEST / 117 / 5 / MAY, 2000 SUPPLEMENT 287S


of mucociliary clearance can be due to enhanced mucussecretion, disruption of normal ciliary activity, and airwayepithelial injury. Experimental evidence demonstratesthat respiratory tract pathogens and their products cancause all of these effects in vitro.

Bacterial Infection and Chronic MucusHypersecretion

Adler et al11 examined the effect of cell free filtrates ofbroth cultures of NTHI, S pneumoniae, and Pseudomonasaeruginosa on the secretion of mucous glycoproteins byexplanted guinea pig airway tissue. Seven of 28 strains(25%) of NTHI, 10 of 26 strains (34%) of S pneumoniae,and 12 of 18 strains (66%) of P aeruginosa stimulatedmucin secretion. This stimulation was a true secretoryeffect and not passive release of preformed intracellularmacromolecules due to cellular damage, as ultrastructuralassessment (by light, transmission, and scanning electronmicroscopy) demonstrated an absence of cytotoxicity. ThePseudomonas stimulatory products were 60- to 100-kdproteases. The NTHI and pneumococcal stimulatory exo-products were 50 to 300 kd in size and did not possessproteolytic activity.

Bacterial Infection and Mucociliary Clearance

The tracheobronchial ciliary escalator is of paramountimportance in maintaining sterility of the lower respiratorytract by transporting bacteria trapped in mucus toward thepharynx.12 Disruption of this ciliary activity is thereforelikely to be very important in the establishment of achronic colonization in the tracheobronchial tree. Wilsonet al13 measured using photometry the effect of cell-freesupernatants of NTHI, P aeruginosa, and Staphylococcusaureus on ciliary beat frequency of strips of human nasalciliary epithelium. Rapid inhibition of ciliary beat fre-quency was seen with NTHI and P aeruginosa but notwith S aureus. On direct examination, ciliary dyskinesiaand ciliostasis were seen. Human neutrophil elastaseinhibits ciliary activity and damages respiratory epitheli-um.14,15 Bacterial products in the airways may be a potentstimulus for neutrophil migration into the airways, andelastase released from these neutrophils can act synergis-tically with bacterial products and cause further inhibitionof tracheobronchial ciliary function.

Bacterial Infection and Airway Epithelial Injury

An important component of the vicious circle hypothe-sis is the potentially damaging effects of bacteria andbacterial products on airway epithelial lining cells. Suchepithelial injury in the large airways would contribute tobacterial persistence, and in the small airways couldcontribute to the respiratory bronchiolitis that causesprogressive airways obstruction. In an in vitro tissueculture model of nasal turbinate epithelium, Read et al16

have demonstrated that NTHI is capable of causing airwayepithelial injury. They studied these epithelia after 30 min,14 h, and 24 h of incubation with a NTHI strain. At 30min, the airway epithelium and cilia were intact and the

bacteria were found associated with the overlying mucuslayer. At 14 h, patchy injury developed to the airwayepithelium, with bacterial cells now associating with thesedamaged epithelial cells but not with intact epithelium. At24 h, detached epithelial cells with adherent bacteria wereseen.

The studies discussed above demonstrate that bacteriathat colonize and infect the lower respiratory tract inCOPD are capable of fostering in the tracheobronchialtree an environment in which they can persist, supportingthe central tenet of the vicious circle hypothesis (Fig 1).Recently, more attention is being directed toward anotherportion of the vicious circle, the possible effects of bacte-rial products and the chronic inflammatory response itengenders on the elastase-anti-elastase balance in thelung. If bacterial products in the tracheobronchial treecould cause neutrophil influx and degranulation in theairways and lung parenchyma, they could contribute tochronic inflammation, parenchymal lung damage, andprogressive small airway obstruction seen in COPD. Evi-dence to support the occurrence of such an effect ofbacterial products in the lower respiratory tract is pre-sented below.

