Infection in COPD Pulmonology Subspeciality Rounds (12/11/2008)Dr.Krock Dr.Vysetti Dr.Vysetti.

Infection in COPDInfection in COPD

Pulmonology Subspeciality RoundsPulmonology Subspeciality Rounds(12/11/2008) (12/11/2008)

Dr.KrockDr.Krock Dr.VysettiDr.Vysetti

Review Article Infection in the Pathogenesis and Course of

Chronic Obstructive Pulmonary Disease

Sanjay Sethi, M.D., and Timothy F. Murphy, M.D.

N Engl J MedVolume 359(22):2355-2365

November 27, 2008

Outline

► Historical PerspectiveHistorical Perspective► ExacerbationsExacerbations

Bacteria as a Cause of ExacerbationsBacteria as a Cause of Exacerbations Viruses as a Cause of ExacerbationsViruses as a Cause of Exacerbations Interaction of Viruses and BacteriaInteraction of Viruses and Bacteria

► Chronic Infection in COPDChronic Infection in COPD Bacterial Colonization and InflammationBacterial Colonization and Inflammation Other Evidence of Chronic InfectionOther Evidence of Chronic Infection Other Chronic InfectionsOther Chronic Infections

► Mechanisms of Chronic Infection in COPDMechanisms of Chronic Infection in COPD Innate Lung DefenseInnate Lung Defense The Vicious CircleThe Vicious Circle

► Antibiotics in COPDAntibiotics in COPD► Future DirectionsFuture Directions

Historical Perspective..Causes for Historical Perspective..Causes for

exacerbationexacerbation..► 1950’s and 1960’s repeated airway infection and 1950’s and 1960’s repeated airway infection and

hypersecretion of mucus.hypersecretion of mucus.► Tobacco smoke.Tobacco smoke.► Frequency of bacterial isolation from sputum found Frequency of bacterial isolation from sputum found

similar in stable COPD and during exacerbations.similar in stable COPD and during exacerbations.► Insufficient evidence to support role of bacteria.Insufficient evidence to support role of bacteria.

► Antibiotic therapy in exacerbations of chronic Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. obstructive pulmonary disease. Ann Intern Med. 1987 Feb.1987 Feb.

► In the past two decades.. In the past two decades.. New molecular, cellular, and New molecular, cellular, and immunologic techniques used to study host–pathogen immunologic techniques used to study host–pathogen interactions have led to a reexamination of the role of infection in interactions have led to a reexamination of the role of infection in chronic obstructive pulmonary disease (COPD).chronic obstructive pulmonary disease (COPD).

► There is now considerable evidence that infection plays a major There is now considerable evidence that infection plays a major role in the pathogenesis and clinical course of COPD.role in the pathogenesis and clinical course of COPD.

► A vicious circle of infection and inflammation is thought to lead to A vicious circle of infection and inflammation is thought to lead to exacerbations of the diseaseexacerbations of the disease

Microbial Pathogens in COPD

Sethi S, Murphy T. N Engl J Med 2008;359:2355-2365

Exacerbations…Bacteria as a cause..Exacerbations…Bacteria as a cause..

► Clinical manifestations from the direct effects of viruses and bacteria Clinical manifestations from the direct effects of viruses and bacteria and from the host response.and from the host response.

► Bacterial Role…Controversy in literature.Bacterial Role…Controversy in literature.► Bronchoscopic sampling with the use of a Protected Specimen Brush Bronchoscopic sampling with the use of a Protected Specimen Brush

yields reliable specimens from the lower airways.yields reliable specimens from the lower airways.► 50% of exacerbations are caused by bacteria.50% of exacerbations are caused by bacteria.► Purulent sputum during an exacerbation is highly correlated with the Purulent sputum during an exacerbation is highly correlated with the

presence of bacteria in the lower respiratory tract.presence of bacteria in the lower respiratory tract.► ? Bacterial Load as a cause.(Am J of Res CC May 2007,Ref No.6)? Bacterial Load as a cause.(Am J of Res CC May 2007,Ref No.6)► Bacterial Infection of the lower respiratory tract represents a Bacterial Infection of the lower respiratory tract represents a

dynamic complex process and acquisition of new strain plays a dynamic complex process and acquisition of new strain plays a central role in pathogenesis(Ref no.7).central role in pathogenesis(Ref no.7).

► Not All Strains Cause Exacerbations.Not All Strains Cause Exacerbations.► Host FactorsHost FactorsImpairement of Immunity,Previous Immunologic exp Impairement of Immunity,Previous Immunologic exp

Implicated.Implicated.

Proposed Model of the Pathogenesis of Bacterial Exacerbations in COPD

Sethi S, Murphy T. N Engl J Med 2008;359:2355-2365

Viruses as a cause…Viruses as a cause…

► Difficult to estimate the proportion of exacerbations by Difficult to estimate the proportion of exacerbations by viruses.viruses.

► Studies relying on cultures-Underestimate & studies Studies relying on cultures-Underestimate & studies relying on PCR overestimate the role.relying on PCR overestimate the role.

► Most Common->RhinovirusesMost Common->Rhinoviruses► Most Severe Most Severe Influenza.Influenza.► Recently recognisedRecently recognisedRSV and Human RSV and Human

metapneumovirus.metapneumovirus.

► When Viruses and Bacteria both cause-Exacerbations are When Viruses and Bacteria both cause-Exacerbations are very Severe.very Severe.

Chronic InfectionChronic Infection

► Airways of COPD pts chronically colonised with respiratory Airways of COPD pts chronically colonised with respiratory pathogens with no acute symptoms.pathogens with no acute symptoms.

