The Challenge Of Interstitial Lung Disease

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As pulmonologists know, identifying, determining the cause, and adequately treating interstitial lung disease (ILD) can be a challenge. Achieving these goals requires early recognition of the problem, a vigorous diagnostic assessment (including a thorough evaluation of clinical, radiologic, physiologic, and pathologic findings), and aggressive therapy. Most ILD presents with chronic and progressive symptoms of cough and breathlessness. With these non-specific symptoms, other common and uncommon chest diseases often must be ruled out. Chronic obstructive pulmonary disease, heart failure, atypical pneumonia, asthma, mycobacterial or fungal disease can each mimic ILD. Unfortunately for ILD patients, many are diagnosed only after developing considerable end-stage lung fibrosis. The irreversibility of this fibrosis underscores the importance of an early diagnosis and aggressive therapy.

Clinical Etiology and Classification: Etiologic Clues

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There is a long list of potential causes of ILD, but the majority of cases are idiopathic (see Table I). Occupational and environmental exposures, sarcoidosis, the idiopathic interstitial pneumonias (such as idiopathic pulmonary fibrosis (IPF)), and ILD related to connective tissue (autoimmune) disease are commonly encountered.

A Comprehensive History

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Many patients ignore their symptoms thinking they may have "slowed down with age" or are in poor physical condition. Direct questioning about the presence of a chronic non-productive cough and dyspnea on exertion often reveals a history of slow but persistently progressive symptoms over several months, if not years. Patients may dismiss these common symptoms as asthma, sinus drainage, or recurrent upper respiratory infections. While chronic progression of symptoms occurs in most ILD, acute presentations (such as with acute interstitial pneumonia) can also occur.

Uncommon symptoms may also offer useful clues. Wheezing suggests airway involvement and can signal eosinophilic pneumonia, hypersensitivity pneumonitis, respiratory bronchiolitis, or Churg-Strauss Syndrome. Pleuritic chest pain, another atypical symptom, can be associated with any of the connective tissue diseases or accompany pneumothoraces that complicate lymphangioleiomyomatosis (LAM) or eosinophilic granuloma of the lung (EG). Occasionally, a patient with sarcoidosis will present with atypical chest pain. While sputum production is uncommon in ILD, hemoptysis may be the presenting complaint of diffuse alveolar hemorrhage, pulmonary vasculitis, LAM, or EG.

Age and gender are both useful variables in establishing a differential diagnosis. For example, an ILD that complicates connective tissue disease is more common in women, with the exception of rheumatoid arthritis, which affects more men. Lymphangioleiomyomatosis (LAM) is seen only in premenopausal women. Idiopathic pulmonary fibrosis develops primarily in those over the age of 60, while sarcoidosis and connective tissue diseases seem to affect patients under the age of 50.

As lung injury can result from a wide variety of respiratory insults, obtaining a thorough medical history helps to identify relevant events such as previous systemic or pulmonary illnesses (such as arthritis, or a thoracic malignancy) and treatments or therapies (such as radiation or chemotherapy). A determination of the patient’s current medication use should include both prescription and non-prescription drugs (oral or inhaled), vitamins and supplements, and recreational drugs. Reviewing past medications may reveal a drug-induced lung disease, which may remain asymptomatic for years. Tobacco use cannot be overlooked as some ILD presents primarily in smokers. Likewise, pursuing a familial association in some ILD may reveal a common exposure or genetic factor. For this reason, a family history to elicit information of similar pulmonary or systemic diseases adds to the overall assessment. Other clues that narrow the diagnostic process can often be found in a review of systems that focuses on systemic symptoms that could relate to an autoimmune disease.

A history would be incomplete without a meticulous review of occupational and environmental exposures. The workplace, home, and even recreational activities or hobbies may result in an important exposure. An occupational history should include the type of work the patient currently or previously performed, the specific types of exposures and whether or not protective equipment was used. Noting specific periods of exposure offers useful detail. An environmental history should include consideration of the entire home, including workshop, garage, hot tubs, humidifiers, pets, and water damage. Exposures during recreational activities and hobbies, such as bird breeding, may likewise put the patient at risk for the development of ILD.

