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Diffuse Parenchymal Lung Disease including occupations, home environment, hobbies, and cur patients with minimal disease, and a normal chest radiograph rent and past medications, as well as over the counter supple- does not rule out DPLD. ments. A history of radiation therapy, a family history of lung Patients for whom a DPLD is suspected should undergo disease or connective tissue disease (CTD), and suggestive complete pulmonary function testing, including lung volume symptoms of CTD should be explored. testing with plethysmography or nitrogen diffusion and Dlco Lung examination findings can range from a normal measurement. The vast majority of DPLDs have restrictive auscultatory examination to the presence of inspiratory Velcro physiologr, although some diseases may exhibit obstructive or crackles or an inspiratory squawk suggestive of fibrosis. mixed obstructive and restrictive deficits. Extrapulmonary examination findings of associated CTD, such TEY POIilTS as joint deformities or Gottron papules, may direct the clini- o The most common presentation of a diffuse parenchymal cian to the cause of the DPLD. Advanced disease may be com- plicated by pulmonary hypertension and cor pulmonale, with lung disease is subacute to chronic exertional dyspnea and examination findings of jugular venous distention, peripheral nonproductive cough. edema, and a pronounced pulmonic component of the second o Patients with a clinical suspicion of diffirse parenchymal heart sound. lung disease should undergo complete pulmonary function It is common for patients with DPLD to have normal rest- testing, including lung volumes and Dico measurement. ing pulse oximetry. Desaturation of greater than 4% with . A normal chest radiograph does not rule out DPLD. ambulation is consistent with a diffusion limitation. which is a hallmark of DPLD. Typically, bilateral diffuse reticular and reticulonodular High-Resolution CT Scanning patterns on chest radiography suggest DPLD. The presence of Noncontrast high-resolution CT (HRCT) of the chest is the consolidation, pleural effusions, pleural calcification, bronchi- imaging modality of choice for evaluation of DPLD. Distribution ectasis, or lymphadenopathy may provide clues to discrete of disease and pattern of pulmonary parenchyma involvement etiologies for DPLD. Chest radiograph can be normal in may suggest the underlying diagnosis (Table 16). Addition of

including occupations, home environment, hobbies, and cur patients with minimal disease, and a normal chest radiograph rent and past medications, as well as over the counter supple- does not rule out DPLD. ments. A history of radiation therapy, a family history of lung Patients for whom a DPLD is suspected should undergo disease or connective tissue disease (CTD), and suggestive complete pulmonary function testing, including lung volume symptoms of CTD should be explored. testing with plethysmography or nitrogen diffusion and Dlco Lung examination findings can range from a normal measurement. The vast majority of DPLDs have restrictive auscultatory examination to the presence of inspiratory Velcro physiologr, although some diseases may exhibit obstructive or crackles or an inspiratory squawk suggestive of fibrosis. mixed obstructive and restrictive deficits. Extrapulmonary examination findings of associated CTD, such TEY POIilTS as joint deformities or Gottron papules, may direct the clini- o The most common presentation of a diffuse parenchymal cian to the cause of the DPLD. Advanced disease may be com- plicated by pulmonary hypertension and cor pulmonale, with lung disease is subacute to chronic exertional dyspnea and examination findings of jugular venous distention, peripheral nonproductive cough. edema, and a pronounced pulmonic component of the second o Patients with a clinical suspicion of diffirse parenchymal heart sound. lung disease should undergo complete pulmonary function It is common for patients with DPLD to have normal rest- testing, including lung volumes and Dico measurement. ing pulse oximetry. Desaturation of greater than 4% with . A normal chest radiograph does not rule out DPLD. ambulation is consistent with a diffusion limitation. which is a hallmark of DPLD. Typically, bilateral diffuse reticular and reticulonodular High-Resolution CT Scanning patterns on chest radiography suggest DPLD. The presence of Noncontrast high-resolution CT (HRCT) of the chest is the consolidation, pleural effusions, pleural calcification, bronchi- imaging modality of choice for evaluation of DPLD. Distribution ectasis, or lymphadenopathy may provide clues to discrete of disease and pattern of pulmonary parenchyma involvement etiologies for DPLD. Chest radiograph can be normal in may suggest the underlying diagnosis (Table 16). Addition of TA,BtE 1 6. Patterns of Disease Associated With a Diagnosis of Diffuse Parenchymal Lung Disease Lung Disease lmaging Comments Acute interstitial pneumonia Diffuse ground glass with consolidation lndistinguishable from ARDS but without a risk factor for ARDS Organizing pneumonia Patchy ground glass, alveolar consolidation, Connective tissue diseases, infections, peripheral and basal predominance drug-related, or idiopathic ldiopathic pulmonary fibrosis/usual Basal-predominant and peripheral- Usual interstitial pneumonia pattern can interstitial pneumonia predominant septal line thickening with be seen in connective tissue disease, traction bronchiectasis and honeycomb asbestosis, and chronic hypersensitivity changes pneumonitis; idiopathic pulmonary fibrosis is diagnosis of exclusion Nonspecific interstitial pneumonia Ground glass, basal predominance ldiopathic and common finding in connective tissue disease Respiratory bronchiolitis Centrilobular nodules and ground-glass May be an asymptomatic finding in an opacity in an upper-lung-predominant active smoker distribution Desquamative interstitial pneumonia Basal-predominant and peripheral- Most cases are smoking related; chest predominant ground-glass opacity with radiograph may be normal in20"/",but occasional cysts HRCT demonstrates ground-glass opacities

