Prolonged bacterial bronchitis: a commonly neglected condition

Prolonged bacterial bronchitis (PBB) is a clinicopathological entity first defined in 2006 and recognised by the American,¹ Australian,² British³ and European⁴ pulmonary societies. Although it is a cause of chronic cough and wheeze, it is omitted from the GINA guidelines.⁵ PBB seems likely to be under-diagnosed and if untreated may have sequelae. For this reason alone, this condition deserves to be better known.

Diagnosis

Young described the typical features of PBB.⁶ Foremost of these is a chronic, recurrent productive cough in a child. Dyspnoea is common. Intermittent low grade fever may be present and chest pain and haemoptysis may also occur. Systemic features are absent. The chest x-ray may be normal or show an infiltrate. In advanced cases bronchial dilation may be present. 

Young admitted that treatment was less than satisfactory and recommended sea air and postural drainage. Field noted the difficulty of distinguishing such cases from asthma.⁷ Smith et al described chronic bronchitis in children and noted the lack of atopy and a neutrophilic predominance in the sputum.⁸ Long-term antibiotic use was found to be beneficial.⁹ Although recognised in textbooks, specific diagnostic criteria were not initially formulated.¹⁰

In 2006 Marchant et al investigated children with chronic productive cough and coined the term protracted bacterial bronchitis.¹¹ The authors proposed four diagnostic criteria: 

• A productive cough for more than three weeks 
• Microbial growth on culture of bronchoalveolar lavage fluid 
• Resolution or significant improvement of symptoms within two weeks on antibiotic treatment 
• Lack of an alternative diagnosis. 

This was the most common single diagnosis (approximately 40% of cases). Neutrophils were predominant in the sputum and the most common pathogens isolated were Streptococcus pneumoniae, Haemophilus influenza and Moraxcella catarrhalis. Additional cases have since been reported.^12,13

Pathology

On bronchoscopy, inflammation of and secretions within the bronchi are found.¹⁴ Malacia of the airways is common.¹⁵ Comparison of high resolution CT and bronchoscopy found the latter to be more sensitive.¹⁶ Although PBB is thought to contribute to the development of bronchiectasis, it appears that bronchiectasis is – at least initially – reversible,¹⁷ illustrating the need for awareness of PBB as up to 50% of adults with bronchiectasis have no known aetiology.¹⁸

Differential diagnosis

The differential diagnosis of chronic cough differs between children and adults. In adults the most usual causes of chronic cough are gastro-oesophgeal reflux, rhinosinusitis and asthma. In children the differential is broader and includes asthma, airway malacia, post viral and bronchiectasis. Although PBB as originally defined requires the absence of an alternative diagnosis, as more cases have been described it is becoming less clear if PBB can co-exist with these differentials or if they simply predispose to its development. The following list is not exhaustive but includes the most commonly encountered alternative diagnosis when PBB has been investigated.

Asthma

Wheeze is common in PBB, occurring in > 80% of cases making asthma the main differential.¹⁴ It is worth noting that asthma like PBB is a clinicopathological entity with a variety of causes. Although generally attributed to an allergic reaction, approximately 50% of people with asthma do not have eosinophilia.¹⁹ Eosinophilic and neutrophilic asthma may be distinct diseases as they are associated with differing lymphocyte populations²⁰ – Th2 and Th17 in the eosinophilic and neutrophilic forms respectively – and airway microbiology.²¹ Cluster analysis also supports this suggestion.²² Antibodies directed against eosinophils and their products are of use in eosinophilic asthma.^23,24

Neutrophil predominance is associated with a poor steroid response.²⁵ The presence or absence of eosinophilia is now included in national guidelines on asthma management.²⁶ If eosinophilic and neutrophilic asthma are actually distinct entities then it is the latter that enters into the differential diagnosis of PBB.

Non-cystic fibrosis bronchiectasis

Non-cystic fibrosis bronchiectasis in children has a broadly similar clinical picture to PBB. Finger clubbing and chest wall deformities are not found in PBB but may be in bronchiectasis, albeit rarely. The response to antibiotics tends to be less durable in bronchectasis. The two conditions can be distinguished on the basis of radiological findings or bronchoscopy.^27,28 Although the natural history of PBB is unknown, it is suspected that untreated PBB may lead to bronciectasis.^12,29 so these conditions may share an overlapping aetiology.

