Definition and epidemiology
Bronchioles are small airways of <2mm diameter, lined by bronchial epithelium and with no cartilage in their walls. Terminal bronchioles lead to alveoli. Many bronchioles need to be affected by disease before a patient becomes symptomatic, when there will be increased airway resistance unresponsive to β2 stimulants. Bronchiolitis is poorly understood and is a mixture of conditions.
Disease seems to affect bronchioles in two main ways:
• Affecting the bronchioles in isolation, with non-specific injury causing subsequent epithelial damage and inflammation, e.g. viral bronchiolitis
• As a bronchiolitis associated with other airway disease where the bronchiolitis may be more of an incidental finding, along with other pathologies, e.g. COP, HP, RB-ILD, LCH.
is unclear. There is probably an initial injury to the epithelium of the bronchioles with subsequent inflammation. Adjacent alveoli are often also involved. There are two main pathological patterns of bronchiolitis. Both can exist in the same patient.
• Proliferative bronchiolitis More common of the two patterns. Non-specific reaction to bronchiolar injury, with organizing exudate within the bronchiolar lumen. Proliferation of intraluminal fibrotic buds, called Masson bodies, seen in bronchioles, alveoli, and alveolar ducts. Associated alveolar wall inflammation and foamy macrophages in alveolar spaces. May completely or partially resolve. Tends to be more responsive to steroids. The pathology merges with that of COP (see pp. [link]–[link])
• Constrictive bronchiolitis Less common. Concentric narrowing of the bronchiolar wall due to cellular infiltrates ± smooth muscle hyperplasia, which may cause extrinsic compression, obliteration, distortion, mucus collection, peribronchiolar fibrosis, and scarring. Patchy in distribution. Typically progressive and unresponsive to steroid therapy. Usually leads to respiratory failure and death.
In practice, these are the commonest situations in which a diagnosis of bronchiolitis is useful:
• Viral bronchiolitis (e.g. RSV)
• Post-lung transplant (bronchiolitis obliterans syndrome, BOS)
• Post-bone marrow transplant
• Connective tissue disease (usually RA)
• In association with ILD and airways disease
• Diffuse pan-bronchiolitis (including Japanese pan-bronchiolitis).
Insidious onset of cough and dyspnoea over weeks to months. There may be an associated medical history, such as recent viral illness, transplant, connective tissue disease, or vasculitis, or a history of mineral dust or drug exposure.
Proliferative bronchiolitis (associated with OP)
• HP (see p. [link])
• Chronic eosinophilic pneumonia (see p. [link])
• Connective tissue disease—RA, polymyositis, dermatomyositis (see p. [link])
• Post-bone marrow, heart, and lung transplant
• Organizing acute infection—mycoplasma, Legionella, influenza, CMV, HIV, PCP.
• ARDS (see p. [link])
• Drug-induced reactions such as L-tryptophan, busulfan, cocaine
• Chronic thyroiditis
• Ulcerative colitis
• Radiation or aspiration pneumonitis
• Distal to bronchial obstruction
• Common variable immunodeficiency syndrome.
• Connective tissue disease, particularly RA, especially women in their 50s and 60s, with long-standing RA. May be related to penicillamine or gold therapy. May improve with TNF-α inhibitor therapy
• Infection—viral (adenovirus, RSV, influenza, parainfluenza), mycoplasma.
• ‘Chronic rejection phenomenon’ in heart, lung, bone marrow transplants—affects up to 65% of lung transplant patients after 5y post-transplant and is the 1° cause of late death, BOS (see pp. [link]–[link]). Patients taking statins post-transplant have a lower incidence of this; reasons unclear
• Diffuse pan-bronchiolitis (including Japanese pan-bronchiolitis)
• Following inhalation injury: mineral dusts, such as asbestos, silica, iron oxide, aluminium oxide, talc, mica, coal, sulfur dioxide, nitrogen oxide, ammonia, chlorine, phosgene—may develop cough days to weeks after exposure
• Drug reaction
• Hypersensitivity reactions
• Ulcerative colitis
• Cryptogenic. Rare, mostly women >40. Cough and dyspnoea. PFT: progressive airflow obstruction and air trapping. TLCO decreased, no bronchodilator response.
