Bronchiolitis (respiratory bronchiolitis, acute bronchiolitis, constrictive or obliterative bronchiolitis, follicular bronchiolitis, diffuse panbronchiolitis, diffuse aspiration bronchiolitis, mineral dust airway disease)

What every physician needs to know:

Bronchiolitis, also referred to as bronchiolar disease, is a generic term used to describe inflammation of the bronchioles, with or without scarring. Bronchiolitis, a common condition in the lung, is encountered in a variety of clinical contexts. Several histologic types of bronchiolitis (“primary” bronchiolar diseases) are recognized and have varying degrees of specificity with respect to etiology.

Bronchiolitis can also be encountered as small airway involvement in interstitial lung diseases such as respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), hypersensitivity pneumonitis (HP), cryptogenic or secondary organizing pneumonia (OP), sarcoidosis, and idiopathic pulmonary fibrosis (IPF). In most cases, RB-ILD and DIP are forms of smoking-related interstitial lung disease.

Hypersensitivity pneumonitis is caused by repeated inhalation of sensitizing agents, and bronchiolitis is commonly seen in this disorder. Organizing pneumonia (also called bronchiolitis obliterans organizing pneumonia, or BOOP), is a nonspecific injury pattern that can be seen in many clinical contexts, including infections, drug-induced lung disease, inflammatory conditions, and connective tissue diseases. When the condition is idiopathic it is referred to as cryptogenic organizing pneumonia (COP).

Bronchiolar involvement can also be seen in predominantly large airway diseases such as bronchiectasis, chronic bronchitis, and cystic fibrosis.

Classification:

Primary bronchiolar diseases include:

• respiratory bronchiolitis

• acute bronchiolitis

• constrictive bronchiolitis (obliterative bronchiolitis, bronchiolitis obliterans)

• follicular bronchiolitis

• diffuse panbronchiolitis

• diffuse aspiration bronchiolitis

• mineral dust airway disease

Are you sure your patient has bronchiolitis? What should you expect to find?

The clinical presentation of bronchiolitis is nonspecific and varies somewhat according to the type of bronchiolitis. In general, the presenting symptoms are cough and exertional dyspnea. The onset of symptoms may be acute, as in acute bronchiolitis, or insidious, as in constrictive bronchiolitis. Extrapulmonary and constitutional symptoms may be present in cases of bronchiolitis that are due to infection, as well as in patients with underlying systemic illness, such as connective tissue disease. Patients with bronchiolitis may be asymptomatic, presenting primarily for evaluation of abnormal chest imaging findings or pulmonary function test results (e.g., some patients with respiratory bronchiolitis).

Beware: there are other diseases that can mimic bronchiolitis:

Because the clinical presentation associated with bronchiolitis is nonspecific and variable, the differential diagnosis is broad; it includes infections, chronic obstructive pulmonary disease, asthma, and various forms of interstitial lung disease.

How and/or why did the patient develop bronchiolitis?

Clinical context is a crucial consideration in diagnosing bronchiolitis. For example, progressively worsening dyspnea and airflow obstruction in patients with solid organ or hematopoietic stem cell transplantation suggests the diagnosis of transplant-related bronchiolitis obliterans (or obliterative bronchiolitis), particularly if pulmonary infiltrates are not seen on chest imaging. Transplant-related bronchiolitis obliterans appears to be the result of multiple factors, including allograft rejection, ischemia-reperfusion injury, infections, and gastroesophageal reflux. A similar phenomenon of progressive airflow obstruction can be encountered in patients with connective tissue diseases like rheumatoid arthritis, in whom autoimmunity, infections, drugs, and other factors contribute to the bronchiolar disease.

Other forms of bronchiolitis also have characteristic epidemiologic associations, such as young age (acute bronchiolitis), smoking (respiratory bronchiolitis), immunodeficiency diseases (follicular bronchiolitis), Asian ancestry (diffuse panbronchiolitis), and inorganic dust exposure (mineral dust airway disease).

Which individuals are at greatest risk of developing bronchiolitis?

Bronchiolitis may assume a variety of clinical presentations and may present at any age.

• Acute bronchiolitis, which is usually due to respiratory viral infections, is typically encountered in infants and children. It is the leading cause of hospitalization in infants.

• Respiratory bronchiolitis, which occurs in adults, is almost always associated with smoking. A small fraction of cases is related to occupational or environmental fume exposures.