Airway malacia

Airway malacia is a common finding in PBB, occurring in 40-70%.^14,15 Malacia may affect the larynx, trachea or bronchi or a combination. This condition may also present with wheeze and recurrent cough. Diagnosis is best made by bronchoscopy. As treatment is supportive only, it is fortunate that this condition resolves itself with age.

Immune deficiency

Immune deficiency may cause chronic cough. The most common deficiencies causing cough are B cell abnormalities.³⁰ While these most commonly lead to deficiencies in IgA and IgG, there may be a specific non-response to some antigens including pneumococci.³¹ The diagnosis of these conditions is based on the immunoglobulin levels and other more specialised tests.

Primary ciliary dyskinesia

Another condition has that been diagnosed while investigating PBB is primary ciliary dyskinesia. This is a collection of rare and difficult to diagnose genetic diseases. The European Respiratory Society has published guidance for its diagnosis but notes that even general pulmonologists will rarely see a case.³² Typically it takes between 20 and 40 visits to the doctor before a diagnosis is made and even then frequently it is made only in adulthood.³³

The European Respiratory Society taskforce estimates suggest that there is one case per 10,000 population but that only a fraction are correctly diagnosed.³⁴ Although this condition may be suspected even before birth with hydrocephalus, Joubert’s syndrome, situs inversus or congenital heart disease being noted on antenatal ultrasound, the diagnosis is usually made later in life. It may present with a chronic productive cough. Recognition of this condition is important because if untreated it may result in bronchiectasis.

Inhaled foreign body

Finally, an important differential that should not be overlooked is an inhaled foreign body. These are most commonly found in boys less than three years old and may present with a chronic cough or wheeze. The chest x-ray is often normal.³⁵ These bodies can remain undetected for many years³⁶ and the associated microbiology is very similar to that found in PBB.³⁷ These lesions are best diagnosed with CT or bronchoscopy.

Management

The original diagnostic criteria for PBB were and are only applicable where facilities exist to carry out bronchoscopies which limits their usefulness. An alternative set of diagnostic criteria have been proposed that do not require this investigation.

Revised diagnostic criteria³⁸

• Presence of a continuous chronic (more than four-week duration) wet or productive cough
• Absence of symptoms or signs suggestive of another cause of wet or productive cough
• The cough resolves following a two- to four-week course of an appropriate oral antibiotic.

While these diagnostic criteria seem reasonable, consensus on their usefulness has yet to be reached. The principal difficulty is deciding how far one should go in eliminating alternative diagnoses. Paul et al have suggested that in suspected cases minimal investigations are needed and that they should simply be treated with prolonged antibiotics.³⁹ While an argument can be made for this approach it is probably too simplistic. 

As has been noted earlier “[It] is important to realise a cough persisting in a child longer than a few weeks requires full investigation and early treatment.”⁴⁰ A child with a prolonged productive cough, in addition to a prolonged course of antibiotics, should have a chest x- ray, a full blood count with differential, immunoglobulin levels, IgE level and if available IgE levels to the common respiratory antigens. 

If the child is old enough to co-operate, pulmonary function tests are desirable. These will not distinguish between asthma and PBB but may provide information useful in the longer-term. The possibility of a foreign body should be borne in mind especially since it may not be visible on the chest x-ray. A sweat test may be useful if there is a family history or clinical suspicion of cystic fibrosis. If symptoms persist despite a prolonged course of antibiotics, a respiratory specialist’s opinion should be sought as a CT or bronchoscopy may be needed to make the diagnosis.

Once the diagnosis has been made, Stalin’s question arises: What is to be done? Currently long-term management of PBB is an evidence-free zone. Given that some children may not respond, at least initially, to the usual childhood vaccines it is probably worth revaccinating them again with the pneumococcal and Haemophilus vaccines given that these organisms are commonly found in this condition. Annual influenza vaccines may be worth considering.

There have been no controlled trials comparing repeated courses of antibiotics as required versus continuous antibiotics. There is no consensus on if and when antibiotic use can be stopped, while desirable microbiological examination of the sputum is not always possible with small children. For this reason there are no existing recommendations as to choice of antibiotic. 

Although the proportion that will develop bronchiectasis with or without adequate treatment is not known, expert opinion suggests that the risk of bronchiectasis may be reduced by adequate treatment.

There is considerable uncertainty about the management of PBB, a condition that is commonly misdiagnosed and deserves to be better known. 

