INERSTITIAL LUNG DISEASE Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin

Interstitial lung disease: Clinical evaluation The diffuse parenchymal lung diseases, often collectively referred to as the interstitial lung diseases (ILDs), are a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations. The descriptive term "interstitial" reflects the pathologic appearance that the abnormality begins in the interstitium, but the term is somewhat misleading, as most of these disorders are also associated with extensive alteration of alveolar and airway architecture

Interstitial lung disorders: major categories Idiopathic interstitial pneumonia Idiopathic pulmonary fibrosis (IPF) Non-specific interstitial   pneumonia (NSIP) Cryptogenic organizing   pneumonia (COP) Respiratory bronchiolitis   interstitial lung disease (RBILD Desquamative interstitial   pneumonia (DIP) Acute interstitial pneumonia (AIP) Connective tissue disease-associated interstitial lung disease (CTD-ILD) Sarcoidosis Lymphoid interstitial   pneumonia (LIP) Hypersensitivity pneumonitis Iatrogenic pneumonitis/fibrosis (drug-induced ILD, radiation injury) Eosinophilic ILD (e.g. eosinophilic pneumonia) Occupational lung disease Inherited disorders (e.g. familial pulmonary fibrosis, Hermansky-Pudlak syndrome) Primary disorders (e.g. pulmonary Langerhans cell histiocytosis)

CLINICAL PRESENTATION — Patients with ILD come to clinical attention for the following ways: Symptoms of progressive breathlessness with exertion (dyspnea) or a persistent nonproductive cough. Pulmonary symptoms associated with another disease, such as a connective tissue disease History of occupational exposure (eg, asbestosis, silicosis) An abnormal chest imaging study Lung function abnormalities on simple office spirometry, particularly a restrictive ventilatory pattern (ie, reduced total lung capacity and forced vital capacity) HISTORY —  Careful documentation of the PMH is important in the initial assessment because the cause of the illness is often recognized from the patient's history. Age and gender — Some of the ILDs are more common in certain age groups or have a male or female predominance. IPF, also called cryptogenic fibrosing alveolitis are over age 50. Lymphangioleiomyomatosis and pulmonary involvement in tuberous sclerosis occur exclusively in premenopausal women ILD associated with rheumatoid arthritis is more common in men.

Onset of symptoms: The acute eosinophilic pneumonia, cryptogenic organizing pneumonia, connective tissue associated ILD) often share features with atypical infectious pneumonias, such as the rapid onset of symptoms, diffuse radiographic opacities, and fever ILDs with a chronic or indolent presentation (eg, idiopathic pulmonary fibrosis, sarcoidosis, pneumoconioses) need to be differentiated from each other and from diseases such as chronic obstructive pulmonary disease and heart failure. Some ILDs, such as hypersensitivity pneumonitis and sarcoidosis, may have an acute, subacute, or chronic presentation Past medical history — Any history of connective tissue disease, inflammatory bowel disease, or malignancy might be a clue to an associated ILD A number of medications have also been associated with ILD, notably amiodarone. Allergic rhinitis and asthma may implicate chronic eosinophilic pneumonia Nasal polyposis and asthma may suggest eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss). An immunocompromised state due to an underlying disease or immunomodulatory therapy may suggest an infectious cause of ILD.

Smoking history — Some diseases occur largely among current or former smokers (eg, pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonitis, respiratory bronchiolitis-interstitial lung disease, and idiopathic pulmonary fibrosis) or among never or former smokers (sarcoidosis and hypersensitivity pneumonitis). Family history — The family history is occasionally helpful, as several familial associations have been identified. However, different types of ILD (eg, idiopathic pulmonary fibrosis and nonspecific interstitial pneumonitis) may occur within a single family An autosomal dominant pattern of inheritance has been reported for idiopathic pulmonary fibrosis (IPF), tuberous sclerosis, and neurofibromatosis Prior medication use and irradiation — A detailed history of all medications taken and any exposure to therapeutic irradiation is needed to exclude the possibility of drug-induced or radiation-induced lung disease Occupational/environmental exposures : In hypersensitivity pneumonitis (extrinsic allergic alveolitis), the development of respiratory symptoms, fever, chills, and an abnormal chest radiograph are often temporally related to the workplace (farmer's lung) or to a hobby (pigeon breeder's disease).