• Constrictive bronchiolitis is commonly encountered as “bronchiolitis obliterans syndrome” in patients with solid organ or hematopoietic stem cell transplantation who experience progressive respiratory symptoms. Constrictive bronchiolitis may also be seen as one form of pulmonary involvement in patients with underlying connective tissue diseases, such as rheumatoid arthritis. Inhalation exposure to certain chemical compounds (e.g., diacetyl encountered in microwave popcorn flavoring and coffee bean processing facilities) has also been associated with constrictive bronchiolitis. There are other rare causes of constrictive bronchiolitis including drugs and a variety of respiratory infections.

• Follicular bronchiolitis is usually seen in patients with connective tissue disease, immunodeficiency disorders, or chronic infections.

• Diffuse panbronchiolitis is an unusual form of bronchiolitis described mainly in the Asian population (particularly in the Japanese).

• Diffuse aspiration bronchiolitis is typically seen in middle-aged or older adults who have risk factors for aspiration, such as a neurologic disorder or gastroesophageal reflux disease (GERD). The aspiration may be clinically occult.

• Mineral dust airway disease is caused by inhalation of inorganic dusts, including silica, silicates, asbestos, iron oxide, aluminum oxide, talc, mica, and coal. The disorder is primarily occupation-related.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

In the context of an acute respiratory illness encountered in an infant or child, blood tests and sputum cultures may confirm the presence of a viral respiratory tract infection and enable the diagnosis of acute viral bronchiolitis. In general, routine laboratory studies are unhelpful in diagnosing bronchiolitis, but they may assist in establishing the clinical context or underlying disease of which the bronchiolitis may be a manifestation. For example, serologies may suggest the presence of an underlying connective tissue disease in a patient suspected of having constrictive bronchiolitis.

What imaging studies will be helpful in making or excluding the diagnosis of bronchiolitis?

In most cases of suspected bronchiolitis, a high-resolution chest CT scan is necessary to define the pattern of radiographic abnormalities, their distribution, and associated findings, such as intrathoracic lymphadenopathy. Expiratory views in addition to the usual inspiratory views should be obtained when constrictive bronchiolitis is suspected to assess for air trapping. Routine chest radiography may reveal abnormal findings but can also appear normal in patients with bronchiolar disease. A chest x-ray or CT scan may reveal that the suspected bronchiolitis is associated with an underlying interstitial pulmonary process or large airway disease.

Some forms of bronchiolitis are associated with characteristic imaging findings.

• High-resolution chest CT imaging in patients with respiratory bronchiolitis demonstrates centrilobular micronodules of ground-glass attenuation (Figure 1).

• CT imaging in constrictive bronchiolitis primarily shows patchy air trapping, evident as a mosaic pattern, a patchwork of regions of differing attenuation accentuated on expiratory views. (Figure 2) (Figure 3).

Figure 1.

Figure 2.

Figure 3.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of bronchiolitis?

Pulmonary function testing is useful in evaluating patients with suspected bronchiolitis, particularly those with chronic forms of bronchiolitis. Varying patterns of abnormalities, including airflow obstruction (seen most commonly), restrictive ventilatory defects and a mixed pattern are encountered depending on the type of bronchiolitis and underlying cause. In the presence of mild bronchiolar disease, pulmonary function tests may be normal.

What diagnostic procedures will be helpful in making or excluding the diagnosis of bronchiolitis?

In some cases of bronchiolitis, the clinical context and characteristic high-resolution chest CT findings may suffice for diagnosing the underlying bronchiolar disease, such as respiratory bronchiolitis in a smoker. A mosaic pattern with evidence of patchy air trapping and airflow obstruction seen on pulmonary function testing suggests the presence of constrictive bronchiolitis. In patients with solid organ or hematopoietic stem cell transplantation, these features are generally sufficient to diagnose transplant-related bronchiolitis obliterans in the absence of any other cause to explain such findings.

In other forms of bronchiolitis, such as follicular bronchiolitis, the chest CT findings are nonspecific, and lung biopsy is generally needed to distinguish bronchiolar disease from other lung disorders. (Figure 4, Figure 5, Figure 6, Figure 7, Figure 8)

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

When a lung biopsy is required, bronchoscopic biopsy may yield the diagnosis if characteristic histopathologic features are seen; for example, bronchoscopy is sometimes useful in the diagnosis of forms of bronchiolitis like diffuse panbronchiolitis or diffuse aspiration bronchiolitis. In most cases, however, surgical lung biopsy, usually via video-assisted thoracoscopic surgery (VATS), is needed. Surgical lung biopsy may be needed to confirm the diagnoses of constrictive bronchiolitis, follicular bronchiolitis, diffuse aspiration bronchiolitis, or mineral airways disease, if clinically indicated.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of bronchiolitis?

