Elsevier

The Lancet

Volume 384, Issue 9944, 23–29 August 2014, Pages 691-702
The Lancet

Series
The role of the microbiome in exacerbations of chronic lung diseases

https://doi.org/10.1016/S0140-6736(14)61136-3Get rights and content

Summary

Culture-independent microbiological techniques have shown a previously unappreciated complexity to the bacterial microbiome of the respiratory tract that forces reconsideration of the interactions between host, bacteria, and the pathogenesis of exacerbations of chronic lung disease. The composition of the lung microbiome is determined by microbial immigration, elimination, and relative growth rates of its members. All these factors change dramatically in chronic lung disease and further during exacerbations. Exacerbations lack the features of bacterial infections, including increased bacterial burden and decreased diversity of microbial communities. We propose that exacerbations are occasions of respiratory tract dysbiosis—a disorder of the respiratory tract microbial ecosystem with negative effects on host biology. Respiratory tract dysbiosis provokes a dysregulated host immune response, which in turn alters growth conditions for microbes in airways, promoting further dysbiosis and perpetuating a cycle of inflammation and disordered microbiota. Differences in the composition of baseline respiratory tract microbiota might help to explain the so-called frequent-exacerbator phenotype observed in several disease states, and might provide novel targets for therapeutic intervention.

Introduction

The natural histories of several chronic lung diseases include exacerbations, which are characterised by abrupt worsening of respiratory symptoms and pulmonary function. Exacerbations cause much of the morbidity, mortality, and expense of chronic lung diseases,1, 2, 3 and are associated with accelerated disease progression.4, 5, 6, 7 Exacerbations are also associated with viral exposure and bacterial growth in cultures of respiratory specimens, but the precise relation between resident bacteria, acute infection, and the pathogenesis of exacerbations is controversial.8, 9

In the past decade, new culture-independent tech­niques for microbial identification such as pyrosequencing have shown a previously unappreciated complexity to the bacterial microbiome in the respiratory tract.10 The lungs and airways, whether in health or in chronic or acute lung disease, harbour diverse communities of microbes that are undetected by conventional culture-based approaches. A new understanding of lung microbiology has called into question long-held beliefs with respect to the pathogenesis of exacerbations of chronic lung disease derived from a half-century of experimentation and observation using culture-based techniques.

Section snippets

What is an exacerbation?

Exacerbations of chronic lung disease are periods of acute worsening of respiratory symptoms. They arise abruptly, within hours to days, and generally prompt an escalation in therapy. Symptoms might include focal respiratory symptoms, such as cough, increased sputum production, dyspnoea, or wheeze, but might also include systemic features such as fever, fatigue, or malaise. The onset of symptoms often precedes worsening of lung function,11 although in some patients with impaired perception of

Modern techniques to study the lung microbiome

Although a comprehensive discussion of modern techniques would exceed the scope of this review, familiarity with basic principles is key to understanding the revelations and difficulties in the field.10, 14, 15

Lung microbiome studies have used various molecular techniques to characterise microbial communities in the respiratory tract, but the most commonly used modern method is high-throughput sequencing of the 16S rRNA gene, a small and highly conserved locus in bacterial DNA. A single

The microbial ecology and topology of the human respiratory tract

A key principle in the speciality of microbial ecology is that local environmental conditions determine the composition of microbial communities. An oft-cited tenet in the field is that “Everything is everywhere, but the environment selects.”32 The growth of a species, and its relative abundance in the microbial community, is a function of nutrient availability, temperature, pH, oxygen concentration, and various other environmental factors. Thus any investigation into the respiratory microbiome

COPD

Exacerbations of COPD are associated with high mortality, rapid decrease in lung function, and increased health-care costs.68 Frequency of exacerbations increases with severity of airway obstruction, but many patients experience exacerbations more frequently than would be predicted by disease severity alone (the so-called frequent exacerbator phenotype).69 Exacerbations are also associated with systemic inflammation,70 airway inflammation,60 and increased airway obstruction due to oedema,

Key lessons and directions for study

Despite the presence of airway inflammation in respiratory exacerbations, a consistent finding across disease states is the lack of evidence that exacerbations are attributable to acute bacterial infections of the airways. Of the eight culture-independent studies across COPD, cystic fibrosis and non-cystic fibrosis bronchiectasis that have compared patients’ respiratory specimens obtained at baseline and during exacerbations, all showed no change in the bacterial density or community diversity

Search strategy and selection criteria

We searched Medline without date or language restrictions. Initial search phrases were “exacerbation[All Fields] and (“microbiota” [mesh terms] or “microbiota” [all fields] or “microbiome” [all fields])” and “disease [all fields] and exacerbation [all fields] and (“microbiology” [subheading] or “microbiology” [all fields] or “bacteria” [all fields] or “bacteria” [mesh terms])” where disease represents “cystic fibrosis”, “COPD”, “bronchiectasis”, “asthma”, or “pulmonary fibrosis”.

References (137)

  • F D'Ovidio et al.

    Prevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplant

    Ann Thorac Surg

    (2005)
  • SK Kaza et al.