References

1. Chang A, Glomb WB. Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1):260-83.
2. Gibson P, Chang AB, Glasgow NJ, Holmes PW, Katelaris P, Kemp AS, Landau LI, Mazzone S, Newcombe P, Van Asperen P, Vertigan AE. CICADA: Cough in children and adults: Diagnosis and assessment. Australian cough guidelines summary statement. Med J Aust. 2010;192(5):265-71.
3. Shields M, Bush A, Everard ML, McKenzie S, Primhak R, British Thoracic Society Cough Guideline Group. BTS guidelines: Recommendations for the assessment and management of cough in children. Thorax. 2008;63(3):1-15.
4. Kantar A, Chang AB, Shields MD, Marchant JM, Grimwood K, Grigg J, Priftis KN, Cutrera R, Midulla F, Brand PLP, Everard ML. ERS statement on protracted bacterial bronchitis in children. Eur Respir J. 2017;50(2):pii: 1602139.
5. Anonymous. 2017 GINA Report, Global strategy for asthma management and prevention 2017.
6. Young F. Chronic non-tuberculous infection of the lungs in children. Br Med J. 1932;1(3717):604-6.
7. Field C. Bronchiectasis in childhood; aetiology and pathogenesis, including a survey of 272 cases of doubtful irreversible bronchiectasis. Pediatrics. 1948;4(2):231-48.
8. Smith T, Ireland TA, Zaatari GS, Gay BB, Zwiren GT, Andrews HG. Characteristics of children with endoscopically proved chronic bronchitis. Am J Dis Child. 1985;139(10):1039-44.
9. Darelid J, Löfgren S, Malmvall BE. Erythromycin treatment is beneficial for longstanding Moraxella catarrhalis associated cough in children. Scand J Infect Dis. 1993;25(3):323-9.
10. Phelan P, Landau LI, Robertson CF. Suppurative lung disease. In: Respiratory illness in children. 4th ed. Oxford, UK: Blackwell Scientific; 1994. pp 295–306.
11. Marchant J, Masters IB, Taylor SM, Cox NC, Seymour GJ, Chang AB. Evaluation and outcome of young children with chronic cough. Chest. 2006;129(5):1132-41.
12. Donnelly D, Critchlow A, Everard ML. Outcomes in children treated for persistent bacterial bronchitis. Thorax. 2007;62(1):80-4.
13. Chang A, Redding GJ, Everard ML. Chronic wet cough: Protracted bronchitis, chronic suppurative lung disease and bronchiectasis. Pediatr Pulmonol. 2008;43(6):519-31.
14. Wang Y, Hao C, Chi F, Yu X, Sun H, Huang L, Wang M, Ji W, Yan Y, Zhu H, Shao X. Clinical characteristics of protracted bacterial bronchitis in Chinese infants. Sci Rep. 2015;5:13731.
15. Kompare M, Weinberger M. Protracted bacterial bronchitis in young children: association with airway malacia. J Pediatr. 2012;160(1):88-92.
16. Douros K, Alexopoulou E, Nicopoulou A, Anthracopoulos MB, Fretzayas A, Yiallouros P, Nicolaidou P, Priftis KN. Bronchoscopic and high-resolution CT scan findings in children with chronic wet cough. Chest. 2011;140(2):317-23.
17. Eastham K, Fall AJ, Mitchell L, Spencer DA. The need to redefine non-cystic fibrosis bronchiectasis in childhood. Thorax. 2004;59(4):324-7.
18. Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, Loebinger MR, Murris M, Cantón R, Torres A, Dimakou K, De Soyza A, Hill AT, Haworth CS, Vendrell M, Ringshausen FC, Subotic D, Wilson R, Vilaró J, Stallberg B, Welte T, Rohde G, Blasi F, Elborn S, Almagro M, Timothy A, Ruddy T, Tonia T, Rigau D, Chalmers JD. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J. 2017;50(3):1700629.
19. Thomson N. Novel approaches to the management of noneosinophilic asthma. Ther Adv Respir Dis. 2016;10(3):211-34.
20. Cosmi L, Liotta F, Annunziato F. Th17 regulating lower airway disease. Curr Opin Allergy Clin Immunol. 2016;16(1):1-6.