Symptoms  Hemoptysis – may occur in the diffuse alveolar hemorrhage syndromes, tuberous sclerosis, lymphangioleiomyomatosis, pulmonary veno-occlusive disease, and granulomatous vasculitides. Diffuse alveolar bleeding may be present without hemoptysis; the clinical manifestations in such patients may be dyspnea and an iron deficiency anemia. Wheezing – is an uncommon manifestation of ILD. It has been described in cases of lymphangitic carcinomatosis, chronic eosinophilic pneumonia, EGPA, and respiratory bronchiolitis Chest pain – uncommon in most ILDs. Described in RA; SLE and MCTD Dyspnea – SOB, dyspnea, is a common complaint. Grading the level of dyspnea is useful as a method to gauge the severity of the disease Spontaneous pneumothorax is a characteristic that may occur in pulmonary Langerhans cell histiocytosis, tuberous sclerosis, lymphangioleiomyomatosis, and neurofibromatosis Cough – A dry cough is common and bothersome in sarcoidosis, bronchiolitis obliterans with or without organizing pneumonia, respiratory bronchiolitis, pulmonary Langerhans cell histiocytosis, hypersensitivity pneumonitis, lipoid pneumonia, and lymphangitic carcinomatosis.

Physical examination of patients with ILD is usually nonspecific Lung examination — The lung examination is frequently abnormal in ILD, but the findings are generally nonspecific. Crackles or "velcro rales" are present on chest examination in most forms of ILD Scattered late inspiratory high-pitched rhonchi, so-called inspiratory squeaks, are frequently heard on chest examination in patients with bronchiolitis, but may also be heard in patients with traction bronchiectasis due to pulmonary fibrosis. Clubbing — is common in some pulmonary disorders (idiopathic pulmonary fibrosis, asbestosis) and rare in others (sarcoidosis, hypersensitivity pneumonitis. Cardiac examination — Usually normal except in more advanced stages of pulmonary fibrosis, when findings are cor pulmonale & PHT Pulmonary hypertension may also be a primary manifestation of some CTD disorders (progressive systemic sclerosis). Cor pulmonale are rare in ILD. When present, is advanced disease. Extrapulmonary findings of systemic disease : alopecia, angiofibromas, cutaneous sarcoidosis, Gottron's papules, heliotrope rash, joint inflammation, "mechanics" hands, muscle weakness, nasal obstruction, peripheral neuropathy, and sclerodactyly

Age at onset of presentation in different interstitial lung diseases Idiopathic pulmonary fibrosis (IPF) has an older age distribution than either pulmonary Langerhans cell histiocytosis (LCH) or sarcoidosis.

LABORATORY TESTS — CBC with differential blood count to check for evidence of anemia, polycythemia, leukocytosis, or eosinophilia Liver function tests: ALT, SGPT, AST, SGOT Tests for possible rheumatic disease Antinuclear antibody (ANA) Rheumatoid factor (RF) Hepatitis serology HIV testing may be appropriate. Sicca features or positive anti-extractable nuclear antigen (ENA) anti-RO (SS-A) anti-La (SS-B) anti-ribonucleoprotein (RNP) serum protein electrophoresis Coagulation studies anti-glomerular basement membrane (GBM) antibodies antiphospholipid antibodies, Urinalysis

LABORATORY TESTS —  Laboratory tests in selected patients with ILD: Additional possible tests for rheumatic disease* Anti-cyclic citrullinated peptide (Anti-CCP) Creatine kinase (CK), aldolase Anti-Jo-1 antibody Anti-neutrophil cytoplasmic antibody (ANCA) Anti-topoisomerase (Scl-70) antibody, anti-PM-1 (PM-Scl) antibody Anti-double stranded (ds) DNA antibodies Serum celiac panel serum IgA endomysial tissue transglutaminase antibodies in patients who may have idiopathic pulmonary hemosiderosis

Chest radiography —  The most common radiographic abnormality on routine chest radiograph is a reticular pattern Nodular or mixed patterns (alveolar filling and increased interstitial markings) are not unusual Radiographic finding of honeycombing (small cystic spaces) correlates with pathologic findings The CXR is normal in 10% of patients with some forms of ILD, particularly those with hypersensitivity pneumonitis An electrocardiogram is obtained to evaluate for evidence of pulmonary hypertension or concurrent cardiac disease.

