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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 2  |  Issue : 1  |  Page : 3-15

Interstitial lung disease: Diagnostic approach


Department of Pulmonary Medicine, Burdwan Medical College and Hospital, Burdwan, West Bengal, India

Date of Web Publication5-Feb-2014

Correspondence Address:
Kaushik Saha
Rabindra Pally, 1st Lane, P. O. Nimta, Kolkata 700 049, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2320-8775.126502

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  Abstract 

Interstitial lung disease (ILD) is a final common pathway of a broad heterogeneous group of parenchymal lung disorders. It is characterized by progressive fibrosis of the lung leading to restriction and diminished oxygen transfer. Clinically, the presenting symptoms of ILD are non-specific (cough and progressive dyspnea on exertion) and are often attributed to other diseases, thus delaying diagnosis and timely therapy. Clues from the medical history along with the clinical context and radiologic findings provide the initial basis for prioritizing diagnostic possibilities for a patient with ILD. An accurate prognosis and optimal treatment strategy for patients with ILDs can only be after an accurate diagnosis. This review will assist pulmonary physicians and medicine specialist in recognition of ILD. Extensive literature search has been made through PubMed and also Book References has been used for writing this review.

Keywords: Clinical evaluation, fiber optic bronchoscopy, high resolution computed tomographic thorax, interstitial lung disease, lung biopsy


How to cite this article:
Saha K. Interstitial lung disease: Diagnostic approach. J Assoc Chest Physicians 2014;2:3-15

How to cite this URL:
Saha K. Interstitial lung disease: Diagnostic approach. J Assoc Chest Physicians [serial online] 2014 [cited 2018 Apr 26];2:3-15. Available from: http://www.jacpjournal.org/text.asp?2014/2/1/3/126502


  Introduction Top


Interstitial lung disease (ILD) is a heterogeneous group of disorder with a common presentation of cough (mostly dry), breathlessness and symptoms related to the systemic disorder when associated with. ILD is also termed as diffuse parenchymal lung disease (DPLD) and classified broadly into idiopathic interstitial pneumonia (IIP) and other than IIP [Figure 1]. [1],[2] After an initial suspicion, a comprehensive evaluation requires the following: (1) A methodical history to include demographics, family history and occupational and environmental exposures [Table 1]; (2) physical examination [Table 1]; (3) chest radiographs; (4) high resolution computed tomographic (HRCT) scans; (5) blood tests; (6) fiber optic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) or transbronchial lung biopsies (TBLB) in selected patients; (7) surgical lung biopsy (SLB) (selected patients). After confirmation or definite diagnosis of the type of ILD (also the causative factor if any), assessment of the severity and dynamics of the disease with and without therapy should be made.
Figure 1: Recent classification of interstitial lung disease. LAM = Lymphangioleiomyomatosis, PLCH = Pulmonary Langerhans Cell Histiocytosis, LIP = lymphoid interstitial pneumonia, IPF = Idiopathic interstitial fibrosis, NSIP = nonspecific interstitial pneumonia

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Table 1: Clinical clues for the diagnosis of ILD


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  Clinical History Top


Demographics

The patient's age, cigarette-smoking status and gender may provide important clues. Idiopathic pulmonary fibrosis (IPF) is always an adult disorder and typically occurs in patients who are older than 60 years of age. Although pulmonary sarcoidosis can manifest in the elderly patient, it is more common in the young- and middle-aged. Pulmonary Langerhans cells histiocytosis (PLCH) generally occurs in young, cigarette-smoking men. Respiratory-bronchiolitis ILD (RB-ILD) is seen exclusively in cigarette smokers and desquamative interstitial pneumonia (DIP) is frequently seen in active smokers. In contrary, smoking may be protective against sarcoidosis and hypersensitivity pneumonitis (HP). [3],[4],[5],[6]

Sarcoidosis, chronic eosinophilic pneumonia (CEP), systemic lupus erythematosus (SLE) and progressive systemic sclerosis occurs commonly in females. Lymphangioleiomyomatosis (LAM) is exclusively seen in females of child bearing age. By contrast, PLCH and IPF are more common in males. [5]

Genetics

A family history is important to identify patients with inheritable ILD. A positive family history can be elicited in only 1-3% of patients with IPF and 6-19% of patient with sarcoidosis. Examples of genetic ILDs include  Hermansky-Pudlak syndrome More Details; Gaucher's disease; lysosomal storage disorders; hypocalciuric hypercalcemia and tuberous sclerosis complex (TSC) (associated with LAM). [7],[8],[9]

Exposures (occupational, hobbies, home environment)