TA,BtE 1 6. Patterns of Disease Associated With a Diagnosis of Diffuse Parenchymal Lung Disease Lung Disease lmaging Comments Acute interstitial pneumonia Diffuse ground glass with consolidation lndistinguishable from ARDS but without a risk factor for ARDS Organizing pneumonia Patchy ground glass, alveolar consolidation, Connective tissue diseases, infections, peripheral and basal predominance drug-related, or idiopathic ldiopathic pulmonary fibrosis/usual Basal-predominant and peripheral- Usual interstitial pneumonia pattern can interstitial pneumonia predominant septal line thickening with be seen in connective tissue disease, traction bronchiectasis and honeycomb asbestosis, and chronic hypersensitivity changes pneumonitis; idiopathic pulmonary fibrosis is diagnosis of exclusion Nonspecific interstitial pneumonia Ground glass, basal predominance ldiopathic and common finding in connective tissue disease Respiratory bronchiolitis Centrilobular nodules and ground-glass May be an asymptomatic finding in an opacity in an upper-lung-predominant active smoker distribution Desquamative interstitial pneumonia Basal-predominant and peripheral- Most cases are smoking related; chest predominant ground-glass opacity with radiograph may be normal in20"/",but occasional cysts HRCT demonstrates ground-glass opacities Hypersensitivity pneumonitis Acute: ground-glass opacification; Acute: associated with flulike illness centrilobular micronodules that are upper- and mid-lung-predominant Chronic: often cannot identify a causative antigen Chronic: mid-lung- and upper-lung- predominant septal lung thickening with traction bronchiectasis; usual interstitial pneumonia pattern may be seen Sa rcoidosis Upper-lobe-predominant; mediastinal and Findings for sarcoidosis often not specific; hilar lymphadenopathy; cystic changes, DPLD with diffuse mediastinaland hilar in clu ding development of aspergilloma; small lymphadenopathy greater than 2 cm in size nodules oriented along bronchovascular should raise suspicion bundles ARDS = acute respiratory distress syndrome; DPLD = diffuse parenchymal lung disease; HRCT = high resolution CT scan.

Hypersensitivity pneumonitis Acute: ground-glass opacification; Acute: associated with flulike illness centrilobular micronodules that are upper- and mid-lung-predominant Chronic: often cannot identify a causative antigen Chronic: mid-lung- and upper-lung- predominant septal lung thickening with traction bronchiectasis; usual interstitial pneumonia pattern may be seen Sa rcoidosis Upper-lobe-predominant; mediastinal and Findings for sarcoidosis often not specific; hilar lymphadenopathy; cystic changes, DPLD with diffuse mediastinaland hilar in clu ding development of aspergilloma; small lymphadenopathy greater than 2 cm in size nodules oriented along bronchovascular should raise suspicion bundles ARDS = acute respiratory distress syndrome; DPLD = diffuse parenchymal lung disease; HRCT = high resolution CT scan. 25

Diffuse Parenchymal Lung Disease expiratory images to accentuate air trapping can elucidate On physiologic testing, patients with any smoking-related small airways disease. Prone images may be helpful to distin- DPLD will have a reduced Drco. RB ILD and SRIF may have guish subpleural reticular opacities and septal thickening from combined restriction and obstruction, whereas DIP typically is dependent atelectasis. associated with pure restrictive disease. PLCH often produces restrictive disease but may have preserved total lung capacity Serologic Testing and evidence ofobstruction when significant cystic disease is For patients with newly detected DPLD of apparently unknown present. COPD is a common comorbidity that may add an cause who are clinically suspected of having idiopathic pul obstructive component to testing in any patient who smokes. monary fibrosis, the American Thoracic Society guidelines For all smoking related DPLDs, the primary management recommend serologic testing to exclude CTD-associated DPLD. is smoking cessation. Glucocorticoids may be considered with Routine testing with C-reactive protein, erythrocyte sedimen- severe disease or in those with refiactory symptoms. tation rate, antinuclear antibodies, rheumatoid factor, myositis KEY POIl{T panel, and anti-cyclic citrullinated peptide antibodies is rec- ommended. See MKSAP 19 Rheumatologz for further discus . The primary management of all smoking-related DPLDs is smoking cessation. sion of testing for connective tissue disease. Lung Biopsy Connective Tissue Diseases When pulmonary tunction tests and HRCT are insufficient for Immune-mediated injury lrom underlying connective tissue making the diagnosis, the physician must consider a broncho- disease can result in DPLD. Typically manifesting in patients