Computed tomography   High resolution computed tomography (HRCT) should be obtained in almost all patients with diffuse pulmonary parenchymal disease. Obtain both supine and prone images to avoid confusing dependent atelectasis with interstitial opacities. HRCT provides greater diagnostic accuracy than the plain chest radiograph If heart failure is suspected, a serum brain natriuretic peptide (BNP) level is measured. An echocardiogram is also obtained when there is suspicion for heart failure or pulmonary hypertension.

Frontal chest radiograph demonstrating bilateral reticular and nodular interstitial infiltrates with upper zone predominance. High-resolution chest CT scan of patient with bilateral reticular and nodular interstitial infiltrates with upper zone predominance.

Bilateral nodular and reticular shadows of interstitial lung disease. Normal chest radiograph Nodular and Reticular opacities Bilateral nodular and reticular shadows of interstitial lung disease. Postero-anterior view of a normal chest radiograph.

PULMONARY FUNCTION TESTING: Spirometry and lung volumes — Most of the ILDs have a restrictive defect with reductions TLC, FRC, RV In contrast, an interstitial pattern on chest radiograph accompanied by obstructive airflow limitation (ie, a reduced FEV1/FVC ratio) on lung function testing is suggestive of any of the following processes: Sarcoidosis Pulmonary Lymphangioleiomyomatosis Hypersensitivity pneumonitis Pulmonary Langerhans cell histiocytosis Tuberous sclerosis Combined chronic obstructive pulmonary disease (COPD) and ILD Constrictive bronchiolitis

PULMONARY FUNCTION TESTING: Diffusing capacity — A reduction in the diffusing capacity (DLCO) is a common, but nonspecific finding in ILD. The decrease in DLCO is due to effacement of the alveolar capillary units but more importantly to the extent of mismatching of ventilation and perfusion of the alveoli. Moderate to severe reduction of DLCO in the presence of normal lung volumes in a patient with ILD suggests one of the following: Combined emphysema and ILD Combined ILD and pulmonary vascular disease Pulmonary Langerhans cell histiocytosis Pulmonary lymphangioleiomyomatosis

PULMONARY FUNCTION TESTING: Gas exchange at rest and on exertion —  Resting ABG may be normal in early ILD or may reveal hypoxemia (secondary to mismatching of ventilation to perfusion) and respiratory alkalosis. Carbon dioxide retention is rare and usually a manifestation of end-stage disease. Bronchoalveolar lavage: The patients with an acute onset of ILD will undergo BAL to evaluate for acute eosinophilic pneumonia, alveolar hemorrhage, malignancy, and opportunistic or atypical infection, which can often be diagnosed on the basis of BAL findings In everyone presenting with hemoptysis and radiographic ILD, BAL is performed promptly to confirm an alveolar source of bleeding and identify infectious etiologies, if present

ROLE OF LUNG BIOPSY — When the results of the above evaluation do not allow the clinician to make a confident diagnosis of a given type or stage of interstitial lung disease (ILD), lung biopsy with multidisciplinary interpretation of the results may be necessary. The decision to pursue lung biopsy must be made on a case-by-case basis, weighing the morbidity of the procedure, the likely diagnoses, the toxicity of therapy, and the values and preferences of the patient Lung biopsy may also be indicated to exclude neoplastic and infectious processes. As an example, sarcoidosis can sometimes have a similar HRCT appearance to lymphangitic carcinomatosis or hypersensitivity pneumonitis. Or, a patient with rheumatoid arthritis might develop ILD due to the underlying disease, drugs used in treatment, or tuberculosis.

Treatment: Significant interstitial lung disease (ILD) predicts poor outcome. For patients who have respiratory symptoms, abnormal and/or declining pulmonary function, initiating treatment with cyclophosphamide plus low dose glucocorticoids (equivalent of ≤10 mg/day of prednisolone. The clinical benefits of immunosuppressive therapy appear to be modest and associated with substantial toxicity The goal of treating ILD is to reduce alveolar and interstitial injury and inflammation, in the hope that progression of interstitial fibrosis will be retarded.

Treatment: Cyclophosphamide can be administered as a monthly intravenous dose (our preference) or as a daily oral dose (eg, ≤2 mg/kg) prednisolone. After a 12 month course of cyclophosphamide, patients are commonly transitioned to maintenance therapy with mycophenolate, mofetil (eg, 1.5 to 3 g daily, usually in two divided doses). Patients whose disease is refractory to the above measures may be candidates for rituximab Selected SSc patients who have severe ILD that is unresponsive to therapy may be referred for lung transplantation.

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