A thorough occupational and environmental history is critical to evaluate ILD. At-risk occupations include miners (pneumoconiosis); sandblasters and granite workers (silicosis); welders, shipyard workers, pipe fitters, electricians, auto-mobile mechanics (asbestosis); farm workers, poultry workers, bird fanciers, bird breeders (HP); and workers in aerospace, nuclear, computer and electronic industries (berylliosis). History of existing, persistent environmental "fibrogenic" factors at home; in the workplace; in automobiles; in frequently visited facilities/homes; associated with hobbies, such as exposure to birds, molds, woodworking; or the use of saunas and hot tubs often are ignored but are equally important and may provide useful clues [Table 2]. [5]

Certain pharmacological agents or drugs may evoke airway (e.g., bronchiolar) or lung injury. Commonly recognized associations include: Methotrexate; amiodarone; bleomycin; busulfan; chemotherapeutic and cytotoxic drugs; crack cocaine; intravenous illicit drugs. A careful work and environmental history is important to determine a possible cause of ILD [Table 2]. [10],[11]
Table 2: Selected occupational exposures and drugs related to the ILD


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Home environment (in rural areas) and occupational exposures are most commonly linked with HP. Two common causes of HP are: Farmer's lung disease (caused by thermophilic actinomycetes or molds in hay) and pigeon breeder's or bird fancier's disease (caused by avian antigens). Other syndromes elicited by thermophilic actinomycetes include air conditioner (humidifier) lung, mushroom worker's lung and bagassosis (from exposure to sugar cane). Other causes of HP include: Hot tub lung (from Klebsiella oxytoxa or Mycobacterium avium); contaminated heated swimming pools; machine operator's lung (from Pseudomonas fluorescens); contamination with mold (in homes or buildings). [12],[13]

Pulmonary symptoms

A detail history is the key to diagnose ILD. Questions should be asked regarding the onset, duration, severity, rate of progression and any associated extrathoracic and constitutional symptoms. Common presenting pulmonary symptoms are progressive cough (mainly dry), persistent progressive shortness of breath or dyspnea. The disease chronology may be divided according to the onset of presenting symptoms: (1) Acute, days up to a few weeks; (2) sub-acute, 4-12 weeks; and (3) chronic, longer than 12 weeks [Table 3]. [3],[4]
Table 3: Clinical patterns of ILD according to onset of presentation


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Dyspnea

It is the most common symptom and on presentation it may be during exertion or at rest. [3],[5],[14] The degree of dyspnea should be assessed by asking specific questions such as after what distance or how many steps or stairs or floors the dyspnea occurs and how long it persists. Non-respiratory factors such as joint pains, muscle cramps or general body weakness must be excluded before assessing the degree of exercise limitation. The recent change in the degree of dyspnea should be assessed as it is linked with the disease severity and prognosis. [3],[5] The rate of progression of disease is of equal importance as patients with IPF, PLCH and ILD associated with connective tissue disease (CTD) present with insidious onset of symptoms.

Cough is the second most common symptom and often the earliest symptom to start with. Cough is mostly dry in IPF and other airway centered disease such as sarcoidosis, HP, or cryptogenic organizing pneumonia (COP). Productive cough may be observed during exacerbation of IPF, pneumonia in ILD and associated bronchitis or traction bronchiectasis. A chronic irritable cough has been associated with lymphangitic carcinomatosis; mucoid or "salty" sputum is suggestive of bronchioloalveolar cell carcinoma. Associated wheeze may be found in Churg-Strauss syndrome, HP (pigeon breeder's lung), or airway-stenotic sarcoidosis. [15]

Hemoptysis may indicate the presence of underlying diffuse alveolar hemorrhage (DAH) syndromes such as Goodpasture syndrome or Wegener disease and rarely due to SLE or pulmonary hemosiderosis or drugs/toxins. The absence of hemoptysis does not exclude DAH (especially chronic) or other underlying conditions that are associated with microscopic hemorrhage (e.g., SLE).

Pleuritic chest pain raises the possibility of a pneumothorax, which is usually seen in patients who have LAM, PLCH, neurofibromatosis (NF) and catemenial syndrome. Pleural effusion is usually associated with collagen vascular disease (rheumatoid arthritis [RA] or SLE) associated, asbestos-related and drug induced ILD. [3],[5]

Extra pulmonary symptoms

Several extra pulmonary (gastrointestinal tract, rheumatologic, cutaneous, musculoskeletal, neurologic, renal) symptoms may provide useful clues.

