Interstitial Lung Disease
Catherine Chen
Adrian Shifren
General Principles
Definition
Interstitial lung disease (ILD) describes a heterogeneous group of over 200 diseases affecting the pulmonary interstitium with varying degrees of involvement of the pleural space, airways, and pulmonary vasculature.
ILD is also termed diffuse parenchymal lung disease (DPLD).
These diseases account for ∼15–20% of general pulmonary practice.
Since ILDs differ greatly in presentation, clinical course, and response to therapy, establishing an accurate diagnosis is essential for determining the optimal management strategy.
This requires effective collaboration between the pulmonologist, thoracic surgeon, radiologist, and pathologist to integrate clinical, physiologic, laboratory, radiographic, and histopathologic data.
Accordingly, the majority of this chapter will focus on the clinical evaluation and diagnosis of ILD.
Classification
Guidelines based on clinical, histopathologic, and radiographic findings have been proposed for subgroups of ILD including idiopathic interstitial pneumonias (IIP), hypersensitivity pneumonitis (HP), lymphangioleiomyomatosis (LAM), and others.
However, due to the heterogeneous nature of these diseases, there is currently no universal classification system that encompasses all ILDs.
A classification system based loosely on etiology and/or disease association is presented in Table 25-1.
Keep in mind that this table is far from comprehensive, and the definition and classification of ILDs will continue to evolve rapidly as we learn more about the pathogenesis of these diseases.
Etiology and Pathogenesis
Environmental and heritable factors both play a significant role in the pathogenesis of ILD, but the relative contribution and importance of these factors is quite variable between diseases and patients.
An increasing number of occupational/environmental exposures and genetic modifiers of disease susceptibility have been elucidated through epidemiologic and genomic analyses, respectively.
However, the complex interactions between these factors and how they affect disease development and progression remain poorly understood.
Alveolar epithelial cell injury is a hallmark of ILD. The source of injury may be extrinsic, as in cases of HP, pneumoconiosis, or radiation pneumonitis.
Alternatively, the injurious insult may arrive via the circulation, as suspected in collagen vascular diseases, vasculitides, or drug-induced lung diseases.
Normally after a limited injury, the initial acute inflammatory response resolves, and tissue repair programs restore lung integrity and homeostasis.
TABLE 25-1 CLASSIFICATION OF DIFFUSE PROLIFERATIVE LUNG DISEASES
A. Known etiologies
Collagen vascular disease:
Scleroderma
Rheumatoid arthritis
Polymyositis/dermatomyositis
Antisynthetase syndrome
Sjögren syndrome
Drug-related:
Antibiotics
Cephalosporins
Nitrofurantoin
Sulfasalazine
Antiarrhythmic
Amiodarone
β-blockers
Anti-inflammatory
NSAIDs
Gold
Penicillamine
Neuropsychiatric
Phenytoin
Carbamazepine
Fluoxetine
Chemotherapeutic
Bleomycin
Methotrexate
Azathioprine
Busulfan
Paclitaxel
Pneumoconioses:
Asbestosis
Coal miner pneumoconiosis
Silicosis
Berylliosis
Hard-metal pneumoconiosis (cobalt)
Talcosis (talc)
Siderosis (iron)
Stannosis (tin)
Hypersensitivity pneumonitis:
Bird fancier lung (pigeons, parakeets, others)
Farmer lung (moldy hay)
Humidifier lung
Hot tub lung
Bagassosis (sugar cane)
Cheese worker lung
Suberosis (cork)
Vasculitis:
Granulomatosis with polyangiitis (GPA)
Microscopic polyangiitis
Goodpasture syndromea
Churg–Strauss syndrome
Behçet disease
B. Unkown etiologies
Idiopathic interstitial pneumonias:
Major IIPs
Idiopathic pulmonary fibrosis (IPF)
Idiopathic nonspecific interstitial pneumonitis (NSIP)
Cryptogenic organizing pneumonia (COP)
Acute interstitial pneumonia (AIP)
Respiratory bronchiolitis-interstitial lung disease (RB-ILD)a
Desquamative interstitial pneumonia (DIP)a
Rare IIPs
Idiopathic lymphoid interstitial pneumonia (LIP)
Idiopathic pleuroparenchymal fibroelastosis
Unclassifiable IIPs
Others:
Familial pulmonary fibrosis
Sarcoidosis
Lymphangioleiomyomatosis (LAM)
Pulmonary Langerhans cell histiocytosis (PLCH)a
Alveolar proteinosis
Amyloidosis
Acute eosinophilic pneumonia
Chronic eosinophilic pneumonia
Pulmonary alveolar microlithiasis
Diffuse pulmonary ossification
Combined pulmonary fibrosis and emphysema (CPFE)a
C. Hereditary diseases with diffuse lung involvement
Tuberous sclerosis
Neurofibromatosis
Hermansky–Pudlak syndrome
Gaucher disease
Niemann–Pick disease
Birt–Hogg–Dubé
a These diseases are strongly associated with tobacco smoking. In the case of Goodpasture syndrome, diffuse alveolar hemorrhage is significantly more common in smokers than nonsmokers.
