Skip to content
Tue. May 26th, 2026
NEWNMCLE
WE ACCEPT KHALTI PAYMENT [NOTE:FOLLOW THE TEXTBOOK]
Home
SKILL TEST
All Products
Test Hall
Class Room
Syllabus for medical officer PSC
MEDICAL
MBBS ENTRANCE TIPS
IOM/MOE/KU SYLLABUS
Syllabus
TSC
Syllabus of Primary Level Teaching License
Syllabus of Secondary Level Teaching License
mode
Audio
stories
App
Contact Us
Login
Sign Up
Interstitial Lung Diseases: Introduction Patients with interstitial lung diseases (ILDs) come to medical attention mainly because of the onset of progressive exertional dyspnea or a persistent nonproductive cough. Hemoptysis, wheezing, and chest pain may be present. Often, the identification of interstitial opacities on chest x-ray focuses the diagnostic approach on one of the ILDs. ILDs represent a large number of conditions that involve the parenchyma of the lung—the alveoli, the alveolar epithelium, the capillary endothelium, and the spaces between those structures—as well as the perivascular and lymphatic tissues. The disorders in this heterogeneous group are classified together because of similar clinical, roentgenographic, physiologic, or pathologic manifestations. These disorders often are associated with considerable rates of morbidity and mortality, and there is little consensus regarding the best management of most of them. ILDs have been difficult to classify because >200 known individual diseases are characterized by diffuse parenchymal lung involvement, either as the primary condition or as a significant part of a multiorgan process, as may occur in the connective tissue diseases (CTDs). One useful approach to classification is to separate the ILDs into two groups based on the major underlying histopathology: (1) those associated with predominant inflammation and fibrosis and (2) those with a predominantly granulomatous reaction in interstitial or vascular areas (Table K-1). Each of these groups can be subdivided further according to whether the cause is known or unknown. For each ILD there may be an acute phase, and there is usually a chronic one as well. Rarely, some are recurrent, with intervals of subclinical disease. Table K-1 Major Categories of Alveolar and Interstitial Inflammatory Lung Disease Lung Response: Alveolitis, Interstitial Inflammation, and Fibrosis Known Cause Asbestos Fumes, gases Drugs (antibiotics, amiodarone, gold) and chemotherapy drugs Radiation Aspiration pneumonia Residual of acute respiratory distress syndrome Smoking-related Desquamative interstitial pneumonia Respiratory bronchiolitis–associated interstitial lung disease Langerhans cell granulomatosis (eosinophilic granuloma of the lung) Unknown Cause Idiopathic interstitial pneumonias Idiopathic pulmonary fibrosis (usual interstitial pneumonia) Acute interstitial pneumonia (diffuse alveolar damage) Cryptogenic organizing pneumonia (bronchiolitis obliterans with organizing pneumonia) Nonspecific interstitial pneumonia Connective tissue diseases Systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis, Sjögren’s syndrome, polymyositis-dermatomyositis Pulmonary hemorrhage syndromes Goodpasture’s syndrome, idiopathic pulmonary hemosiderosis, isolated pulmonary capillaritis Pulmonary alveolar proteinosis Lymphocytic infiltrative disorders (lymphocytic interstitial pneumonitis associated with connective tissue disease) Eosinophilic pneumonias Lymphangioleiomyomatosis Amyloidosis Inherited diseases Tuberous sclerosis, neurofibromatosis, Niemann-Pick disease, Gaucher’s disease, Hermansky-Pudlak syndrome Gastrointestinal or liver diseases (Crohn’s disease, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis) Graft-versus-host disease (bone marrow transplantation; solid organ transplantation) Lung Response: Granulomatous Known Cause Hypersensitivity pneumonitis (organic dusts) Inorganic dusts: beryllium, silica Unknown Cause Sarcoidosis Granulomatous vasculitides Granulomatosis with polyangiitis (Wegener’s), allergic granulomatosis of Churg-Strauss Sarcoidosis Granulomatous vasculitides Granulomatosis with polyangiitis (Wegener’s), allergic granulomatosis of Churg-Strauss Sarcoidosis , idiopathic pulmonary fibrosis (IPF), and pulmonary fibrosis associated with CTDs are the most common ILDs of unknown etiology. Among the ILDs of known cause, the largest group includes occupational and environmental exposures, especially the inhalation of inorganic dusts, organic dusts, and various fumes or gases (Table K-2). A clinical diagnosis is possible for many forms of ILD, especially if an occupational and environmental history is pursued aggressively. High-resolution computed tomography (HRCT) scanning improves the diagnostic accuracy and may eliminate the need for tissue examination in many cases, especially in IPF. For other forms, tissue examination, usually obtained by thoracoscopic lung biopsy, is critical to confirmation of the diagnosis. Table K-2 Estimated Relative Frequency of the Interstitial Lung Diseases Diagnosis Relative Frequency, % Idiopathic interstitial pneumonias 40 Idiopathic pulmonary fibrosis 55 Nonspecific interstitial pneumonia 25 Respiratory bronchiolitis—ILD and desquamative interstitial pneumonia 15 Cryptogenic organizing pneumonia 3 Acute interstitial pneumonia <1 Occupational and environmental 26 Sarcoidosis 10 Connective tissue diseases 9 Drug radiation 1 Pulmonary hemorrhage syndromes <1 Other 13 Pathogenesis The ILDs are nonmalignant disorders not caused by identified infectious agents. The precise pathway(s) leading from injury to fibrosis is known. Although there multiple initiating agent(s) of injury, the immunopathogenic responses lung limited, mechanisms repair have common features (Fig. K-1). Fig. K-1 : Proposed mechanism for pathogenesis pulmonary