key: cord-0035055-dp5hap2j
authors: nan
title: Alveolar Diseases
date: 2006
journal: Diffuse Lung Diseases
DOI: 10.1007/88-470-0430-6_5
sha: 576e8d2f273ed55c3ba54f8d76b123bf892665b8
doc_id: 35055
cord_uid: dp5hap2j

nan

Diffuse (alveoli and alveolar septa) Histopathologic differential diagnoses:

• DAD associated with infections: granulomas, viral inclusions, necrotic foci, abscesses; identification of the microorganism with special stains • DAD superimposed on UIP (accelerated UIP): associated with the characteristic UIP pattern • DAD due to other causes: not idiopathic but secondary to other causes (shock, trauma, physical or chemical causes, etc.) • OP: predominantly intraalveolar foci of fibroblastic organization, intense inflammatory infiltrate, bronchiolar involvement (not constant)

Katzenstein AL. Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol 1986, 10: 256

Basic radiological signs, typical of the early stage (1-7 days): • Parenchymal consolidation (A) • Ground-glass opacities ( ) Akira M. Computed tomography and pathologic findings in fulminant forms of idiopathic interstitial pneumonia. J Thorac Imaging 1999, 14: 76 Diffuse (alveoli and alveolar septa)

Histopathologic differential diagnoses: • DAD associated with infections: granulomas, viral inclusions, necrotic foci, abscesses; demonstration of the microorganism with special stains • DAD superimposed on UIP (accelerated UIP): the characteristic UIP pattern appears, that is, spatially and temporally heterogeneous fibrosis originating from the subpleural regions, with fibroblastic foci at the interface with normal parenchyma • OP: predominantly intraalveolar foci of fibroblastic organization, intense inflammatory infiltrate, bronchiolar involvement (not constant)

A possible variant of DAD, acute fibrinous and organizing pneumonia (AFOP), has recently been reported, which is histologically characterized by intraalveolar fibrin accumulation in the form of "fibrin balls" without the classic hyaline membranes and associated with foci of organizing pneumonia in the bronchioles and alveolar ducts 

Goodman LR. Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: CT, clinical, and functional correlations. Radiology 1999, 213: 545 Bilateral and patchy, prevalently symmetrical in ARDS due to extrapulmonary causes, and asymmetrical in ARDS due to a primary pulmonary cause Diffuse, although the opacities tend to become more uniform and dense in the dependent areas, especially in ARDS due to extrapulmonary causes Diffuse, although consolidation is more extensive at the lung bases

The degree of opacification tends to increase in the more dependent regions as a result of the parenchyma progressively collapsing under the weight of the dense lung above Lung volume may be reduced

Other non-constant radiological signs: • Regular reticular pattern due to septal thickening • Association of reticular pattern and ground-glass attenuation (A)(crazy paving) • Pleural effusion (moderate)(D)

Desai SR. Acute respiratory distress syndrome: imaging of the injured lung. Clin Radiol 2002, 57: 8 Radiological differential diagnoses: • AIP: the radiological pattern may be identical since AIP is an idiopathic form of ARDS • PE: the opacities are more uniform, frankly gravitational and without air bronchogram. A reticular pattern is almost always present, and cardiomegaly and pleural effusion are common • Fluid overload: increase in the diameter of the superior vena cava (due to increased volume of circulating blood) and thickening of the chest wall soft tissues Gluecker T. Clinical and radiologic features of pulmonary edema. Radiographics 1999 Radiographics , 19: 1507 Ketai LH. A new view of pulmonary edema and acute respiratory distress syndrome. J Thorac Imaging 1998, 13: 147

Patients requiring mechanical ventilation have a higher risk of developing the typical complications of ARDS (ventilator-associated pneumonia, multiple organ failure) or complications associated with treatment (barotraumas with pneumothorax, pneumomediastinum and chest wall emphysema)

Maffessanti & Dalpiaz

Prognosis is poor and the disease may be fatal in 35-40% of cases. Ninety percent of deaths occur within the first 2 weeks of onset of the symptoms. The presence of infections or multiorgan failure has negative prognostic implications. Survivors may recover normal pulmonary function or in some cases experience pulmonary fibrosis

