- Email: [email protected]
PBB: definition, mechanisms, and treatment
Comment
Protracted bacterial bronchitis (PBB) is the commonest cause of chronic wet cough in children attending Australian respiratory clinics.1 As a possible forerunner to other chronic suppurative lung diseases, such as bronchiectasis, PBB creates an opportunity for studying the early pathobiology of these disorders. This early pathobiology is important because once bronchiectasis is well-established, its disease mechanisms, as exemplified by the airway microbiota, can change.2 Moreover, understanding the initial pathogenesis increases the prospects of developing effective early interventions. The clinical entity of PBB was originally based on three criteria; presence of chronic wet or productive cough; evidence of bacterial infection in bronchoalveolar lavage cultures; and cough resolution after a 2 week course of antibiotics.3 These criteria arose from clinical findings and each has since been validated. Although not without initial controversy regarding the existence of PBB, the disorder is now incorporated into many national paediatric chronic cough guidelines3 and the European paediatric respiratory curriculum. Despite its recent description, astute clinicians described PBB-like disorders decades ago and postulated they were part of a pre-bronchiectatic state.4 Since our description in 2006, we and others3,5 have further defined PBB. Because it is not feasible to obtain lower airway cultures from every child with a chronic (>4 weeks) wet cough, we modified the second criterion to the absence of other causes of wet or productive cough. Despite prospective studies reporting children with PBB being aged younger than 5 years, older children can also be affected.1,3 Parents describe several doctor visits (>75% report more than five doctor visits) before diagnosis and they have impaired cough-specific and generic quality of life scores, which improve significantly once their child’s cough resolves.1 Although many parents also report previous wheeze, auscultation confirmed wheeze by doctors is unusual and the prevalence of atopic features (systemic and airway eosinophilia, elevated immunoglobulin E or RAST positivity) is similar to children without PBB.3 Because PBB is a chronic endobronchial infection (figure), the child seems otherwise well without chronic sinus or ear disease.3 Baseline immune function is normal,3 and whereas chest X-rays generally show perihilar changes,1 chest computed scans are normal and are not recommended for making the diagnosis of uncomplicated PBB. Spirometry is also normal,1
as are respiratory system reactance and resistance measured by the forced oscillatory technique (unpublished data). By contrast, chest CT scans in children with bronchiectasis show the classic signet ring abnormality and the spirometry and immune function might be abnormal dependent on the underlying cause and severity of the bronchiectasis. Tracheobronchomalacia commonly (up to 74%) co-exists with PBB,3,5 but chronic inflammation can also cause large airway abnormalities, which presents a diagnostic challenge to differentiate between the two. In a cohort of 104 children with PBB, tracheobronchomalacia had similar prevalence to that found in non-PBB controls (68% vs 53%).3 PBB is more common in children attending childcare (OR 8·4, 95% CI 2·3–30·5),3 raising the possibility of viral infections preceding PBB. Indeed, findings of prospective studies have shown adenovirus species C was commonly co-detected with Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis in BAL samples from young children with PBB or bronchiectasis.6 Bacterial 16S rRNA gene pyrosequencing and phylogenetic analysis also showed that children with PBB and bronchiectasis shared similar lower airway core microbiota.2 This contrasts with adults in which the core pulmonary microbiota differ from one another and from the children with the same disease.2 Pathobiological studies report upregulated innate immunity markers rather than an immunodeficiency profile. Children with PBB have significantly higher TLR-2 and TLR-4 mRNA relative expression7 and higher human β-defensin-2 (hBD2)8 and mannose-binding lectin (MBL) concentrations8 than children without PBB. By contrast, lipopolysaccharide