fibrosis. naturally exposed repetitive a variety exogenous endogenous stimuli. Several local systemic factors (e.g., fibroblasts, circulating fibrocytes, chemokines, growth factors, clotting factors) contribute healing functional recovery. Dysregulation this intricate network through genetic predisposition, autoimmune conditions, or superimposed diseases can lead aberrant wound healing, with result Alternatively, excessive may overwhelm even intact reparative fibrosis. As mentioned above, two major histopathologic patterns granulomatous pattern in which inflammation predominate. Granulomatous Lung Disease This process characterized an accumulation T lymphocytes, macrophages, epithelioid cells organized into discrete structures (granulomas) parenchyma. lesions progress Many patients disease remain free severe impairment function or, when symptomatic, improve after treatment. main differential diagnosis between sarcoidosis hypersensitivity pneumonitis . Inflammation Fibrosis The initial insult epithelial surface that causes air spaces alveolar walls K-2). If becomes chronic, spreads adjacent portions interstitium vasculature eventually interstitial Important found include usual pneumonia (UIP), nonspecific pneumonia, respiratory bronchiolitis desquamative organizing diffuse damage (acute organizing), lymphocytic pneumonia. development irreversible scarring (fibrosis) walls, airways, most feared outcome all these conditions because it often progressive leads significant derangement ventilatory gas exchange. Fig. K-2 Cellular basis disease. Multiple microinjuries activate (top left), turn induce antifibrinolytic environment spaces, enhancing clot formation. Alveolar secrete migration proliferation fibroblasts differentiation myofibroblasts (bottom left). Subepithelial produce gelatinases increase basement membrane disruption allow fibroblast–myofibroblast right). Angiogenic neovascularization. Both intraalveolar extracellular matrix proteins, mainly collagens. An imbalance collagenases inhibitors metalloproteinases provokes deposit Signals responsible myofibroblast apoptosis seem be absent delayed increasing cell survival. Myofibroblasts angiotensinogen that, as angiotensinII, death, further impairing reepithelialization. Abbreviations: FGF-2, fibroblast factor 2; MMPs, metalloproteinases; PAI-1, PAI-2, plasminogen activator inhibitor 1, PDGF, platelet-derived factor; TGF-β, transforming β; TIMPs, TNF-α, tumor necrosis α; VEGF, vascular endothelial factor. History Duration Illness Acute presentation (days weeks), although unusual, occurs allergy (drugs, fungi, helminths), acute (AIP), eosinophilic pneumonitis. These confused atypical pneumonias opacities on chest x-ray. Subacute (weeks months) occur but seen especially sarcoidosis, drug-induced ILDs, syndromes, cryptogenic (COP), immunologic complicates lupus erythematosus (SLE) polymyositis. In symptoms signs form chronic (months years). Examples IPF, Langerhans histiocytosis (PLCH) (also known granulomatosis, granuloma, X), pneumoconioses, CTDs. Episodic presentations unusual pneumonitis, COP, vasculitides, hemorrhage, Churg-Strauss syndrome. Age Most ILD associated CTD, lymphangioleiomyomatosis (LAM), PLCH, inherited forms (familial Gaucher’s disease, Hermansky-Pudlak syndrome) present ages 20 40 years. Most IPF older than 60 years. Gender LAM involvement tuberous sclerosis exclusively premenopausal women. addition, syndrome CTDs more women; exception rheumatoid arthritis (RA), men. Because occupational exposures, pneumoconioses also frequently men. Family History Familial has been mutations three genes: surfactant protein Cgene, A2 gene, ATP-binding cassette transporter A3 gene. Familial several including UIP. Older age, male sex, history cigarette smoking risk familial Family associations (with autosomal dominant pattern) neurofibromatosis. clustering increasingly sarcoidosis. genes rare identified, i.e., microlithiasis, syndrome, Niemann-Pick along homeostasis proteinosis control LAM. Smoking History Two-thirds 75% smoking. Patients (DIP), Goodpasture’s bronchiolitis, usually current former smokers. Occupational Environmental History A strict chronologic listing patient’s lifelong employment must sought, specific duties exposures. , symptoms, fever, chills, abnormal roentgenogram temporally related hobby (pigeon breeder’s disease) workplace (farmer’s lung) . Symptoms diminish disappear patient leaves site exposure days; similarly, reappear returns site. Other Past History Parasitic infections cause eosinophilia, therefore travel should taken suspected ILD. History HIV infection elicited processes at time during clinical course, e.g., infection, AIP, hemorrhage. Respiratory Signs Dyspnea prominent complaint ILD, idiopathic pneumonias, PLCH. Some patients, silicosis, lipoid lymphangitis carcinomatosis, extensive parenchymal x-ray without dyspnea, early course illness. Wheezing uncommon manifestation described Clinically pain ILDs. However, substernal discomfort Sudden worsening if pain, indicate spontaneous pneumothorax, sclerosis, LAM, Frank hemoptysis blood-streaked sputum rarely presenting manifestations (DAH) vasculitides. Fatigue weight loss ILDs. Physical Examination The findings specific. commonly, physical examination reveals tachypnea bibasilar end-inspiratory dry crackles, less likely heard diseases. Crackles absence radiographic abnormalities radiograph. Scattered late inspiratory high-pitched rhonchi—so-called squeaks—are bronchiolitis. cardiac normal except middle stages hypertension cor pulmonale become evident Cyanosis clubbing digits some advanced disease. Laboratory Antinuclear antibodies anti-immunoglobulin (rheumatoid defined CTD. A raised lactate dehydrogenase (LDH) level finding Elevation serum angiotensin-converting enzyme Serum precipitins confirm suspected, they diagnostic process. Antineutrophil cytoplasmic anti-basement useful vasculitis suspected. electrocardiogram unless present; then demonstrates right-axis deviation, right ventricular hypertrophy, atrial enlargement hypertrophy. Echocardiography dilation hypertrophy presence hypertension. Chest Imaging Studies Chest X-Ray ILD first radiograph, commonly reticular pattern. nodular mixed filling increased markings present. subgroup exhibit predilection upper zones [sarcoidosis, berylliosis, RA (necrobiotic form), ankylosing spondylitis]. correlates poorly stage honeycombing pathologic small cystic fibrosis; present, portends poor prognosis. cases, radiograph does diagnosis. Computed Tomography High-resolution computed tomography superior plain detection confirmation K-3). HRCT allows better assessment extent distribution investigation Coexisting best recognized scanning, mediastinal adenopathy, carcinoma, emphysema. appropriate setting sufficiently characteristic preclude need biopsy asbestosis, lymphangitic When required, scanning determining area samples taken. Fig. K-3 Idiopathic High-resolution CT image shows bibasal, peripheral predominant abnormality traction bronchiectasis honeycombing. showed typical pneumonia. Pulmonary Function Testing Spirometry Volumes Measurement important assessing restrictive defect reduced total capacity (TLC), residual capacity, volume Forced expiratory one second (FEV1) forced vital (FVC) reduced, changes decreased TLC. FEV1 FVC ratio increased. volumes decrease stiffness worsens progression. few obstructive airflow limitation testing (uncommon LAM). Pulmonary studies proved prognostic value particularly (NSIP). Diffusing Capacity A reduction diffusing carbon monoxide (DlCO) This due part effacement capillary units but, important, mismatching ventilation perfusion (V. Q.). regions compliance either cellular infiltration ventilated still maintain adequate blood flow, ventilation-perfusion mismatch acts like true venous admixture. severity DlCO correlate stage. Arterial Blood Gas The resting arterial revealhypoxemia (secondary perfusion) alkalosis. O2 tension (or saturation oximetry) rest rule out exercise sleep. Carbon dioxide (CO2) retention end-stage disease. Cardiopulmonary Exercise Testing Because always exercise-induced go undetected, perform measurement gases detect exchange. Arterial oxygen desaturation, failure dead space appropriately [i.e., high Vd Vt (dead tidal volume) ratio], rate lower expected recruitment provide information about physiologic Serial exchange excellent method following activity responsiveness treatment, IPF. Increasingly, 6-min walk test used obtain global evaluation submaximal distance desaturation tend baseline mirror course. Fiberoptic Bronchoscopy Bronchoalveolar Lavage (BAL) In selected DAH cancer, proteinosis), analysis BAL fluid narrowing possibilities among various types (Table role defining progression response therapy remains understood, usefulness management established. Table Diagnostic Value Interstitial Disease Condition Bronchoalveolar Finding Sarcoidosis Lymphocytosis; CD4:CD8>3.5 most specific of diagnosis Hypersensitivity pneumonitis Marked lymphocytosis (>50%) Organizing pneumonia Foamy macrophages; mixed pattern of increased cells characteristic; decreased CD4:CD8 ratio Eosinophilic lung disease Eosinophils >25% Diffuse alveolar bleeding Hemosiderin-laden macrophages, red blood cells Diffuse alveolar damage, drug toxicity Atypical hyperplastic type II pneumocytes Opportunistic infections Pneumocystis carinii, fungi, cytomegalovirus-transformed cells Lymphangitic carcinomatosis, alveolar cell carcinoma, pulmonary lymphoma Malignant cells Alveolar proteinosis Milky effluent, foamy macrophages and lipoproteinaceous intraalveolar material (periodic acid–Schiff stain–positive) Lipoid pneumonia Fat globules in macrophages Pulmonary Langerhans cell histiocytosis Increased CD1+ Langerhans cells, electron microscopy demonstrating Birbeck granule in lavaged macrophage (expensive and difficult to perform) Asbestos-related pulmonary disease Dust particles, ferruginous bodies Berylliosis Positive lymphocyte transformation test to beryllium Silicosis Dust particles by polarized light microscopy Lipoidosis Accumulation of specific lipopigment in alveolar macrophages Tissue and Cellular Examination Lung biopsy is the most effective method for confirming the diagnosis and assessing disease activity. The findings may identify a more treatable process than originally suspected, particularly chronic hypersensitivity pneumonitis, COP, respiratory bronchiolitis–associated ILD, or sarcoidosis. Biopsy should be obtained before the initiation of treatment. A definitive diagnosis avoids confusion and anxiety later in the clinical course if the patient does not respond to therapy or experiences serious side effects from it. Fiberoptic bronchoscopy with multiple transbronchial lung biopsies (four to eight biopsy samples) is often the initial procedure of choice, especially when sarcoidosis, lymphangitic carcinomatosis, eosinophilic pneumonia, Goodpasture’s syndrome, or infection is suspected. If a specific diagnosis is not made by transbronchial biopsy, surgical lung biopsy by video-assisted thoracic surgery or open thoracotomy is indicated. Adequate-sized biopsies from multiple sites, usually from two lobes, should be obtained. Relative contraindications to lung biopsy include serious cardiovascular disease, honeycombing and other roentgenographic evidence of diffuse end-stage disease, severe pulmonary dysfunction, and other major operative risks, especially in the