Depending on the clinical course, the following radiological patterns may be observed: • Progressive regression of opacities with complete healing of lesions • Regression of the alveolar opacities with persisting reticular pattern and distortion of lung parenchyma anteriorly • Progressive increase in opacities with appearance of linear opacities and remodeling of the lung architecture (fibrosis) and formation of paradoxical hyperlucencies due to vascular obstruction Desai SR. Acute respiratory distress syndrome: CT abnormalities at long-term follow-up. Radiology 1999, 210: 29 

Neutrophilic leukocytosis in the peripheral blood is a common finding, and hematological changes ascribable to disseminated intravascular coagulation (DIC) are relatively common

The diagnosis is made on the basis of the clinical picture (acute onset in the absence of left cardiac failure and with apparent predisposing condition), radiological pattern (bilateral opacities at chest radiograph) and functional findings (PaO2/FiO2 <200; pulmonary capillary wedge pressure <18 mmHg)

Surgical lung biopsy is rarely required. Transbronchial lung biopsy is of no diagnostic value, however, it can significantly narrow the differential diagnosis

In early ARDS, the BAL fluid shows a marked increase in neutrophils, whereas in late ARDS lymphocytes and eosinophils predominate. The finding of a high number of neutrophils in late stage ARDS indicates a negative prognosis. The cytologic preparations of BAL fluid should also examined for reactive type II pneumocytes (the atypia of these cells may be severe enough to mimic carcinoma), as well as fragments of hyaline membranes. Increased concentrations of toxic oxygen species, proteases and cytokines/chemokines (TNF-alpha, IL-1 and IL-8) have been found in the supernatant In intensive care units, BAL is particularly useful for differentiating ARDS from: 1. diffuse alveolar hemorrhage (bloody fluid, erythrocytes and hemosiderin-laden macrophages); 2. acute eosinophilic pneumonia (marked increase in eosinophils); 3. drug-induced pulmonary toxicity (CD8+ lymphocytosis and foamy macrophages); 4. fast-growing neoplasms (cancer cells); 5. infections with associated acute lung injury (direct visualization or positive quantitative culture of the causative microorganism); 6. cryptogenic organizing pneumonia (CD8+ lymphocytosis, neutrophils and foamy macrophages) Bronchioloalveolar carcinoma (BAC) is a primary lung tumor that may present in a focal (more frequent) or diffuse form, both at onset and during the course of the disease. This chapter will cover only the diffuse form Alveolar carcinoma, pulmonary adenomatosis DEMOGRAPHICS BAC is thought to originate from a bronchiolar stem cell capable of differentiating into different cell types.

The multifocal form may result from a single lesion spreading through the airways or the synchronous growth of independent neoplastic clones. A viral etiology (retrovirus) has also been suggested based on the morphological similarity of BAC to jaagsiekte (a contagious viral disease in sheep)

BAC accounts for 1-9% of all primary lung tumors. Age at diagnosis ranges from 50 to 70 years, and there is no racial or gender predilection BAC features may be seen in old focal or diffuse scar lesions

