Pathophysiology and causes
Definition and epidemiology
Bronchioles are small airways of diameter <2 mm, lined by bronchial epithelium and with no cartilage in their walls. Terminal bronchioles lead to alveoli. Considerable numbers of bronchioles need to be affected by disease before a patient becomes symptomatic. When they are affected, they cause increased airway resistance. Bronchiolitis is poorly understood.
Disease seems to affect bronchioles in two main ways:
As a process affecting the bronchioles in isolation, with non-specific injury causing subsequent epithelial damage and inflammation
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, hypersensitivity pneumonitis, RB-ILD, Langerhans' cell histiocytosis.
Pathophysiology 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. Often associated alveolar wall inflammation and foamy macrophages in alveolar spaces. May completely or partially resolve. Tends to be more responsive to steroid treatment. The pathology merges with that of COP )
Constrictive bronchiolitis Rare. Concentric narrowing of the bronchiolar wall due to cellular infiltrates آ± 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 (RSV)
Post-lung transplant (obliterative bronchiolitis)
Post-bone marrow transplant
Connective tissue disease (usually rheumatoid arthritis)
In association with interstitial lung disease and airways disease
Rare but important: Japanese panbronchiolitis.
Causes of bronchiolitis
Proliferative bronchiolitis (associated with organizing pneumonia)
Hypersensitivity pneumonitis )
Chronic pulmonary eosinophilia )
Connective tissue diseaseâ€”rheumatoid arthritis, polymyositis, dermatomyositis )
Post bone marrow, heart and lung transplant
Organizing acute infectionâ€”mycoplasma, legionella, influenza, CMV, HIV, PCP.
Vasculitides, including Wegener's granulomatosis )
Drug-induced reactions, such as L-tryptophan, busulfan, cocaine
Radiation or aspiration pneumonitis
Distal to bronchial obstruction
Common variable immunodeficiency syndrome.
Connective tissue disease, particularly rheumatoid arthritis, especially women in their 50s and 60s, with longstanding rheumatoid arthritis. May be related to penicillamine therapy
Infectionâ€”viral (adenovirus, RSV, influenza, parainfluenza), mycoplasma.
â€?Chronic rejection phenomenonâ€™ in heart, lung, bone marrow transplantsâ€”affects up to 65% of lung transplant patients after 5 years post-transplant and is the primary cause of late death, bronchiolitis obliterans syndrome (see page 388). Patients taking statins post-transplant have a lower incidence of this; reasons unclear
Following inhalation injury: mineral dusts, such as asbestos, silica, iron oxide, aluminium oxide, talc, mica, coal, sulphur dioxide, nitrogen oxide, ammonia, chlorine, phosgeneâ€”may develop cough days to weeks after exposure
Cryptogenic. Rare, mostly women > 40. Cough and dyspnoea. PFT: progressive airflow obstruction and air trapping. KCO decreased, no bronchodilator response.
Insidious onset of cough and dyspnoea, over weeks to months. There may be an associated medical history, such as a transplant, connective tissue disease, or vasculitis, or a history of mineral dust or drug exposure. Possible history of recent viral illness.
PFTs Obstructive defect may be found, with no bronchodilator reversibility, particularly in constrictive bronchiolitis. Proliferative bronchiolitis can cause a restrictive or mixed defect
CXR can be normal, or may show hyperinflation, especially with constrictive bronchiolitis, diffuse infiltrates with proliferative bronchiolitis, which may be migratory
HRCT can be very 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, although 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, the â€?tree in budâ€™ appearance. CT is also useful to assess for signs of associated interstitial lung disease
Open or thoracoscopic lung biopsy may be required to make the diagnosis, as transbronchial biopsies are usually inadequate. The small airways must be carefully examined.
Treat any underlying disorder
Long-term macrolide antibiotics, such as erythromycin 200â€“600 mg/day may improve symptoms, lung function, and mortality, especially in those with diffuse panbronchiolitis 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 organizing pneumonia. 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
Diffuse panbronchiolitis/Japanese panbronchiolitis
This is a distinct condition involving both the upper and lower respiratory tracts, with bronchiolar inflammation and chronic sinusitis. It occurs particularly amongst the Japanese and is rarely found outside the Far East, although this may be due to a lack of disease recognition. An infectious aetiology has been postulated as the cause of this disease, but no organism has been consistently identified. It can be familial and is associated with HLA-Bw54 in Japan. It is more prevalent in men, with a mean age at presentation of 50. It occurs particularly in non-smokers and there is a history of chronic sinusitis that precedes the chest symptoms often by years. Patients have a productive
cough with purulent sputum, exertional dyspnoea, wheeze, and weight loss. There may be signs of progressive respiratory failure and cor pulmonale. Chest examination may reveal crackles and wheezes.
PFTs are obstructive, although may show a mixed pattern, with minimal airway hyperresponsiveness. kCO is reduced
CXR and CT may show diffuse ill-defined nodules, bronchiectasis, and air trapping
Cold agglutinins may be positive, although mycoplasma tests are negative
BAL shows marked neutrophilia
Sputum cultures may show growth of Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, or Staphylococcus aureus, which should be treated
Open or thoracoscopic lung biopsy may provide the definitive diagnosis, although this may not be considered necessary in areas where panbronchiolitis 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.
Treatment is with low-dose erythromycin 400â€“600 mg/day for 2â€“6 months, which confers a significant survival benefit, most likely related to its anti-inflammatory effects, rather than its antibacterial effects. Untreated, 50% 5-year mortality.
This is an infective illness, common in infants, who present with wheezing, tachypnoea, respiratory distress, and tachycardia. It is most commonly caused by respiratory syncytial virus (RSV), but also adenovirus, influenza, parainfluenza, mycoplasma, and chlamydia. 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.
Treatment is supportive, with oxygen, fluids, steroids, and bronchodilators if severe.