Lung Biopsy Connective Tissue Diseases When pulmonary tunction tests and HRCT are insufficient for Immune-mediated injury lrom underlying connective tissue making the diagnosis, the physician must consider a broncho- disease can result in DPLD. Typically manifesting in patients scopic or surgical lung biopsy. Careful assessment of risk fac with an established CTD, lung disease can occasionally arise tors, alternate diagnostic strategies, and etl'ect ofthe results of belbre the development of extrapulmonary findings. Younger patients who present with DPLD have a higher prevalence of Iung biopsy on treatment should be discussed within a multi CTD. CTD related DPLDs encompass all major HRCT patterns disciplinary team, including a thoracic radiologist, thoracic oI DPLD (Table 17). Nonspecific interstitial pneumonia is more surgeon, and pulmonary specialist with expertise in DPLD. common than usual interstitial pneumonia (UIP) in patients XEY POIl{I with CTD. Furthermore, patients with CTD treated with doses r Noncontrast high-resolution CT scan ofthe chest is the of methotrexate greater than 15 mg/wk, and sometimes other imaging modality of choice for evaluation of diffuse agents, may be at risk for drug induced DPLD. parenchymal lung disease. One syndrome in patients with CTD ILD that warrants particular attention is the antisynthetase syndrome. This syn drome presents as polymyositis or dermatomyositis with radi Diffuse Parenchymal Lung ographic evidence of ILD in combination with one or more Diseases With a Known Cause anti aminoacyl IRNA synthetase antibodies. Patients may not Smoking-Related Diffuse Parenchymal have overt signs of systemic disease; however, ILD may be Lung Disease severe and rapidly progressive. See MKSAP 19 Rheumatologz DPLDs that occur almost exclusively in individuals who are for further discussion of antisynthetase syndrome. current smokers include respiratory bronchiolitis associated Glucocorticoids and immunomodulatory therapy with interstitial lung disease (RB ILD); desquamative interstitial agents such as mycophenolate mofetil, methotrexate, cyclo pneumonia (DIP), a more severe form of smoking related DPLD; phosphamide, and rituximab may be used in consultation pulmonary Langerhans cell histiocytosis (PLCH); and smoking with rheumatologr and pulmonary specialists. related interstitial fibrosis (SRIF). Smoking in conjunction with other endogenous or exogenous factors may also contribute to Hypersensitivity Pneumonitis IPF as well as combined pulmonary fibrosis and emphysema. Repetitive inhalation of specific antigens in a sensitized Typical findings on IIRCT include ground glass opacities patient can result in hypersensitivity pneumonitis (HP), an with fine centrilobular nodules in RB ILD, dilfuse ground immunologic response that results in noncaseating granulo- glass opacification r.t'ith lower zone predominance in DIP, and mas and peribronchial mononuclear cell and giant cell dilluse thin-walled cysts and nodular lesions in upper and mid inflammation. The antigens are typically complex proteins lung zones in PLCH. Patients with PLCH also have a predilec that can ccime from several sources, including agricultural tion to recurrent pneumothoraces. Demonstrating abnormal dusts, thermophilic fungi, and bacteria, but they can also be numbers of Langerhans cells with 5100 or CDla staining in low molecular weight organic compounds. There are three bronchoalveolar lavage fluid or on tissue obtained by either forms of HP, and each presents differently. The acute Ibrm, transbronchial or open lung biopsy confirms the diagnosis. which is the most easily identified form, results after a large SRIF is an entity that radiologically mimics RB ILD. exposure to an inciting antigen. The patient typically devel However, it is pathologically distinct, with deposition of hya- ops f'ever, cough, and fatigue within 12 hours of exposure. linized collagen in alveolar septa and minimal inflammation. Chest radiography can demonstrate diffuse micronodular

scopic or surgical lung biopsy. Careful assessment of risk fac with an established CTD, lung disease can occasionally arise tors, alternate diagnostic strategies, and etl'ect ofthe results of belbre the development of extrapulmonary findings. Younger patients who present with DPLD have a higher prevalence of Iung biopsy on treatment should be discussed within a multi CTD. CTD related DPLDs encompass all major HRCT patterns disciplinary team, including a thoracic radiologist, thoracic oI DPLD (Table 17). Nonspecific interstitial pneumonia is more surgeon, and pulmonary specialist with expertise in DPLD. common than usual interstitial pneumonia (UIP) in patients XEY POIl{I with CTD. Furthermore, patients with CTD treated with doses r Noncontrast high-resolution CT scan ofthe chest is the of methotrexate greater than 15 mg/wk, and sometimes other imaging modality of choice for evaluation of diffuse agents, may be at risk for drug induced DPLD. parenchymal lung disease. One syndrome in patients with CTD ILD that warrants particular attention is the antisynthetase syndrome. This syn drome presents as polymyositis or dermatomyositis with radi Diffuse Parenchymal Lung ographic evidence of ILD in combination with one or more Diseases With a Known Cause anti aminoacyl IRNA synthetase antibodies. Patients may not Smoking-Related Diffuse Parenchymal have overt signs of systemic disease; however, ILD may be Lung Disease severe and rapidly progressive. See MKSAP 19 Rheumatologz DPLDs that occur almost exclusively in individuals who are for further discussion of antisynthetase syndrome. current smokers include respiratory bronchiolitis associated Glucocorticoids and immunomodulatory therapy with interstitial lung disease (RB ILD); desquamative interstitial agents such as mycophenolate mofetil, methotrexate, cyclo pneumonia (DIP), a more severe form of smoking related DPLD; phosphamide, and rituximab may be used in consultation pulmonary Langerhans cell histiocytosis (PLCH); and smoking with rheumatologr and pulmonary specialists. related interstitial fibrosis (SRIF). Smoking in conjunction with other endogenous or exogenous factors may also contribute to Hypersensitivity Pneumonitis IPF as well as combined pulmonary fibrosis and emphysema. Repetitive inhalation of specific antigens in a sensitized Typical findings on IIRCT include ground glass opacities patient can result in hypersensitivity pneumonitis (HP), an with fine centrilobular nodules in RB ILD, dilfuse ground immunologic response that results in noncaseating granulo- glass opacification r.t'ith lower zone predominance in DIP, and mas and peribronchial mononuclear cell and giant cell dilluse thin-walled cysts and nodular lesions in upper and mid inflammation. The antigens are typically complex proteins lung zones in PLCH. Patients with PLCH also have a predilec that can ccime from several sources, including agricultural tion to recurrent pneumothoraces. Demonstrating abnormal dusts, thermophilic fungi, and bacteria, but they can also be numbers of Langerhans cells with 5100 or CDla staining in low molecular weight organic compounds. There are three bronchoalveolar lavage fluid or on tissue obtained by either forms of HP, and each presents differently. The acute Ibrm, transbronchial or open lung biopsy confirms the diagnosis. which is the most easily identified form, results after a large SRIF is an entity that radiologically mimics RB ILD. exposure to an inciting antigen. The patient typically devel However, it is pathologically distinct, with deposition of hya- ops f'ever, cough, and fatigue within 12 hours of exposure. linized collagen in alveolar septa and minimal inflammation. Chest radiography can demonstrate diffuse micronodular 27

