Hospital Medicine

Interstitial pulmonary fibrosis

I. Problem/Condition.

Interstitial pulmonary fibrosis is a group of heterogeneous disorders that are classified together because they affect the interstitium of the lungs and need to be distinguished from obstructive lung diseases. Fibrosis is generally the pathologic result of prolonged disease. These diseases may be classified according to clinicial presentation, cause, radiologic manifestations, or pathologic manifestations.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

The differential diagnosis for interstitial pulmonary fibrosis is extremely large. While there are multiple methods by which to classify these diseases, one that is frequently used is to classify by the cause of the fibrosis. There are seven categories that are frequently used:

1. Inhaled substances: These can be further subdivided into organic and inorganic substances. This inorganic subdivision includes the pneumoconioses such as silicosis, coal, beryllosis, and asbestosis. The organic subdivision includes hypersensitivity pneumonitis.

2. Drug induced pulmonary fibrosis: Drugs that have frequently been implicated in the pathogenesis of pulmonary fibrosis are antibiotics, chemotherapeutic agents, antiarrhythmic agents, and statins. The list of drugs that have been reported to lead to pulmonary fibrosis is extensive, but the most frequently encountered are amiodarone and adriamycin.

3. Rheumatologic interstitial lung disease: Connective tissue disorders frequently associated with pulmonary fibrosis include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, ankylosing spondylitis, Churg-Strauss, Wegner's granulomatosis, and Goodpasture's syndrome.

4. Infectious causes: The most commonly associated infection is tuberculosis, however, pneumocystis pneumonia, respiratory synctial virus, and atypical pneumonias have been implicated.

5. Idiopathic: The idiopathic pneumonias include idiopathic pulmonary fibrosis and sarcoidosis. Idiopathic pulmonary fibrosis has historically been difficult to classify. There are multiple histological subtypes, but the extent to which they represent different diseases is still unclear. The classification system for these diseases is complicated and has been altered many times.

The typical pathologic manifestation in idiopathic pulmonary fibrosis is usual interstitial pneumonia (UIP). UIP affects men more than women and generally presents with unexplained cough and dyspnea. High resolution computed tomography shows bibasilar reticular opacities, honeycombing, and traction bronchiectasis. It has an unrelenting course with patients generally dying of respiratory failure within 5-10 years of diagnosis. There are limited treatment options and usually lung transplantation provides the only cure.

Another histologic subtype is desquamative interstitial pneumonia (DIP). It is relatively uncommon and is associated almost exclusively with cigarette smokers, although there have been cases associated with connective tissue disease. It has less severe radiological and pathologic findings as UIP and has a better prognosis. With steroids and smoking cessation, the 10 year survival rate is between 75% and 85%.

DIP shares overlapping histologic features with respiratory bronchiolitis associated interstital lung disease (RB-ILD). RB-ILD is also seen in cigarette smokers, is extremely rare, and has an excellent prognosis.

Acute interstitial pneumonia (AIP), also known as Hamman-Rich syndrome, contrasts with the other idiopathic pulmonary fibroses in that it is acute in nature. It presents with a rapid onset of progressive respiratory failure. The typical radiographic finding is diffuse opacities and is similar in presentation to ARDS. AIP, however, is idiopathic, without the inciting event that would be typical of ARDS. It has a poor prognosis and the majority of patients die of respiratory failure.

Nonspecific interstitial pneumonia (NSIP) is another chronic, idiopathic interstital lung disease that is the second most prevalent histologic subtype. It varies histologically from the other entities listed above and has a subacute onset. NSIP has a better prognosis than UIP.

Lymphoid interstitial pneumonia (LIP) is a benign polyclonal proliferation. It is definied as idiopathic, but may be associated with autoimmune disease and infection, both causing derangements in the immune system. The presentation is chronic and the prognosis is variable with some patients dying and some having spontaneous remission of disease.