stimulated BAL cells from PBB cases and controls produce similar cytokine responses.8 The lower airway profile is characterised by intense neutrophilic inflammation with marked proinflammatory mediator responses (IL-8, MMP-9, IL-1β) that correlate with BAL neutrophil percentages (r=0·66, 0·48, 0·75, respectively; all p<0·001).7,9 We have shown in experimental and validation cohorts that the BAL fluid from children with PBB have significantly higher levels of gene and protein expression of IL-1β, α-defensin, IL-1 pathway members, and CXCR2 than children without PBB.9 IL-1β levels were also associated with duration and severity of cough.9 Additionally, the gene expression of the IL-1β signalling molecules pellino-1 and IL-1 receptorassociated kinase 2 were significantly higher in those
www.thelancet.com/respiratory Published online August 19, 2015 http://dx.doi.org/10.1016/S2213-2600(15)00243-X
Chassenet/Science Photo Library
PBB: definition, mechanisms, and treatment
Lancet Respir Med 2015 Published Online August 19, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00243-X
1
Comment
aspiration) and there are other diagnoses to consider for a child with chronic wet cough.1 Further clinical and mechanistic studies in PBB are needed. These include: whether the third diagnostic criterion should be changed from 2 weeks of antibiotics to 2–4 weeks of antibiotics as required in a small number of children; monitoring the effect of antibiotic-resistant organisms on the diagnosis and management of PBB; multicentre intervention trials and; understanding the long-term outcomes. Although its extent in adults is unknown, PBB shares common pathobiological features with bronchiectasis and other neutrophilic airway disorders prevalent in this older age group. Figure: A bronchoscopic image from a child aged 10 months with protracted bacterial bronchitis showing secretions partly obscuring the left lower lobe bronchus The child’s broncho-alveolar lavage fluid grew Streptococcus pneumoniae (108 colony forming units (cfu)/ml), Haemophilus influenzae (108 cfu/ml), and Moraxella catarrhalis (107 cfu/ml).
with recurrent episodes (>three in the next 12 months) compared with those without recurrent PBB (≤three in the next 12 months).9 PBB is treated with 2 weeks of an appropriate antibiotic targeting the aforementioned respiratory bacteria (usually amoxicillin-clavulanic acid).10 The longer course needed to clear infection might result from bacterial community biofilms forming in the lower airways. Whether neutrophil extracellular nets, defective apoptosis or efferocytosis, and other mechanisms for airway neutrophilia persistence also has a role is unknown and warrants further investigation. Although prudent antibiotic prescription is important and should be avoided in patients with an uncomplicated acute respiratory illness, clinicians should also recognise the therapeutic role of antibiotics in chronic wet cough. Withholding antibiotics when chronic endobronchial suppuration is present as in PBB might lead to ongoing infection and inflammation and even bronchiectasis. Although PBB can recur, the actual rate and risk factors are unknown and worthy of further investigation as recurrent PBB is associated with more intense (and possibly persistent) activation of IL1 signalling pathways.9 Findings of preliminary analyses of our ongoing studies showed that children with recurrent PBB are more likely to be diagnosed with bronchiectasis in the following 2 years. Lastly, PBB can co-exist with other disorders (eg, asthma, immunodeficiency, and 2
*Anne B Chang, Keith Grimwood, Peter G Gibson, John W Upham Child Health Division, Menzies School of Health Research, Darwin, NT 0811, Australia (ABC); Department of Respiratory and Sleep Medicine, Queensland Children’s Medical Research Institute, Queensland University of Technology, Queensland Children’s Health Service, South Brisbane, QLD, Australia (ABC); Menzies Health Institute Queensland, Griffith University and Gold Coast University Hospital, Gold Coast, QLD, Australia (KG); Priority Research Centre for Asthma and Respiratory Diseases, The University of Newcastle, Callaghan, NSW, Australia (PGG); Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute; John Hunter Hospital, New Lambton Heights, NSW, Australia (PGG); and School of Medicine, The University of Queensland, Brisbane, QLD, Australia (JWU) [email protected] ABC and PGG are supported by National Health and Medical Research Council (NHMRC) practitioner fellowships (1058213 and 1058552). This work was supported by a NHMRC project grant (1042601) and a NHMRC Centre for Research Excellence for lung health in Aboriginal and Torres Strait Islanders grant (1040830). KG and JWU declare no competing interests. 1