A history of dyspepsia or gastroesophageal reflux disorder may suggest scleroderma related ILD. Overt aspiration or dysphagia may suggest scleroderma or mixed CTD. Lower gastro-intestinal symptoms may suggest inflammatory bowel disease. [3],[5] Gastroesophageal reflux is a common symptom in patients with ILD and suspected to have a role in causation or exacerbation of ILD. [16]

The presence of arthritis may suggest a CTD or sarcoidosis and combined muscle and skin symptoms suggest polydermatomyositis. Skin lesions such as lupus pernio suggest sarcoidosis. Other skin lesions can occur in NF, TSC or SLE. Albinism can occur in patients with the Hermansky-Pudlak syndrome. [3],[5]

Neurologic symptoms (cranial nerve involvement, Bell's palsy) suggest the possibility of vasculitis or sarcoidosis. Polyuria and polydyspsia of diabetes insipidus is suggestive of sarcoidosis or PLCH. Hematuria raises the possibility of pulmonary-renal syndromes. [3],[5]


  Physical Examination Top


Pulmonary signs

Crackles on lung auscultation, described as "dry," "Velcro-strap," end-inspiratory and predominantly basilar, are detected in more than 80% of patients who have IPF. Crackles due to other ILD auscultated on physical examination despite a normal chest radiograph can occur in granulomatous ILDs (e.g., sarcoidosis). Mid-inspiratory high-pitched squeaks are reported in the primary bronchiolitides and other diseases with airway-centered pathology (e.g., HP). [3],[5],[17]

Signs of pulmonary hypertension may be encountered in the later stages of all chronic ILDs as a result of progressive interstitial fibrosis and alveolar hypoxemia, but have been identified more specifically as part of the pathogenesis in CTD-associated ILD and pulmonary veno-occlusive disease. In patients with advanced IPF (extensive bilateral honeycomb cysts with traction bronchiectasis) demonstrating hypoxia at rest, secondary pulmonary hypertension maybe presents. Such patients usually have forced vital capacity (FVC) <50% predicted and/or diffusion capacity for carbon monoxide (DLCO) <30% predicted. [3],[5],[17]

Extra pulmonary signs

Clubbing may be seen in patients who have IPF, but can also occur in patients who have asbestosis, chronic HP and DIP. [3],[5]

Skin abnormalities, peripheral lymphadenopathy and hepatosplenomegaly are associated with sarcoidosis. Characteristic skin rashes and lesions also occur in CTD, amyloidosis, PLCH, TSC and NF. Subcutaneous nodules (especially around the elbow and metacarpophalangeal joints) are suggestive of RA. [3],[5]

Muscle tenderness and proximal weakness raise the possibility of polymyositis. Signs of arthritis may be associated with sarcoidosis or CTD. Fever, erythema nodosum and arthritis raise the likelihood of Löfgren's syndrome (in sarcoidosis). Sclerodactyly, Raynaud's phenomenon and telangiectatic lesions are characteristic features of scleroderma and calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia (CREST) syndrome. Iridocyclitis, uveitis, or conjunctivitis may be associated with sarcoidosis, Behcet's disease, inflammatory bowel disease and autoimmune syndromes. Oculocutaneous albinism raises the possibility that ILD is associated with Hermansky-Pudlak syndrome. Abnormalities of the central nervous system suggest the diagnosis of sarcoidosis (cranial nerve abnormalities, diabetes insipidus and anterior pituitary dysfunction), PLCH (diabetes insipidus), or TSC (epilepsy, mental retardation). [3],[5],[17],[18]


  Diagnostic Tests Top


Laboratory testing

Laboratory blood testing alone is rarely diagnostic, but may be strongly supportive in the appropriate clinical setting [Table 4]. Routine laboratory tests include a complete blood count with leukocyte differential, platelet count, erythrocyte sedimentation rate (ESR), chemistry profile (serum electrolytes, serum urea nitrogen, creatinine, liver function tests and calcium). Anti-nuclear antibody (ANA), rheumatoid factor (RF) should be obtained in the setting of history or physical findings that are suggestive of CTD. Low titers of ANA (1:160) and RF occur in 10-20% of patients who have IPF. Such patients may manifest other typical clinical features of CTD later in the course of the disease. Slightly elevated ESR, C-reactive protein and hypergammaglobulinemia are common and non-specific findings. An elevated level of angiotensin-converting enzyme may be seen with sarcoidosis, but is insensitive and non-specific as it is also abnormal in other disease (e.g., silicosis, HP, LIP, acute respiratory distress syndrome). [5],[19]
Table 4: Useful laboratory tests needed to reach the etiological diagnosis of ILD