Diffuse Parenchymal Lung Disease TABLE 1 7. Connective Tissue Diseases Associated With Diffuse Parenchymal Lung Disease Connective Typical DPLD Patterns and Associated Tissue Disease Pulmonary Manifestations Rheumatoid Usual interstitial pneumonia arth ritis Nonspecific interstitial pneumonia Organizing pneumonia Rheumatoid nodules Other pulmonary manifestations: pleuritis and pleural effusion, airway disease Systemic Nonspecific interstitial pneumonia sclerosis Other pulmonary mani{estations: pulmonary hypertension, aspiration from esophageal dysmotility Polymyositis/ Nonspecific interstitial pneumonia dermatomyositis Organizing pneumonia Systemic lupus Nonspeci{ic interstitial pneumonia erythematosus Organizing pneumonia Lymphocytic interstitial pneumonia Ft G U RE 5. Chest CT scan demonstrating hypersensitivity pneumonitis with Other pulmonary manifestations: acute patchy, bi lateral g rou nd'glass opacities (red arow) a nd centrilobula r micronodu les pneumonitis, pulmonary hemorrhage, (blue arrow) in the midlung section. pleuritis, thromboembolic disease, pulmonary hypertension, shrinking lung syndrome Removal of exposure to the offending antigen is essential Sjogren Nonspecific interstitial pneumonia in the treatment of HP. To identily potential antigens, a careful syndrome history is vital, as serologic testing is olten limited and may not Lymphocytic interstitial pneumonia include antibodies to the responsible antigen. Glucocorticoids Mixed connective Nonspecific interstitial pneumonia tissue disease and sometimes other immunosuppressants are often used for Organizing pneumonia those with more severe symptoms. ANCA-associated Usual interstitial pneumonia vasculitis TEY POITT Less commonly, nonspecific interstitial pneumonia . Removal of exposure to the offending antigen is essential r ANCA = antineutrophil c'.toplasmic anti body; DPLD = diffuse parenchymal lung in the treatment of hypersensitivity pneumonitis. disease _

TABLE 1 7. Connective Tissue Diseases Associated With Diffuse Parenchymal Lung Disease Connective Typical DPLD Patterns and Associated Tissue Disease Pulmonary Manifestations Rheumatoid Usual interstitial pneumonia arth ritis Nonspecific interstitial pneumonia Organizing pneumonia Rheumatoid nodules Other pulmonary manifestations: pleuritis and pleural effusion, airway disease Systemic Nonspecific interstitial pneumonia sclerosis Other pulmonary mani{estations: pulmonary hypertension, aspiration from esophageal dysmotility Polymyositis/ Nonspecific interstitial pneumonia dermatomyositis Organizing pneumonia Systemic lupus Nonspeci{ic interstitial pneumonia erythematosus Organizing pneumonia Lymphocytic interstitial pneumonia Ft G U RE 5. Chest CT scan demonstrating hypersensitivity pneumonitis with Other pulmonary manifestations: acute patchy, bi lateral g rou nd'glass opacities (red arow) a nd centrilobula r micronodu les pneumonitis, pulmonary hemorrhage, (blue arrow) in the midlung section. pleuritis, thromboembolic disease, pulmonary hypertension, shrinking lung syndrome Removal of exposure to the offending antigen is essential Sjogren Nonspecific interstitial pneumonia in the treatment of HP. To identily potential antigens, a careful syndrome history is vital, as serologic testing is olten limited and may not Lymphocytic interstitial pneumonia include antibodies to the responsible antigen. Glucocorticoids Mixed connective Nonspecific interstitial pneumonia tissue disease and sometimes other immunosuppressants are often used for Organizing pneumonia those with more severe symptoms. ANCA-associated Usual interstitial pneumonia vasculitis TEY POITT Less commonly, nonspecific interstitial pneumonia . Removal of exposure to the offending antigen is essential r ANCA = antineutrophil c'.toplasmic anti body; DPLD = diffuse parenchymal lung in the treatment of hypersensitivity pneumonitis. disease _ Drug-lnduced Diffuse Parenchymal Lung Disease disease but may be normal. Physical examination will reveal Many medications have been implicated in the development of inspiratory crackles. If HRCT is performed, it will demon- DPLD (Table 18). Duration of exposure to the development of strate diffuse centrilobular micronodules and ground-glass disease can vary even for the same agent. For instance, ami opacities (Figure 5). After removal from the offending antigen, odarone lung toxicity has an acute form presenting with acute symptoms usually resolve within approximately 48 hours. lung injury/acute respiratory distress syndrome. as well as a Recurrence of symptoms if the patient is rechallenged is the chronic indolent form with reticular abnormalities and sub- hallmark of the disease. pleural nodules. Prompt treatment by removal of the offending Subacute and chronic forms of HP occur after more pro- agent is important for resolution of symptoms. For those with longed lower level antigen exposure. "Bird fancier's lung dis- more severe symptoms, glucocorticoids may have some ben ease" is an example ofa chronic disorder caused by inhalation efit, although data are anecdotal. of avian proteins from feathers, skin, or guano. These patients experience cough, fatigue, weight loss, and shortness of Radiation Pneumonitis breath. As in the acute form. the HRCT scan will show micro Radiation pneumonitis typically occurs 4 to 12 weeks after nodules and ground-glass opacities, but there is also evidence radiation exposure. Patients present with cough, shortness ol of septal thickening and fibrosis. In the disease's most severe breath, and radiographic infiltrates. Fever, pleuritic chest pain. and chronic form, significant traction bronchiectasis and hon fatigue, and weight loss are accompanying nonspecific symp eycomb changes will be evident. Evidence of severe fibrosis on toms. Differential diagnosis often includes infection and drug- CT imaging significantly increases the risk for disease progres- induced lung injury. On imaging, a well-defined nonanatomic sion and death. demarcation between normal and abnormal lung consistent

