- Email: [email protected]
Non cystic fibrosis bronchiectasis
PAEDIATRIC RESPIRATORY REVIEWS (2006) 7S, S255–S257
Non cystic fibrosis bronchiectasis Cass Byrnes* Auckland University & Starship Children’s Hospital, New Zealand
Bronchiectasis (Bx), an old disease, was a popular topic of study mid last century producing a series of articles in 1956– 1963 describing the characteristics of affected children before falling into relative obscurity. However a resurgence in the literature since the late 1990s has resulted in similar descriptions demonstrating clear concern about the incidence of children affected, particularly in certain communities – Alaskan native,1 Aboriginal,2 Maori & Pacific Islanders,3 Turkish4,5 with rates (likely underestimated) at between 0.2–14.7/ 1,000. There have only been 2 national studies of incidence in children to date – Finland6 at 0.5/100,000 and New Zealand7 at 3.7/100,000. Diagnosis has moved from autopsy to bronchography to HRCT scan with criteria8 defined as lack of normal tapering, bronchi with an internal diameter greater than the external diameter of the accompanying artery, or visualization of bronchi within 1 cm of the pleura. Concern also surrounds the severity of the disease in those diagnosed. The paediatric studies that describe the degree of lung involvement1–7,9 give this as 39–82% with 4 or more lobes involved, 61–93% with bilateral disease and only 9%,3 29%1 and 43%5 with single lobe involvement. TB, pertussis, measles and certain types of adenovirus are traditionally implicated. In the more recent series, aetiology has been ascribed to infection 25–95%, unknown 0–50% (noting that those less willing to ascribe to infectious disease without definitive proof had higher numbers in the unknown category), aspiration including foreign body 4–10%, immunodeficiency 0–17%, cilia abnormalities 0–13%. However, recognise with these figures that not all investigations were done in all the populations. The infections above are still apparent, but more now are secondary to pneumonia with organisms unknown. A history of hospitalized pneumonia gave a relative risk of 15.2 for developing Bx, and associations were also strong with recurrent hospitalised pneumonia, * Tel.: +64 9 3737599/89770; Fax: +64 9 3737 486. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.185
severe pneumonia episodes with longer hospital stay, presence of atelectasis and requirement for oxygen.10 A more recent study11 determined a diagnosis in 74% of 136 children and investigations resulted in a change in management in 56% carried out in 2 quaternary and comparatively resource rich hospitals. This study also presented the diagnostic yield of the investigations which ranged from 0 to 47% which is a good model of evaluating the use of, often expensive, investigations. Yield will vary depending on population characteristics and referral pattern. Also disquieting is the duration of symptoms (recurrent persistent) before the diagnosis is made and, presumably, a more comprehensive management plan is devised. The medians from these studies give this delay from 17 months to 4.8 years. Also, in studies describing adult clinics, up to 50% are thought to have commenced the disease in childhood.12 In the main, of those in whom sputum culture is possible, haemophilus influenzae is the most common organism, followed by streptococcal pneumoniae. This is very different from both the paediatric cystic fibrosis (CF) and the adult Bx populations where pseudomonas aeruginosa is more common. The mainstay of treatment to date has been antibiotic therapy and physiotherapy with surgery an option only for localized disease. There are a few studies describing antibiotic benefit (mostly in adult populations) but virtually no literature specifically examining the benefits of on physiotherapy. A Cochrane review regarding long term antibiotics suggests a benefit for the use of prolonged treatment in adult trials lasting 4 weeks to one year.13 Inhaled antibiotics, also in adult trials, have shown positive results using amoxicillin,14 and aminoglycosides15,16 in patients with chronic pseudomonas infection. Nebulised hypertonic saline in concentrations from 3 to 14% has been shown to improve mucus clearance in other respiratory diseases. Hypertonic saline does increase ciliary
S256
