Pathology Archive 2

AUTOIMMUNE AND IDOPATHIC PULMONARY DISORDERS 

Acute Eosinophilic Pneumonia 

Acute Interstitial Pneumonia 

Allergic Angiitis and Granulomatosis 

Alveolar microlithiasis 

Alveolar proteinosis 

Amyloid 

Angiocentric Immunoproliferative Lesion/ Angiocentric Lymphoma 

Ankylosing Spondylitis 

Bronchiolitis obliterans and organizing pneumonia 

Bronchocentric Granulomatosis 

Castleman's disease 

Chronic eosinophilic pneumonia 

Churg-Strauss Syndrome 

Cryptogenic organizing pneumonia 

Desquamative interstitial pneumonia 

Diffuse panbronchiolits 

Diffuse pulmonary ossification 

Drug Induced Lung Disease 

Chemotherapeutic agents: 
- Bleomycin 
- Busulfan 
- Carmustine (BCNU) 
- Cyclophosphamide 
- Cytosine arabinoside 
- Interleukin-2 
- Methotrexate

Amiodarone 
Gold salts 
Nitrofurantoin 
OKT-3 
Oxygen 
Penicillamine 
Interferon 

Eosinophilic Granuloma 

Eosinophilic lung disease 

1- Idiopathic eosinophilic lung disease: 

.....a. Loffler's syndrome 

.....b. Acute eosinophilic pneumonia 

.....c. Chronic eosinophilic pneumonia 

.....d. Idiopathic hypereosinophilic syndrome 

2- Eosinophilic lung disease of specific etiology 

3- Eosinophilic lung disease associated with angiitis 

Extrinsic Allergic Alveolitis 

Fibrosing Mediastinitis 

Follicular Bronchiolitis 

Goodpasteur's syndrome 

Hamman-Rich syndrome 

Hypersensitivity pneumonitis 

Idiopathic Giant Bullous Emphysema (Vanishing Lung) 

Idiopathic pulmonary hemosiderosis 

Idiopathic pulmonary fibrosis: (Cryptogenic fibrosing alveolitis) 

1- Desquamative interstitial pneumonia 

2- Usual interstitial pneumonia 

3- Nonspecific interstitial pneumonia 

Langerhans cell histiocytosis 

Loffler's syndrome 

Lymphangioleiomyomatosis 

Lymphocytic Interstitial Pneumonitis (LIP) 

Lymphomatoid granulomatosis 

Mixed Connective Tissue Disease 

Mounier-Kuhn syndrome 

Nonspecific interstitial pneumonia 

Polymyositis / Dermatomyositis 

Relapsing polychondritis 

Respiratory bronchiolitis 

- Respiratory bronchiolitis associated interstitial lung disease 

Rheumatoid Arthritis 

Sarcoidosis 

Sjogren's Syndrome 

Systemic lupus erythematosis 

Systemic sclerosis (Scleroderma) 

Tracheobronchopathia osteochondroplastica 

Usual interstitial pneumonia 

Vanishing Lung Syndrome 

Wegener's granulomatosis 

Acute Eosinophilic Pneumonia 

Acute Interstitial Pneumonia  (Hamman-Rich Syndrome)

Clinical:

X-ray:

Allergic Angiitis and Granulomatosis 

Alveolar microlithiasis 

Clinical:

X-ray:

Computed Tomography: On CT, there is a gradient in the distribution of the calcifications which tend to cluster in the posterior and inferior subpleural spaces and along the bronchovascular bundles. Calcific polygonal lines can also be seen. Calcified nodules larger than 1 mm (up to 5 mm) are visible on HRCT scans. Areas of ground-glass opacification have been described. Thin walled sub-pleural cysts indicative of early fibrosis can be seen on HRCT images.

Scintigraphy: There is intense pulmonary uptake of radiotracer on Tc-MDP bone scan.

Alveolar proteinosis 

Clinical:

Pulmonary alveolar proteinosis can be understood as a syndrome of altered surfactant homeostasis, leading to a pathologic accumulation of surfactant [6]. Because surfactant homestasis is complex, there are many potential points of disruption- overproduction of phospholipids byt type II pneumocytes, impairment of clearance of phospholipids by macrophages, or both [6]. As a consequence of this disruption, floccular periodic acid-Schiff (PAS) positive proteinaceous and lipid rich material is deposited within the alveoli. There are two forms of alveolar proteinosis described: a "primary" or idiopathic form occuring in the absence of an identifiable associated disease or exposure (possibly related to an immunologic disturbance), and a "secondary" form provoked by or associated with another condition. Secondary alveolar proteinosis has been described in association with: 1) infections of the lung; 2) hematologic malignancies and other conditions altering a patients immune status (AIDS); and 3) exposure to inhaled mineral dusts (silica, aluminum, titanium) and chemicals (insecticides).

Patients generally present between the age of 20-50 years with progressive shortness of breath and mild, usually non-productive cough. Weight loss, fatigue, and malaise may also be present. However, up to 30% of patients will be asymptomatic even with florid CXR findings. Males are affected more than females (2 to 4:1). Physical exam findings are usually non-specific, but clubbing (25%) and cyanosis (21%) can be seen. An elevated serum lactate dehydrogenase level is the most common associated laboratory abnormality. Patients also have elevated levels of lung surfactant proteins A and D in both the serum and BAL fluid. The intrapulmonary shunt fraction while breathing 100% oxygen is typically elevated (average 20%). Most patients have restrictive lung disease with decreases in total lung capacity, forced vital capacity, forced expiratory volume in 1 second, and diffusion capacity for carbon monoxide [6]. The disorder usually follows a variable course with exacerbation's and remissions. Spontaneous improvement or recovery occurs in 25-50% of cases. Previously up to 30% mortality within several years had been reported, but the actual mortality may be less than 10% [4]. Treatment is whole lung bronchopulmonary lavage to remove abnormal surfactant which can lead to improved oxygenation as alveoli re-expand, but this is not required in all cases. After treatment, marked improvement in the disease and radiographic findings are usually apparent [6]. About 80% of patients respond favorably to lung lavage [6]. Lung transplant can be used in selected cases, but the disorder can recur in the transplanted lung [7].

Concomitant superinfection can occur, classically with Nocardia, but more recently described with Mycobacerium avium-intracellulare and pneumocystis carinii. [1]

X-ray:

CXR: On CXR there are small acinar nodules which may coalesce to form areas of consolidation- typically in a "bat-wing" configuration which may mimic pulmonary edema, although the heart size is normal and pleural effusions are typically absent. The involvement is occasionally asymmetric or unilateral. Lymphadenopathy and pleural effusion are rare (although an effusion can be seen following lavage [6]). Changes typically resolve slowly over weeks to months. Later there is diffuse reticulogranularity and changes consistent with interstitial lung disease.

Computed tomography: HRCT demonstrates areas of patchy ground glass opacification or consolidation and peripheral or central ill-defined nodular opacities. Smooth interlobular septal thickening is also seen and intralobular interstitial thickening is common in association with the ground-glass opacifications. The septal thickening produces an underlying polygonal pattern referred to as "crazy paving." The "crazy paving" pattern can also be seen in cases of mucinous bronchoalveolar cell carcinoma [8], lipoid pneumonia, ARDS, and drug-induced pneumonitis [5].

Amyloid 

Clinical:

1- Diffuse pulmonary disease:

2- Nodular pulmonary disease:

3- Tracheobronchial disease:

Angiocentric Immunoproliferative Lesion/ Angiocentric Lymphoma 

Ankylosing Spondylitis 

Clinical:

X-ray:

Bronchiolitis obliterans and organizing pneumonia 

Bronchiolitis Obliterans Organizing Pneumonia (BOOP):

Cryptogenic Organizing Pneumonia (COP)

Clinical:

Bronchiolitis obliterans with organizing pneumonia (BOOP) is a histologic description and not a specific diagnosis. Etiologies of BOOP include toxic fume or dust inhalation (extrinsic allergic alveolitis), post infectious (mycoplasma, fungal, or viral), connective tissue disease (idiopathic inflammatory myopathies, rheumatoid arthritis, Sjogren's syndrome [9]), smoking, chronic graft-vs-host disease, organ transplantation, and drug toxicity. Bleomycin, gold salts, cyclophosphamide, and methotrexate are the most common drugs associated with this form of lung injury [8]. Amiodarone, nitrofurantoin, penicillamine, and sulfasalazine are less common causes of drug induced BOOP [8]. BOOP has also been described in the contralateral lung following radiation therapy [6]. Commonly an etiologic factor is not identified and the condition is idiopathic (cryptogenic) in up to 50% of cases.