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3 4
5 6
7
8 9 10
Chang AB, Robertson CF, van Asperen PP, et al. Children with chronic cough: when is watchful waiting appropriate? Development of likelihood ratios for assessing children with chronic cough. Chest 2015; 147: 745–53. van der Gast CJ, Cuthbertson L, Rogers GB, et al. Three clinically distinct chronic pediatric airway infections share a common core microbiota. Ann Am Thorac Soc 2014; 11: 1039–48. Wurzel D, Marchant JM, Yerkovich ST, et al. Prospective characterisation of protracted bacterial bronchitis in children. Chest 2014; 145: 1271–78. Field CE. Bronchiectasis in childhood: II. Aetiology and pathogenesis, Including a Survey of 272 Cases of Doubtful Irreversible Bronchiectasis. Pediatrics 1949; 4: 231–48. Kompare M, Weinberger M. Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia. J Pediatr 2012; 160: 88–92. Wurzel DF, Mackay IM, Marchant JM, et al. Adenovirus Species C Is Associated With Chronic Suppurative Lung Diseases in Children. Clin Infect Dis 2014; 59: 34–40. Marchant JM, Gibson PG, Grissell TV, et al. Prospective assessment of protracted bacterial bronchitis: airway inflammation and innate immune activation. Pediatr Pulmonol 2008; 43: 1092–99. Chang AB, Yerkovich ST, Gibson PG, et al. Pulmonary innate immunity in children with protracted bacterial bronchitis. J Pediatr 2012; 161: 621–25. Baines KJ, Upham JW, Yerkovich ST, et al. Mediators of neutrophil function in children with protracted bacterial bronchitis. Chest 2014; 146: 1013–20. Weinberger M, Fischer A. Differential diagnosis of chronic cough in children. Allergy Asthma Proc 2014; 35: 95–103.
www.thelancet.com/respiratory Published online August 19, 2015 http://dx.doi.org/10.1016/S2213-2600(15)00243-X
Protracted bacterial bronchitis (PBB) is the commonest cause of chronic wet cough in children attending Australian respiratory clinics.1 As a possible forerunner to other chronic suppurative lung diseases, such as bronchiectasis, PBB creates an opportunity for studying the early pathobiology of these disorders. This early pathobiology is important because once bronchiectasis is well-established, its disease mechanisms, as exemplified by the airway microbiota, can change.2 Moreover, understanding the initial pathogenesis increases the prospects of developing effective early interventions. The clinical entity of PBB was originally based on three criteria; presence of chronic wet or productive cough; evidence of bacterial infection in bronchoalveolar lavage cultures; and cough resolution after a 2 week course of antibiotics.3 These criteria arose from clinical findings and each has since been validated. Although not without initial controversy regarding the existence of PBB, the disorder is now incorporated into many national paediatric chronic cough guidelines3 and the European paediatric respiratory curriculum. Despite its recent description, astute clinicians described PBB-like disorders decades ago and postulated they were part of a pre-bronchiectatic state.4 Since our description in 2006, we and others3,5 have further defined PBB. Because it is not feasible to obtain lower airway cultures from every child with a chronic (>4 weeks) wet cough, we modified the second criterion to the absence of other causes of wet or productive cough. Despite prospective studies reporting children with PBB being aged younger than 5 years, older children can also be affected.1,3 Parents describe several doctor visits (>75% report more than five doctor visits) before diagnosis and they have impaired cough-specific and generic quality of life scores, which improve significantly once their child’s cough resolves.1 Although many parents also report previous wheeze, auscultation confirmed wheeze by doctors is unusual and the prevalence of atopic features (systemic and airway eosinophilia, elevated immunoglobulin E or RAST positivity) is similar to children without PBB.3 Because PBB is a chronic endobronchial infection (figure), the child seems otherwise well without chronic sinus or ear disease.3 Baseline immune function is normal,3 and whereas chest X-rays generally show perihilar changes,1 chest computed scans are normal and are not recommended for making the diagnosis of uncomplicated PBB. Spirometry is also normal,1