elderly. Treatment: Interstitial Lung Disease Although the course of ILD is variable, progression is common and often insidious. All treatable possibilities should be carefully considered. Since therapy does not reverse fibrosis, the major goals of treatment are permanent removal of the offending agent, when known, and early identification and aggressive suppression of the acute and chronic inflammatory process, thereby reducing further lung damage. Hypoxemia (PaO2 <55 mmHg) at rest andor with exercise should be managed supplemental oxygen. Management of cor pulmonale may required as the disease progresses . Pulmonary rehabilitation has been shown to improve quality life in patients ILD. Drug Therapy Glucocorticoids are mainstay therapy for suppression alveolitis present ILD, but success rate is low. There have no placebo-controlled trials glucocorticoids so there direct evidence that steroids survival many diseases which they commonly used. Glucocorticoid recommended symptomatic ILD eosinophilic pneumonias, COP, CTD, sarcoidosis, hypersensitivity pneumonitis, acute inorganic dust exposures, radiation DAH, drug-induced ILD. In organic disease, both chronic stages. The optimal dose proper length treatment most ILDs not known. A common starting prednisone, 0.5–1 mg kg a once-daily oral (based on patient’s lean body weight). This continued 4–12 weeks, time patient reevaluated. If stable improved, tapered 0.25–0.5 maintained this level an additional depending course. Rapid tapering shortened course glucocorticoid can result recurrence. condition continues decline glucocorticoids, second agent (see below) often added prednisone lowered 0.25 perd. Cyclophosphamide azathioprine (1–2 weight day), without tried variable IPF, vasculitis, progressive systemic sclerosis, other ILDs. An objective response usually requires least 8–12 weeks occur. situations these drugs failed could tolerated, agents, including methotrexate, colchicine, penicillamine, cyclosporine, tried. However, their role remainsdetermined. Many cases irreversible despite discussed above, lung transplantation then considered . Individual Forms ILD Idiopathic Fibrosis IPF form idiopathic interstitial pneumonia. Separating IPF from forms fibrosis important step evaluation all presenting distinctly poor bad prognosis. Clinical Manifestations Exertional dyspnea, nonproductive cough, inspiratory crackles digital clubbing physical examination. HRCT scans typically show patchy, predominantly basilar, subpleural reticular opacities, associated traction bronchiectasis honeycombing (Fig. K-3).Atypical findings suggest alternative diagnosis include extensiveground-glass abnormality, nodular upper midzone predominance, prominent hilar mediastinal lymphadenopathy. function tests reveal restrictive pattern, reduced DlCO, arterial hypoxemia exaggerated elicited by exercise. Histologic Findings Confirmation presence UIP pattern histologic examination essential confirm diagnosis. Transbronchial biopsies helpful making UIP, surgical biopsy required. The hallmark chief diagnostic criterion heterogeneous appearance low magnification alternating areas normal lung, inflammation, foci proliferating fibroblasts, dense collagenfibrosis, honeycomb changes. These changes affect peripheral, parenchyma severely. inflammation patchy consists lymphoplasmacytic infiltrate alveolar septa, hyperplasia type 2 pneumocytes. fibrotic zones composed mainly collagen, although scattered fibroblasts consistent finding. extent fibroblastic proliferation predictive progression. Areas change cystic air spaces frequently lined bronchiolar epithelium filled mucin. Smooth-muscle seen change. some features similar found stage several specific disorders, such pneumoconioses (e.g., asbestosis), injury, certain nitrofurantoin), aspiration, organized pneumonia, PLCH. Commonly, histopathologic situations, thus allowing separation lesions UIP-like pattern. Consequently, term usual pneumonia used whom lesion another condition. Treatment: Issues Patients Ipf Untreated progression high mortality rate. effective IPF. Chronic microaspiration secondary gastroesophageal reflux play pathogenesis natural history coexisting emphysema [combined pulmonary (CPFE)] more likely require long-term oxygen develop hypertension dismal outcome than those emphysema. Patients deterioration infections, embolism, pneumothorax. Heart failure ischemic heart problems accounting nearly one-third deaths. also experience accelerated phase rapid clinical prognosis (so-called exacerbations IPF). defined worsening dyspnea within few days 4 weeks; newly developing diffuse abnormality consolidation superimposed background pattern; hypoxemia; absence infectious failure, sepsis. ranges 10–57%, apparently follow-up. During episodes, damage UIP. No management Often mechanical ventilation required, it successful, hospital up three-fourths patients. who survive, recurrence exacerbation results death times. Lung medical meet established criteria. Nonspecific Interstitial Pneumonia This defines subgroup pneumonias distinguished clinically pathologically DIP, AIP, BOOP. Importantly, occur context underlying disorder, connective tissue pneumonitis. Patients NSIP clinical, serologic, radiographic, pathologic characteristics highly suggestive autoimmune criteria undifferentiated disease. Idiopathic subacute process presentation younger age, women never smoked. It febrile illness. shows bilateral, lower lobe volume loss K-4). Patchy airspace abnormalities present, unusual. key feature uniformity involvement across section, cellular fibrosing. less temporal spatial heterogeneity little found. variant rare. Unlike (UIP), majority good (5-year estimated <15%), showing improvement after