Drug-lnduced Diffuse Parenchymal Lung Disease disease but may be normal. Physical examination will reveal Many medications have been implicated in the development of inspiratory crackles. If HRCT is performed, it will demon- DPLD (Table 18). Duration of exposure to the development of strate diffuse centrilobular micronodules and ground-glass disease can vary even for the same agent. For instance, ami opacities (Figure 5). After removal from the offending antigen, odarone lung toxicity has an acute form presenting with acute symptoms usually resolve within approximately 48 hours. lung injury/acute respiratory distress syndrome. as well as a Recurrence of symptoms if the patient is rechallenged is the chronic indolent form with reticular abnormalities and sub- hallmark of the disease. pleural nodules. Prompt treatment by removal of the offending Subacute and chronic forms of HP occur after more pro- agent is important for resolution of symptoms. For those with longed lower level antigen exposure. "Bird fancier's lung dis- more severe symptoms, glucocorticoids may have some ben ease" is an example ofa chronic disorder caused by inhalation efit, although data are anecdotal. of avian proteins from feathers, skin, or guano. These patients experience cough, fatigue, weight loss, and shortness of Radiation Pneumonitis breath. As in the acute form. the HRCT scan will show micro Radiation pneumonitis typically occurs 4 to 12 weeks after nodules and ground-glass opacities, but there is also evidence radiation exposure. Patients present with cough, shortness ol of septal thickening and fibrosis. In the disease's most severe breath, and radiographic infiltrates. Fever, pleuritic chest pain. and chronic form, significant traction bronchiectasis and hon fatigue, and weight loss are accompanying nonspecific symp eycomb changes will be evident. Evidence of severe fibrosis on toms. Differential diagnosis often includes infection and drug- CT imaging significantly increases the risk for disease progres- induced lung injury. On imaging, a well-defined nonanatomic sion and death. demarcation between normal and abnormal lung consistent 28

i : Diffuse Parenchymal Lung Disease TABLE 18. Selected Drug-lnduced Parenchymal Lung Diseases Drug Clinical Points Radiographic Findings and Treatment : Amiodarone More common in: Multiple radiographic presentations possible, including ground-glass opacities, subpleural nodules, and Older patients reticular abnormalities lncreased dosage and higher cumulative dose Very long half-life prevents clearance from the pulmonary First year oftherapy (but can occur late) parenchyma: j I Rare improvement with discontinuation of the drug : alone

Amiodarone More common in: Multiple radiographic presentations possible, including ground-glass opacities, subpleural nodules, and Older patients reticular abnormalities lncreased dosage and higher cumulative dose Very long half-life prevents clearance from the pulmonary First year oftherapy (but can occur late) parenchyma: j I Rare improvement with discontinuation of the drug : alone i High risk for recurrence with tapering of glucocorticoids i Methotrexate Occurs in less than 5% of treated patients Diffuse reticu lar and ground-glass attenuation Unpredictable time to presentation Patients generally do well after stopping medication r No clear correlation between dose and disease severity Glucocorticoids are often given; duration is based on response Nitrofurantoin Acute (more common): Acute: Faint bilateral lower lobe septal lines; moderate pleural effusions may be present; often resolves with Fevers, chills, cough, shortness of breath, chest pain; discontinuation but will recurwith repeat exposure rash can occur in 10Y"-20"/" of patients Chronic: Reticular opacities with subpleural lines and Peripheral eosinophilia common thickened peri-bronchovascular areas; possible benefit Chronic: of glucocorticoids from anecdotal reports Distinct from the acute form Onset months to years after prolonged exposure Bu su lfa n Occurs in lessthan 8% of treated patients Multiple patterns, including ground-glass opacities, reticu lation, bibasilar septal lines, asymmetric Currently used solely as a preparative regimen for peripheral and peribronchial consolidation, HSCT; often combined with other agents associated centrilobular nodules, and dependent consolidation with pulmonary toxicity Optimaltreatment unknown and is often supportive lnjury typically occurs 30 days to 1 year after exposure Glucocorticoids may be used for more progressive disease Bleomycin Risk significantly increases with cumulative dose lmaging patterns suggest the multiple possible pathologic findings seen: lncreased age, kidney disease, concomitant chemotherapy or irradiation also increase risk for Consolidation with ground glass (diffuse alveolar toxicity damage) Typically subacute presentation 1-6 months after Septal line thickening, traction bronchiectasis, and exposure; may show hypersensitivity pneumonitis, honeycomb change (end-stage fibrosis) diffuse alveolar damage, or usual interstitial pneumonia pathologically but with more rapid clinical onset and Patchy ground glass with subpleural consolidation or progressive course peribronchial consolidation (organizing pneumonia) Diffuse ground glass with centrilobular micronodules (hypersensitivity pneumonitis) Glucocorticoids used for more severe disease; disease may recur with tapering of steroids

i High risk for recurrence with tapering of glucocorticoids i Methotrexate Occurs in less than 5% of treated patients Diffuse reticu lar and ground-glass attenuation Unpredictable time to presentation Patients generally do well after stopping medication r No clear correlation between dose and disease severity Glucocorticoids are often given; duration is based on response Nitrofurantoin Acute (more common): Acute: Faint bilateral lower lobe septal lines; moderate pleural effusions may be present; often resolves with Fevers, chills, cough, shortness of breath, chest pain; discontinuation but will recurwith repeat exposure rash can occur in 10Y"-20"/" of patients Chronic: Reticular opacities with subpleural lines and Peripheral eosinophilia common thickened peri-bronchovascular areas; possible benefit Chronic: of glucocorticoids from anecdotal reports Distinct from the acute form Onset months to years after prolonged exposure Bu su lfa n Occurs in lessthan 8% of treated patients Multiple patterns, including ground-glass opacities, reticu lation, bibasilar septal lines, asymmetric Currently used solely as a preparative regimen for peripheral and peribronchial consolidation, HSCT; often combined with other agents associated centrilobular nodules, and dependent consolidation with pulmonary toxicity Optimaltreatment unknown and is often supportive lnjury typically occurs 30 days to 1 year after exposure Glucocorticoids may be used for more progressive disease Bleomycin Risk significantly increases with cumulative dose lmaging patterns suggest the multiple possible pathologic findings seen: lncreased age, kidney disease, concomitant chemotherapy or irradiation also increase risk for Consolidation with ground glass (diffuse alveolar toxicity damage) Typically subacute presentation 1-6 months after Septal line thickening, traction bronchiectasis, and exposure; may show hypersensitivity pneumonitis, honeycomb change (end-stage fibrosis) diffuse alveolar damage, or usual interstitial pneumonia pathologically but with more rapid clinical onset and Patchy ground glass with subpleural consolidation or progressive course peribronchial consolidation (organizing pneumonia) Diffuse ground glass with centrilobular micronodules (hypersensitivity pneumonitis) Glucocorticoids used for more severe disease; disease may recur with tapering of steroids HSCT = hematopoietic stem cell transplantation.