Idiopathic BOOP is also referred to as "cryptogenic organizing pneumonia". Most cases of idiopathic BOOP occur in patients between the ages of 40 and 60 years and there is no sex predilection. Patients generally present with a history of a flu-like illness prodrome with a dry, non-productive cough that lasts 2 to 12 weeks, malaise, gradual dyspnea, and a low-grade fever. There is no association with smoking [9]. The ESR is elevated and greater than 60 mm in about 30% of patients [9]. Pulmonary function studies usually demonstrate restrictive abnormalities. On bronchoalveolar lavage the differential white count may show a characteristic "mixed pattern" with increased lymphocytes (20-40%), neutrophils (about 10%), and eosinophils about 5%) [9]. The lymphocyte CD4/CD8 ratio is decreased [9].The diagnosis should not be made without biopsy confirmation [7]. There is NO response to antibiotics, but the process often has a good response to treatment with steroids. Clinical manifestations improve within 48 hours of initiation of therapy, but complete resolution of radiographic infiltrates usually takes several weeks. The duration of treatment is variable, but is usually between 6 and 12 months [9]. Relapses may occur following cessation of steroid therapy in about one-third of cases [2], and do not indicate a potential negative outcome [9]. Overall prognosis for typical BOOP (patchy alveolar opacities) is excellent following steroid therapy [9]. Factors associated with a poor outcome include a predominantly interstitial pattern on imaging, lack of a lymphocytosis on BAL fluid, and an associated underlying disorder [9].

BOOP is referred to as a proliferative bronchiolitis- on histologic analysis, there is obliterative granulation tissue plugs (Masson bodies) found within the lumen of the small airways (alveolar ducts and respiratory bronchioles) due to bronchiolar epithelial damage (bronchiolitis obliterans). Organizing pneumonia is seen in the surrounding lung parenchyma. A constrictive bronchiolitis with concentrically scarred/ stenotic bronchioles may also be noted histologically, but this is not the characteristic finding associated with BOOP.

X-ray:

CXR: The radiologic manifestations of BOOP are those of an organizing pneumonia. On CXR there is bilateral patchy, peripheral alveolar infiltrates (organizing pneumonia) or ground glass opacities in over two-thirds of cases. The consolidations are predominantly subpleural in up to 50-60% of patients. Unilateral, focal, or lobar consolidations are seen less commonly. All lung zones may be affected. Diffuse small linear and nodular opacities are seen in 20-40% of cases. A reticular interstitial pattern is found in a minority of cases. The disorder can progress to fibrosis, but honeycombing is usually absent. Effusions are noted in 10% of cases on plain film and adenopathy is not usually identified.

Computed tomography: On HRCT, subpleural, patchy, basilar dense consolidations (80-90%) with air bronchograms and/or ground-glass densities (60%) producing a pattern of mosaic attenuation are the characteristic findings (in up to 50% of affected patients, especially the immune compromised), but this finding is non-specific as it may also be seen in chronic infection (TB, MAI), sarcoidosis, alveolar cell carcinoma, lymphoma, and chronic aspiration. Large, peripheral areas of irregularly marginated mass-like consolidation have also been described and may be seen in up to 20% of cases [5].

Peribronchial thickening is common. Centrilobular nodular densities ranging in size from 1 to 10 mm (sometimes larger), which may be well or poorly defined, may also be seen (30-50% of cases) and correlate with areas of organizing pneumonia. Adenopathy is more commonly noted by CT (25%) and effusion is found in up to 30% of cases [3]. The presence of dense consolidations helps to distinguish BOOP from DIP, and fibrosis is also not observed in BOOP.

Bronchocentric Granulomatosis 

Clinical:

X-ray:

Castleman's disease 

Clinical:

There are 2 forms: Hyaline Vascular (generally localized) and Plasma Cell Variant (generally multicentric). Cases with mixed histologic features [5] and transition between the two types have been described [4].

1- Hyaline vascular:

2- Plasma cell variant:

X-ray:

MR imaging has been performed in a small number of cases and typically demonstrates heterogeneous signal intensity higher than skeletal muscle on T1 images and marked hyperintensity on T2 images [7]. Peripheral foci of decreased signal correspond to vascular flow voids [7]. The lesions enhance after the administration of gadolinium [7].

On angiography, the masses in the hyaline vascular subtype show a prolonged dense tumor blush in the capillary phase. Pre-operative embolization has been used to decrease intra-operative bleeding [5].

Mulicentric variant (Predominantly plasma cell type): There is typically no dominant mass. Multiple, enhancing nodes may be seen in the chest, axilla, retroperitoneum, mesentery, and inguinal regions. Splenomegaly and ascites may also be seen in these cases [7]. Thin section CT findings include the presence of poorly defined centrilobular nodules, thin-walled cysts, and interlobular septal thickening [8]. These findings are felt to be related to an associated lymphocytic interstitial pneumonitis

Chronic eosinophilic pneumonia 

There are 3 forms of eosinophilic lung disease:

1- Idiopathic eosinophilic lung disease:
a. Loffler's syndrome
b. Acute eosinophilic pneumonia
c. Chronic eosinophilic pneumonia
d. Idiopathic hypereosinophilic syndrome

2- Eosinophilic lung disease of specific etiology

3- Eosinophilic lung disease associated with angiitis

1- Idiopathic Eosinophilic Lung Disease:

A. Loffler's Syndrome:

Clinical:

In Loffler's syndrome (or simple pulmonary eosinophilia) patients develop transient pulmonary consolidations associated with peripheral eosinophilia and present with wheezing or a history of atopia. Serum analysis will commonly demonstrate a leukocytosis and an eosinophilia of at least 10% is required for the diagnosis. Treatment is not necessary as the condition resolves within 1 month. Although no cause can be found in up to one-third of patients, most are eventually discovered to have a drug reaction or parasitic infection [7].

CXR reveals a single (or multiple) area (s) of ill-defined, non-segmental consolidation predominantly in the lung periphery ("reverse pulmonary edema appearance") that are usually transient and migratory. Pleural effusion and adenopathy are not associated with this condition. Less commonly, the disorder can appear as a single or multiple pulmonary nodules. On HRCT, areas of ground-glass attenuation can be seen about the areas of consolidation or nodules [7].

B. Acute Eosinophilic Pneumonia:

Clinical:

Idiopathic acute eosinophilic pneumonia is characterized clinically by an acute febrile illness lasting one to five days. Affected patients have myalgias, pleuritic chest pain, and the rapid onset of hypoxemic respiratory failure often requiring mechanical ventilation. The disorder may be a hypersensitivity reaction to a specific agent, but not etiology has been demonstrated. Histologically, there is edema and eosinophils within the alveolar space, and to a lesser degree within the interstitial space. Lung injury results from release of eosinophilic granules. Bronchoalveolar lavage will demonstrate an abundant eosinophilia (over 20%). Peripheral blood eosinophilia may be absent initially, but is elevated during the subsequent clinical course [7]. Patients have a rapid (within 3 days) and complete response to treatment with corticosteroids. Relapse following cessation of steroid therapy is not common. [1,2]

X-ray:

CXR: On CXR there is initially subtle bilateral interstitial abnormalities (reticular densities) which progress rapidly (over 6 to 48 hours) to a diffuse interstitial and airspace disease (similar to pulmonary edema in appearance). Pleural effusions are also commonly found in up to two-thirds of cases.

Computed tomography: CT scanning frequently demonstrates the presence of bilateral patchy areas of ground-glass density accompanied by interlobular septal thickening. Areas of patchy consolidation can also be identified. The findings may difficult to distinguish from adult respiratory distress syndrome, overhydration pulmonary edema, or an atypical bacterial or viral pneumonia. [1,2]

C- Chronic Eosinophilic Pneumonia:

Clinical:

Affected patients typically present between the ages of 30 - 50 years and women are affected more than men. Most patients complain of a few month history of mild symptoms, such as adult onset asthma (about 30-50% of cases), low grade fever, or malaise; however, dyspnea and a more acutely symptomatic presentation can occur. Females are affected twice as frequently as males. No specific etiology has been described, but the disorder may also represent a hypersensitivity reaction. Peripheral eosinophilia is present in up to 85% of affected patients, although it may be absent at the time of presentation in up to one-third. Eosinophils are also found in the lung interstitium- bronchoalveolar lavage (BAL) fluid will often contain 20 to 40% eosinophils which normally constitute less than 1% of cells found on BAL. There is a dramatic response to steroid therapy, but prolonged therapy (6 months) is often required and the relapse rate is high. [3,4,5,6]

X-ray:

CXR: The classic CXR findings are similar to Loffler's syndrome with patchy, peripheral air space consolidations (a photographic negative of a pulmonary edema type pattern). Unlike Loffler's, however, the infiltrates do not change rapidly and are slow to clear. The peripheral distribution of the infiltrates may not be evident by plain film in more than 50% of cases, in which case, patchy non-segmental areas of consolidation will be identified. Nodules are present in 20% of cases, while pleural effusions are found in under 10% of cases [7].

Computed tomography: A discussion of the CT findings in patients with chronic eosinophilic pneumonia is provided below. It should be noted, that findings have been described in only a small number of patients (see references).

On HRCT, patchy bilateral, peripheral, non-segmental regions of consolidation that often have sharp demarcation from normal lung. Non-peripheral regions of consolidation may also be seen. Some of the opacities may appear streaky or band-like. Cavitation within areas of peripheral infiltrate has been described. Interlobular interstitial thickening and intralobular reticular opacities have been described in association with the areas of consolidation. Areas of ground glass opacification are also commonly seen. Mediastinal adenopathy has been reported in half the cases in one study, but the number of patients studied was small. The appearance may be indistinguishable from BOOP. Following institution of steroid treatment, the consolidations can begin to clear in as soon as two weeks- typically from the periphery. [3,4,5,6] 

D- Idiopathic Hypereosinophilic Syndrome:

Clinical:

Idiopathic hypereosinophilic syndrome is a rare, fatal, multiorgan system disorder characterized by blood eosinophilia (greater than 1,500/ml) for over 6 months. Patients are usually between the ages of 30-50 years and males are affected seven times more frequently than women. Pulmonary involvement is found in 40% of cases.