6. Malignancy: The malignancy most implicated in causing fibrosis is lymphangioleiomyomatosis (LAM). This is an aggressive malignancy that affects women with a mean age of onset of 39 years. Patient typically present with progressive dyspnea and pulmonary function testing will show a markedly reduced DLCO. Chest radiographs can range from normal to hyperinflation.

The diagnosis should be suspected in any woman of child bearing age with a spontaneous pneumothorax. The pathologic finding is an abnormal proliferation of atypical interstitial smooth muscle and cyst formation. The prognosis is poor with a median survival of 8 to 10 years after diagnosis. There is no proven treatments although hormonal manipulation and immunosuppressants are frequently attempted. Lung transplantation exists as the only known curative option.

7. Miscellaneous: This category is used to capture diseases that don't easily fit into one of the categories above.

The first is radiation pneumonitis. This is often associated with the use of pulmonary toxic chemotherapeutic options and can happen many months to years after the radiation exposure. The second is eosinophilic granuloma also known as pulmonary histiocytosis X. It is a rare interstitial disease that affects young adults who are cigarette smokers. It is characterized by infiltration of the interstitium by Langerhans cells. Patients present with dyspnea and cough. This disease should also be considered in any young person with a spontaneous pneumothorax. It has an apical distribution on radiographs and diagnosis must be made pathologically. Smoking cessation is key in treatment, with no other treatments of any proven benefit.

Like many of the diseases above, lung transplantation provides an option for patients with end stage fibrosis. The last disease in the miscellaneous category is cystic fibrosis.

B. Describe a diagnostic approach/method to the patient with this problem.

Many of the interstitial pulmonary lung diseases present similarly with progressive dyspnea and cough. To differentiate between them, it is important to take an extremely thorough history, perform a physical examination, obtain chest radiography and high resolution computed tomography (CT) of the chest, and often to perform a biopsy to obtain a pathologic and histologic diagnosis.Sub-Heading2B

1. Historical information important in the diagnosis of this problem.

A thorough history is crucial to diagnosing interstitial pulmonary fibrosis. Since the presenting symptoms are nonspecific and include cough and dyspnea, a careful history can alert the provider to consider interstitial pulmonary fibrosis. The following elements of history must be included:

1. Age and gender - Many of the interstitial lung diseases are more prevalent in certain genders and with certain age ranges. A differential can be narrowed with this information.

2. Duration of symptoms - Whether the onset was acute, subacute, or chronic can also narrow a differential diagnosis. Most of the interstitial lung diseases are chronic in nature and an acute onset can point to something more rapid in onset such as infection.

3. Cigarette smoking - Some of these diseases have strong associations with smoking.

4. Past medical history - Exploring a history of rheumatologic disease, past pulmonary diseases, and malignancy is crucial. In addition, recognizing what medications have been used to treat these conditions will also be an important part of a medical history. For any patient with a past malignancy, inquiring about radiation treatments is important.

5. Past drug use - A thorough medication history is important. A practitioner will espeically want to ask about amiodarone, chemotherapeutics, and antibiotics.

6. Occupational and environmental exposures - Any exposure to silica dust, beryllium, coal, or asbestos should make a practitioner consider a pneumoconiosis. A detailed work and hobby history must be performed. Environmental exposures can lead to hypersensitivity pneumonitis and so asking about molds, pets, air conditioners, hot tubs, and bird exposure is important.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

The lung examination in patients with interstitial pulmonary fibrosis is often nonspecific. Dry rales are often demonstrated on pulmonary exam in many forms of interstitial fibrosis. Clubbing will be seen in any patient with chronic hypoxia. Its presence often suggests advanced disease. Cardiac examination will usually be normal. Late in disease, the findings of cor pulmonale secondary to pulmonary hypertension might be evident. Lastly, a physical examination should look for any signs of extrapulmonary disease such as joint inflammation in rheumatologic disease or skin findings consistent with sarcoidosis.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

There are very few laboratory tests that will point specifically to a certain diagnosis. If rheumatologic disease is considered, an antinuclear antibody and antibody testing for systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematous can be performed. If there is renal involvement in the presentation, ANCA and antiglomerular basement membrane antibody testing can be undertaken to diagnose Wegner's granulomatosis or Goodpasture's syndrome.