as are respiratory system reactance and resistance measured by the forced oscillatory technique (unpublished data). By contrast, chest CT scans in children with bronchiectasis show the classic signet ring abnormality and the spirometry and immune function might be abnormal dependent on the underlying cause and severity of the bronchiectasis. Tracheobronchomalacia commonly (up to 74%) co-exists with PBB,3,5 but chronic inflammation can also cause large airway abnormalities, which presents a diagnostic challenge to differentiate between the two. In a cohort of 104 children with PBB, tracheobronchomalacia had similar prevalence to that found in non-PBB controls (68% vs 53%).3 PBB is more common in children attending childcare (OR 8·4, 95% CI 2·3–30·5),3 raising the possibility of viral infections preceding PBB. Indeed, findings of prospective studies have shown adenovirus species C was commonly co-detected with Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis in BAL samples from young children with PBB or bronchiectasis.6 Bacterial 16S rRNA gene pyrosequencing and phylogenetic analysis also showed that children with PBB and bronchiectasis shared similar lower airway core microbiota.2 This contrasts with adults in which the core pulmonary microbiota differ from one another and from the children with the same disease.2 Pathobiological studies report upregulated innate immunity markers rather than an immunodeficiency profile. Children with PBB have significantly higher TLR-2 and TLR-4 mRNA relative expression7 and higher human β-defensin-2 (hBD2)8 and mannose-binding lectin (MBL) concentrations8 than children without PBB. By contrast, lipopolysaccharide stimulated BAL cells from PBB cases and controls produce similar cytokine responses.8 The lower airway profile is characterised by intense neutrophilic inflammation with marked proinflammatory mediator responses (IL-8, MMP-9, IL-1β) that correlate with BAL neutrophil percentages (r=0·66, 0·48, 0·75, respectively; all p<0·001).7,9 We have shown in experimental and validation cohorts that the BAL fluid from children with PBB have significantly higher levels of gene and protein expression of IL-1β, α-defensin, IL-1 pathway members, and CXCR2 than children without PBB.9 IL-1β levels were also associated with duration and severity of cough.9 Additionally, the gene expression of the IL-1β signalling molecules pellino-1 and IL-1 receptorassociated kinase 2 were significantly higher in those
www.thelancet.com/respiratory Published online August 19, 2015 http://dx.doi.org/10.1016/S2213-2600(15)00243-X
Chassenet/Science Photo Library
PBB: definition, mechanisms, and treatment
Lancet Respir Med 2015 Published Online August 19, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00243-X
1
Comment
aspiration) and there are other diagnoses to consider for a child with chronic wet cough.1 Further clinical and mechanistic studies in PBB are needed. These include: whether the third diagnostic criterion should be changed from 2 weeks of antibiotics to 2–4 weeks of antibiotics as required in a small number of children; monitoring the effect of antibiotic-resistant organisms on the diagnosis and management of PBB; multicentre intervention trials and; understanding the long-term outcomes. Although its extent in adults is unknown, PBB shares common pathobiological features with bronchiectasis and other neutrophilic airway disorders prevalent in this older age group. Figure: A bronchoscopic image from a child aged 10 months with protracted bacterial bronchitis showing secretions partly obscuring the left lower lobe bronchus The child’s broncho-alveolar lavage fluid grew Streptococcus pneumoniae (108 colony forming units (cfu)/ml), Haemophilus influenzae (108 cfu/ml), and Moraxella catarrhalis (107 cfu/ml).