Findings on the chest radiograph are varied including patchy areas of reticular densities, poorly defined nodules, or consolidation. Pleural effusions can be found in up to 50% of cases. Areas of ground-glass attenuation may be identified at CT. [7]
 

2- Eosinophilic Lung Disease of Specific Etiology:

The clinical and radiographic findings are similar to that of idiopathic eosinophilic lung disease, however, an etiologic agent can be identified. Etiologies include:

• Drugs: Also referred to as "drug induced eosinophilic lung disease." Agents implicated include sulfonamides (most commonly), aspirin, penicillin, nitrofurantoin, aerosolized pentamidine, and methotrexate. Peripheral eosinophilia and elevated IgE levels are common. Peripheral opacities are common on CXR and the condition usually responds to cessation of the causative agent. Steroids may occasionally be required. [8]
• Parasites: Ascariasis, Schistosomiasis, Strongyloides, or Viseral larva migrans
• Fungi: Allergic bronchopulmonary aspergillosis
• Pulmonary eosinophilia with asthma.

3- Eosinophilic Lung Disease associated with Angiitis/ Granulomatosis:

Due to Churg-Strauss, Bronchocentric granulomatosis, Wegener's granulomatosis, Polyarteritis nodosa, or Sjogren's syndrome.

Churg-Strauss Syndrome 

Clinical:

Churg-Strauss is a granulomatous vasculitis with no sex predominance that primarily affects patients between the ages 40-50 years. It is the least common of the angiitis and granulomatous diseases of the lungs. It is strongly associated with a history of longstanding progressive severe asthma and marked peripheral eosinophilia is found in 30-40% of patients. Patients also frequently complain of allergic rhinitis (55-70%), nasal polyps, and sinusitis [6]. The American College of Rheumatology developed a set of criteria for the diagnosis of Churg-Strauss syndrome. The six criteria are 1- asthma; 2- eosinophilia greater than 10% of the WBC differential count; 3- neuropathy; 4- migratory or transient pulmonary opacities; 5- paranasal sinus abnormality; and 6- extravascular eosinophils at biopsy. A patient with vasculitis is considered to have Churg-Strauss if at least 4 of these 6 criteria are met [2].

The vasculitis associated with the disorder is a systemic process that affects both arteries and veins [7]. Upper airway disease and pulmonary involvement occur in about 70% of patients [3]. Cutaneous lesions (purpura or nodules) are the most common extra-pulmonary finding and occur in up to two-thirds of patients. A migratory small joint arthritis occurs in 50% of patients [6]. A peripheral mononeuritis multiplex occurs in up to 75% of patients [6]. Glomerulonephritis is uncommon, but renal involvement (renal vasculitis) can be seen in up to 38% of patients. Cardiac involvement is more common (up to 47% of cases) than in Wegeners [5]. Cardiac abnormalities include eosinophilic myocarditis and coronary vessel vasculitis [6]. Other symptoms include headaches, fever, malaise, arthralgia, and gastrointestinal symptoms. Abdominal pain is very common, usually secondary to an eosinophilic gastroenteritis or vasculitis [6]. Elevated serum levels of IgE are typical and rheumatoid factor levels are elevated in 52% of patients [5]. About 50% of patients with Churg-Strauss sydrome are ANCA positive and the p-ANCA staining pattern predominates. Further evaluation with an ELISA test is usually performed to ensure that the p-ANCA staining pattern is the result of myeloperoxidase (MPO) antigens and not some other nuclear antigen [6].

Treatment with corticosteroids is generally effective- 5 year survival approaches 85%. The addition of cyclophosphamide can result in a decreased relapse rate, but must be weighed against the potential complications of this therapy (15-45 fold increased risk for urological malignancies and hemorrhagic cystitis) [6].

X-ray:

CXR: On CXR pulmonary opacities can be found in 26-77% of cases and the film is normal in about 25% of patients. Localized, parenchymal opacities/areas of consolidation are usually bilateral, patchy/non-segmental, and peripheral. Cavitation is rare. Pulmonary infiltrates may be transient (similar to those seen in patients with chronic eosinophilic pneumonia) or nodular. Extensive air-space opacitis in the setting of hemoptysis suggests massive intraalveolar hemorrhage. Pleural effusions are seen in 5-30% of cases and can be eosinophilic. Hilar nodal enlargement has occasionally been reported [3].

Computed tomography: In the limited number of patients studied by CT [2] findings include peripheral areas of parenchymal consolidation/ground glass attenuation similar to chronic eosinophilic pneumonia are commonly identified. Much less commonly, parenchymal nodules (from 5mm to 3.5 cm), which may be cavitary or contain air bronchograms, can be seen. Bronchial dilatation and bronchial wall thickening may also be seen.

Cryptogenic organizing pneumonia 

Desquamative interstitial pneumonia 

Interstitial Pneumonitis/ Idiopathic Pulmonary Fibrosis/ Fibrosing Alveolitis:

The clinical term idiopathic pulmonary fibrosis (or cryptogenic fibrosing alveolitis) describes a progressive disorder of the lung parenchyma characterized by fibrosis and variable intra-alveolar and interstitial exudate. It is often used interchangeably with the histologic terms desquamative interstitial pneumonitis (DIP) and usual interstitial pneumonitis (UIP). However, once a histologic diagnosis has been obtained, it is more appropriate to use the histologic terminology. The distinction between DIP and UIP is controversial- some authors feel that DIP is an early manifestation of UIP, while others feel that it is a distinct clinical entity. In patients with interstitial pneumonitis, determinants for a favorable prognosis include a younger age at onset, female sex, a normal oxygen saturation, a near normal chest radiograph, a cellular alveolar infiltrate on histologic analysis (DIP), and underlying progressive systemic sclerosis (scleroderma). 

Recently described disorders considered in this category of interstitial pneumonias include acute interstitial pneumonia (AIP- previously referred to Hamman-Rich syndrome), non-specific interstitial pneumonia (NIP), and respiratory bronchiolitis with interstitial lung disease (RB-ILD) whic some authors feel is part of the spectrum of DIP. 

Desquamative Interstitial Pneumonia:
Alveolar macrophage pneumonia
Clinical:
Desquamative interstitial pneumonitis (DIP) may be a self limited disease or may progress to usual interstitial pneumonitis (UIP), although progression to UIP is controversial [8]. DIP is much less common than UIP. Affected patients are typically 8 to 10 years younger than those with UIP and about 90% of affected patients are smokers. Men are affected twice as frequently as women. Although patients may be asymptomatic, they can present with slowly progressive dyspnea, non-productive cough, or clubbing. Treatment consists of steroids and response to therapy is better than UIP- nearly 60% of patients. Overall, patients with DIP have a much better prognosis than those with UIP- the five year mortality is about 5%. Unfortunately, only about 15% of patients with interstitial pneumonitis present with histologic findings suggestive of DIP. 

DIP can be distinguished from UIP on histologic analysis which reveals an abundance of macrophages within the air spaces, minor fibrotic changes, and preservation of the alveolar architecture. 

X-ray:
CXR: On CXR there are usually linear irregular opacities predominantly in the bases (60%) with preserved lung volumes, but the film can be normal (15-20%). A basal ground glass alveolar pattern sparing the costophrenic angles is seen in 20%. Diffuse ground glass opacities occur in 15%. The CXR can be normal in 3 to 22% of cases. 

Computed tomography: On HRCT areas of patchy ground glass attenuation within the lungs are the predominant finding and is present in all cases [8,11] (reflecting the presence of intra-alveolar macrophages and interstitial inflammation). The opacities are typically bilateral, symmetric (up to 85% of cases), peripheral, and predominantly involve the lung bases. The appearance can be indistinguishable from that seen in acute hypersensitivity pneumonitis. Other disorders which produce a similar appearance include respiratory bronchiolitis interstitial lung disease, drug toxicity, BOOP, and pulmonary alveolar proteinosis. If present, findings of fibrosis (intra/interlobular septal thickening) are limited in extent and relatively mild. Small cysts may be seen and represent dilated bronchioles, reversible bronchiolectasis, and dilated alveolar ducts [8]. 

Usual Interstitial Pneumonia:
Clinical:
UIP is the most common form of chronic interstitial pneumonitis (10 to 20 times more prevalent than DIP). Most cases occur sporadically, although familial forms have been reported. Patients typically present between the ages of 50-70 years with progressive dyspnea and a dry cough. Clinical findings include late inspiratory velcro rales, clubbing (80%), restrictive defects on pulmonary function testing, a decreased diffusion capacity for carbon monoxide, and lymphocytosis on lavage. Increased BAL eosinophils can be seen and suggest a poor prognosis [6]. Men are affected more frequently than women. UIP may be idiopathic (50%), familial (earlier age of onset, mode of inheritance unknown) [12], or related to drug exposure (bleomycin, cyclophosphamide, methotrexate, Adriamycin). Between 20-30% of patients with UIP have an underlying collagen vascular disease (rheumatoid arthritis [most commonly]or systemic sclerosis). 