Radiological testing is usually the best first step in diagnosing pulmonary fibrosis, however, it is rarely the last. The most common abnormality on chest radiograph is nonspecific reticular abnormalities, however, nodular and mixed patterns are frequently seen, as is a normal chest radiograph. Only the presence of honeycombing will make a definitive diagnosis of fibrosis, and still the specific diagnosis will not have been made.

Almost all patients will need to undergo high resolution CT. There are patterns of findings that correlate with specific diseases. Again, though, it is rare that CT scanning can lead to an absolute diagnosis.

Pulmonary function testing is frequently obtained. The pattern seen on spirometry can help to narrow the differential diagnosis. It is most helpful in determining the severity of lung involvement. The majority of the interstitial pulmonary diseases have a restrictive pattern and often a reduced DLCO.

Some patients with concern for interstitial pulmonary fibrosis will undergo bronchoscopy with bronchoalveolar lavage (BAL). BAL is most helpful in diagnosing malignancy, sarcoidosis, hypersensitivity pneumonitis, eosinophilic granuloma, or infection.

Most often, patients with a presumed interstitial pulmonary fibrosis require a lung biopsy in order to make a clear pathologic and histologic diagnosis. The value of gaining a tissue diagnosis must be carefully weighed against the risk of morbidity and mortality since many of these patients already have tenuous pulmonary status at the time of diagnosis.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

There are no specific criteria to diagnose interstitial pulmonary fibrosis. The diagnosis is made by combining clinical information with radiographic and histologic findings. There are certain key points that can aid in pointing to a specific diagnosis. Clearly occupational exposures or findings that suggest rheumatologic disease aid in diagnosing the pneumoconioses and rheumatologic interstitial lung disease. As discussed above, a history of medications that are implicated in pulmonary fibrosis is important for diagnosis.

Probably the most important criteria used in diagnosis is correlating radiologic patterns with specific diseases. Patterns on high resolution CT are well described. A normal HRCT is often seen in sarcoidosis and hypersensitivity pneumonitis. In asbestosis, the lung parenchyma can appear normal, but pleural plaques may be described. Interstitial findings isolated to the lower zones is consistent with idiopathic pulmonary fibrosis/usual interstitial pneumonitis and asbestosis. Findings isolated to the apical zones is more consistent with granulomatous disease and pneumoconioses. Sarcoidosis and LAM tend to have a more central distribution.

Diseases that tend to have more diffuse radiologic appearances include drug induced pneumonitis, radiation pneumonitis, sarcoidosis, and rheumatologic interstitial lung diseases. It is important to remember that there can be significant overlap and that none of the radiographic patterns seen are pathognomonic for any one interstitial pulmonary disorder.

Diagnosis can be made just by using clinical information and radiographic data. If there is a tissue biopsy, this will guide the diagnostics.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

A sedimentation rate and C-reactive protein do not correlate with any of the interstitial pulmonary fibrotic diseases.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Interstitial Pulmonary Fibrosis.

The initial management of interstitial lung disease focuses on supportive care. After a patient comes to medical attention, the diagnostic work up including laboratory testing, radiographic examination, and pathologic diagnosis can take some time. During this time, patients need to be assessed for hypoxia and given supplemental oxygen if needed. If there pulmonary status is poor, as is often measured by 6-minute walk, they can be referred for pulmonary rehabilitation.

Pulmonary function testing can indicate disease severity and if there are signs of obstructive disease, that can be treated with appropriate inhalers. Current smokers need to be immediately started on a smoking cessation program. Those with current occupational or environmental exposures must be removed from the inciting source. If patients are currently taking a suspected drug, that drug must be discontinued. Finally, steps must be taken to prevent against further comorbidities and so appropriate vaccinations are recommended.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

None

IV. What's the evidence?

N/A

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