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Serum precipitins that are focused on known exposures may be considered if the environmental history suggests HP; however, false-negative results may be encountered and similarly, the presence of precipitating antibody may represent sensitization to an environmental antigen and not disease. Random "HP panels" are almost never helpful in the absence of a specific exposure and seldom provides useful information. A careful history elucidation is key to diagnosing HP. If pulmonary vasculitis or DAH is suspected, cytoplasmic/perinuclear antineutrophil cytoplasmic antibody, anti-glomerular basement membrane antibody, ANA and urine sediment should be checked. Proximal muscle weakness or tenderness should prompt measurement of aldolase, creatine kinase, anti-Jo-1 anti-body and possibly an electromyogram and muscle biopsy to rule out polymyositis. [3],[5],[19]

A clinically suspected or histopathologic diagnosis of LIP should prompt measurement of serologies to rule out a CTD, particularly Sjögren's syndrome, immunoglobulin levels (to evaluate for associated common variable immunodeficiency) and a human immunodeficiency virus test. Peripheral blood lymphocyte proliferation that is stimulated by the antigen that may cause the ILD (e.g., the beryllium lymphocyte proliferation test) has high sensitivity for chronic berylliosis. [5],[19]

Pulmonary function testing

Initial PFTs should include a spirometry (with and without bronchodilator challenge), plethysmographic lung volumes and DLCO (corrected to hemoglobin). PFTs cannot diagnose a specific ILD and cannot distinguish between active lung inflammation versus fibrosis, but are important in the objective assessment of respiratory symptoms as well as in paring the differential diagnosis, grading the severity of disease and monitoring response to therapy or progression. [3],[5],[20]

PFT abnormalities generally reflect the effects of elevated elastic recoil (restrictive lung defect) and alveolar-capillary dysfunction (decreased DLCO), although increased lung volume (e.g., LAM) and increased DLCO (e.g., DAH) can be seen. A typical PFT pattern in ILD is a restrictive lung defect with symmetrically decreased lung volumes (total lung capacity [TLC], functional residual capacity and residual volume [RV] 80% predicted); decreased forced expiratory volume in 1 s (FEV 1 ) and FVC decreased in parallel with a normal or elevated FEV 1 /FVC ratio; and a decreased DLCO. Co-existing obstructive airflow defect, when present can aid with diagnosis. A mixed pattern of restriction and obstruction (decreased FEV 1 /FVC ratio, elevated RV, lack of supranormal airflows on a flow-volume loop, or a significant response to bronchodilator) in the patient without co-existing emphysema may suggest sarcoidosis, HP, RB-ILD, PLCH, TSC, LAM and ILD associated with asthma (CEP, Churg-Strauss syndrome). An obstructive defect without significant restriction may reflect obliterative bronchiolitis (without associated organizing pneumonia) and constrictive bronchiolitis. [3],[5],[20],[21],[22]

A DLCO that is decreased out of proportion to other tests may indicate concomitant pulmonary vascular disease such as in scleroderma, CREST syndrome, pulmonary veno-occlusive disease and chronic pulmonary emboli and can be seen occasionally in pulmonary alveolar proteinosis, pulmonary Langerhans cell granulomatosis (LCG) and LAM. Since TLC and FVC are effort and muscle strength-dependent maneuvers, occasionally a restrictive pattern (TLC 80%) may be due in part or wholly to respiratory muscle weakness (e.g., polymyositis) and will be revealed by decreased maximal inspiratory pressure, maximal expiratory pressure and decreased maximum minute ventilation. Presence of air-trapping (↑RV) in the absence of significant airflow obstruction (↓FEV 1 /FVC) should raise the possibility of underlying respiratory muscle weakness. [3],[5],[20],[21],[22]

Chest radiograph: Useful diagnostic patterns

A diffusely abnormal chest radiograph is often the initial finding that alerts the physician to the possibility of ILD. The clinician should make every effort to obtain previous chest radiographs for review. This may allow one to ascertain the onset, chronicity, rate of progression, or stability of the patient's disease. Classification of abnormalities on routine chest radiograph that are based on distribution, location and overall appearance are useful in narrowing the differential diagnosis [Table 5].
Table 5: Diagnostic clues based on a chest radiograph