combination azathioprine. Fig. K-4 : Nonspecific High-resolution CT through bronchiectasis. sparing immediately adjacent pleura. Histology showed mild fibrosis. Acute Pneumonia (Hamman-Rich Syndrome) AIP rare, fulminant injury characterized histologically biopsy. Most older 40 years. AIP respiratory distress syndrome (ARDS) probably corresponds subset ARDS. onset abrupt previously healthy individual. prodromal illness, lasting 7–14 before presentation, common. Fever, manifestations presentation. Diffuse, air-space opacification chest radiograph. symmetric attenuation. Bilateral present. distribution seen. ARDS confirmation organizing damage. Therefore, moderate severe failure. Mechanical (>60%), with most patients dying within 6 months of presentation. Recurrences have been reported. However, those who recover often have substantial improvement in lung function. The main treatment is supportive. It is not clear that glucocorticoid therapy is effective. Cryptogenic Organizing Pneumonia COP is a clinicopathologic syndrome of unknown etiology. The onset is usually in the fifth and sixth decades. The presentation may be of a flulike illness with cough, fever, malaise, fatigue, and weight loss. Inspiratory crackles are frequently present on examination. Pulmonary function is usually impaired, with a restrictive defect and arterial hypoxemia being most common. The roentgenographic manifestations are distinctive, revealing bilateral, patchy, or diffuse alveolar opacities in the presence of normal lung volume. Recurrent and migratory pulmonary opacities are common. HRCT shows areas of air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening and dilation. These changes occur more frequently in the periphery of the lung and in the lower lung zone. Lung biopsy shows granulation tissue within small airways, alveolar ducts, and airspaces, with chronic inflammation in the surrounding alveoli. Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids. Foci of organizing pneumonia is a nonspecific reaction to lung injury found adjacent to other pathologic processes or as a component of other primary pulmonary disorders [e.g., cryptococcosis, granulomatosis with polyangiitis (Wegener’s), lymphoma, hypersensitivity pneumonitis, and eosinophilic pneumonia]. Consequently, the clinician must carefully reevaluate any patient found to have this histopathologic lesion to rule out these possibilities. ILD Associated with Cigarette Smoking Desquamative Interstitial Pneumonia DIP is a rare but distinct clinical and pathologic entity found almost exclusively in cigarette smokers. The histologic hallmark is the extensive accumulation of macrophages in intraalveolar spaces with minimal interstitial fibrosis. The peak incidence is in the fourth and fifth decades. Most patients present with dyspnea and cough. Lung function testing shows a restrictive pattern with reduced DlCO and arterial hypoxemia. The chest x-ray and HRCT scans usually show diffuse hazy opacities. Clinical recognition of DIP is important because the process is associated with a better prognosis (10-year survival rate is ~70%) in response to smoking cessation. There are no clear data showing that systemic glucocorticoids are effective in DIP. Respiratory Bronchiolitis–Associated ILD Respiratory bronchiolitis–associated ILD (RB-ILD) is considered to be a subset of DIP and is characterized by the accumulation of macrophages in peribronchial alveoli. The clinical presentation is similar to that of DIP. Crackles are often heard on chest examination and occur throughout inspiration; sometimes they continue into expiration. The process is best seen on HRCT lung scanning, which shows bronchial wall thickening, centrilobularnodules, ground-glass opacity, and emphysema with air trapping. RB-ILD appears to resolve in most patients after smoking cessation alone. Pulmonary Langerhans Cell Histiocytosis This is a rare, smoking-related, diffuse lung disease that primarily affects men between the ages of 20 and 40 years. The clinical presentation varies from an asymptomatic state to a rapidly progressive condition. The most common clinical manifestations at presentation are cough, dyspnea, chest pain, weight loss, and fever. Pneumothorax occurs in ~25% of patients. Hemoptysis and diabetes insipidus are rare manifestations. The radiographic features vary with the stage of the disease. The combination of ill-defined or stellate nodules (2–10 mm in diameter), reticular or nodular opacities, bizarre-shaped upper zone cysts, preservation of lung volume, and sparing of the costophrenic angles are characteristics of PLCH. HRCT that reveals a combination of nodules and thin-walled cysts is virtually diagnostic of PLCH. The most common pulmonary function abnormality is a markedly reduced DlCO, although varying degrees of restrictive disease, airflow limitation, and diminished exercise capacity may occur. The characteristic histopathologic finding in PLCH is the presence of nodular sclerosing lesions that contain Langerhans cells accompanied by mixed cellular infiltrates. The nodular lesions are poorly defined and are distributed in a bronchiolocentric fashion with intervening normal lung parenchyma. As the disease advances, fibrosis progresses to involve adjacent lung tissue, leading to pericicatricial air space enlargement, which accounts for the concomitant cystic changes. Discontinuance of smoking is the key treatment, resulting in clinical improvement in one-third of patients. Most patients with PLCH experience persistent or progressive disease. Death due to respiratory failure occurs in ~10% of patients. ILD Associated with Connective Tissue Disorders Clinical findings suggestive of a CTD (musculoskeletal