• PFTs Obstructive defect may be found, with air trapping and no bronchodilator reversibility, in constrictive bronchiolitis. Proliferative bronchiolitis can cause a restrictive or mixed defect. Impaired TLCO in both
• CXR can be normal or may show hyperinflation, especially with constrictive bronchiolitis, diffuse infiltrates with proliferative bronchiolitis, which may be migratory
• HRCT is helpful and may be performed prone in full expiration. (Prone CT is used to minimize any gravity-dependent changes.) Normal bronchioles are too small to be seen; indirect signs of disease may be hyperinflation, air trapping, causing a mosaic pattern and subsegmental atelectasis. Bronchioles with thickened walls due to inflammation and dilatation may be seen. CT is also useful to assess for signs of associated ILD
• Open or thoracoscopic lung biopsy may be required to make the diagnosis, as TBBs are usually inadequate. The small airways need particularly careful examination.
• Treat any underlying disorder
• Cough suppressants
• Long-term macrolide antibiotics, such as erythromycin 200–600mg/day, may improve symptoms, lung function, and mortality, especially in those with diffuse pan-bronchiolitis and cryptogenic bronchiolitis. Erythromycin lowers the neutrophil count by an unknown mechanism and reduces the number of lymphocytes
• Steroids are effective in cases of proliferative bronchiolitis and can treat the associated OP, e.g. 0.5–1mg/kg prednisolone/day, maximum 60mg/day. They may also be beneficial in bronchiolitis due to inhalation injury, both in early and later stages. Relapses of the bronchiolitis may occur on stopping the steroids.
Bronchiolitis: specific conditions
This is a distinct condition and used to be thought of as rare outside Japan. Described 30y ago in Japan as a condition involving both the upper and lower respiratory tracts, with bronchiolar inflammation and chronic sinusitis. An infectious aetiology was postulated as the cause of this disease, but no particular organism has been consistently found. It can be familial and is associated with HLA-B54 (specific to East Asians) and A11 (Korea). Rarely seen in people of Asian descent living abroad. More prevalent in men, mean age at presentation 45, occurs particularly in non-smokers. Chronic sinusitis can precede the chest symptoms often by years. Most patients have a productive cough with copious purulent sputum, exertional dyspnoea, wheeze, and weight loss. There may be progressive respiratory failure with signs of cor pulmonale and crackles and wheezes on auscultation. More recently, a very similar clinical condition has been increasingly described outside Japan in which sinusitis is less commonly found. This diffuse version is also an idiopathic inflammatory and suppurative disorder of the respiratory bronchioles, causing progressive and severe airways obstruction. It is presumably very similar to the Japanese variety and probably under-recognized.
• PFTs are obstructive although may show a mixed pattern, with minimal airway hyperresponsiveness. TLCO is reduced
• CXR and CT may show diffuse ill-defined nodules (sometimes ‘tree-in-bud’), bronchiectasis, and air trapping
• Sputum cultures may repeatedly show growths of Haemophilus influenzae, Pseudomonas aeruginosa, and less commonly Streptococcus pneumoniae, Klebsiella pneumoniae, or Staphylococcus aureus. These should be treated but can be hard to eradicate
• Cold agglutinins may be positive; mycoplasma tests are negative
• BAL shows marked neutrophilia, along with mild blood neutrophilia
• Open or thoracoscopic lung biopsy, although this may not be considered necessary in areas where pan-bronchiolitis is prevalent. Bronchiolar histology is characteristic, although not pathognomonic, with transmural infiltrate of lymphocytes, plasma cells, and foamy macrophages. The intraluminal exudates may be organized to form a polypoid plug.
with low-dose erythromycin 400–600mg/day for 6 months, and, in some Japanese studies, over 2y, confers a significant survival benefit, most likely related to its anti-inflammatory and immunomodulatory effects (inhibits many cytokines), as well as reducing mucin secretion, rather than through its antibacterial effects. Untreated, 50% 5y mortality. With treatment, >90% 10y survival. Azithromycin 250mg three times a week may be a suitable alternative but less experience. Relapses occur but usually respond to macrolides again.
This is a seasonal epidemic viral infective illness, common in infants <2y, who present with coryza, low-grade fever, cough, wheezing, tachypnoea, respiratory distress, hyperinflation, and tachycardia. It is most commonly caused by RSV, but also adenovirus, influenza, parainfluenza, rhinovirus, human metapneumovirus, coronavirus, and human bocavirus. Mycoplasma and Chlamydophila cause a similar picture of wheeze and lower respiratory tract infection. In adults, acute bronchiolitis is caused by the same organisms but is less severe.
• CXR may be normal or show hyperinflation, occasionally with patchy opacities, consolidation, and collapse
• Histologically, there is acute and chronic inflammation of bronchioles, with necrosis, sloughing, oedema, and inflammatory exudates in the bronchiolar lumen.
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