with recurrent episodes (>three in the next 12 months) compared with those without recurrent PBB (≤three in the next 12 months).9 PBB is treated with 2 weeks of an appropriate antibiotic targeting the aforementioned respiratory bacteria (usually amoxicillin-clavulanic acid).10 The longer course needed to clear infection might result from bacterial community biofilms forming in the lower airways. Whether neutrophil extracellular nets, defective apoptosis or efferocytosis, and other mechanisms for airway neutrophilia persistence also has a role is unknown and warrants further investigation. Although prudent antibiotic prescription is important and should be avoided in patients with an uncomplicated acute respiratory illness, clinicians should also recognise the therapeutic role of antibiotics in chronic wet cough. Withholding antibiotics when chronic endobronchial suppuration is present as in PBB might lead to ongoing infection and inflammation and even bronchiectasis. Although PBB can recur, the actual rate and risk factors are unknown and worthy of further investigation as recurrent PBB is associated with more intense (and possibly persistent) activation of IL1 signalling pathways.9 Findings of preliminary analyses of our ongoing studies showed that children with recurrent PBB are more likely to be diagnosed with bronchiectasis in the following 2 years. Lastly, PBB can co-exist with other disorders (eg, asthma, immunodeficiency, and 2
*Anne B Chang, Keith Grimwood, Peter G Gibson, John W Upham Child Health Division, Menzies School of Health Research, Darwin, NT 0811, Australia (ABC); Department of Respiratory and Sleep Medicine, Queensland Children’s Medical Research Institute, Queensland University of Technology, Queensland Children’s Health Service, South Brisbane, QLD, Australia (ABC); Menzies Health Institute Queensland, Griffith University and Gold Coast University Hospital, Gold Coast, QLD, Australia (KG); Priority Research Centre for Asthma and Respiratory Diseases, The University of Newcastle, Callaghan, NSW, Australia (PGG); Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute; John Hunter Hospital, New Lambton Heights, NSW, Australia (PGG); and School of Medicine, The University of Queensland, Brisbane, QLD, Australia (JWU) [email protected] ABC and PGG are supported by National Health and Medical Research Council (NHMRC) practitioner fellowships (1058213 and 1058552). This work was supported by a NHMRC project grant (1042601) and a NHMRC Centre for Research Excellence for lung health in Aboriginal and Torres Strait Islanders grant (1040830). KG and JWU declare no competing interests. 1
2
3 4
5 6
7
8 9 10
Chang AB, Robertson CF, van Asperen PP, et al. Children with chronic cough: when is watchful waiting appropriate? Development of likelihood ratios for assessing children with chronic cough. Chest 2015; 147: 745–53. van der Gast CJ, Cuthbertson L, Rogers GB, et al. Three clinically distinct chronic pediatric airway infections share a common core microbiota. Ann Am Thorac Soc 2014; 11: 1039–48. Wurzel D, Marchant JM, Yerkovich ST, et al. Prospective characterisation of protracted bacterial bronchitis in children. Chest 2014; 145: 1271–78. Field CE. Bronchiectasis in childhood: II. Aetiology and pathogenesis, Including a Survey of 272 Cases of Doubtful Irreversible Bronchiectasis. Pediatrics 1949; 4: 231–48. Kompare M, Weinberger M. Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia. J Pediatr 2012; 160: 88–92. Wurzel DF, Mackay IM, Marchant JM, et al. Adenovirus Species C Is Associated With Chronic Suppurative Lung Diseases in Children. Clin Infect Dis 2014; 59: 34–40. Marchant JM, Gibson PG, Grissell TV, et al. Prospective assessment of protracted bacterial bronchitis: airway inflammation and innate immune activation. Pediatr Pulmonol 2008; 43: 1092–99. Chang AB, Yerkovich ST, Gibson PG, et al. Pulmonary innate immunity in children with protracted bacterial bronchitis. J Pediatr 2012; 161: 621–25. Baines KJ, Upham JW, Yerkovich ST, et al. Mediators of neutrophil function in children with protracted bacterial bronchitis. Chest 2014; 146: 1013–20. Weinberger M, Fischer A. Differential diagnosis of chronic cough in children. Allergy Asthma Proc 2014; 35: 95–103.
www.thelancet.com/respiratory Published online August 19, 2015 http://dx.doi.org/10.1016/S2213-2600(15)00243-X