► Significance:Even in stable COPD pts colonizations Significance:Even in stable COPD pts colonizations associated with host inflammatory and immune response.associated with host inflammatory and immune response.

► Airway inflammation related to colonization if neutrophilic Airway inflammation related to colonization if neutrophilic with IL-8 as the major mediator.with IL-8 as the major mediator.

► IL-8 and Neutrophils play a key role in the development of IL-8 and Neutrophils play a key role in the development of the COPD.the COPD.

► Associated with increased sputum production and Associated with increased sputum production and worsening airflow obstructionworsening airflow obstruction

► Colonization(smoldering infection) induced inflammation Colonization(smoldering infection) induced inflammation probably contributes to the progression of the disease.probably contributes to the progression of the disease.

► Supported by Pathologic and Radiologic EvidenceSupported by Pathologic and Radiologic Evidence

The Vicious-Circle Hypothesis of Infection and Inflammation in COPD

Sethi S, Murphy T. N Engl J Med 2008;359:2355-2365

Antibiotics In COPDAntibiotics In COPD

► Antibiotics –Rx of mod-Severe exacerbations when Antibiotics –Rx of mod-Severe exacerbations when purulent sputum is present.purulent sputum is present.

► Predictive Factors for poor clinical outcomes.Predictive Factors for poor clinical outcomes.► Stratified Approach based on GOLD(2008) and Canadian Stratified Approach based on GOLD(2008) and Canadian

guidelines for management of acute exacerbations of guidelines for management of acute exacerbations of chronic bronchitis(2003)chronic bronchitis(2003)

► Choice of Antibiotic Choice of Antibiotic Evidence ?Evidence ?► (Chest 2007)Metaanalysis of RCT’s comparing first line (Chest 2007)Metaanalysis of RCT’s comparing first line

Vrs Second line Antibiotics for Acute exacerbations of Vrs Second line Antibiotics for Acute exacerbations of Chronic Bronchitis.Second line more effective.Chronic Bronchitis.Second line more effective.

Algorithm for Antibiotic Treatment in Patients with Acute Exacerbations of COPD

Sethi S, Murphy T. N Engl J Med 2008;359:2355-2365

Out PatientOut Patient

In PatientIn Patient

Ongoing trials and Future Research..Ongoing trials and Future Research..

► Usefulness of Intermittent Pulsed Rx with Antibiotics or Usefulness of Intermittent Pulsed Rx with Antibiotics or Antiinflammatory action of antibiotics in treatment of Antiinflammatory action of antibiotics in treatment of exacerbations.exacerbations.

► More understanding of environmental factors,viruses and More understanding of environmental factors,viruses and bacteria in the pathogenesis of COPD exacerbations.bacteria in the pathogenesis of COPD exacerbations.

Questions…Questions…

1.1. Which one of the following factors causes most Which one of the following factors causes most exacerbations of chronic obstructive pulmonary exacerbations of chronic obstructive pulmonary disease (COPD)?disease (COPD)?

A. Air pollution. A. Air pollution. B. Change in temperature. B. Change in temperature. C. Change in humidity. C. Change in humidity.  D. Infection.  D. Infection.

Q2Q2

► Which one of the following viruses is most Which one of the following viruses is most commonly associated with infectious commonly associated with infectious exacerbations of COPD?exacerbations of COPD?

 A. Adenovirus. A. Adenovirus. B. Coronavirus. B. Coronavirus. C. Parainfluenza virus C. Parainfluenza virus D. Rhinovirus.  D. Rhinovirus.

Q3Q3

► Which one of the following mediators plays a Which one of the following mediators plays a major role in inducing airway inflammation related major role in inducing airway inflammation related to bacterial colonization?to bacterial colonization?

 A. Endothelin-2. A. Endothelin-2. B. Interleukin-8.  B. Interleukin-8.  C. Phospholipase A3.  C. Phospholipase A3.  D. Prostaglandin E2.  D. Prostaglandin E2.

Q4Q4► Antibiotics are especially beneficial for the Antibiotics are especially beneficial for the

treatment of moderate and severe exacerbations treatment of moderate and severe exacerbations of COPD in which one of the following of COPD in which one of the following circumstances?circumstances?

A : Purulent sputum is a presenting symptom. A : Purulent sputum is a presenting symptom. B : The duration of symptoms exceeds 72 hours. B : The duration of symptoms exceeds 72 hours. C : The patient has diabetes. C : The patient has diabetes. D : The patient is febrile.D : The patient is febrile.

Q5Q5

5.What are the most prevalent bacterial pathogens 5.What are the most prevalent bacterial pathogens in the lungs of patients with COPD?in the lungs of patients with COPD?

A.H.Influenza and Pseudomonas aeruginosaA.H.Influenza and Pseudomonas aeruginosa

B.M.catarrhalisB.M.catarrhalis

C.S.pneumonia.C.S.pneumonia.

Q6Q6

Is it appropriate to start antibiotics for an acute Is it appropriate to start antibiotics for an acute exacerbation of COPD?exacerbation of COPD?

Not Beneficial for Mild exacerbation.Not Beneficial for Mild exacerbation.

Initial Antibiotic choice (before any specific infectious Initial Antibiotic choice (before any specific infectious agent is identified) based on the pts age ,risk agent is identified) based on the pts age ,risk factors,FEV1,No of exacerbations per year, recent factors,FEV1,No of exacerbations per year, recent antibiotic exposure and presence of cardiac disease.antibiotic exposure and presence of cardiac disease.

THANK YOU !!THANK YOU !!