transportability of Bx sputum and both hypertonic (7%) and isotonic saline increased sputum weight but with a significant difference in favour of hypertonic.17 RhDNase has not been shown to be helpful, possibly detrimental, and proves the point that therapies successful in other diseases (the obvious comparison here is CF) require proper evaluation in this condition and in children.18,19 Not yet available, the inhalation of mannitol resulted in improved tracheobronchoalveolar clearance of a particulate radio aerosol, improved mucus clearance after 24 h,20 improved mucus characteristics for cough clearability and improved quality of life (QOL) after 12 days of treatment.21 There is not enough research to comment on the use of asthma medication in this area. The only mildly positive result seen is in the use of inhaled corticosteroids where 2 trials with a total of 54 adult patients of 4 and 6 weeks duration suggested a trend only in improving FVC and FEV122 and a further study showed improvement in exacerbation scores and sputum purulence scores.23 Interestingly, a recent study in adults with Bx24 using pulmonary rehabilitation techniques from other adult diseases showed that physical training (45 min 3 times per week) in 2 groups improved QOL, endurance exercise capacity with mean increases of 607.3 m and 392.8 m and walking distance by 205.7% and 174.9% compared to a control group. However, 3 months after the training had ceased only the group that had received additional inspiratory muscle training continued to demonstrate these benefits. Exercise and inspiratory muscle training are underutilized and cheap management strategies. Median lung function in all the paediatric studies1–5 was been abnormal with medians for FVC 68–86% and FEV1 63–71%, however progress over time has been difficult to assess in this heterogeneous group of patients. Earlier it was suggested that once established and treated, lung function remained stable.25 However we have shown deterioration similar to, but not as much as, a comparison CF group, but with lower levels of lung function when the groups were a mean age of 10 years.26 Lung function as a primary outcome for treatment trials, except for assessment of acute treatment, has been a disappointing measure as it does not change dramatically over months which are when most reassessments have taken place. Better is the use of number of exacerbations or admissions, days in hospital, exercise and/or QOL measures. Finally while established Bx is clearly irreversible, within studies some cases with local and/or mild disease have been described as showing improvement or resolution – this may be another reason for us to encourage early diagnosis and promote early treatment.
THE PEARLS 1. Paediatric Bx is under diagnosed. There is increasing recognition in certain populations. However many adults present with Bx in whom symptoms have commenced in childhood.
C. BYRNES 2. There is a significant delay between onset of recurrent or persistent symptoms and the diagnosis being made. 3. Bx is a pathological state and seeking an underlying diagnosis is a principle of care. 4. If positive sputum cultures occur with pseudomonas aeruginosa or staphylococcal aureus – ensure CF has been definitively excluded. 5. While established Bx is clearly irreversible - in a small number with minimal or localized disease, there are descriptions of reversibility. 6. Long term oral antibiotic therapy has been shown to be helpful. 7. Nebulised antibiotic therapy provides local antibiotic treatment without systemic side effects and may be increasingly useful in the long term. 8. As in other areas, there are studies suggesting the benefits of macrolide therapy in this patient group. 9. Exercise is an under-rated strategy – it should be included in individual management plans. 10. While physical training gave short term improvement, the addition of inspiratory muscle training resulted in maintenance of benefit over months. 11. Inhaled mannitol may also be of future use. 12. More research is desirable in this area, but difficult to develop with minimal drug company aid. 13. Cost of this disease – in terms of investigation, days of school and work lost and the long term management –— is high.
AREAS OF RESEARCH LIKELY TO BE BENEFICIAL Prospective follow up of children with risk factors for Bx development; chronic productive cough, 2 or more pneumonias, or after certain respiratory infections such as adenovirus. Study of progression and development of chronic infections to determine characteristics that result in worsening disease. The effect of exercise programmes over time. Trials of antibiotic therapy – macrolides, inhaled antibiotics.
ACKNOWLEDGEMENTS Thanks to the Starship Hospital bronchietasis clinical and reseach team –— D, Elizabeth Edwards, D, Jacdo Twiss, Sarah Butler, Pamline Lolohea.