pain, weakness, fatigue, fever, joint pain or swelling, photosensitivity, Raynaud’s phenomenon, pleuritis, dry eyes, dry mouth) should be sought in any patient with ILD. The CTDs may be difficult to rule out since the pulmonary manifestations occasionally precede the more typical systemic manifestations by months or years. The most common form of pulmonary involvement is the nonspecific interstitial pneumonia histopathologic pattern. However, determining the precise nature of lung involvement in most of the CTDs is difficult due to the high incidence of lung involvement caused by disease-associated complications of esophageal dysfunction (predisposing to aspiration and secondary infections), respiratory muscle weakness (atelectasis and secondary infections), complications of therapy (opportunistic infections), and associated malignancies. Progressive Systemic Sclerosis (Pss) Clinical evidence of ILD is present in about one-half of patients with PSS, and pathologic evidence in three-quarters. Pulmonary function tests show a restrictive pattern and impaired diffusing capacity, often before any clinical or radiographic evidence of lung disease appears. Pulmonary vascular disease alone or in association with pulmonary fibrosis, pleuritis, or recurrent aspiration pneumonitis is strikingly resistant to current modes of therapy. Rheumatoid Arthritis ILD associated with RA is more common in men. Pulmonary manifestations of RA include pleurisy with or without effusion, ILD in up to 20% of cases, necrobiotic nodules (nonpneumoconiotic intrapulmonary rheumatoid nodules) with or without cavities, Caplan’s syndrome (rheumatoid pneumoconiosis), pulmonary hypertension secondary to rheumatoid pulmonary vasculitis, organized pneumonia, and upper airway obstruction due to crico-arytenoid arthritis. Systemic Lupus Erythematosus Lung disease is a common complication in SLE. Pleuritis with or without effusion is the most common pulmonary manifestation. Other lung manifestations include the following: atelectasis, diaphragmatic dysfunction with loss of lung volumes, pulmonary vascular disease, pulmonary hemorrhage, uremic pulmonary edema, infectious pneumonia, and organized pneumonia. Acute lupus pneumonitis characterized by pulmonary capillaritis leading to alveolar hemorrhage is uncommon. Chronic, progressive ILD is uncommon. It is important to exclude pulmonary infection. Although pleuropulmonary involvement may not be evident clinically, pulmonary function testing, particularly DlCO, reveals abnormalities in many patients with SLE. Polymyositis and Dermatomyositis (PM/DM) ILD occurs in ~10% of patients with PM/DM. Diffuse reticular or nodular opacities with or without an alveolar component occur radiographically, with a predilection for the lung bases. ILD occurs more commonly in the subgroup of patients with an anti-Jo-1 antibody that is directed to histidyl tRNA synthetase. Weakness of respiratory muscles contributing to aspiration pneumonia may be present. A rapidly progressive illness characterized by diffuse alveolar damage may cause respiratory failure. Sjögren’s Syndrome General dryness and lack of airway secretion cause the major problems of hoarseness, cough, and bronchitis. Lymphocytic interstitial pneumonitis, lymphoma, pseudolymphoma, bronchiolitis, and bronchiolitis obliterans are associated with this condition. Lung biopsy is frequently required to establish a precise pulmonary diagnosis. Glucocorticoids have been used in the management of ILD associated with Sjögren’s syndrome with some degree of clinical success. Drug-Induced ILD Many classes of drugs have the potential to induce diffuse ILD, which is manifest most commonly as exertional dyspnea and nonproductive cough. A detailed history of the medications taken by the patient is needed to identify drug-induced disease, including over-the-counter medications, oily nose drops, and petroleum products (mineral oil). In most cases, the pathogenesis is unknown, although a combination of direct toxic effects of the drug (or its metabolite) and indirect inflammatory and immunologic events are likely. The onset of the illness may be abrupt and fulminant, or it may be insidious, extending over weeks to months. The drug may have been taken for several years before a reaction develops (e.g., amiodarone), or the lung disease may occur weeks to years after the drug has been discontinued (e.g., carmustine). The extent and severity of disease are usually dose-related. Treatment consists of discontinuation of any possible offending drug and supportive care. Eosinophilic Pneumonia Pulmonary Alveolar Proteinosis (Pap) Although not strictly an ILD, PAP resembles and is therefore considered with these conditions. It has been proposed that a defect in macrophage function, more specifically an impaired ability to process surfactant, may play a role in the pathogenesis of PAP. This diffuse disease is characterized by the accumulation of an amorphous, periodic acid–Schiff-positive lipoproteinaceous material in the distal air spaces. There is little or no lung inflammation, and the underlying lung architecture is preserved. PAP is an autoimmune disease with a neutralizing antibody of immunoglobulin G isotype against granulocyte-macrophage colony-stimulating factor (GM-CSF). These findings suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance. There are three distinct classes of PAP: acquired (>90% of all cases), congenital, and secondary. Congenital PAP is transmitted in an autosomal recessive manner and is caused by homozygosity for a frameshift mutation (121ins2) in the SP-B gene, which leads to an unstable SP-B mRNA, reduced protein levels, and secondary disturbances of SP-C processing. Secondary PAP is rare