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Table I. Etiologic Classification of ILD
Idiopathic Interstitial Pneumonias	Rheumatologic Diseases
Idiopathic pulmonary fibrosis (IPF)	Systemic lupus erythematosus
Desquamative interstitial pneumonia (DIP)	Rheumatoid arthritis
Acute interstitial pneumonia (AIP, Hamman-Rich syndrome)	Progressive systemic sclerosis
Respiratory bronchiolitis-interstitial lung disease (RB-ILD)	Sjorgren's syndrome
Cryptogenic organizing pneumonia (COP) or idiopathic bronchiolitis obliterans with organizing pneumonia (BOOB)	Polymyositis/dermatomyositis
Lymphocytic interstitial pneumonia (LIP)	Mixed connective tissue disease
	Ankylosing spondylitis
Occupational and Environmental Exposures	Behcet's syndrome
Inorganic (examples)	Wegener's granulomatosis
Silica (silicosis)	Churg-Strauss syndrome
Silicates (asbestosis)	Goodpasture's syndrome
Hard metal dusts (giant cell interstitial pneumonia (GIP))
Beryllium (berylliosis)	Unclassified Diseases
Organic (causes of hypersensitivity pneumonitis)	Sarcoidosis
Microbial agents (examples)	Pulmonary histiocytosis X (eosinophilic granuloma of the lung)
Bacteria, e.g., thermophilic bacteria, Bacillus sp.,	Chronic gastric acid aspiration
Bacteria, e.g., thermophilic bacteria, Bacillus sp.,	Lymphangioleiomyomatosis (LAM)
Fungi, e.g., Aspergillus sp., Penicillium sp. (farmer's lung)	Tuberous sclerosis
Amoebae e.g., Naegleria sp., Acanthamoeba sp. (humidifier lung)	Pulmonary alveolar proteinosis (PAP)
Animal/insect proteins (examples)	Eosinophilic pneumonia
Avian droppings, feathers, serum (bird breeder's disease)	Lipoid pneumiona
Pelts, urine, serum (animal handler's lung)	Diffuse alveolar hemorrhage
Chemicals (examples)	Amyloidosis
Isocyanates,trimellitic anhydride(chemical worker's lung	Neoplastic Diseases
Drugs, Poisons, and Radiation (examples)	Lymphangitic carcinomatosis
Chemotherapeutic agents (busulfan, bleomycin, methotrexate)	Bronchoalveolar cell carinoma
Antibiotics (nitrofurantoin, sulfasalazine)	Pulmonary lymphoma
Cardiovascular drugs (Amiodarone, Tocainide, ACE inhibitors)	Infections (active or remote)
Anti-inflammatories (gold salts, penicillamine)	Mycobacterial
Neurotropics/psychotropics	Fungal
Others (paraquat, cocaine, radiation, oxygen)	Viral
	Bacterial
	Cardiovascular
	Chronic left ventricular failure
	Mitral stenosis
	Pulmonary veno-occlusive disease

The Physical Exam

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Abnormal lung auscultatory findings are almost always found in ILD. Fine, mid-to-end inspiratory dry rales (crackles) generally indicate lung fibrosis. However the underlying cause of the findings cannot generally be based solely on the physical exam as signs often overlap across many specific ILDs. If the bronchioles are affected, as in hypersensitivity pneumonitis, there are often mid-inspiratory crackles. A prominent P2 component of the second heart sound, an elevated jugular venous pressure, and peripheral edema may represent pulmonary hypertension and right heart failure. On examination of the extremities, clubbing occurs most often in idiopathic pulmonary fibrosis, while joint swelling (synovitis) and deformities suggest an underlying autoimmune or connective tissue disease. The finding of dry eyes or mucous membranes, skin rashes, adenopathy, hepatosplenomegaly, or muscle tenderness suggests a systemic disease such as sarcoidosis, underlying connective tissue disease, malignancies, or vasculitis.