REFERENCES 1. 2. 3. 4.
Singleton. et al. Pediatr Pulmonol 2000; 29: 182–187. Chang. et al. Med J Aust 2002; 177: 200–204. Edwards. et al. J Paediatr & Child Health 2003; 39: 111–117. Karakoc. et al. Eur Respir J 1997; 10: 171.
NON CYSTIC FIBROSIS BRONCHIECTASIS
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Karakoc. et al. Pediatr Pulmonol 2001; 32: 175–178. Sayajakangas. et al. Cent Eur J Public Health 1998; 6: 235–237. Twiss. et al. Arch Dis Child 2005; 90: 737–740. Naidich. et al. J Comput Assist Tomogr 1982; 6: 437–444. Eastham. et al. Thorax 2004; 59: 324–327. Valery. et al. Paediatr Infect Dis J 2004; 23: 902–908. Li. et al. Eur Respir J 2005; 26: 8–14. Pasteur. et al. Am J Respir Crit Care Med 2000; 162(4 pt 1): 1277–1284. Evans. et al. Cochrane Database Syst Rev, 2005. Evans. et al. Respir Med 2003; 97: 851–858. Barker. et al. Am J Respir Crit Care Med 2000; 162: 481–485.
S257
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
Scheinberg. et al. Chest 2005; 127: 1420–1426. Kellet. et al. Respir Med 2005; 99: 27–31. Wills. et al. Am J Respir Crit Care Med 1996; 154: 413–417. O’Donnell. et al. Chest 1998; 113: 1329–1334. Daviskas. et al. Chest 2001; 119: 414–421. Daviskas. et al. Respirology 2005; 10: 46–56. Ram. et al. Cochrane Database Syst Rev, 2001. Tsang. et al. Thorax 2005; 60: 239–243. Newall. et al. Thorax 2005; 60: 943–948. Landau. et al. Thorax 1974; 29: 304–312. Twiss. et al. Thorax 2006; 61: 414–418.
Non cystic fibrosis bronchiectasis Cass Byrnes* Auckland University & Starship Children’s Hospital, New Zealand
Bronchiectasis (Bx), an old disease, was a popular topic of study mid last century producing a series of articles in 1956– 1963 describing the characteristics of affected children before falling into relative obscurity. However a resurgence in the literature since the late 1990s has resulted in similar descriptions demonstrating clear concern about the incidence of children affected, particularly in certain communities – Alaskan native,1 Aboriginal,2 Maori & Pacific Islanders,3 Turkish4,5 with rates (likely underestimated) at between 0.2–14.7/ 1,000. There have only been 2 national studies of incidence in children to date – Finland6 at 0.5/100,000 and New Zealand7 at 3.7/100,000. Diagnosis has moved from autopsy to bronchography to HRCT scan with criteria8 defined as lack of normal tapering, bronchi with an internal diameter greater than the external diameter of the accompanying artery, or visualization of bronchi within 1 cm of the pleura. Concern also surrounds the severity of the disease in those diagnosed. The paediatric studies that describe the degree of lung involvement1–7,9 give this as 39–82% with 4 or more lobes involved, 61–93% with bilateral disease and only 9%,3 29%1 and 43%5 with single lobe involvement. TB, pertussis, measles and certain types of adenovirus are traditionally implicated. In the more recent series, aetiology has been ascribed to infection 25–95%, unknown 0–50% (noting that those less willing to ascribe to infectious disease without definitive proof had higher numbers in the unknown category), aspiration including foreign body 4–10%, immunodeficiency 0–17%, cilia abnormalities 0–13%. However, recognise with these figures that not all investigations were done in all the populations. The infections above are still apparent, but more now are secondary to pneumonia with organisms unknown. A history of hospitalized pneumonia gave a relative risk of 15.2 for developing Bx, and associations were also strong with recurrent hospitalised pneumonia, * Tel.: +64 9 3737599/89770; Fax: +64 9 3737 486. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.185