21. Taylor S, Leong LEX, Choo JM, Wesselingh S, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, Baraket M, Marks GB, Gibson PG, Simpson JL, Rogers GB. Inflammatory phenotypes in patients with severe asthma are associated with distinct airway microbiology. J Allergy Clin Immunol. 2017;S0091-6749(17):30743-1.
22. Guiddir T, Saint-Pierre P, Purenne-Denis E, Lambert N, Laoudi Y, Couderc R, Gouvis-Echraghi R, Amat F, Just J. Neutrophilic steroid-refractory recurrent wheeze and eosinophilic steroid-refractory asthma in children. J Allergy Clin Immunol Pract. 2017;5(5):1351-61.
23. Farne H, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834.
24. Bel E, Ten Brinke A. New anti-eosinophil drugs for asthma and COPD: Targeting the trait! Chest. 2017;S0012-3692(17):31022-X.
25. Chang H, Lee TH, Jun JA, Baek AR, Park JS, Koo SM, Kim YK, Lee HS, Park CS. Neutrophilic inflammation in asthma: mechanisms and therapeutic considerations. Expert Rev Respir Med. 2016;11(1):29-40.
26. Terl M, Sedlák V, Cap P, Dvořáková R, Kašák V, Kočí T, Novotna B, Seberova E, Panzner P, Zindr V. Asthma management: A new phenotype-based approach using presence of eosinophilia and allergy. Allergy. 2017;72(9):1279-87.
27. Chang A, Byrnes CA, Everard ML. Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis. Paediatr Respir Rev. 2010;12(2):97-103.
28. Goyal V, Grimwood K, Marchant J, Masters IB, Chang AB. Does failed chronic wet cough response to antibiotics predict bronchiectasis? Arch Dis Child. 2015;99(6):522-25.
29. King P, Holdsworth SR, Farmer M, Freezer N, Villanueva E, Holmes PW. Phenotypes of adult bronchiectasis: onset of productive cough in childhood and adulthood. COPD. 2009;6(2):130-6.
30. Brower K, Del Vecchio MT, Aronoff SC. The etiologies of non-CF bronchiectasis in childhood: a systematic review of 989 subjects. BMC Pediatr. 2014;14:4.
31. Sharma S, Casey JR, Pichichero ME. Reduced serum IgG responses to pneumococcal antigens in otitis-prone children may be due to poor memory B-cell generation. J Infect Dis. 2012;205(8):1225-9.
32. Kuehni C, Lucas JS. Diagnosis of primary ciliary dyskinesia: summary of the ERS task force report. Breathe (Sheff). 2017;13(3):166-78.
33. Behan L, Dunn Galvin A, Rubbo B, Masefield S, Copeland F, Manion M, Rindlisbacher B, Redfern B, Lucas JS. Diagnosing primary ciliary dyskinesia: an international patient perspective. Eur Respir J. 2016;48(4):1096-107.
34. Kuehni C, Frischer T, Strippoli MP, Maurer E, Bush A, Nielsen KG, Escribano A, Lucas JS, Yiallouros P, Omran H, Eber E, O’Callaghan C, Snijders D, Barbato A; ERS task force on primary ciliary dyskinesia in children. Factors influencing age at diagnosis of primary ciliary dyskinesia in European children. Eur Respir J. 2010;36(6):1248-58.
35. Amer H, El-Anwar MW, Raafat A, AlShawadfy M, Sobhy E, Ahmed SA, Maaty AM. Laryngo-tracheo-bronchial foreign bodies in children: Clinical presentations and complications. Iran J Otorhinolaryngol. 2017;29(92):155-9.
36. Pellissier A, Kebdani S, Lacheheb M, Lainez S, Froudarakis ME, Vergnon JM. 41 Years into the bronchial tree: A very obstructive cap. Clin Respir J 2016.
37. Gruber M, van Der Meer G, Ling B, Barber C, Mills N, Neeff M, Salkeld L, Mahadevan M. The bacterial species associated with aspirated foreign bodies in children. Auris Nasus Larynx. 2017;II S0385-8146(16):30394-7.
38. Chang AB UJ, Masters IB, et al. Protracted bacterial bronchitis: The last decade and the road ahead. Pediatr. 2016;51:225-42.
39. Paul S, Sanapala S, Bhatt JM. Recognition and management of children with protracted bacterial bronchitis. Br J Hosp Med (Lond). 2015;76(7):398-404.
40. Patterson D, Moncrieff A. Diseases of children. 4th ed. London: Edward Arnold & Co; 1947. pp 648–62