i High risk for recurrence with tapering of glucocorticoids i Methotrexate Occurs in less than 5% of treated patients Diffuse reticu lar and ground-glass attenuation Unpredictable time to presentation Patients generally do well after stopping medication r No clear correlation between dose and disease severity Glucocorticoids are often given; duration is based on response Nitrofurantoin Acute (more common): Acute: Faint bilateral lower lobe septal lines; moderate pleural effusions may be present; often resolves with Fevers, chills, cough, shortness of breath, chest pain; discontinuation but will recurwith repeat exposure rash can occur in 10Y"-20"/" of patients Chronic: Reticular opacities with subpleural lines and Peripheral eosinophilia common thickened peri-bronchovascular areas; possible benefit Chronic: of glucocorticoids from anecdotal reports Distinct from the acute form Onset months to years after prolonged exposure Bu su lfa n Occurs in lessthan 8% of treated patients Multiple patterns, including ground-glass opacities, reticu lation, bibasilar septal lines, asymmetric Currently used solely as a preparative regimen for peripheral and peribronchial consolidation, HSCT; often combined with other agents associated centrilobular nodules, and dependent consolidation with pulmonary toxicity Optimaltreatment unknown and is often supportive lnjury typically occurs 30 days to 1 year after exposure Glucocorticoids may be used for more progressive disease Bleomycin Risk significantly increases with cumulative dose lmaging patterns suggest the multiple possible pathologic findings seen: lncreased age, kidney disease, concomitant chemotherapy or irradiation also increase risk for Consolidation with ground glass (diffuse alveolar toxicity damage) Typically subacute presentation 1-6 months after Septal line thickening, traction bronchiectasis, and exposure; may show hypersensitivity pneumonitis, honeycomb change (end-stage fibrosis) diffuse alveolar damage, or usual interstitial pneumonia pathologically but with more rapid clinical onset and Patchy ground glass with subpleural consolidation or progressive course peribronchial consolidation (organizing pneumonia) Diffuse ground glass with centrilobular micronodules (hypersensitivity pneumonitis) Glucocorticoids used for more severe disease; disease may recur with tapering of steroids HSCT = hematopoietic stem cell transplantation. with the radiation field is pathognomonic but not always pre agents, including doxorubicin, etoposide, gemcitabine, pacli- sent. Other lung abnormalities, such as organizing pneumo- taxel, and pemetrexed, which trigger pathologic changes in nia, may also be observed outside the field of exposure. the lung tissue previously exposed to radiation. Observation may be appropriate for those with mild disease. Glucocorticoids are used for patients with severe symptoms or t(lv Porrrs hypoxemia. From 6 to 12 months after radiation exposure, o Radiation pneumonitis typically presents 4 to 12 weeks additional findings on HRCT may develop, including septal after initial radiation exposure with cough, shortness of thickening, traction bronchiectasis, and volume loss consist- breath, and a new radiographic infiltrate. ent with chronic fibrosis. Individuals exposed to radiation are . Treatment of severe forms of radiation pneumonitis also at risk for the development of radiation recall pneumoni typically is glucocorticoids, whereas observation may be tis, which can occur when lung tissue is subsequently exposed appropriate for those with mild disease. to certain immune checkpoint inhibitors and chemotherapy

with the radiation field is pathognomonic but not always pre agents, including doxorubicin, etoposide, gemcitabine, pacli- sent. Other lung abnormalities, such as organizing pneumo- taxel, and pemetrexed, which trigger pathologic changes in nia, may also be observed outside the field of exposure. the lung tissue previously exposed to radiation. Observation may be appropriate for those with mild disease. Glucocorticoids are used for patients with severe symptoms or t(lv Porrrs hypoxemia. From 6 to 12 months after radiation exposure, o Radiation pneumonitis typically presents 4 to 12 weeks additional findings on HRCT may develop, including septal after initial radiation exposure with cough, shortness of thickening, traction bronchiectasis, and volume loss consist- breath, and a new radiographic infiltrate. ent with chronic fibrosis. Individuals exposed to radiation are . Treatment of severe forms of radiation pneumonitis also at risk for the development of radiation recall pneumoni typically is glucocorticoids, whereas observation may be tis, which can occur when lung tissue is subsequently exposed appropriate for those with mild disease. to certain immune checkpoint inhibitors and chemotherapy 29

Diffuse Parenchymal Lung Disease rc FIGU RE 1 0. Chen radiograph showing stage I pulmonary sarcoidosis with hilar lymphadenopathy and normal lung parenchyma.