Bacterial Infection and Airway Inflammation

The presence of bacteria in the lower airways in patientswith stable COPD has been labeled colonization. How-ever, this bacterial presence is definitely abnormal, as thelower respiratory tract in the absence of lung disease isnormally sterile.8,9 This abnormal colonization of thetracheobronchial tree is not confined to the large airways.It has been shown to extend to the peripheral airways bybronchoscopic protected specimen brushings culture.17

Even during colonization, bacteria in these airways arelikely to be in a constant state of turnover, releasingextracellular products, undergoing lysis with release of avariety of proteins, lipo-oligosaccharide (LOS) and pepti-doglycan. LOS is a potent inflammatory stimulus; in fact,repeated instillation of LOS can lead to development ofemphysema in hamsters.18 It is therefore quite likely thatthis colonization actually is a low-grade smoldering infec-tion that induces chronic airway inflammation. In the largeairways, such inflammation would contribute to mucusproduction; in the small airways, it could contribute torespiratory bronchiolitis and progressive airway obstruc-tion. Direct evidence from patients with COPD thatcolonization of the airways induces inflammation is forth-coming.19,20 Indirect evidence includes in vitro experi-ments with NTHI LOS and from patients with cysticfibrosis (CF), another disease associated with airway bac-terial colonization.

Khair et al21 incubated explant cultures of humanbronchial epithelium with NTHI LOS at two differentconcentrations, 10 mg/mL and 100 mg/mL. Epithelialpermeability and intracellular adhesion molecule-1 ex-pression, and release of interleukin (IL)-6, IL-8, andtumor necrosis factor-a into the culture medium weremeasured. IL-6 and tumor necrosis factor-a secretion andintracellular adhesion molecule-1 expression by the bron-chial epithelial cells was significantly increased by only the



higher concentration of LOS (100 mg/mL), while IL-8expression was stimulated by both 10 mg/mL and 100mg/mL LOS. The levels of inflammatory mediators at-tained in the culture medium were adequate to increaseneutrophil chemotaxis and adherence in vitro. There wasno increase in epithelial permeability.

Konstan et al22 compared airway inflammation in 18adolescents or adults with mild CF (FEV1 of 79 6 4%predicted) with 23 healthy control subjects. The CFpatients were free of symptoms of acute infection andwere therefore presumed to be have mucosal bacterialcolonization with little inflammatory response or ongoinglung destruction. BAL was obtained in these subjects forquantitative bacterial culture, cell counts, Ig, and elastasemeasurement. P aeruginosa was isolated from the BAL in16 patients, S aureus and NTHI in 6 patients each, whileall the samples from the healthy control subjects weresterile. A marked inflammatory response was seen in theCF patients, with total (mean 6 SEM) cell counts in theBAL of epithelial lining fluid of 68 6 32 3 106 cells/mL vs5 6 13106 cells/mL in healthy control subjects; differen-tial cell count in the CF patients revealed an intenseneutrophilia (57%) vs 3% in control subjects. IgG, IgA,and IgM were elevated 2.5- to sixfold in the patientsdemonstrating an active local immune response. Fifteen of18 patients had free elastase in BAL, while none waspresent in the control subjects, and the concentrationsmeasured were greatly in excess of the nanomolar quantityrequired to interfere with local host defenses, cause mucinsecretion, and stimulate IL-8 release, etc. This shows that

in CF there is an active inflammatory response in thelower airways to bacterial colonization.

Chronic Bacterial Infection of Respiratory Tissues

Bacterial pathogens implicated in COPD such as NTHIhave always been regarded as extracellular pathogens thatinfect the airway lumen. Recently, NTHI infection of therespiratory tissue by has been demonstrated in both upperand lower respiratory tract.23,24 Whether chronic Chla-mydia pneumoniae infection of the respiratory tract isassociated with COPD has also been recently investigat-ed.25 These studies have used detection techniques moresensitive than bacterial cultures for determining the pres-ence of bacterial organisms in tissue and have made somevery interesting and somewhat surprising observations.