For patients with idiopathic pulmonary fibrosis response to steroid therapy is rare [13]. Steroid therapy may result in improvement in the appearance of ground glass opacities, but progression to end-stage lung disease does not seem to be affected by therapy [1,7]. In fact, the host of side effects associated with high-dose corticosteroid therapy may cause more harm than good in many of these patients [13]. Treatment with cytotoxic agents have been shown to be of only limited benefit. Lung transplantation is a therapeutic alternative in selected patients. Prognosis is poor, with a five year survival of approximately 40-50% following the onset of dyspnea (the median survival after diagnosis is 2 to 2.8 years [15]). For patients with idiopathic pulmonary fibrosis, those with fibrosis involving more than 25% of the lungs (as determined by HRCT) have the worst prognosis [13]. Some patients have phases of accelerated deterioration superimposed upon the chronic course of their illness. 

Complications of UIP: Patients with UIP are at an increased risk for bronchogenic carcinoma. Up to 6-12% of patients may develop bronchogenic carcinoma- most commonly adenocarcinoma. 

X-ray:
CXR: A ground glass pattern may be seen on CXR in the early stages of the alveolitis and may reflect the more cellular form of the disorder [DIP]. Later a there is a reticular pattern/ reticulonodularity predominantly in the bases with a shaggy heart boarder and loss of lung volume. Honey comb lung represents end-stage disease. Up to 10% of patients with diffuse interstitial lung disease can have normal chest radiographs and CT is much more sensitive (88-95% compared to about 80% by CXR) in the detection of interstitial lung disease. Nonetheless, a normal HRCT does not exclude the diagnosis. 

HRCT: The interstitial changes of UIP are predominantly peripheral. A hallmark of UIP is it's patchy distribution with a predilection for the lung bases- particularly the sub-pleural regions of the posterobasal segments of the lower lobes (the central lung zones are spared until late in the course of the disorder). Intralobular interstitial thickening is most commonly seen in patients with idiopathic pulmonary fibrosis and it produces a reticular or web-like pattern characteristically in the sub-pleural lung periphery. Associated irregular septal thickening and intralobular (centrilobular) bronchovascular thickening are sometimes noted. Irregular perivascular interstitial thickening is common and produces irregular interfaces between the lung and the pulmonary vessels. Subpleural lines can be seen, and may resolve following initiation of therapy- possibly representing resolution of atelectatic changes due to decreased lung compliance. 

In the setting of interstitial lung disease the presence of areas of ground glass opacity have been shown to reflect active parenchymal inflammation (in 65-85% of cases), provided that these areas are not associated with evidence of fibrosis, traction bronchiectasis, or bronchiolectasis. This is because ground glass attenuation may merely reflect chronic interstitial fibrosis which appears as ground glass density due to partial volume averaging with cystic changes that may be too small to be resolved anatomically [11]. 

Late in the disorder there is honeycombing, traction bronchiectasis, and considerable architectural distortion. Honeycombing can be found in up to 96% of patients with end-stage idiopathic pulmonary fibrosis. The honeycomb cysts usually range from 2 to 20 mm, typically share walls, and frequently occur in several layers in the sub-pleural lung. A normal HRCT does not exclude early interstitial lung disease and can be seen in up to 12% of patients [5]. Pleural disease is not a feature of UIP. Occasionally, dense subpleural pulmonary fibrosis may mimic pleural thickening. The presence of enlarged mediastinal lymph nodes is associated with UIP secondary to systemic sclerosis. 

Nonspecific Interstitial Pneumonia:
Clinical:
NIP describes a group of interstitial pneumonias which cannot be classified histologically as UIP, DIP, AIP, or BOOP. The main features that separate this disorder from the more usual interstitial pneumonia (UIP) are the more temporal homogeneity of the histologic process (occuring over a narrow time span) and a more benign clinical course with a substantially better prognosis [15]. The disorder is differentiated from DIP by the lack of significant intraalveolar macrophage accumulation [9]. Affected patients may have associated collagen vascular disease (16%) or history of noxious agent exposure (17%). Patients are most commonly middle aged females who present with dyspnea, dry cough, and low grade fever. The average duration of illness is about 8 months. NIP is subdivided into 2 sub-categories: 1- cellular (better prognosis and response to corticosteroids) and 2- fibrotic (generally worse prognosis with this subtype) [11]. Prognosis is significantly better than for patients with UIP- with about 50% of patients responding to steroid therapy. [2,3] Following treatment, the abnormalities seen on CT (including reticular abnormalities and traction bronchiectasis) completely or partially resolve [15]. 

X-ray:
CXR: Irregular linear opacities and air-space consolidations have been described in association with NIP. 

Computed tomography: NSIP has a variable appearance at HRCT [14]. Bilateral, patchy ground glass opacities are found in 76% to 100% of cases [15]. Areas of ground-glass attenuation are symmetric in up to 86% of patients and are commonly subpleural (68%) [14]. The ground-glass attenuation is frequently associated with bronchiectasis [15]. Predominantly basilar, subpleural air space consolidation is also very common (16-70% of cases). Irregular linear opacities are found in 30-87% of cases and are subpleural in up to 96% [14] of cases. Mediastinal adenopathy can be found in 4-30% of cases. Honeycombing is generally not a feature of this disorder [9], although it was found in 26% to 30% of cases in some studies [14,16]. Small (under 5 mm), bilateral, poorly defined, centrilobular nodules may be seen in 14% of cases [14]. On following up exams after treatment, areas of ground-glass opacification will decreased or resolve [10]. 

Diffuse panbronchiolits 

Clinical:

Panbronchiolitis is a chronic inflammatory disease of unknown etiology that is seen almost exclusively in Asians. The disorder is not necessarily associated with smoking [2]. Histologically, there is thickening and mononuclear inflammatory infiltration of the walls of the respiratory bronchioles. Symptoms include chronic cough, progressive exertional dyspnea, wheezing, and recurrent sinus and airway infection. Advanced disease is associated with chronic Pseudomonas aeruginosa infection. Death is usually secondary to respiratory failure or P. aeruginosa pneumonia. Between 60-70% of affected patients will be HLA-Bw54 positive. Initial treatment with erythromycin is beneficial, but the long term prognosis remains poor [3]. Lung transplant has been used in selected cases, but the disorder can recur in the transplanted lung [4].

X-ray:

CXR: CXR will demonstrate the presence of small nodular opacities up to 2 mm in size.

Computed tomography: On HRCT small, ill-defined centrilobular nodules are identified in 25% of cases and represent chronic inflammation and fibrosis in and around the respiratory bronchioles and the adjacent alveolar ducts. In patients with more severe disease, dilatation of bronchioles, intralumenal secretions, and bronchiolar wall thickening are present and appear as branching linear opacities. Areas of decreased attenuation (producing mosaic attenuation) in the lung periphery may be identified and reflect air trapping. Bronchiectasis can also be seen.

Diffuse pulmonary ossification 

Clinical:

Drug Induced Lung Disease 

Chemotherapeutic agents: 
- Bleomycin 
- Busulfan 
- Carmustine (BCNU) 
- Cyclophosphamide 
- Cytosine arabinoside 
- Interleukin-2 
- Methotrexate

Amiodarone 
Gold salts 
Nitrofurantoin 
OKT-3 
Oxygen 
Penicillamine 
Interferon 

Clinical:

Drugs, particularly cytotoxic agents, can result in a variety of lung injury including diffuse alveolar damage, interstitial pneumonitis, pulmonary edema, pulmonary hemorrhage, eosinophilic lung disease, BOOP, bronchiolitis obliterans, and pulmonary veno-occlusive disease. Four common drug-related processes in the lung are interstitial pneumonitis and fibrosis, hypersensitivity reaction, non-cardiogenic pulmonary edema, and bronchiolitis obliterans.

1. Interstitial pneumonitis and fibrosis:

Interstitial pneumonitis and fibrosis are typically associated with cytotoxic drugs such as bleomycin, methotrexate, and busulfan. Other agents, however, can also produce this type of injury including amiodarone, penicillamine, and nitrofurantoin. The radiologic findings are similar to UIP/DIP, however, the abnormalities are typically bilateral and symmetric (as opposed to the patchy distribution of abnormalities associated with UIP/DIP).

2. Hypersensitivity reaction:

Hypersensitivity reactions occur most commonly to methotrexate, nitrofurantoin, bleomycin, cyclophosphamide, and sulfonamides. The reaction is unrelated to the cumulative dose of drug received. On laboratory analysis, up to 40% of patients will demonstrate a peripheral eosinophilia. HRCT findings include patchy areas of ground glass attenuation or even consolidation. CT has been shown to be more sensitive in the detection of drug induced pulmonary toxicity (38% vs. 15% by CXR). Early there are areas of ground-glass attenuation, but with progressive damage, coarse reticular opacities and areas of consolidation develop [2].

3. Non-cardiogenic pulmonary edema:

Pulmonary edema is associated with cytotoxic agents (mitomycin-C and cyclophosphamide [5]), aspirin, and narcotics. The onset is sudden, and usually within a few days of the onset of treatment.

4. Bronchiolitis obliterans:

Bronchiolitis obliterans is primarily associated with penicillamine and sulfasalazine agents.

5. Diffuse alveolar damage:

DAD is a common manifestation of pulmonary drug toxicity. It is frequently caused by cytotoxic agents such as cyclophosphamide, bleomycin, and carmustine.