Diagnostic Testing

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The plain chest radiograph can be quite helpful in identifying the presence of ILD and generating a diagnostic differential; however, it cannot make a definitive diagnosis. The chest radiograph may have been abnormal for years prior to diagnosis and review of past radiographs can be helpful in determining the cause of disease. High-resolution computerized tomography (HRCT) is more sensitive in identifying changes and more specific in suggesting particular diagnosis than the simple chest radiograph and should be obtained during the evaluation of almost all cases of ILD (see Table II).

Pulmonary function testing is a necessary evaluation in determining both the type and severity of the lung function changes. Measurement of lung volumes, spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), and gas exchange at rest and with exercise all provided specific, but incomplete clues to the diagnosis.

Bronchoalveolar lavage (BAL) has a limited role in the initial diagnosis of ILD and is most helpful in identifying ILDs in which elevated numbers of eosinophils or lymphocytes are common. It is only rarely that BAL can make a definitive diagnosis.

A confirmed and confident diagnosis of an ILD usually requires a lung biopsy to combine with the clinical, radiographic, physiologic and laboratory clues. Because the most appropriate therapeutic management of ILD depends upon identifying a specific diagnosis, pathologic evaluation is usually required. Transbronchial, open or video-assisted thorascopic (VATS) lung biopsies are performed depending upon the specific patient circumstance; however, the amount of tissue obtained from a transbronchial biopsy is quite limited and usually insufficient to make a confident diagnosis.

Mechanisms Of Disease

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Researchers have proposed a common pathogenic process at work in those diseases that are characterized by progressive fibrosis. Understanding this process aids in the understanding of patient management.

Alveolar and/or epithelial cells may be injured by inhalation or through the vascular system. Acute injury seems to progress to chronic inflammation aided by T lymphocytes and macrophages. Continued exposure to an antigen or failure of the lung’s intrinsic anti-inflammatory mechanisms have

been suspected as the cause of persisting inflammation. Whatever the cause, this inflammation progresses to a scar, and this fibrotic change ultimately interferes with gas exchange. In some ILD, the alveoli fill with lipoproteins, blood, malignant cells, or eosinophils. In others, there is an unexplained proliferation of smooth muscle mass. Still others result in amyloid deposits in the alveolus and the alveolar capillary membrane.

Less extensive pathologic changes are potentially reversible. The primary goal of treatment is to suppress the inflammatory response and reverse the deposition of granulation tissue.

Patient Management

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Most patients with ILD will require treatment, though the type of intervention, medication dosages, and length of therapy depends upon the specific ILD. Identifying etiologic factors can lead to a surprisingly simple and effective management. In patients with hypersensitivity pneumonitis, removing the patient from the pertinent exposure may be all that is necessary for successful therapy. If the patient remains exposed, the disease will likely recur or persist, becoming chronic and progressive. Tobacco smoking offers a similar illustration. Respiratory bronchiolitis-interstitial lung disease can improve or stabilize with smoking cessation. Likewise, drug-induced ILD may respond to stopping the medication and use of corticosteroid therapy.

The goal, with the available therapies, is to begin treatment before end-stage fibrosis is present. Immunosuppressive drugs are used to control the inflammatory component of the disease, with corticosteroids being the standard choice. However, corticosteroid dosages are often high, and related side effects may require a decrease in dosage or termination of treatment, even if the patient has responded. Clinicians may add cytotoxic drugs (such as cyclophosphamide and azathioprine) after initial high-dose steroids or in combination with lower dose steroids. This approach provides a type of "steroid sparing" benefit.

The response to therapy in ILD varies quite widely. Some types will respond in days (such as eosinophilic pneumonia), others in weeks or months (such as bronchiolitis obliterans with organizing pneumonia (BOOP)), and some may not respond at all (particularly the fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF)). Depending upon the disease, therapy may be considered successful with an improvement or stabilization of symptoms and radiographic and physiologic abnormalities, as the natural history of most ILD is a gradual worsening of all of these parameters.