Diffuse Parenchymal Lung Disease rc FIGU RE 1 0. Chen radiograph showing stage I pulmonary sarcoidosis with hilar lymphadenopathy and normal lung parenchyma. a diagnosis of exclusion. Diagnosis, with a few exceptions (Table 2O), typically requires bronchoscopic biopsy, with tis- sue obtained from a lymph node or from the pulmonary parenchyma. The diagnosis is made by the finding of nonca seating granulomas with exclusion of potential mimicking tIGURE 9. Representative chestOscan cuts demonstrating combined pulmonary fibrosis and emphysema, with upper lobe emphysema (/; red arrowl infections (mycobacteria, fungi), exclusion of other systemic and lower lobe subpleural reticular and fibrotic changes ( B; blue arrowl. granulomatous diseases, and ideally involvement of more than one organ system. patients are asymptomatic, and lung involvement is inciden Development of pulmonary hypertension in patients tally found on chest radiography performed for other reasons with sarcoidosis is a poor prognostic indicator, with a median (Figure 1O). Findings from chest radiography can help predict survival of approximately 3 years. the probability ofspontaneous resolution (Table 19). CT scan- The primary treatment of sarcoidosis is glucocorticoids, ning can show pulmonary parenchymal disease or intratho although many patients do not need to be treated. In addition, racic lymphadenopathy, either alone or in combination. spontaneous resolution without treatment is common and is Presence of nodules along bronchovascular bundles on HRCT related to the radiographic stage ofdisease (see Table 19). The imaging suggests sarcoidosis as the cause of the disease. decision to treat and assessment of response to treatment Pulmonary function testing is typically abnormal and should be based on symptoms and organ dysfunction, not findings can be obstructive, restrictive, or both. Sarcoidosis is radiographic findings. For those without symptoms or organ

a diagnosis of exclusion. Diagnosis, with a few exceptions (Table 2O), typically requires bronchoscopic biopsy, with tis- sue obtained from a lymph node or from the pulmonary parenchyma. The diagnosis is made by the finding of nonca seating granulomas with exclusion of potential mimicking tIGURE 9. Representative chestOscan cuts demonstrating combined pulmonary fibrosis and emphysema, with upper lobe emphysema (/; red arrowl infections (mycobacteria, fungi), exclusion of other systemic and lower lobe subpleural reticular and fibrotic changes ( B; blue arrowl. granulomatous diseases, and ideally involvement of more than one organ system. patients are asymptomatic, and lung involvement is inciden Development of pulmonary hypertension in patients tally found on chest radiography performed for other reasons with sarcoidosis is a poor prognostic indicator, with a median (Figure 1O). Findings from chest radiography can help predict survival of approximately 3 years. the probability ofspontaneous resolution (Table 19). CT scan- The primary treatment of sarcoidosis is glucocorticoids, ning can show pulmonary parenchymal disease or intratho although many patients do not need to be treated. In addition, racic lymphadenopathy, either alone or in combination. spontaneous resolution without treatment is common and is Presence of nodules along bronchovascular bundles on HRCT related to the radiographic stage ofdisease (see Table 19). The imaging suggests sarcoidosis as the cause of the disease. decision to treat and assessment of response to treatment Pulmonary function testing is typically abnormal and should be based on symptoms and organ dysfunction, not findings can be obstructive, restrictive, or both. Sarcoidosis is radiographic findings. For those without symptoms or organ TABLE 19. Chest Radiograph Staging of Pulmonary Sarcoidosis Stage Radiographic Pattern Clinical Course and Comments 0 Normal Hilar lymphadenopathy with normal lung parenchyma >90% rate of spontaneous resolution without treatment il Hilar lymphadenopathy with abnormal lung parenchyma Approximately 50% rate of spontaneous improvement without treatment ilt No lymphadenopathy with abnormal lung parenchyma Approxi mately 20o/o r ale of sponta neous m provement i

TABLE 19. Chest Radiograph Staging of Pulmonary Sarcoidosis Stage Radiographic Pattern Clinical Course and Comments 0 Normal Hilar lymphadenopathy with normal lung parenchyma >90% rate of spontaneous resolution without treatment il Hilar lymphadenopathy with abnormal lung parenchyma Approximately 50% rate of spontaneous improvement without treatment ilt No lymphadenopathy with abnormal lung parenchyma Approxi mately 20o/o r ale of sponta neous m provement i without treatment IV Parenchymal changes with fibrosis and architectural distortion 32

I Occupational Lung Disease TABLE 20. Clinical Presentations of Sarcoidosis That TABLE 21" Occupational Lung Disease Screening Do Not Require a Biopsy Q.uestionnaire Syndrome Additional Findings/Symptoms Occupation Asymptomatic No evidence of fevers, malaise, or night What do you do every day at your job? bilateral hilar sweats to suggest a malignancy Have you always done these tasks at work? lymphadenopathy Have you had other duties? Lofgren syndrome Bilateral hilar lymphadenopathy, migratory polyarthralgia, erythema nodosum, and How long have you been working in this job? Have you had a fever similar job elsewhere? Heerfordt Anterior uveitis, parotitis, fever (uveoparotid What other types of work have you done?" syndrome fever), and facial nerve palsy Type and Extent of Exposure Describe your work area. ls there adequate ventilation? ls there dysfunction, observation is appropriate. If treatment is required, visible dust in the air? ls visibility across the work area limited glucocorticoid therapy is appropriate. For patients with more because of the amount of dust in the air? severe or prolonged symptoms, adverse effects from chronic Are you exposed to vapors, gases, dust, or fumes in your work? glucocorticoids should be considered. In this setting, adjunctive Does your employer require you to wear personal protective glucocorticoid sparing therapies are often used. Pulmonary equipment? lf so, do you wear it for the full extent of your exposure? consultation should be considered for management of persis- tent disease. For patients with pulmonary hypertension or Do you know the amount and type of chemicals used?