Intracellular NTHI Infection of Respiratory Tissues

Forsgren et al23 examined hypertrophied adenoid tissueremoved at adenoidectomy from 10 children with nasalobstruction for the presence of intracellular NTHI. Threecomplementary techniques were used: in situ hybridiza-tion with a fluorescent-labeled probe specific for 16sribosomal RNA of NTHI, transmission electron micros-copy, and culture of the adenoid tissues after treatmentwith an aminoglycoside to kill extracellular bacteria. Theydetected NTHI in the adenoids of all 10 patients with insitu hybridization, mostly in the reticular crypt epitheliumand in subepithelial locations. Transmission electron mi-

Figure 2. Potential pathways by which infection-induced lung damage could contribute to thepathology of COPD.



croscopy confirmed these findings, and culture techniquesshowed that these intracellular bacteria were viable. Thereservoir for these bacteria appeared to be large subepi-thelial mononuclear cells, likely macrophages, which con-tained up to 200 viable and actively dividing intracellularNTHI per cell. This was confirmed by enriching macro-phages from the adenoid cell suspension and demonstrat-ing high titers of bacteria on culture in these enrichedcells.

Forty-nine explanted lungs from patients undergoinglung transplantation were examined for the presence ofNTHI by Moller et al.24 The underlying lung disease wasCOPD in 16, CF in 16, bronchiectasis in 5, and noninfec-tious pulmonary diseases in 12 patients. The presence ofNTHI was determined by staining tissue sections with amonoclonal antibody that binds to an epitope on the outermembrane protein P6 of NTHI and with polymerase chainreaction (PCR) for the same outer membrane protein withDNA extracted from the lung tissue as a template. NTHIwas present in tissue sections by immunostaining and PCRin 24 of 49 (49%) patients overall. When classified byunderlying disease, lung explants were positive for NTHIin 10 of 16 CF (62%), 8 of 16 COPD (50%), 2 of 5bronchiectasis (40%), and 4 of 12 noninfectious diseases(33%) specimens. NTHI was present in a significantlygreater proportion of tissue sections from patients withCOPD and CF than from patients with bronchiectasis andnoninfectious diseases (58% and 47% vs 33% and 29%,respectively; p , 0.0001). NTHI was found in subepithe-lial tissues and in macrophages, and were found with equalfrequency in all parts of the lung, central and peripheralairways, and in the parenchyma.

These two studies demonstrate that NTHI residesintracellularly, especially in macrophages, and in the sub-epithelial zone in human respiratory tissues. These bacte-ria are protected from antibiotics and bactericidal antibod-ies, and may act as reservoirs of infection.26 Tissueinfection by NTHI could also contribute to the pathogen-esis of COPD directly or indirectly. Chronic low-gradeinfection could directly induce a chronic inflammatoryresponse in the parenchyma and the airways of the lungthat could be additive or synergistic to the inflammatoryeffects of tobacco smoke. Indirectly, such an infectioncould enhance the damaging effects of tobacco smoke onrespiratory tissues. On the other hand, it is possible thatthis tissue infection is simply a marker of compromisedlocal immunity. Whether tissue infection by NTHI is seenin early COPD and the effect of this infection in tissuemodels needs to be investigated.

Chronic C pneumoniae infection in COPD

C pneumoniae is an obligate intracellular atypical bac-terial pathogen. Acute C pneumoniae infection can causebronchitis and pneumonia. Chronic infection with C pneu-moniae is being actively investigated as a cause of severalsystemic diseases, especially coronary artery disease.27 vonHertzen et al25 studied whether the incidence of chronicC pneumoniae infection is increased in COPD. Presenceof chronic C pneumoniae infection was determined bythree different methods: serum antibodies to C pneu-

moniae (IgG and IgA and circulating immune complexes),sputum IgA antibodies to C pneumoniae, and PCR ofsputum for C pneumoniae DNA. Two of the three meth-ods had to yield positive results in a patient to concludethat he or she had a chronic C pneumoniae infection.Thirty-four patients with severe COPD, and 13 patientswith mild to moderate COPD were compared with 23patients with community-acquired pneumonia who servedas control subjects. The incidence of chronic C pneu-moniae infection (as defined above) was 71% in patientswith severe COPD, 46% in mild to moderate COPD, and0% in the control group. Whether this chronic infectioncontributes to the pathogenesis of COPD as discussedabove or is a reflection of compromised local immunitywarrants further investigation.