Supplemental oxygen helps to prevent complications from hypoxia. With its use, patients experience an improved sense of well-being, tolerate activity and exercise, and report improved rest and sleep. A routine exercise program may be included as part of a comprehensive approach. Exercise contributes to aerobic cardiovascular fitness, bone mass while on corticosteroid therapy, weight control, and an overall sense of well-being. All patients with ILD should be considered for a pneumococcal vaccine and a yearly influenza vaccine.

Unfortunately, clinical deterioration is common in ILD. As the disease progresses, radiographic and physiologic abnormalities worsen and gas exchange deteriorates. However, an increase in respiratory symptoms may not be progressive disease but may signal complications of the disease or therapy. Hypoxemia, for example, is known to lead to secondary complications such as pulmonary hypertension and right heart failure and is a major contributor to mortality in ILD. Treatment itself can cause complications and clinical deterioration, such as infection, respiratory and peripheral muscle weakness and osteoporosis.

Evaluation and Referral

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Failure to establish a confident diagnosis is a common error made in the management of ILD. Pulmonologists have the ability to perform and interpret specialized testing, and to put together the clinical, physiologic, radiographic, laboratory, and pathologic clues necessary for a clear diagnosis. Referral to a pulmonologist for initial evaluation and diagnosis, or follow-up after a specific diagnosis is made, can be extremely beneficial, particularly if there are questions about the cause of the disease, progressive symptoms, or complications of the primary disease or therapy.

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Table II. Useful Patterns of Diagnostic Tests
Test/Pattern	Examples of Common Diagnoses
Simple Chest Radiograph
Decreased lung volumes	Idiopathic pulmonary fibrosis (IPF), asbestosis, rheumatologic diseases
Increased lung volumes	Lymphangioleiomyomatosis (LAM), eosinophilic granuloma of the lung (EG), bronchiolitis
Mid-upper zone predominance	Sarcoidosis, silicosis, hypersensitivity pneumonitis, EG
Lower zone predominance	IPF, asbestosis
Peripheral zone	Cryptogenic organizing pneumonia (COP) or bronchiolitis obliterans with organizing pneumonia (BOOP), eosinophilic pneumonia
Micronodules	Infection, sarcoidosis, hypersensitivity pneumonitis
Septal thickening	Malignancy, chronic congestive heart failure
Honeycombing	IPF, asbestosis, chronic hypersensitivity pneumonitis, rheumatologic diseases
Migratory or remitting infiltrates	COP or BOOP, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis (ABPA)
Pleural disease	Asbestosis, malignancy, rheumatologic diseases
Pneumothorax	LAM, EG, tuberous sclerosis
Adenopathy	Sarcoidosis, malignancy, infection
Normal	Hypersensitivity pneumonitis, bronchiolitis
High-Resolution Computed Tomography (by type of radiographic abnormality)
Reticular lines	IPF, asbestosis, sarcoidosis, chronic hypersensitivity pneumonitis, rheumatologic diseases
Honeycombing	IPF, asbestosis, sarcoidosis, chronic hypersensitivity pneumonitis, rheumatologic diseases
Airspace opacity, "ground-glass"	COP or BOOP, chronic eosinophilic pneumonia (CEP), pulmonary alveolar proteinosis, lymphoma, sarcoidosis
Nodules	Granulomatous diseases, pneumoconioses, malignancy
Septal thickening	Infection, edema, malignancy
Cystic changes	Eosinophilic granuloma, LAM
Bronchoalveolar Lavage
Eosinophilia (>35%)	Eosinophilic pneumonias
Lymphocytosis (>35%)	Sarcoidosis, chronic beryllium disease, hypersensitivity pneumonitis, lymphocytic interstitial pneumonia (LIP), lymphoma, malignancy, drug-induced lung disease
Bloody lavage with hemosiderin-laden macrophages	Diffuse alveolar hemorrhage
Organisms on stain or culture	Infection
Positive cytology	Malignancy
Lipid-laden macrophages	Lipoid pneumonia

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