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HRCT

HRCT has evolved into a standard procedure during the evaluation of almost all patients who have ILD. It is a more sensitive test than plain chest radiograph in identifying ILD (sensitivity >90%) and the image pattern of parenchymal abnormalities on HRCT often suggest a particular set of diagnostic possibilities [Table 6]. HRCT also identifies "mixed" patterns of disease (e.g., ILD plus emphysema) or additional pleural, hilar or mediastinal abnormalities. It has a better correlation with physiologic impairment and is especially useful in guiding the site of BAL or lung biopsy. A completely normal HRCT of the chest essentially rules out IPF but does not rule out microscopic inflammation and granulomatous changes. [23],[24],[25]
Table 6: HRCT pattern approach to ILD


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Exercise testing

Occasionally, PFTs and resting arterial blood gas (ABG) analysis may be entirely normal in patients who in the early stages of ILD, with the only physiologic abnormality being an abnormal ABG sampling obtained during exercise (decreased PaO 2 , widening P (A-a) O 2 gradient). Hence gas exchange evaluation at rest and with ambulation using pulse oximetry (i.e., 6-min or modified walk test) should be initially performed as they guide diagnostic and therapeutic interventions and also direct the use of oxygen therapy. [20],[21],[22]

A formal cardiopulmonary exercise testing allows measurement of peak oxygen consumption, exercise gas exchange and dead space ventilation in patients with early ILD with minimal or no symptoms and who do not demonstrate significant oxygen desaturation while undergoing a 6-min walk test. [20],[21],[22]

Bronchoscopy

FOB with BAL or TBLBs may substantiate specific diagnoses in some patients (e.g., sarcoidosis, LCG, LAM, CEP, COP [provided the clinical context is appropriate]). BAL may be adequate to diagnose specific infections (e.g., tuberculosis, histoplasmosis, coccidioidomycosis, endemic fun-gal infections) and selected non-infectious diseases (e.g., LCG or LAM). Further, BAL cell profiles may narrow the differential diagnosis [Table 7]. Increases in BAL lymphocytes suggest sarcoidosis, HP, or other granulomatous processes. When BAL lymphocytes exceed 50%, HP is likely. Further, marked increases in BAL eosinophils (25%) strongly suggest acute or CEP. However, mild increases in lymphocytes or eosinophils have no diagnostic value. Increases in neutrophils can be seen in a wide array of fibrotic disorders as well as bacterial pneumonia. Due to small sample size and sampling variability, BAL and TBBs cannot establish the diagnosis of IPF or IIPs. [26],[27]
Table 7: Bronchoalveolar lavage cell profiles in common ILDs


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SLB

Video-assisted thoracoscopic surgical biopsy should be performed in patients with DPLD when BAL or TBLBs are not definitive (unless specific contraindications exist). [28],[29] Given the potential morbidity (and rarely, mortality) associated with SLB, this procedure is not warranted in debilitated or elderly patients. SLB achieves three purposes: (1) Establishes a precise diagnosis; (2) assesses the extent of inflammation and fibrosis; (3) identifies a histopathological pattern (i.e., in the context of IIP). In the setting of IIPs, distinguishing non-specific interstitial pneumonia from usual interstitial pneumonia may be difficult, even with experienced pulmonary pathologists. Hence, when SLB is performed in patients with ILD, at least two biopsies should be obtained from different lobes to assure diagnostic accuracy. [28],[29],[30]


  Classification of Disease Behavior Top


After a complete diagnostic evaluation, confirmed ILD cases should be classified according to the disease behavior [Table 8]. This classification helps the clinician for guiding the approach of treatment and monitoring an individual patient diagnosed as ILD. [3]
Table 8: Classification of ILD according to disease behavior to decide treatment approach and monitoring strategy


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  Conclusion Top


ILDs are a heterogeneous group of parenchymal lung diseases that vary widely in etiology, pathogenesis, histopathology, clinicoradiologic presentation and clinical course. Diagnosis of these diseases is done by an organized formulation of the clinical evaluation, PFTs, tempo of the disease process and radiologic findings, as well as a selective use of laboratory investigations, serologic tests, echocardiography, bronchoscopy and SLB [Figure 2]. A lung biopsy specimen is required for correlation of histopathologic findings with the clinical context and radiologic findings. I summarize common types of ILD in [Table 9] for better understanding of those disorders. Understanding of these disorders is important to achieve a specific diagnosis to facilitate the optimal management for patients with ILDs.
Figure 2: Diagnostic algorithm of interstitial lung disease. COP = cryptogenic organizing pneumonia, HP = hypersensitivity pneumonitis, LAM = lymphangioleiomyomatosis, MDD = multidisciplinary discussion, NSIP = nonspecific interstitial pneumonia, IPF = idiopathic pulmonary fibrosis, SLB = surgical lung biopsy

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Table 9: Summary of diagnostic clues for some common types of ILD


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  References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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