TABLE 20. Clinical Presentations of Sarcoidosis That TABLE 21" Occupational Lung Disease Screening Do Not Require a Biopsy Q.uestionnaire Syndrome Additional Findings/Symptoms Occupation Asymptomatic No evidence of fevers, malaise, or night What do you do every day at your job? bilateral hilar sweats to suggest a malignancy Have you always done these tasks at work? lymphadenopathy Have you had other duties? Lofgren syndrome Bilateral hilar lymphadenopathy, migratory polyarthralgia, erythema nodosum, and How long have you been working in this job? Have you had a fever similar job elsewhere? Heerfordt Anterior uveitis, parotitis, fever (uveoparotid What other types of work have you done?" syndrome fever), and facial nerve palsy Type and Extent of Exposure Describe your work area. ls there adequate ventilation? ls there dysfunction, observation is appropriate. If treatment is required, visible dust in the air? ls visibility across the work area limited glucocorticoid therapy is appropriate. For patients with more because of the amount of dust in the air? severe or prolonged symptoms, adverse effects from chronic Are you exposed to vapors, gases, dust, or fumes in your work? glucocorticoids should be considered. In this setting, adjunctive Does your employer require you to wear personal protective glucocorticoid sparing therapies are often used. Pulmonary equipment? lf so, do you wear it for the full extent of your exposure? consultation should be considered for management of persis- tent disease. For patients with pulmonary hypertension or Do you know the amount and type of chemicals used? severe disease with significant activity limitation resulting Do have Data Sheets from rwo ace? from lung impairment, evaluation for lung transplantation Temporal Relationship of Symptoms to the Work is appropriate. Environment For nonpulmonary manifestations of sarcoidosis, see Before symptoms began, were there any changes in the MKSAP l9 Rheumatologr. processes at work or new exposures?

severe disease with significant activity limitation resulting Do have Data Sheets from rwo ace? from lung impairment, evaluation for lung transplantation Temporal Relationship of Symptoms to the Work is appropriate. Environment For nonpulmonary manifestations of sarcoidosis, see Before symptoms began, were there any changes in the MKSAP l9 Rheumatologr. processes at work or new exposures? XEY POIXTS When you are off work, do your symptoms improve? o More than 90% of patients with sarcoidosis have lung Are there others at work who have developed similar symptoms? involvement; radiographic staging can predict the prob- Has a process change at work resulted in improved symptoms? ability of spontaneous resolution. Other Relevant Exposures . The primary treatment of symptomatic sarcoidosis is glucocorticoids, often followed by glucocorticoid sparing Do you perform activities at home that may expose you to organic or inorganic dust (for example, refurbishing old cars or therapies. woodworking)? o lofgren syndrome consists of erythema nodosum, arthritis, Do you have any pet birds at home? Do you have any pets? fever, and hilar lymphadenopathy; a biopsy is not needed Have you always lived in the area? to confirm the diagnosis. Have you traveled recently? "Obtain a full accounting of other jobs.

o More than 90% of patients with sarcoidosis have lung Are there others at work who have developed similar symptoms? involvement; radiographic staging can predict the prob- Has a process change at work resulted in improved symptoms? ability of spontaneous resolution. Other Relevant Exposures . The primary treatment of symptomatic sarcoidosis is glucocorticoids, often followed by glucocorticoid sparing Do you perform activities at home that may expose you to organic or inorganic dust (for example, refurbishing old cars or therapies. woodworking)? o lofgren syndrome consists of erythema nodosum, arthritis, Do you have any pet birds at home? Do you have any pets? fever, and hilar lymphadenopathy; a biopsy is not needed Have you always lived in the area? to confirm the diagnosis. Have you traveled recently? "Obtain a full accounting of other jobs. Occupational Lung Disease introduced in various industries. Factors suggesting an under When to Suspect an Occupational lying occupational lung disease include patient concerns Lung Disease about an exposure, a temporal association with an exposure, Occupational lung disease can affect any part of the respira unexplained signs or symptoms, and evidence of coworkers tory tract, including sinuses, airways, the lung parenchyma, with similar symptoms. In addition, patients may experience and the surrounding pleura. As a result, signs and symptoms relief of symptoms when away from the work environment associated with occupational exposure include rhinitis, reac and recurrence of symptoms on their return. For the patient tive airways disease, reactive airways dysfunction syndrome with occupational Iung disease, similar to those with diffuse (see Airways Disease section), COPD, pleural disease, diffuse parenchymal lung disease, cough and dyspnea on exertion are parenchymal lung disease, and malignancy. Occupational lung common. diseases can present acutely, subacutely, or slowly after many years of exposure. Therefore, a careful employment history that includes occupational exposures is essential for diagnosis Key Elements of the (Table 2f). Clinical presentations related to silica and asbestos Exposure History exposures are well characterized and recognized. However, The time course from exposure to the development of signs new agents that may lead to respiratory diseases are frequently and symptoms of occupational lung disease is highly variable.

Occupational Lung Disease introduced in various industries. Factors suggesting an under When to Suspect an Occupational lying occupational lung disease include patient concerns Lung Disease about an exposure, a temporal association with an exposure, Occupational lung disease can affect any part of the respira unexplained signs or symptoms, and evidence of coworkers tory tract, including sinuses, airways, the lung parenchyma, with similar symptoms. In addition, patients may experience and the surrounding pleura. As a result, signs and symptoms relief of symptoms when away from the work environment associated with occupational exposure include rhinitis, reac and recurrence of symptoms on their return. For the patient tive airways disease, reactive airways dysfunction syndrome with occupational Iung disease, similar to those with diffuse (see Airways Disease section), COPD, pleural disease, diffuse parenchymal lung disease, cough and dyspnea on exertion are parenchymal lung disease, and malignancy. Occupational lung common. diseases can present acutely, subacutely, or slowly after many years of exposure. Therefore, a careful employment history that includes occupational exposures is essential for diagnosis Key Elements of the (Table 2f). Clinical presentations related to silica and asbestos Exposure History exposures are well characterized and recognized. However, The time course from exposure to the development of signs new agents that may lead to respiratory diseases are frequently and symptoms of occupational lung disease is highly variable. 33