Specific Drug Induced Hypersensitivity Reactions:

Clinical:

Mechanisms of pulmonary injury associated with certain drugs include direct toxicity or a hypersensitivity reaction. Symptoms include the insidious onset of dyspnea, cough, and decreased lung volumes and diffusing capacity on pulmonary function testing. Some drugs associated with hypersensitivity reactions include:

1- Chemotherapeutic agents:

a) Bleomycin:

Bleomycin is the chemotherapeutic agent most commonly associated with pulmonary toxicity. Bleomycin is concentrated in the lung- as a result, some degree of pulmonary toxicity develops in about 4-20% of treated patients [3,4]. Diffuse alveolar damage is the most common manifestation of lung injury for this agent [7]. Doses in excess of 400 mg are associated with an increased risk for pulmonary toxicity [1,3]. The frequency and severity of toxicity increase with age, cumulative dose, and reinstitution of therapy within 6 months of discontinuation [3,4,7]. Lung damage is potentiated by concurrent radiation therapy or oxygen administration. The pulmonary abnormalities are also not confined to the radiation port, but may involve the entire lung [3]. There also appears to be a synergistic effect between bleomycin and cyclophosphamide [4]. The onset of clinical symptoms usually occurs 4 to 10 weeks after treatment. Patients complain of dyspnea, non-productive cough, and fever. Diffusing capacity for cardon monoxide (DLCO) is decreased and lung volumes are usually decreased as well. The course of bleomycin toxicity is variable. With mild toxicity discontinuation of the agent may lead to reversal of the abnormalities. In patients with pulmonary fibrosis the prognosis is poor, but a trial of steroids is warranted.

On chest radiographs, bibasilar reticular or fine nodular opacities are the earliest findings in bleomycin toxicity. With more severe involvement, these opacities progress to involve the middle and upper lung zones. The presence of multiple pulmonary nodules has also been reported with bleomycin toxicity (especially in association with a BOOP-type reaction [6,7]) and can mimic metastatic disease [2]. Rarely, patients may experience an anaphylactic response to the agent which can lead to pulmonary edema- treatment with steroids is more effective in these patients [3]. CT can detect parenchymal findings indicative of pulmonary toxicity prior to plain film findings [3].

b) Busulfan:

A dose greater than 500 mg is associated with a 4-10% incidence of pulmonary toxicity and concurrent radiation therapy increases the risk. Toxicity occurs from one month to 12 years after administration of the agent. Diffuse alveolar damage is the most common manifestation of busulfan-induced lung injury. Prognosis is poor. [6]

c) Carmustine (BCNU):

Carmustine is a nitrosurea compound used primarily to treat CNS malignancies with an incidence of pulmonary toxicity between 20-30% of treated patients. Pulmonary toxicity is dose related (cummulative dose greater than 1500 mg/m2 is associated with a 50% incidence of pulmonary toxicity [7]). Increased risk for toxicity is associated with underlying lung disease, prior thoracic radiation, and combination chemotherapy with cyclophosphamide. Patients present with progressive dyspnea on exertion and dry cough. The overall mortality from pulmonary toxicity is greater than 90% [3]. Radiographic abnormalities are usually not detected until patients have been symptomatic for some time. Typically there is bibasilar interstitial fibrosis [3], although other authors claim that diffuse alveolar damage is the most common lung injury associated with this agent [6,7].

d) Cyclophosphamide:

The incidence of cyclophosphamide pulmonary toxicity is rare. Diffuse alveolar damage is the most common manifestation of cyclophosphamide induced lung disease [7]. Symptoms may begin 2 weeks to 13 years following treatment. There is no relationship between development of lung injury and dose or duration of administration [6,7]. Patients present with dyspnea on exertion, cough, and fever. Treatment is with discontinuation of the agent and steroids with good to variable response. Overall mortality is about 50%. Radiographic findings are of basilar interstitial disease [3]. Diffuse alveolar damage can also occur with the use of this agent [6].

e) Cytosine arabinoside:

Also known as Ara-C, it is an antineoplastic agent. Acute pulmonary toxicity has been reported after treatment with intermediate or high dose levels. Patients complain of fever, dry cough, dyspnea, and hypoxemia. Symptoms usually develop during the course of administration of the agent, but may be delayed for close to one month. The chest radiograph may initially show apredominantly basilar interstitial or mixed interstitial-alveolar pattern. This progresses to a diffuse alveolar pattern in most cases which improved rapidly over 3 to 7 days. Pathologically, there is pulmonary edema with a highly proteinaceous interstitial and intra-alveolar infiltrate. [3]

f) Interleukin-2:

IL-2 stimulates production of circulating lymphokine-activated killer cells. IL-2 is associated with a high incidence of toxic reactions including non-cardiogenic pulmonary edema (likely the result of a leaky capillary syndrome). Radiographic findings can range from a mild interstitial edema to frank alveolar edema. The findings generally occur within 2 to 8 days of initiation of therapy and resolve within 4 days of termination of treatment. [3]

g) Methotrexate:

The incidence of pulmonary toxicity in patients receiving methotrexate between 5-10% [7]. The toxicity is NOT dose related, although patients that receive treatment more frequently (ie: daily or weekly) may be more susceptible to lung injury [3]. Patients generally present with fever, chills, malaise, headache, cough, and dyspnea within weeks of initiation of therapy. Peripheral eosinophilia is found in about 50% of cases and a skin eruption is seen in up to 17% of patients. The prognosis is good and the toxicity usually regresses after cessation of the agent. Radiographic findings usually clear over time (although pulmonary fibrosis may develop) [3]. Overall mortality from pulmonary toxicity is 10%.

Methotrexate toxicity begins as an interstitial pattern (reticular or reticulo-nodular), but can present with air space consolidation. The pattern can be primarily nodular. Associated adenopathy (10%) or pleural effusion can be seen. Rarely patients may present with acute pleuritis (associated with the presence of a pleural effusion) or non-cardiogenic pulmonary edema (following intrathecal administration of the agent).

2- Amiodarone:

Amiodarone is a triiodinated agent used in the treatment of cardiac dysrhythmias that accumulates in the lung largely within macrophages and type II pneumocytes. Pulmonary toxicity is seen in 5 to 10% of patients and usually occurs after 1 to 10 months of therapy. Pulmonary toxicity is dose related and is more likely to occur with doses greater than 400 mg/day. There are two distinct clinical presentations for patients with amiodarone pulmonary toxicity. Most patients present with subacute symptoms of dyspnea and a non-productive cough. A more acute onset mimicking an infectious pneumonitis occurs in about one-third of patients. The most frequent physiologic impairment is a decrease in the carbon monoxide diffusing capacity (DLCO). The prognosis is good and pulmonary toxicity is reversible in the majority of patients after discontinuation of the drug. Clinical symptoms resolve within 2 to 4 weeks and the chest radiographic findings clear slowly over about 3 months.

Radiographic findings may precede the onset of clinical symptoms. Radiographs often demonstrate a diffuse interstitial pattern with patchy alveolar opacities (patients who present with acute symptoms are more likely to have alveolar opacities). CT scan findings include septal thickening, interstitial fibrosis, and high attenuation consolidations (tend to be peripheral and basilar with attentuation's of 82 to 174 HU). Increased attenuation of the liver and spleen are also characteristic of amiodarone exposure. [3]

3- Gold salts:

Gold salts are used in the treatment of rheumatoid arthritis. The incidence of pulmonary toxicity is less than 1% and is typically a hypersensitivity pneumonitis. Toxicity usually develops 4 to 16 weeks after initiation of therapy, but can occur more rapidly. Patients present with dyspnea, cough, and fever. Eosinophilia is found in about 40% of cases. Reaction is dose related, often treated with steroids, and resolves after the drug is discontinued. Clinical improvement usually occurs over several weeks to months, but patients can have residual pulmonary dysfunction. [3]

The chest radiograph usually shows a basilar reticulonodular pattern, but mixed interstitial-alveolar or purely alveolar opacities have also been described.

4- Nitrofurantoin:

Nitrofurantoin is used to treat urinary tract infections and lung injury is uncommon (under 1% of patients receiving the medication) [6-8]. Because of the frequency with which this medication is prescribed, however, patients presenting with pulmonary toxicity are not uncommon. The agent more commonly produces an acute hypersensitivity pneumonitis usually within 2 weeks of administration with peripheral eosinophilia, fever, dyspnea, and cough [6-8]. Prognosis is good with most patients recovering after discontinuation of the agent [6]. Radiographically, acute toxicity manifests as pulmonary edema with bilateral opacities with a basilar predominance [6,8]. Chronic toxicity is less common and usually occurs after months or years of administration of the agent. Symptoms are incidious in onset and appears identical to chronic interstitial fibrosis.

5- OKT-3:

OKT3 is a murine monclonal antibody directed against the T3 antigen of human T-cells (blocking their normal function) used to treat rejection of allografts. Severe pulmonary edema can complicate the first administration of the agent and is associated with fluid over-load prior to initiation of therapy. [3]

6- Oxygen:

Prolonged therapy with tensions between 80-100% can lead to lung damage.