Summary

Figure 2 summarizes the known and proposed mecha-nisms by which bacterial infection of the tracheobronchialtree can produce the symptom complex, pathologic fea-tures, and pathophysiology of COPD. This model parallelsin many respects the mechanisms by which tobaccosmoking causes chronic bronchitis and airway obstruction.This proposed mechanism therefore emphasizes how to-bacco smoking and tracheobronchial infection can syner-gistically induce this chronic disabling disease.

Future Directions

There are several unanswered questions regarding bac-terial infection in COPD that can be exciting areas ofinvestigation. Which bacterial products (eg, LOS, outermembrane proteins) are present in the lower airways inchronic bronchitis and at what concentration? What arethe mechanisms by which these bacteria and their com-ponents incite airway inflammation? Is this airway inflam-mation correlated with progression of airway obstructionin these patients?

Answering such questions will enable us to place the roleof bacteria in this chronic disabling disease in the correctperspective. If bacteria do play a role in progression ofobstruction, then important new areas of therapeutic inter-vention open up, including vaccines and antimicrobialtherapy to prevent persistent bacterial colonization.

ACKNOWLEDGMENT: The author thanks Adeline Thurstonfor secretarial assistance.

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19 Sethi S, Musher DM, Everts V, et al. Bacterial colonizationenhances airway inflammation in COPD [abstract]. Am JRespir Crit Care Med 1999; 159:A820

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Bronchial Inflammation*

Its Relationship to ColonizingMicrobial Load and a1-AntitrypsinDeficiency

Robert A. Stockley, DSc, MD; Adam T. Hill, MB ChB;Susan L. Hill, PhD; and Edward J. Campbell, MD

Neutrophil elastase is capable of generating many ofthe features of chronic bronchial disease. In patientswith COPD, airways inflammation with neutrophilrecruitment and elastase release is positively corre-lated with colonizing bacterial load in the stableclinical state (p < 0.0005). In addition, a1-antitrypsindeficiency is associated with a greater neutrophilload, higher elastase activity, leukotriene-B4 concen-tration, and serum protein leak than matched pa-tients without deficiency (p < 0.005). These dataconfirm an effect of bronchial colonization on air-ways inflammation in COPD and indicate the role ofa1-antitrypsin in its modulation.

(CHEST 2000; 117:291S–293S)

Key words: a1-antitrypsin deficiency; bacteria; COPD; inflam-mation

Abbreviations: a1-AT 5 a1-antitrypsin; LTB4 5 leukotrieneB4; MPO 5 myeloperoxidase; NE 5 neutrophil elastase; SLPI 5secretory leukoproteinase inhibitor

T he presence of bronchial disease is often a feature ofpatients with COPD. It is associated with inflamma-

tion, as indicated by the presence of increased numbers ofneutrophils,1 a reduction in mucociliary clearance, mucusgland hyperplasia, and epithelial damage,2 all of whichmay facilitate bacterial colonization.

Neutrophil elastase (NE) has been shown to producemany of the features of bronchial disease, including the

*From the Department of Medicine (Drs. Stockley, Hill, andHill), Queen Elizabeth Hospital, Birmingham B15 2TH, UK; andthe University of Utah (Dr. Campbell), Salt Lake City, UT.Supported by a noncommercial educational grant from Bayer aspart of the ADAPT Programme.Correspondence to: Robert A. Stockley, DSc, MD, Department ofMedicine, Queen Elizabeth Hospital, Birmingham B15 2TH, UK



Download - Bacterial Infection and the Pathogenesis of COPD* · Bacterial Infection and the Pathogenesis of COPD* Sanjay Sethi, MD Bacterial infection of the lower respiratory tract can impact

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