In the diffuse form of BAC the most common symptoms (often present 6 months to 1 year before diagnosis) are cough (50-70%), sputum production (20-50%), bronchorrhea >100 ml/day (5-25%), chest pain (30-50%), dyspnea (25-50%), hemoptysis (10-25%) and weight loss (25%) Physical examination reveals localized or diffuse rales and at times signs of pleural effusion Lung function tests are often normal. There may be a restrictive ventilatory defect with reduced D L CO and hypoxemia, which may be severe due to a physiologic shunt Bronchorrhea is indicative of diffuse disease and may be so massive as to cause hypovolemia and prerenal failure with hyponatremia Mucinous BAC consists of columnar cells with round basal nuclei and abundant clear cytoplasm rich in mucin that often form micropapillae. In this variant, which may present as a solitary nodule, multiple nodules or alveolar consolidation (diffuse pneumonitis variant), dissemination often occurs through the airways with the formation of satellite nodules and rapid development of diffuse intrathoracic disease Non-mucinous BAC may exhibit the two distinct cell types of the distal lobule: one is similar to Clara cells, with cuboid or cylindrical eosinophilic cytoplasm with apical projections and PAS-positive granules; the other is similar to type II pneumocytes, and consists of squamoid cells with round nuclei and finely vacuolated or even foamy cytoplasm. The nuclei of either of these cell types may show eosinophilic inclusions surrounded by a clear halo. Dissemination through the airways is rare in this variant Mixed or indeterminate BAC consists of a mixture of mucinous and non-mucinous cells or indeterminate cells which grow along the alveolar walls without invading the stroma Non-mucinous BAC is often associated with central alveolar collapse leading to fibrosis. The fibrosis should not be mistaken for the scars seen at the center of peripheral adenocarcinomas (scar cancer) Diffuse along the alveolar septa It is not uncommon to find foci of adenocarcinoma with stromal invasion associated with features of bronchioloalveolar growth; consequently, the histopathologic diagnosis of a "pure" BAC requires extensive sampling to exclude the presence of stromal invasion A four-point grading system for stromal invasion has recently been proposed which has prognostic implications. Invasion is absent in BAC (grade 0) and present to varying degrees in adenocarcinoma (grades 1, 2, 3) Brambilla E. The new World Health Organization classification of lung tumours. Eur Respir J 2001 Respir J , 18: 1059 Sakurai H. Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis. Am J Surg Pathol 2004, 28: 198 Histopathologic differential diagnoses:

• Atypical adenomatous hyperplasia: the lesion is smaller than 5 mm, the cells are arranged in a single layer, and cytological atypia is not prominent • Bronchiolar metaplasia (lambertosis): the lesion is centrilobular and originates from the bronchiole. There may be an identifiable connection with clearly benign epithelium. The cells are often ciliated and show no evidence of malignancy or nuclear inclusions • Type II pneumocyte hyperplasia: the cellular monotony and lepidic growth pattern typical of BAC are absent, and the transition to normal epithelium is gradual • Clara cell, papillary and alveolar adenomas: small, well-circumscribed lesions without cytologic atypia • Sclerosing hemangioma: papillary, well-circumscribed lesion with areas of recent and old hemorrhage and sclerosis • Metastases: infiltration of the septa, marked atypia, history of neoplasm Although both primary and metastatic adenocarcinomas (e.g. of the colon and pancreas) may exhibit bronchioloalveolar-type (lepidic) growth patterns at the periphery, they also show stromal, vascular (hematic or lymphatic) or pleural invasion Basic radiological signs:

• Multiple areas of parenchymal consolidation ( ) • Ground-glass opacities with irregular hazy contours (A) • Air bronchogram within the lesions giving the appearance of a leafless tree (D) One of the parenchymal opacities usually predominates in terms of density or extension Unilateral or bilateral, usually asymmetrical, often patchy Peripheral and subpleural (50%) Basal (50%) Lung volume is normal, although bulging of the fissural border may be noted in extensive lobar consolidation Other radiological characteristics: • Nodules with hazy margins ( ) or true large opacities (© Large rounded opacities: BAC) • Internal hyperlucencies appearing as pseudocavitations or pseudocysts • Low-attenuating parenchymal consolidation with enhancing vessels after administration of contrast material (angiogram sign) • Linear bands of septal thickening associated with the ground-glass opacity (crazy paving)(A) • Adenopathy, pleural effusion, calcifications (of the mucoid matrix)

Im JG. Lobar bronchioloalveolar carcinoma: "angiogram sign" on CT scans. Radiology 1990, 176: 749 Recent research suggests that a pattern of well-defined nodules, once thought to be possible in BAC, is instead due to hematogenous spread of components of classical adenocarcinoma The pseudocavitary hyperlucencies are related to bronchiolar obstruction, even though true cavitations may also occur (rarely) Gaeta M. Radiolucencies and cavitation in bronchioloalveolar carcinoma: CT-pathologic correlation. Eur Radiol 1999, 9: 55 All diseases characterized by chronic parenchymal consolidation enter the differential diagnoses:

• Slowly resolving infections: the clinical history and the regression of the opacities in subsequent radiograms are the key to the diagnosis • OP: the peripheral and/or peribronchial areas of consolidation tend to be triangular or polygonal in shape • PAP: bilateral, symmetrical, more extensive in the axial plane; widespread crazy paving • CEP: the areas of consolidation are more distinctly subpleural and prevail in the upper lung fields • MALToma: differentiation may be impossible, except for a slower progression; the differential diagnosis is based on the biopsy findings • Exogenous lipoid pneumonia: clinical history, at times negative density at CT Aquino SL. Distinction of consolidative bronchioloalveolar carcinoma from pneumonia: do CT criteria work? AJR Am J Roentgenol 1998, 171: 359

The clinical progression of the diffuse form of BAC is very rapid, with death sometimes occurring within weeks of diagnosis. The most frequent causes of death are respiratory failure, pulmonary embolism, cardiac tamponade, pneumothorax and pneumonia

The existing areas of consolidation become more compact and homogeneous, and new areas of consolidation appear, even contralaterally, as a result of bronchogenic spread, in a relentless progression

About half of patients show increased serum carcinoembryonic antigen levels, whereas a smaller proportion have increased amylasemia and CA 19-9. Patients with bronchorrhea may have elevated azotemia due to prerenal failure and electrolyte disturbances

In an appropriate clinical and radiological setting, the repeated finding of well-differentiated cancer cells in the sputum is considered diagnostic (25-50% of cases)

In some cases, the diagnosis requires a histological sample which may be obtained by transbronchial or transthoracic lung biopsy. However, the diagnostic certainty of a "pure" BAC requires extensive samples and therefore surgical lung biopsy Analysis of the BAL fluid often reveals the presence of well-differentiated neoplastic alveolar cells, although this finding is not sufficient for differentiating BAC from a primary or metastatic adenocarcinoma 

The causative agent and pathogenesis are unknown Idiopathic CB is a rare clinical-pathological syndrome seen in middle-aged adults, and more commonly in females. It accounts for 4% of all obstructive pulmonary diseases There are no known risk factors, not even cigarette smoking

The main symptoms are dyspnea, dry cough and rarely wheezing. Systemic symptoms such as malaise and asthenia may also be noted. The symptoms may be present for several months before diagnosis Chest physical examination is generally unhelpful, although there have been rare reports of wheezes, rales and ronchi Typically there is an irreversible obstructive ventilatory pattern. The obstruction is often severe and accompanied by a reduced DLCO Kraft M. Cryptogenic constrictive bronchiolitis. A clinicopathologic study. Am Rev Respir Dis. 1993 , 148: 1093 PATHOLOGY CB usually presents as an isolated lesion of the bronchioles, with only minimal, if any, changes to the surrounding parenchyma. The basic lesions include:

• Narrowing and distortion of the lumen of the small airways due to submucosal or adventitial fibrosis ( ). In the more severe cases the lumen may be completely obliterated (A) • Hypertrophy of the bronchiolar wall smooth muscle • Bronchiolar ectasia with mucostasis • Bronchiolar metaplasia of the alveolar epithelium ("bronchiolization" or "lambertosis") The bronchiole and accompanying branch of the pulmonary artery have a similar diameter and are uniformly distributed in the peripheral parenchyma. Any variation to this condition suggests small airways disease. In addition, the normal bronchiole has a layer of loose connective tissue beneath the epithelium. In patients with small airways disease fibrous tissue is deposited in this area

Basic radiological signs:

• Well-defined patchy areas of reduced parenchymal density (D), which stand out on a background of normal lung • Paucity (reduction in number and diameter) of vascular structures within the pathological areas without distortion of the lobular architecture (mosaic pattern) • Expiratory air-trapping ( )

In about one third of cases the diseased areas are visible on expiratory scans only The hypoperfusion results from reflex vasoconstriction in the areas of the lung which are less ventilated due to bronchiolar narrowing. The narrowing also produces air-trapping in these areas which is welldepicted on expiratory CT scans Hansell DM. HRCT of obliterative bronchiolitis and other small airways diseases. Semin Roentgenol 2001, 36: 51 Stern EJ. Small-airway diseases of the lungs: findings at expiratory CT. AJR Am J Roentgenol 1994, 163: 37 Generally bilateral, asymmetrical and patchy