7- Penicillamine:

Penicillamine is used in the treatment of lead poisoning, WIlson's disease, cystinurea, rheumatoid arthritis, and scleroderma. Pulmonary toxicity is RARE, but four types of toxicity have been described: pulmonary-renal syndrome, bronchiolitis obliterans, chronic alveolitis-interstitial fibrosis, and hypersensitivity pneumonitis.

Bronchiolitis obliterans can occur 3 to 14 months after initiation of treatment. Patients present with subacute onset of cough and dyspnea. Radiographs may be normal, show hyperinflation, or show opacities (reticular or alveolar). Mortality is 38% and residual pulmonary dysfunction persists in those that survive. [3].

Pulmonary-renal syndrome can occur from 10 months to 20 years following initiation of therapy and resembles Goodpasteurs syndrome with alveolar hemorrhage and a necrotizing glomerulonephritis. Affected patients are acutely ill with abrupt onset of dyspnea, cough, hemoptysis, and hematuria. Treatment is with corticosteroids, immunosuppressive agents, and plasmapheresis. Mortality is 36% despite these aggressive measures. [3]

8- Interferon:

Up to one third of patients treated with interferon develop non-specific symptoms of cough, fever, and malaise in the first few months of treatment [9]. Up to 7% of patients on interferon can develop sarcoid [9]. Patients present with fine 1-2 mm nodular opacities which can be identified on both chest radiographs and HRCT [9]. Prognosis for interferon-induced sarcoid is good when the medication can be discontinued

Eosinophilic Granuloma 

(Langerhans Cell Granulomatosis or Langerhans Cell Histiocytosis)

Langerhans' cell histiocytosis (Histiocytosis X) describes a group of syndromes who share a common pathologic feature of infiltration of involved tissues by Langerhans' cells [12]. Classically, there is involvement of the skeletal system with a characteristic lytic bone lesion (young children) or a more acute disseminated form which occurs in infants. Pulmonary involvement is not unusual in systemic forms of Langerhans' cell histiocytosis (LCH), but symptoms are rarely prominant [12]. Localized pulmonary Langerhans'cell histiocytosis (also sometimes refered to as pulmonary eosinophois a rare pulmonary disease that occurs predominantly in young adults. It has several unique clinical features which justify its classifcation as a distinct clinicopathologic entity [12]. The precise incidence and prevalence of pulmonary LCH are unknown, although studies of lung-biopsy specimens from patients with interstitial lung disease identified pulmonary LCH in only 5% of cases [13].

Clinical:

Pulmonary involvement in langerhans cell granulomatosis is characterized by a granulomatous infiltration of the alveolar septae and bronchial walls with Langerhans' cells which produce small nodules (1 mm to 5 mm in size). The infiltrate can lead to progressive lung destruction and widespread cystic change. The disorder is rare, accounting for only 3.4-5% of cases of chronic diffuse interstitial lung disease. Patients with isolated pulmonary involvement are usually young adults (age 20 to 40 years), Caucasian, and there is an equal frequency in men and women (although young men appear to have the worst prognosis). The disorder is rare in blacks. There is a strong association with smoking (90-95% of cases occur in smokers) and symptoms often improve with cessation of smoking. There are no known genetic factors that predispose persons to pulmonary LCH [13]. Between one-quarter and one-third of patients are asymptomatic at presentation. Symptomatic patients may present with cough (66%), progressive dyspnea, weight loss, fever, diabetes insipidus (25%), or pneumothorax (10-25% of patients). Hemoptysis occurs in less than 5% of patients [13]. There is no consistent pulmonary function test finding, but mild airway obstruction is common. A reduction in the carbon monoxide diffusing capacity is present in 60% to 90% of cases [13]. On bronchoalveolar lavage (BAL), there is an increased number of cells, particularly macrophages, but this may merely be a manifestation of patients smoking history [12]. Langerhans' cells can also be found on BAL, but this finding is not specific for the disorder [12,13]. When the proportion of Langerhans' cells in the BAL fluid is greater than 5%, a diagnosis of pulmonary LCH is very likely [13]. However, a confident diagnosis of pulmonary LCH can often be made based upon the patients age, smoking history, and characteristic HRCT findings- especially if patients are to be followed without treatment [12]. When tissue confirmation is required, the diagnosis is best make by open lung biopsy via video-assisted thoracoscopy [12,13]. Transbronchial biopsy has a low diagnostic yield (ranging from 10-40%) because of the patchy nature of the disease and the small amounts of tissue obtained [12,13].

The course of pulmonary disease is variable- remission occurs in about 25-30% of patients, stabilization in 30-50%, and progression in 25-30% [2,9]. Death from respiratory failure or cor pulmonale occurs in 5% [9]. Asymptomatic or minimally symptomatic patients tend to have the best outcomes [13]. Decreased survival is associated with an very young or old age at diagnosis, persistence of systemic symptoms, recurrent pneumothoraces, extrathoracic disease (except bone lesions), diffuse cystic lesions on CXR, a lower FEV1/FVC ratio at diagnosis, a higher RV/TLV ratio at diagnosis, and need for steroid therapy [7,12].

Treatment consists of cessation of smoking which leads to stabilization of symptoms in most patients [13]. Corticosteroids are used for progressive or systemic disease [13]. Cytotoxic agents (such as cyclophosphamide) can be employed for patients that do not respond to smoking cessation and steroids [13]. No treatment has been confirmed to be useful and no double-blind therapeutic trials have been reported [12,13]. Lung transplantation has also been performed for treatment of LCH. There are no specific guidelines for which patients with pulmonary LCH should be candidates for lung transplantation [13]. Patients with rapidly declining lung function, severe pulmonary symptoms, and lack of response to other treatments are the best candidates for lung transplant consideration [13], but the disorder may recur in the transplanted lung in up to 25% of patients [8,9,15].

The etiology of the disorder is not known, but the bronchocentricity and tendency to regress following cessation of smoking suggest a reactive immune response in the bronchioles to an inhaled antigen in cigarette smoke mediated by the Langerhans' cell system [4,8,13]. The recurrence of the disease after transplantation suggests that extrapulmonary factors also play a role in disease pathogenesis, or that the condition may represent a neoplastic disorder [8]. An association between EG and lymphoma has been described [12,13]. Bronchogenic carcinoma has been identified with increased frequency in patients with pulmonary LCH [12]. Lung scaring and smoking may contribute to the development of lung cancer in these cases [12,13]. Although intriguing, there is likely insufficient evidence either to prove or to refute the association between pulmonary LCH and malignanct neoplasms [13].

Histopathology:

Langerhans' cells are part of the widespread system of "dendritic cells" which arise from bone marrow stem cells and they are normally present in the human lung [7-9]. They can be distinguished from histiocytes by cytoplasmic immunostaining with S100 antigen [8,9]. Two other unique features of Langerhans' cells are the presence of Birbeck granules (rod-shaped intracellular structures identified by electron microscopy) and the presence of CD1a antigen on the cell surface [13]. As a result, some authors prefer to term the disorder Langerhans cell "granulomatosis" as the Langerhans cell is not a member of the mononuclear phagocytic system (ie: not a macrophage or "histiocyte") [7]. Because Langerhans' cells may be identified in several pathologic pulmonary processes, the mere presence of pulmonary Langerhans' cells is not diagnostic of pulmonary LCH [13].

X-ray:

CXR: The CXR is normal in under 10% of cases [12].There is usually diffuse reticulonodularity (3-10 mm nodules which may cavitate) in a symmetric upper lobe predominance (bases tend to be spared) with preservation of lung volumes [13]. Associated pneumothorax is found in 15-25% of cases. Pleural effusion is rare. In the late stage, there may be diffuse cysts which spare only the costophrenic angles.

Based upon the radiographic findings, disorders which can be entertained in the differential diagnosis for LCH include: Sarcoid, Silicosis, hypersensitivity pneumonitis, and lymphangioleiomyomatosis (during the later stages of the disorder when cytic lesions predominate) [13].

Computed tomography: On HRCT the distribution of the disease is similar to that on CXR with an upper lobe predominance. Findings include centrilobular opacities, small nodules (1 to 5 mm, but up to 1.5 cm), cystic cavitation of small nodules, and cysts- initially thick walled and later thin walled (typically lesions progress in this fashion). Some authors feel that the nodules do not cavitate and that the cysts represent paracicatrical emphysematous change adjacent to the nodules. The cysts are usually less than 10 mm in size, although cysts larger than 10 mm are found in over half the cases. The walls of the cysts are usually thin (1mm or less), but can be variable, and the cysts are not necessarily round (they may be bilobed or branching). The intervening lung parenchyma appears normal. In the late stage, there may be diffuse cysts, with no nodules evident (about 20% of cases [6]), while in the early stages, only nodules may be seen [3]. In the late stages, the disorder may be indistinguishable from lymphangiomyomatosis- but sparing of the costophrenic angles suggests the diagnosis of histiocytosis X [6]. Mediastinal adenopathy has been described in some series, but is usually uncommon [2]. Other authors report medistinal adenopathy in up to 30% of EG patients [10].

Scintigraphy: Gallium-67 scans are generally negative [12].