Adapted from British Thoracic Society and Standards of Care Committee. The diagnosis, assessment and treatment of diffuse parenchymal lung disease in adults. Thorax. 1999;54(Suppl 1):S1–S28; and Schwarz M, King TE, Raghu G. Approach to the evaluation and diagnosis of interstitial lung disease. In: Schwarz M, King T Jr, eds. Interstitial Lung Disease. Hamilton, Ontario: BC Decker; 1998.
However, with recurrent or persistent injury the reparative response becomes maladaptive; this leads to dysregulation of the normal injury repair response, resulting disruption of lung architecture and function.
Indeed, lung biopsy specimens from patients with ILD frequently show varying degrees of inflammation and/or fibrosis.
In addition to recurrent injury and aberrant repair of the airway epithelium, other factors may contribute to the pathogenesis of ILD.
Studies have revealed an association between short telomere length and idiopathic pulmonary fibrosis (IPF); these findings are consistent with the increased prevalence of IPF in elderly patients and implicate accelerated cellular aging or stem cell exhaustion as additional mechanisms of disease in some ILDs.
Diagnosis
A suggested algorithm for the evaluation of ILD is presented in Figure 25-1.
 FIGURE 25-1. Evaluation of diffuse proliferative lung diseases. (Adapted from American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:277–304; and British Thoracic Society and Standards of Care Committee. The diagnosis, assessment and treatment of diffuse parenchymal lung disease in adults. Thorax. 1999;54(Suppl 1):S1–S28.) |
Clinical Presentation
History
A comprehensive history is a very important part of the patient evaluation.
It can significantly narrow the differential diagnosis, guide the physical examination, and reduce the need for extensive diagnostic testing.
Dyspnea is the most common presenting symptom.
Patients may initially present with dyspnea only with moderate or heavy exertion.
As the disease progresses, breathlessness with mild or minimal exertion becomes apparent.
Eventually patients become dyspneic at rest.
Depending on the specific disease, dyspnea may present insidiously over months to years as in IPF, or pursue a more aggressive course over weeks to months as in acute interstitial pneumonia or acute eosinophilic pneumonia.
Episodic dyspnea may occur in cases of HP where repeated exposure to an inciting environmental agent causes waxing and waning symptoms.
Therefore, it is important to accurately quantify the duration and severity of the patient’s dyspnea.
Cough is also a frequent complaint associated with ILD.
A nonproductive cough is common in cases of IPF, HP, and sarcoidosis.
Chest pain is unusual.
When present it may be associated with inflammation of the pleural space (systemic lupus erythematosus, rheumatoid arthritis), pneumothorax (LAM), or an atypical cause of ILD (sarcoidosis).
Occult coronary artery disease is common in elderly patients with advanced lung disease and limited functional capacity. Therefore, coronary ischemia should be considered in the differential.
Wheezing is less frequent in general.
It may be more prevalent in ILDs involving the airways such as HP, respiratory bronchiolitis-interstitial lung disease (RB-ILD), or sarcoidosis.
Other diseases involving the airways, such as chronic bronchitis or asthma, may occur concurrently.
Hemoptysis is also infrequent. It may occur in ILDs associated with vasculitis, connective tissue diseases or diffuse alveolar hemorrhage, such as Goodpasture syndrome, microscopic polyangiitis, and granulomatosis with polyangiitis (GPA, known previously as Wegener granulomatosis).
Constitutional symptoms, such as fevers, chills, weight loss, night sweats, and fatigue occur with variable frequency. Significant unintentional weight loss should also raise the possibility of a concurrent malignancy, since patients with certain ILDs such as IPF, lymphoid interstitial pneumonia (LIP), and asbestosis are known to have an increased incidence of lung malignancy.
Past and current medical histories are important for diagnosing ILDs secondary to systemic conditions such as collagen vascular disease, vasculitides, and other autoimmune diseases (Table 25-1).
In some cases, the systemic disease is already present at the time of diagnosis.
However, in certain ILDs associated with systemic disease, ILD may be the initial manifestation of the disease.
In rare cases ILD can be the only manifestation of the disease.
The clinician should maintain a high index of clinical suspicion, and in the correct clinical context, such as a younger female presenting with ILD, diagnostic testing should be performed to exclude the presence of collagen vascular disease.
Social history should be obtained to identify known risk factors for certain ILDs.
Cigarette smoking has an integral causal relationship with diseases such as RB-ILD, desquamative interstitial pneumonia (DIP), and pulmonary Langerhans cell histiocytosis (PLCH).
In addition, diffuse alveolar hemorrhage occurs in nearly 100% of patients with Goodpasture syndrome who smoke and only around 20% of those who do not.
Conversely, ILDs such as HP, chronic eosinophilic pneumonia, and sarcoidosis appear to be less common in cigarette smokers.
Recreational drug abuse has also been described as a cause of ILD.
Occupational and environmental histories are an essential part of any DLPD workup.
A large number of occupational and environmental exposures have been implicated as causative agents for ILDs.
The occupational history should cover the patient’s entire lifetime since the time between exposure and disease onset may span many years.
Details of each exposure, including duration, frequency, intensity, and presence or absence of respiratory protection should be recorded.
The occupational history of close contacts should also be established, as exposure to an inciting agent (e.g., asbestos) may not occur only in the workplace.
Environmental (nonwork-related) exposures including pets, hobbies, and recreational activities should also be reviewed.
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