severe pneumonia episodes with longer hospital stay, presence of atelectasis and requirement for oxygen.10 A more recent study11 determined a diagnosis in 74% of 136 children and investigations resulted in a change in management in 56% carried out in 2 quaternary and comparatively resource rich hospitals. This study also presented the diagnostic yield of the investigations which ranged from 0 to 47% which is a good model of evaluating the use of, often expensive, investigations. Yield will vary depending on population characteristics and referral pattern. Also disquieting is the duration of symptoms (recurrent persistent) before the diagnosis is made and, presumably, a more comprehensive management plan is devised. The medians from these studies give this delay from 17 months to 4.8 years. Also, in studies describing adult clinics, up to 50% are thought to have commenced the disease in childhood.12 In the main, of those in whom sputum culture is possible, haemophilus influenzae is the most common organism, followed by streptococcal pneumoniae. This is very different from both the paediatric cystic fibrosis (CF) and the adult Bx populations where pseudomonas aeruginosa is more common. The mainstay of treatment to date has been antibiotic therapy and physiotherapy with surgery an option only for localized disease. There are a few studies describing antibiotic benefit (mostly in adult populations) but virtually no literature specifically examining the benefits of on physiotherapy. A Cochrane review regarding long term antibiotics suggests a benefit for the use of prolonged treatment in adult trials lasting 4 weeks to one year.13 Inhaled antibiotics, also in adult trials, have shown positive results using amoxicillin,14 and aminoglycosides15,16 in patients with chronic pseudomonas infection. Nebulised hypertonic saline in concentrations from 3 to 14% has been shown to improve mucus clearance in other respiratory diseases. Hypertonic saline does increase ciliary
S256
transportability of Bx sputum and both hypertonic (7%) and isotonic saline increased sputum weight but with a significant difference in favour of hypertonic.17 RhDNase has not been shown to be helpful, possibly detrimental, and proves the point that therapies successful in other diseases (the obvious comparison here is CF) require proper evaluation in this condition and in children.18,19 Not yet available, the inhalation of mannitol resulted in improved tracheobronchoalveolar clearance of a particulate radio aerosol, improved mucus clearance after 24 h,20 improved mucus characteristics for cough clearability and improved quality of life (QOL) after 12 days of treatment.21 There is not enough research to comment on the use of asthma medication in this area. The only mildly positive result seen is in the use of inhaled corticosteroids where 2 trials with a total of 54 adult patients of 4 and 6 weeks duration suggested a trend only in improving FVC and FEV122 and a further study showed improvement in exacerbation scores and sputum purulence scores.23 Interestingly, a recent study in adults with Bx24 using pulmonary rehabilitation techniques from other adult diseases showed that physical training (45 min 3 times per week) in 2 groups improved QOL, endurance exercise capacity with mean increases of 607.3 m and 392.8 m and walking distance by 205.7% and 174.9% compared to a control group. However, 3 months after the training had ceased only the group that had received additional inspiratory muscle training continued to demonstrate these benefits. Exercise and inspiratory muscle training are underutilized and cheap management strategies. Median lung function in all the paediatric studies1–5 was been abnormal with medians for FVC 68–86% and FEV1 63–71%, however progress over time has been difficult to assess in this heterogeneous group of patients. Earlier it was suggested that once established and treated, lung function remained stable.25 However we have shown deterioration similar to, but not as much as, a comparison CF group, but with lower levels of lung function when the groups were a mean age of 10 years.26 Lung function as a primary outcome for treatment trials, except for assessment of acute treatment, has been a disappointing measure as it does not change dramatically over months which are when most reassessments have taken place. Better is the use of number of exacerbations or admissions, days in hospital, exercise and/or QOL measures. Finally while established Bx is clearly irreversible, within studies some cases with local and/or mild disease have been described as showing improvement or resolution – this may be another reason for us to encourage early diagnosis and promote early treatment.