Eosinophilic lung disease 

1- Idiopathic eosinophilic lung disease: 

.....a. Loffler's syndrome 

.....b. Acute eosinophilic pneumonia 

.....c. Chronic eosinophilic pneumonia 

.....d. Idiopathic hypereosinophilic syndrome 

2- Eosinophilic lung disease of specific etiology 

3- Eosinophilic lung disease associated with angiitis 

Extrinsic Allergic Alveolitis 

Fibrosing Mediastinitis 

Follicular Bronchiolitis 

Goodpasteur's syndrome 

Hamman-Rich syndrome 

Hypersensitivity pneumonitis 

Idiopathic Giant Bullous Emphysema (Vanishing Lung) 

Idiopathic pulmonary hemosiderosis 

Idiopathic pulmonary fibrosis: (Cryptogenic fibrosing alveolitis) 

1- Desquamative interstitial pneumonia 

2- Usual interstitial pneumonia 

3- Nonspecific interstitial pneumonia 

Langerhans cell histiocytosis 

Loffler's syndrome 

Lymphangioleiomyomatosis 

Lymphocytic Interstitial Pneumonitis (LIP) 

Lymphomatoid granulomatosis 

Angiocentric immunoproliferative lesion/Angiocentric lymphoma

Clinical:

Lymphomatoid granulomatosis has recently been termed- Angiocentric immunoproliferative lesion (AIL). It is an angiodestructive lymphoreticular and granulomatous disease with a prediclection for extranodal involvement- most commonly the lungs. The lymphoid infiltrate surrounds muscular arteries and veins early in the disease course, and typically invades the walls of the vessels which results in vascular compromise and infarction.

The majority of affected patients are middle aged (40-60) and present with cough, hemoptysis, malaise, rash, and weight loss. Skin lesions (ulcers, subcutaneous nodules, or maculopapular eruptions) are found in up to 40-50% of cases (the most frequent site of extra-pulmonary disease), and CNS involvement occurs in 20-30% (peripheral neuropathy, cranial nerve palsey, or mass lesion). Skin lesions occur prior to chest radiologic abnormalities in up to one-third of patients. Unlike Wegener's, involvement of the paranasal sinuses and kidneys are not typical features of the disease, although they can be affected. The disease typically has a rapid onset and progression- mortality approaches 60%, particularly in patients with CNS or liver involvement. An association with the Ebstein Barr (E-B) virus has been described- most cases of AIL represent a proliferation of E-B virus infected B-cells with a prominent T-cell reaction and vasculitis [4].

Diagnosis usually requires open lung biopsy as transbronchial biopsy is positive in only about 30% of cases. The disordered is graded based upon the degree of cytologic atypia from Grade I (little or no atypia) to Grade 3 (prominent atypia- angiocentric lymphoma). About one-third of patients with grade I lesions progress to malignant lymphoma, while nearly two-thirds of patients with grade 2 lesions will develop lymphoma (look for presence of mediastinal/ hilar adenopathy to suggest the development of lymphoma). Combination cytotoxic therapy is the treatment of choice, but is generally unsuccessful. Overall prognosis is poor and most patients do not survive more than 2 years [5].

X-ray:

The CXR appearance is similar to Wegener's granulomatosis- bilateral lung nodules ranging in size from 1 to 5 cm are found in up to 70-80% of cases. Nodules may sharp or poorly defined. Cavitation occurs in about 20-25% of nodules. Findings are bilateral in 90% of cases. Diffuse, coarse, reticulonodular infiltrates may also be seen less commonly (4 to 40%). Adenopathy is rare in the absence of lymphoma. Pleural effusions are uncommon and if present suggest pleural involvement (although other authors describe the presence of effusions in up to 30% of cases [5]).

On CT, the findings include the presence of multiple well or poorly defined nodules (5 to more than 60) generally less than 1 cm in size (but up to 6 cm) [4]. The nodules have a peribronchovascular distribution and small nodules can coalesce to form larger conglomerations [4]. Thin walled cysts (1-2 cm) can be seen in up to 60% of cases

Mixed Connective Tissue Disease 

Mounier-Kuhn syndrome 

Nonspecific interstitial pneumonia 

Polymyositis / Dermatomyositis 

Relapsing polychondritis 

Respiratory bronchiolitis 

Clinical:

CXR: CXR can be normal or show non-specific, lower lobe, irregular small opacities. The disorder typically involves the lung in a patchy fashion.

Computed tomography: The majority of patients with respiratory bronchiolitis have normal CT scans. When abnormalities are present they consist of multiple areas of ground glass opacity most prominent in the upper lobes [2,4] and ill-defined centrilobular parenchymal and subpleural nodules within the mid to upper lung zones (similar to hypersensitivity pneumonitis, but nodules are less diffuse) [4] and bronchial dilatation.

Respiratory Bronchiolitis Associated Interstitial Lung Disease:

CXR: On CXR diffuse or basilar, bilateral, small linear and nodular opacities are found in 70% of cases, but the film can be normal in up to 21% of cases. Thickening of the walls of the central or peripheral bronchi can be seen in about 75% of cases [5]. Areas of atelectasis are found in just over 10% of cases. Adenopathy and pleural effusion are not seen.

Computed tomography: The CT features of RB-ILD overlap with those of DIP, hypersensitivity penumonitis, and non-specific interstitial pneumonitis [5]. On CT scattered areas of ground glass opacification is the most common finding (66%) and can mimic desquamative interstitial pneumonitis or respiratory bronchiolitis [4]. Ill-defined centrilobular opacities can be seen due to bronchiolar inflammation [3]. The changes tend to have an upper lobe predominance, but may be diffuse [3]. Septal thickening and irregular linear opacities are infrequent [1]. Thickening of the walls of the central or peripheral airways can be seen [5].

- Respiratory bronchiolitis associated interstitial lung disease 

Rheumatoid Arthritis 

Clinical:

Pulmonary manifestations include:

• Pleural effusions/ Pleural Thickening: Pleural disease is the most common intrathoracic manifestation of rheumatoid arthritis [3]. Up to 5% of patients with RA have radiographic evidence of a pleural effusion sometime during the course of their disease, however, only about 20% of affected patients will be symptomatic [3]. Pleural manifestations are more common in men and in patients with longstanding severe arthritis [3]. Effusions are typically small, unilateral, and associated with periods of active arthritis [3]. The effusion typically resolve over weeks to months with treatment of the active arthritis (but they can last longer) [3]. The effusion is characteristically exudative with a low glucose level (less than 50 mg/dl in 75% of patients), low white cell count (less than 5000/mm3), and a low pH (less than 7.2) [3].
• Interstitial lung disease: The interstitial lung disease associated with rheumatoid arthritis is histologically indistinguishable from idiopathic pulmonary fibrosis (UIP), although RA patients uncommonly progress to respiratory failure [3]. A lower lobe predominance is also characteristic. Males are affected more than females. Radiologically detectable disease occurs in about 10-30% of rheumatoid patients. Arthritis precedes development of interstitial lung disease in 90% of cases [3], and 90% of patients have a positive serum rheumatoid factor. On HRCT findings include sub-pleural nodules (3-30mm) in up to 22% of patients, pseudoplaques, areas of ground glass attenuation (14%), fine reticular interstitial disease with a basilar predominance, and later honeycombing [1].
• Necrobiotic nodules: The presence of necrobiotic nodules in the lungs is usually associated with the presence of cutaneous nodules. They are found in fewer than 1% of RA patients. The nodules often develop concomitantly with joint disease, but they may precede the onset of arthritis. Affected patients are typically asymptomatic, although cough, dyspnea, and hemoptysis have been described as presenting symptoms. The nodules are more common in men and can range in size from 0.5 to 7.0 cm [3]. Nodules do not calcify, are usually peripheral, and have an upper and mid-lung predominance [3]. Cavitation may be identified in up to 50% of nodules [3]. The nodule is often centered on a necrotic inflammed blood vessel, suggesting that vasculitis may be the initial insult. The clinical course of patients with rheumatoid pulmonary nodules is usually benign. The nodules may resolve spontaneously, recur, or develop at one site while resolving in another [3].
• Caplan's syndrome: Caplan's syndrome is characterized by rheumatoid arthritis with pulmonary rheumatic nodules in coal workers typically with preexisting mild pneumoconiosis [3]. The nodules typically measure between 0.5 to 5 cm in size and may cavitate.
• Drug induced lung disease: Drugs used in the treatment of rheumatoid arthritis have also been associated with the development of interstitial lung disease. Drug induced interstitial pneumonitis can occur in 5% to 10% of patients treated with methotrexate. It characteristically elicits no eosinophilic response and will resolve when the drug is discontinued [3]. Interstitial pneumonitis is also associated with gold therapy. The pneumonitis also usually resolves when the drug is stopped [3].
• Pulmonary arteritis and pulmonary hypertension: Systemic vasculitis in patients with rheumatoid arthritis is rare [3]. The most common presenting symptom is hemoptysis in the setting of a pulmonary-renal syndrome. Treatment usually involves corticosteroids and cyclophosphamide [3].
• Airway Disease: Airway disease has only recently been described in patients with RA. Bronchiectasis and bronchiolectasis have also been identified in up to 30% of patients [2]. Bronchiolitis obliterans [3], constrictive bronchiolitis, and follicular bronchiolitis [5] have also been described.
• Pericarditis (20-50%) or myocarditis

Sarcoidosis 

Clinical:

The specific etiology of sarcoidosis has not yet been identified, but it likely the result of an interaction between environmental exposures and genetic susceptibility [8]. Thoracic sarcoidosis is a great mimic of other diseases including lymphoma, tuberculosis, and many causes of chronic pulmonary infiltrates. Sarcoid begins as an alveolitis/ non-granulomatous pneumonitis with a T-cell infiltrate. T-cells release factors which attract macrophages which in turn form giant cells and non-caseating granulomas within the interstitium. The end result is interstitial fibrosis [4].