    IL-8 released from human lung epithelial cells induced by cystic fibrosis pathogens Burkholderia cepacia complex affects the growth and intracellular survival of bacteria

    Int J Med Microbiol

    (2011)
  • PP Freestone et al.

    Pseudomonas aeruginosa-catecholamine inotrope interactions: a contributory factor in the development of ventilator-associated pneumonia?

    Chest

    (2012)
  • JA Wedzicha et al.

    COPD exacerbations: defining their cause and prevention

    Lancet

    (2007)
  • TM Wilkinson et al.

    Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD

    Chest

    (2006)
  • WW Busse et al.

    Role of viral respiratory infections in asthma and asthma exacerbations

    Lancet

    (2010)
  • MN Hurley et al.

    Results of antibiotic susceptibility testing do not influence clinical outcome in children with cystic fibrosis

    J Cyst Fibros

    (2012)
  • AL Smith et al.

    Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis

    Chest

    (2003)
  • DH Smith et al.

    A national estimate of the economic costs of asthma

    Am J Respir Crit Care Med

    (1997)
  • TA Lieu et al.

    The cost of medical care for patients with cystic fibrosis in a health maintenance organization

    Pediatrics

    (1999)
  • TA Seemungal et al.

    Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2000)
  • GC Donaldson et al.

    Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease

    Thorax

    (2002)
  • TG Liou et al.

    Predictive 5-year survivorship model of cystic fibrosis

    Am J Epidemiol

    (2001)
  • RP Dickson et al.

    The role of the bacterial microbiome in lung disease

    Expert Rev Respir Med

    (2013)
  • M Chan-Yeung et al.

    Changes in peak flow, symptom score, and the use of medications during acute exacerbations of asthma

    Am J Respir Crit Care Med

    (1996)
  • DB Sanders et al.

    Return of FEV1 after pulmonary exacerbation in children with cystic fibrosis

    Pediatr Pulmonol

    (2010)
  • M Hamady et al.

    Microbial community profiling for human microbiome projects: tools, techniques, and challenges

    Genome Res

    (2009)
  • XC Morgan et al.

    Chapter 12: Human microbiome analysis

    PLoS Comput Biol

    (2012)
  • RP Dickson et al.

    Changes in the lung microbiome following lung transplantation include the emergence of two distinct pseudomonas species with distinct clinical associations

    PLoS One

    (2014)
  • A Suau et al.

    Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut

    Appl Environ Microbiol

    (1999)
  • ES Charlson et al.

    Topographical continuity of bacterial populations in the healthy human respiratory tract

    Am J Respir Crit Care Med

    (2011)
  • MM Tunney et al.

    Lung microbiota and bacterial abundance in paitents bronchiectasis when clinically stable and during exacerbation

    Am J Respir Crit Care Med

    (2013)
  • Structure, function and diversity of the healthy human microbiome

    Nature

    (2012)
  • GB Rogers et al.

    Clinical measures of disease in adult non-CF bronchiectasis correlate with airway microbiota composition

    Thorax

    (2013)
  • YJ Huang et al.

    Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma

    J Allergy Clin Immunol

    (2011)
  • AA Pragman et al.

    The lung microbiome in moderate and severe chronic obstructive pulmonary disease

    PLoS One

    (2012)
  • E Goleva et al.

    The effects of airway microbiome on corticosteroid responsiveness in asthma

    Am J Respir Crit Care Med

    (2013)
  • LN Segal et al.

    Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation

    Microbiome

    (2013)
  • AF Goddard et al.

    Direct sampling of cystic fibrosis lungs indicates that DNA-based analyses of upper-airway specimens can misrepresent lung microbiota

    Proc Natl Acad Sci USA

    (2012)
  • MJ Cox et al.

    Airway microbiota and pathogen abundance in age-stratified cystic fibrosis patients

    PLoS One

    (2010)
  • J Zhao et al.

    Decade-long bacterial community dynamics in cystic fibrosis airways

    Proc Natl Acad Sci USA

    (2012)
  • PL Molyneaux et al.

    Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2013)
  • J Zhao et al.

    Modeling the impact of antibiotic exposure on human microbiota

    Sci Rep

    (2014)
  • Baas Becking LGM. Geobiology or introduction to the science of the environment: with bibliography and index: Van...
  • PS Hasleton

    The internal surface area of the adult human lung

    J Anat

    (1972)
  • DS Dock et al.

    The pulmonary blood volume in man

    J Clin Invest

    (1961)
  • HF Helander et al.

    Surface area of the digestive tract—revisited

    Scand J Gastroenterol

    (2014)
  • A Morris et al.

    Comparison of the respiratory microbiome in healthy nonsmokers and smokers

    Am J Respir Crit Care Med

    (2013)
  • B Lighthart

    Mini-review of the concentration variations found in the alfresco atmospheric bacterial populations

    Aerobiologia

    (2000)
  • RM Bowers et al.

    Sources of bacteria in outdoor air across cities in the midwestern United States

    Appl Environ Microbiol

    (2011)
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