In some secondary forms of localized CB, such as post-infectious CB in Swyer-James syndrome (MacLeod), the lesions may predominate in one lung or lobe In contrast, severe and extensive disease (rare) may have an almost uniform distribution similar to emphysema Swyer-James syndrome is the effect of post-infectious CB usually due to viral infections contracted in early infancy. Damage to the bronchioles leads to incomplete development of the distal respiratory structures and to the formation of bronchiectasis proximally. Pulmonary vascularity is consequently reduced Variable Variable Lung volume is normal or increased, except in Swyer-James syndrome in which the volume of the affected areas is reduced Other radiological signs:

• Increased density of the normally ventilated areas ( ) where the vessels are enlarged (A) due to hyperperfusion, at times to the point of simulating disease (pseudo-ground-glass opacity) • Direct signs of airway disease (bronchial wall thickening ( ), bronchiolectasis, etc.)

A number of diseases, such as extrinsic allergic alveolitis, and airway infections (mycoplasma) may show an alternation of areas of three different levels of density (head-cheese pattern): true ground-glass opacities, areas of normally ventilated parenchyma, and hyperlucent areas due to air-trapping Waitches GM. High-resolution CT of peripheral airways diseases. Radiol Clin North Am 2002, 40: 21 Diffuse Lung Diseases

Maffessanti & Dalpiaz CB Distribution Radiological differential diagnoses:

• Chronic pulmonary thromboembolism: the vessels within the areas of oligemia are reduced in number and diameter, but there is no expiratory air-trapping. The central pulmonary arteries may be dilated due to chronic arterial hypertension • Diseases responsible for patchy ground-glass opacities: the pulmonary vessels are equally welldepicted and have similar diameters both in the hypodense and hyperdense areas. There is no expiratory air-trapping • Panlobular emphysema: the hyperlucency is diffuse rather than patchy and bilaterally symmetrical with lower lobe predominance. In addition, there is distortion with straightening and rigidity of the vascular markings • Postobstructive emphysema: the hyperlucency is uniform rather than patchy even if the affected area is limited. The cause of the obstruction can usually be identified

Overall, HRCT is able to differentiate CB from other causes of mosaic perfusion in more than 70% of cases 

Recurrent bronchiolar superinfections, with clinically obrious flare-ups Clinical course varies from rapid evolution to long periods of stability. There is no definitely effective treatment.

Radiological course is variable. Among the secondary forms of CB, those due to rheumatoid arthritis, graft versus host disease in bone marrow transplant, and chronic rejection in lung transplant are progressive and have a poor response to therapy. The microgranulomatous forms (sarcoidosis, HP) may regress completely or partially with regression of the disease

Laboratory findings are usually non-specific and unhelpful for diagnosis

Idiopathic CB should be suspected in the presence of an irreversible obstructive ventilatory defect without a previous history or clinical findings of associated diseases. The diagnostic suspicion can be confirmed by HRCT in the majority of cases

Transbronchial lung biopsy is rarely diagnostic and surgical lung biopsy may become indispensable for reaching a diagnosis in doubtful cases, in cases with possible multifactorial etiology or when considering a lung transplant The BAL fluid shows marked neutrophilia (>25%) and an increase in neutrophil products such as collagenase and myeloperoxidase. BAL neutrophilia tends to decrease in patients responding to treatment 

Chronic eosinophilic pneumonia (CEP) is an idiopathic condition characterized by an abnormal accumulation of eosinophils in the lungs. The clinical course lasts more than 3 months

The etiology is unknown, although there have been occasional reports of association with aspergillus infection, rheumatoid arthritis, and cutaneous vasculitis. The frequent association with atopy and elevated IgE levels suggests a Gell and Coombs type I immune reaction mechanism. The lungs of these patients contain a high number of activated eosinophils that produce eosinophil cationic protein (ECP) and an increase in activated helper lymphocytes (CD4+) that produce interleukins (IL): IL-5, IL-6 and IL-10

The disease is rare and the true prevalence and incidence are unknown. Women are more frequently affected (2:1), with a peak incidence between 20 and 50 years of age. There have been rare reports of familial cases