THE PEARLS 1. Paediatric Bx is under diagnosed. There is increasing recognition in certain populations. However many adults present with Bx in whom symptoms have commenced in childhood.
C. BYRNES 2. There is a significant delay between onset of recurrent or persistent symptoms and the diagnosis being made. 3. Bx is a pathological state and seeking an underlying diagnosis is a principle of care. 4. If positive sputum cultures occur with pseudomonas aeruginosa or staphylococcal aureus – ensure CF has been definitively excluded. 5. While established Bx is clearly irreversible - in a small number with minimal or localized disease, there are descriptions of reversibility. 6. Long term oral antibiotic therapy has been shown to be helpful. 7. Nebulised antibiotic therapy provides local antibiotic treatment without systemic side effects and may be increasingly useful in the long term. 8. As in other areas, there are studies suggesting the benefits of macrolide therapy in this patient group. 9. Exercise is an under-rated strategy – it should be included in individual management plans. 10. While physical training gave short term improvement, the addition of inspiratory muscle training resulted in maintenance of benefit over months. 11. Inhaled mannitol may also be of future use. 12. More research is desirable in this area, but difficult to develop with minimal drug company aid. 13. Cost of this disease – in terms of investigation, days of school and work lost and the long term management –— is high.
AREAS OF RESEARCH LIKELY TO BE BENEFICIAL Prospective follow up of children with risk factors for Bx development; chronic productive cough, 2 or more pneumonias, or after certain respiratory infections such as adenovirus. Study of progression and development of chronic infections to determine characteristics that result in worsening disease. The effect of exercise programmes over time. Trials of antibiotic therapy – macrolides, inhaled antibiotics.
ACKNOWLEDGEMENTS Thanks to the Starship Hospital bronchietasis clinical and reseach team –— D, Elizabeth Edwards, D, Jacdo Twiss, Sarah Butler, Pamline Lolohea.
REFERENCES 1. 2. 3. 4.
Singleton. et al. Pediatr Pulmonol 2000; 29: 182–187. Chang. et al. Med J Aust 2002; 177: 200–204. Edwards. et al. J Paediatr & Child Health 2003; 39: 111–117. Karakoc. et al. Eur Respir J 1997; 10: 171.
NON CYSTIC FIBROSIS BRONCHIECTASIS
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Karakoc. et al. Pediatr Pulmonol 2001; 32: 175–178. Sayajakangas. et al. Cent Eur J Public Health 1998; 6: 235–237. Twiss. et al. Arch Dis Child 2005; 90: 737–740. Naidich. et al. J Comput Assist Tomogr 1982; 6: 437–444. Eastham. et al. Thorax 2004; 59: 324–327. Valery. et al. Paediatr Infect Dis J 2004; 23: 902–908. Li. et al. Eur Respir J 2005; 26: 8–14. Pasteur. et al. Am J Respir Crit Care Med 2000; 162(4 pt 1): 1277–1284. Evans. et al. Cochrane Database Syst Rev, 2005. Evans. et al. Respir Med 2003; 97: 851–858. Barker. et al. Am J Respir Crit Care Med 2000; 162: 481–485.
S257
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
Scheinberg. et al. Chest 2005; 127: 1420–1426. Kellet. et al. Respir Med 2005; 99: 27–31. Wills. et al. Am J Respir Crit Care Med 1996; 154: 413–417. O’Donnell. et al. Chest 1998; 113: 1329–1334. Daviskas. et al. Chest 2001; 119: 414–421. Daviskas. et al. Respirology 2005; 10: 46–56. Ram. et al. Cochrane Database Syst Rev, 2001. Tsang. et al. Thorax 2005; 60: 239–243. Newall. et al. Thorax 2005; 60: 943–948. Landau. et al. Thorax 1974; 29: 304–312. Twiss. et al. Thorax 2006; 61: 414–418.