As described in the previous section, bronchoscopic or surgical lung biopsy may be needed to confirm the presence and the histopathologic pattern of bronchiolitis.

If you decide the patient has bronchiolitis, how should the patient be managed?

Because bronchiolitis may be associated with a wide variety of causes and underlying disorders, the specific type of bronchiolitis and the clinical context should be considered in evaluating management options. In general, treatment approaches include avoidance of exposure to the causative agent, treatment of the underlying systemic disease, and use of specific drugs, including corticosteroids (inhaled or systemic), other immunosuppressives, and macrolides.

• For acute bronchiolitis, supportive care of the child at home, including ensuring adequate fluid intake and nasal bulb suctioning, may suffice in caring for those with mild illness. Hospitalization is usually required for patients with moderate or severe acute bronchiolitis that manifests in respiratory distress, dehydration, poor feeding, or lethargy. Inpatient management may include oxygen supplementation, intravenous fluid administration, bronchodilators, corticosteroids, antibiotics, and (occasionally) mechanical ventilation.

• For respiratory bronchiolitis and mineral dust airway disease, the main management strategy is avoidance of additional inhalational exposure to the offending agent–that is, cigarette smoke and inorganic dusts, respectively.

• Optimal management of constrictive bronchiolitis requires identification of the underlying cause or systemic disease when present. For patients with bronchiolitis obliterans syndrome, treatment involves intensification of immunosuppressive therapy and use of macrolides. Constrictive bronchiolitis associated with connective tissue disease is managed with corticosteroids and immunomodulatory agents aimed at the underlying systemic disease. Corticosteroids and immunomodulatory agents are also used in patients for whom the underlying cause of the constrictive bronchiolitis cannot be identified (cryptogenic constrictive bronchiolitis). However, these agents appear to be of limited efficacy. For patients with constrictive bronchiolitis associated with inhalational agents, additional exposure needs to be avoided.

• Follicular bronchiolitis is usually treated by managing the underlying condition, that is, the connective tissue disease or immunodeficiency disorder.

• Macrolide therapy is the treatment of choice for patients with diffuse panbronchiolitis and appears to have a mortality benefit.

• Diffuse aspiration bronchiolitis is managed with anti-gastroesophageal reflux measures. Fundoplication may be needed to prevent recurrent aspiration in patients who do not respond to aggressive medical management.

What is the prognosis for patients managed in the recommended ways?

Prognosis depends on the type of bronchiolitis:

• Acute bronchiolitis is usually a self-limited disease that is managed well with supportive therapy.

• Respiratory bronchiolitis is a common, smoking-related disease that is generally not associated with significant respiratory impairment. Some patients with respiratory bronchiolitis may have associated interstitial lung disease–either so called respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) or desquamative interstitial pneumonia (DIP), which are also smoking-related in most cases. These disorders may result in significant respiratory impairment and, in some instances, may lead to respiratory failure.

• Not uncommonly, constrictive bronchiolitis worsens despite administration of corticosteroids, other immunosuppressive agents, or macrolide therapy. Progressive constrictive bronchiolitis may result in respiratory failure and death in patients who are solid organ or hematopoietic stem cell transplant recipients, in those with a connective tissue disorders, and in those with cryptogenic disease.

• The prognosis for patients with follicular bronchiolitis is determined by the underlying disease. By itself, follicular bronchiolitis is generally not associated with significant morbidity.

• Prior to the therapeutic use of macrolide therapy, diffuse panbronchiolitis was characterized by progressive respiratory dysfunction and recurrent bacterial infections, with nearly half of patients succumbing to respiratory failure within five years of diagnosis. Macrolide therapy has improved the prognosis associated with diffuse panbronchiolitis such that the ten-year survival rate is now above 90 percent.

• Diffuse aspiration bronchiolitis generally does not result in progressive respiratory impairment when it is correctly diagnosed and managed.

• Mineral dust airway disease is usually diagnosed on lung biopsy and is not associated with significant morbidity, especially if additional exposure is avoided.

What other considerations exist for patients with bronchiolitis?

In some patients with bronchiolitis, the bronchiolar disease may represent only a minor component of a broader interstitial lung process, such as hypersensitivity pneumonitis or a large airway disease like bronchiectasis. Evaluation of the clinical context, along with radiologic findings, particularly on high-resolution chest CT, should clarify the issue (Figure 4).

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