Patients generally present between the age of 20 to 40 years. Blacks (African-Americans) are affected more than whites (3 to 15:1) and females more than males (for black population [9]). Sarcoid is rarely seen in Afrian and South American blacks [9]. The disorder is rare in children and when it occurs, usually affects white males. Familial disease is seen much more frequently in blacks (17% of cases) [8]. Sarcoid seems to have an earlier onset and more aggressive clinical course in blacks [8]. Smokers are not an an increased risk for sarcoid, and smoking may have an inverse relationship to the disorder [8]. The development of sarcoid has been seen in association with interferon therapy [16]. Up to 7% of patients receiving interferon may develop sarcoid [16].

Most patients are asymptomatic (25-50%), but they can present with insidious onset exertional dyspnea, non-productive cough, low grade fever, decreased vital capacity, FRC, and diffusing capacity. Lab analysis in patients with sarcoid reveals an elevated angiotensin converting enzyme (ACE) level in 56-67% of patients with stage I, 72-87% with stage II, and 56-95% of patients with stage III disease [4]. ACE levels may correlate with disease activity- ACE is a product of macrophages and is an indicator of granuloma burden in the body [9]. Other findings include anergy, peripheral lymphopenia (depressed cellular immunity), and hypergammaglobulinemia. Hypercalcemia/ hypercalciuria is found in 2-15% of patients and is secondary to macrophages and granulomas which are extra-renal sources of 1,25-OH Vit. D. The Kveim-Siltzbach test is positive in 90% of patients with active disease. PFT's can reveal either a restrictive or obstructive pattern. Interstitial disease results in low lung complicance, while peribronchial lesions can obstruct small airways [9].

It is important to remember that sarcoid is a systemic process which can involve other organ systems: Bone (up to 15%), Liver/Spleen (25-70%), CNS (9%- basal granulomatous meningitis; hypothalamus; cranial neuropathy), Skin (10% to 30%- erythema nodosum, lupus pernio), Eyes (25%- uveitis), and the Myocardium. The trachea is involved in 1-3% of cases- most commonly the subglottic region.

Lofgren's syndrome refers to an acute febrile illness accopanied by bilateral hilar adenopathy and erythema nodosum in a patient with sarcoid [9]. They may also have uveitis or parotitis and arthralgias of large joints. These findings are associated with a favorable prognosis. [4]

Lupus pernio refers to the presence of violaceous (blue-purple) raised skin lesions on the cheeks and nose in a patient with sarcoid. It is associated with a poor prognosis.

In HIV: A number of cases have been described of new onset sarcoid in HIV patients following initiation of antiretroviral therapy with rise in CD4 count [10,12]. This may be related to immune restoration [10,12]. The radiologic features are similar to sarcoid in non-HIV patients [12].

Treatment:
Steroids can relieve symptoms and suppress inflammation. Indications for steroid therapy include CNS, occular, cardiac and progressive pulomary involvement, as well as hypercalcemia. Initial response to steroid treatment does not preclude progression to pulmonary fibrosis. [9]. For the treatment of end-stage lung secondary to sarcoid, lung transplant can be performed. Unfortunately, the disorder recurs in the transplanted lung in up to 35% of cases [14].

Staging:

Staging is based upon the CXR findings (4): Stage 0- Normal CXR; Stage 1- Mediastinal/ Hilar adenopathy; Stage 2- Adenopathy plus parenchymal infiltrates; Stage 3- Lung infiltrates only (adenopathy has resolved); and Stage 4- Fibrosis/ Cystic changes.

At presentation about 5-10% of patients have stage 0 disease; 50% stage I; 25-30% stage II; and 15% stage III [9]. Prognosis is directly correlated with the patients staging. About 65-70% of patients with stage I disease will demonstrate spontaneous clearing of radiographic abnormalities and only about 7% will progress to stage II (4). About 30-50% of patients with stage II disease and 10-20% of patients with stage III disease have radiographs that return to normal. Overall about 20% of affected patients will progress to pulmonary fibrosis. Non-whites tend to have extrathoracic manifestations and an overall poorer prognosis [9]. There is a 5% mortality rate due directly to sarcoid [9].

Complications:

1- Pulmonary fibrosis: About 10-20% of patients progress to stage 4 disease. The disorder proves fatal in only 4 to 10% of cases, usually the result of pulmonary fibrosis and cor pulmonale.

2- Mycetoma/Aspergilloma: A complication of stage 4 disease. Although the characteristic finding is that of a fungus ball within an apical cavity, pleural thickening may may be the earliest indication of Aspergillus superinfection- occuring 2-3 years prior to the appearance of an intracavitary fungus ball. The pleural thickening is often striking and may achieve a thickness of 2 cm or more (5).

3- Pneumothorax: Most cases occur in association with diffuse pulmonary parenchymal disease- particularly fibrocystic disease and are probably due to rupture of subpleural bleb. The incidence of pneumothorax is said to be higher in blacks than in caucasians- likely due to the greater likelihood for disease progression in blacks (5).

4- Cardiac arrhythmias: Due to cardiac involvement.

X-ray:

CXR: Plain film CXR abnormalities are found in over 90% of patients with sarcoid at sometime during the course of their disease (1). Bilateral hilar adenopathy is found in 95% of cases, right paratracheal adenopathy in 70%, and AP window adenopathy in 30-50%. Subcarinal nodes can also be involved in up to 25% of patients. Lymph node calcifications are found in 3-20% (5). Calcification can be amorphous, popcorn-like, or uncommonly egg-shell in appearance (5%). Calcification of affected nodes is related to duration of disease. Calcification is seen in 3% of cases after 5 years, and in 20% of cases after 10 years. RARE nodal findings include isolated mediastinal adenopathy (anterior, middle, or least commonly- posterior mediastinal adenopathy), or isolated unilateral hilar adenopathy (1-3%) (5). Older patients are more likely to have atypical patterns of adenopathy [9].

The interstitial lung disease can have a variety of appearances: a reticulo-nodular pattern is the most common and is typically bilateral and symmetric. An acinar or "alveolar" pattern with small indistinct nodular opacities can be seen. The densities can be discrete or coalesce producing areas of apparent parenchymal consolidation with air bronchograms. The infiltrates can be peripheral and mimic pulmonary infiltrates associated with eosinophilia (1). Despite the appearance of airspace disease, the abnormality is still the result of interstitial disease. Multiple nodules have also been described, particularly in young black females and are usually very responsive to steroid therapy. Pleural effusions are RARE (0-5%), can be uni- or bilateral, are usually small to moderate in size, and are usually straw colored exudates with a lymphocyte predominance (5). A negative gallium scan is a reliable indicator of clinical inactivity.

Computed tomography: CT is more sensitive than CXR in the detection of adenopathy and parenchymal lung disease [9]. Mediastinal adenopathy is easily demonstrated.

HRCT is used to evaluate for parenchymal lung disease. On HRCT there is nodular thickening of the bronchial walls and along vessels. Similar changes may be noted along the fissures. These findings are related to the presence of non-caseating granulomas which are distributed within the bronchial mucosa, and along the lymphatics in the bronchovascular bundles, interlobular septa, and subpleural regions. Subpleural nodules (3-10mm in size) are found in 60-80% of cases. When identified, the previous finding is associated with a very high diagnostic success rate for transbronchial biopsy (80-95%) [3]. Large nodules greater than 1 cm in diameter occur as a result of coalescence of small nodules and are often surrounded by many tiny satellite nodules [17]. Other findings include ill-defined centrilobular nodules which may coalesce and nodular or irregular thickening of the interlobular septae. Nodular or irregular (occasionally smooth) thickening of the perivascular interstitium is also particularly common in sarcoid. The distribution of perivascular interstitial thickening may be patchy. Endobronchial granulomata in patients with sarcoid may rarely (1% of cases) result in significant airway narrowing [13]. Parenchymal bands can be seen in patients with sarcoid. Areas of ground glass attenuation can also be identified and reflect the presence of microscopic interstitial granulomas, rather than alveolitis. Air trapping at the level of the secondary lobules has also been described and is felt to be related to narrowing of the small airways as a result of peribronchiolar granulomas [2,11]. Air trapping will appear as areas of decreased attenuation on expiratory images. Parenchymal opacities with air bronchograms may be seen in sacoid (alveolar sarcoid), but are uncommon. The extent of abnormalities on CT unfortunately correlate poorly with the patients level of functional impairment. Severe fibrosis and end-stage changes result in architecture distortion and traction bronchiectasis which is difficult to distinguish from other causes of end-stage lung disease.

Skeletal lesions tends to involve the small bones of the hands and feet and there is usually associated skin changes. Findings include a reticular trabecular pattern, mottled appearance, or cyst-like lesions. The lesions are hot on bone scan.

Sjogren's Syndrome 

Systemic lupus erythematosis 

Systemic sclerosis (Scleroderma) 

Tracheobronchopathia osteochondroplastica 

Usual interstitial pneumonia 

Vanishing Lung Syndrome 

Wegener's granulomatosis