among adults and is caused by lysinuric protein intolerance, acute silicosis and other inhalational syndromes, immunodeficiency disorders, and malignancies (almost exclusively of hematopoietic origin) and hematopoietic disorders. The typical age of presentation is 30–50 years, and males predominate. The clinical presentation is usually insidious and is manifested by progressive exertional dyspnea, fatigue, weight loss, and low-grade fever. A nonproductive cough is common, but occasionally expectoration of “chunky” gelatinous material may occur. Polycythemia, hypergammaglobulinemia, and increased LDH levels are common. Markedly elevated serum levels of lung surfactant proteins A and D have been found in PAP. In the absence of any known secondary cause of PAP, an elevated serum anti-GM-CSF titer is highly sensitive and specific for the diagnosis of acquired PAP. BAL fluid levels of anti-GM-CSF antibodies correlate better with the severity of PAP than do serum titers. Radiographically, bilateral symmetric alveolar opacities located centrally in middle and lower lung zones result in a “bat-wing” distribution. HRCT shows a ground-glass opacification and thickened intralobular structures and interlobular septa. Whole-lung lavage(s) through a double-lumen endotracheal tube provides relief to many patients with dyspnea or progressive hypoxemia and also may provide long-term benefit. Pulmonary Lymphangioleiomyomatosis Pulmonary LAM is a rare condition that afflicts premenopausal women and should be suspected in young women with “emphysema,” recurrent pneumothorax, or chylous pleural effusion. It is often misdiagnosed as asthma or chronic obstructive pulmonary disease. Pathologically, LAM is characterized by the proliferation of atypical pulmonary interstitial smooth muscle and cyst formation. The immature-appearing smooth-muscle cells react with monoclonal antibody HMB45, which recognizes a 100-kDa glycoprotein (gp100) originally found in human melanoma cells. Whites are affected much more commonly than are members of other racial groups. The disease accelerates during pregnancy and abates after oophorectomy. Common complaints at presentation are dyspnea, cough, and chest pain. Hemoptysis may be life threatening. Spontaneous pneumothorax occurs in 50% of patients; it may be bilateral and necessitate pleurodesis. Meningioma and renal angiomyolipomas (hamartomas), characteristic findings in the genetic disorder tuberous sclerosis, are also common in patients with LAM. Chylothorax, chyloperitoneum (chylous ascites), chyluria, and chylopericardium are other complications. Pulmonary function testing usually reveals an obstructive or mixed obstructive-restrictive pattern, and gas exchange is often abnormal. HRCT shows thin-walled cysts surrounded by normal lung without zonal predominance. Progression is common, with a median survival of 8–10 years from diagnosis. No therapy is of proven benefit in LAM. Progesterone (10 mg/d), luteinizing hormone–releasing hormone analogues, and sirolimus have been used. Oophorectomy is no longer recommended, and estrogen-containing drugs should be discontinued. Lung transplantation offers the only hope for cure despite reports of recurrent disease in the transplanted lung. Syndromes of Ild with Diffuse Alveolar Hemorrhage Injury to arterioles, venules, and the alveolar septal (alveolar wall or interstitial) capillaries can result in hemoptysis secondary to disruption of the alveolar-capillary basement membrane. This results in bleeding into the alveolar spaces, which characterizes DAH. Pulmonary capillaritis, characterized by a neutrophilic infiltration of the alveolar septae, may lead to necrosis of these structures, loss of capillary structural integrity, and the pouring of red blood cells into the alveolar space. Fibrinoid necrosis of the interstitium and red blood cells within the interstitial space are sometimes seen. Bland pulmonary hemorrhage (i.e., DAH without inflammation of the alveolar structures) also may occur. The clinical onset is often abrupt, with cough, fever, and dyspnea. Severe respiratory distress requiring ventilatory support may be evident at initial presentation. Although hemoptysis is expected, it can be absent at the time of presentation in one-third of the cases. For patients without hemoptysis, new alveolar opacities, a falling hemoglobin level, and hemorrhagic BAL fluid point to the diagnosis. The chest radiograph is nonspecific and most commonly shows new patchy or diffuse alveolar opacities. Recurrent episodes of DAH may lead to pulmonary fibrosis, resulting in interstitial opacities on the chest radiograph. An elevated white blood cell count and falling hematocrit are common. Evidence for impaired renal function caused by focal segmental necrotizing glomerulonephritis, usually with crescent formation, also may be present. Varying degrees of hypoxemia may occur and are often severe enough to require ventilatory support. DlCO may be increased, resulting from the increased hemoglobin within the alveoli compartment. Evaluation of either lung or renal tissue by immunofluorescent techniques indicates an absence of immune complexes (pauci-immune) in granulomatosis with polyangiitis (Wegener’s), microscopic polyangiitis pauci-immune glomerulonephritis, and isolated pulmonary capillaritis. A granular pattern is found in the CTDs, particularly SLE, and a characteristic linear deposition is found in Goodpasture’s syndrome. Granular deposition of IgA-containing immune complexes is present in Henoch-Schönlein purpura. The mainstay of therapy for the DAH associated with systemic vasculitis, CTD, Goodpasture’s syndrome, and isolated pulmonary capillaritis is IV methylprednisolone, 0.5–2 g daily in divided doses for up to 5 days, followed by a gradual tapering, and then maintenance on an oral preparation. Prompt initiation of therapy is important, particularly in the face of renal insufficiency, since early initiation of therapy has the best chance of preserving renal function. The decision to start other immunosuppressive therapy (cyclophosphamide or azathioprine) acutely depends on the severity of illness. Goodpasture’s Syndrome Pulmonary hemorrhage and glomerulonephritis are features in most patients with this disease. Autoantibodies to renal glomerular and lung alveolar basement membranes are present. This syndrome can present and recur as DAH without an associated glomerulonephritis. In such cases, circulating anti-basement membrane antibody is often absent, and the only way to establish the diagnosis is by demonstrating linear immunofluorescence in lung tissue. The underlying histology may be bland hemorrhage or DAH associated with capillaritis. Plasmapheresis has been recommended as adjunctive treatment. Inherited Disorders Associated with ILD Pulmonary opacities and respiratory symptoms typical of ILD can develop in related family members and in several inherited diseases. These diseases include the phakomatoses, tuberous sclerosis and neurofibromatosis (Chap. 379), and the lysosomal storage diseases, Niemann-Pick disease and Gaucher disease (Chap. 361). The Hermansky-Pudlak syndrome is an autosomal recessive disorder in which granulomatous colitis and ILD may occur. It is characterized by oculocutaneous albinism, bleeding diathesis secondary to platelet dysfunction, and the accumulation of a chromolipid, lipofuscin material in cells of the reticuloendothelial system. A fibrotic pattern is found on lung biopsy, but the alveolar macrophages may contain cytoplasmic ceroid-like inclusions. ILD with a Granulomatous Response in Lung Tissue or Vascular Structures Inhalation of organic dusts, which cause hypersensitivity pneumonitis, or of inorganic dust, such as silica, which elicits a granulomatous inflammatory reaction leading to ILD, produces diseases of known etiology (Table K-1) . Sarcoidosis is prominent among granulomatous diseases of unknown cause in which ILD is an important feature. Granulomatous Vasculitides The granulomatous vasculitides are characterized by pulmonary angiitis (i.e., inflammation and necrosis of blood vessels) with associated granuloma formation (i.e., infiltrates of lymphocytes, plasma cells, epithelioid cells, or histiocytes, with or without the presence of multinucleated giant cells, sometimes with tissue necrosis). The lungs are almost always involved, although any organ system may be affected. Granulomatosis with polyangiitis (Wegener’s) and allergic angiitis and granulomatosis (Churg-Strauss syndrome) primarily affect the lung but are associated with a systemic vasculitis as well. The granulomatous vasculitides generally limited to the lung include necrotizing sarcoid granulomatosis and benign lymphocytic angiitis and granulomatosis. Granulomatous infection and pulmonary angiitis due to irritating embolic material (e.g., talc) are important known causes of pulmonary vasculitis. Lymphocytic Infiltrative Disorders This group of disorders features lymphocyte and plasma cell infiltration of the lung parenchyma. The disorders either are benign or can behave as low-grade lymphomas. Included are angioimmunoblastic lymphadenopathy with dysproteinemia, a rare lymphoproliferative disorder characterized by diffuse lymphadenopathy, fever, hepatosplenomegaly, and hemolytic anemia, with ILD in some cases. Lymphocytic Interstitial Pneumonitis This rare form of ILD occurs in adults, some of whom have an autoimmune disease or dysproteinemia. It has been reported in patients with Sjögren’s syndrome and HIV infection. Lymphomatoid Granulomatosis This multisystem disorder of unknown etiology is an angiocentric malignant (T cell) lymphoma characterized by a polymorphic lymphoid infiltrate, an angiitis, and granulomatosis. Although it may affect virtually any organ, it is most frequently characterized by pulmonary, skin, and central nervous system involvement. Bronchocentric Granulomatosis Rather than a specific clinical entity, bronchocentric granulomatosis (BG) is a descriptive histologic term that is applied to an uncommon and nonspecific pathologic response to a variety of airway injuries. There is evidence that BG is caused by a hypersensitivity reaction to Aspergillus or other fungi in patients with asthma. About one-half of the patients described have had chronic asthma with severe wheezing and peripheral blood eosinophilia. In patients with asthma, BG probably represents one pathologic manifestation of allergic bronchopulmonary aspergillosis or another allergic mycosis. In patients without asthma, BG has been associated with RA and a variety of infections, including tuberculosis, echinococcosis, histoplasmosis, coccidioidomycosis, and nocardiosis. The chest roentgenogram reveals irregularly shaped nodular or mass lesions with ill-defined margins, which are usually unilateral and solitary, with upper lobe predominance. Glucocorticoids are the treatment of choice, often with an excellent outcome, although recurrences may occur as therapy is tapered or stopped. Global Considerations Limited epidemiologic data exist describing the prevalence or incidence of ILD in the general population. With a few exceptions, e.g., sarcoidosis and certain occupational and environmental exposures, there appear to be no significant differences in the prevalence or incidence of ILD among various populations. For sarcoidosis, there are important environmental, racial, and genetic differences .
error:
Content is protected !!