Atopy, allergen immunotherapy

The onset of disease is insidious, with symptoms being present for at least 2-3 months before diagnosis. The most common symptoms are: cough (80-90%), fever as high as 40°C (80-90%), dyspnea, weight loss, night sweats and malaise. Asthma accompanies or precedes the illness in about 50% of cases. Hemoptysis, chest pain and myalgia are rarely noted

Chest physical examination is non-specific, with wheezes, rales and signs of pulmonary consolidation These often reveal a restrictive or mixed ventilatory pattern with reduced D L CO. In the acute phases there may be severe hypoxemia. After remission, an obstructive ventilatory defect is common at times associated with irreversible small airways obstruction 

The intraalveolar aggregates of eosinophils often contain necrotic foci (eosinophilic abscesses). Macrophages and pneumocytes typically have dense eosinophilic cytoplasm. There may be numerous foci of intraalveolar fibroblastic organization as in OP, and interstitial lymphoplasmacellular infiltrate. Giant cells and mild non-necrotizing vasculitis of arterioles and venules may also be present Diffuse intraalveolar Histopathologic differential diagnoses:

• DIP: eosinophils are rare in the alveolar spaces, and there is a predominance of macrophages.

Type II pneumocyte hyperplasia is less prominent, and there is no necrosis within the intraalveolar aggregates • LCH: stellate scars and small cysts with Langerhans' cells. Eosinophils are fewer and interstitial • Churg-Strauss syndrome: necrotizing granulomas rich in eosinophils ("red" necrosis). Necrotizing vasculitis is also present • Wegener's granulomatosis, eosinophilic variant: patchy necrosis containing neutrophils ("blue" necrosis) and intense vasculitis. The eosinophilic infiltrate is interstitial and mixed with granulomatous inflammation The classical appearance has been described as photographic negative of the "butterfly" or "batwing" pattern seen in alveolar edema Radiological differential diagnoses: • OP: the lesions are not only confined to the lung periphery, but are also bronchocentric and predominate in the lower lobes. In addition, a macronodular appearance or a pattern of round opacities is frequent. There may be patchy air-trapping. Septal thickening or parenchymal bands are uncommon • Slowly-resolving bacterial infections: distribution is different from that typically seen in CEP, and the clinical findings are not suggestive of CEP • Churg-Strauss syndrome: the areas of consolidation may have a random distribution and be migratory. The differential diagnosis is nonetheless difficult • Drug toxicity (amiodarone-induced lung disease): the areas of parenchymal consolidation are often hyperdense and tend to be located in the lower lobes. Hyperdensity of the liver and spleen and at times of the myocardium may be present 

Response to steroid treatment is generally dramatic with improvement of symptoms within 24 hours and clinical and radiological remission within 3 weeks. Progression to diffuse lung fibrosis is rare. The disease tends to recur frequently after discontinuation of steroid treatment (75%)

Steroid treatment failure should prompt reconsideration of the diagnosis of CEP During regression, consolidation tends to disappear centrifugally and may be temporarily followed by subpleural curvilinear bands. If the disease is left untreated, the opacities may progressively increase in number and even migrate Ebara H. Chronic eosinophilic pneumonia: evolution of chest radiograms and CT features. J Comput Assist Tomogr 1994, 18: 737

In 85% of patients, peripheral eosinophilia is present (10-40% of white blood cells or more than 500 eosinophils/mmc). Erythrocyte sedimentation rate (ESR) may exceed 100 mm/hour. There may be hypochromic anemia, thrombocytosis and elevated IgE levels

Persistence of peripheral eosinophilia >1500 cells/mmc for more than 6 months should suggest a diagnosis of hypereosinophilic syndrome

The association of characteristic clinical, laboratory and radiological findings are required for diagnosis

In addition to CEP, a number of other conditions can cause pulmonary eosinophilia (see the table "Eosinophilic lung diseases" at the end of this chapter). Differential diagnosis among these diseases is complex. However, the following criteria apply: 1. normal total IgE levels in a patient with eosinophilic pneumonia rule out allergic bronchopulmonary aspergillosis and helminth infestation; 2. asthma is usually present in subjects with allergic bronchopulmonary aspergillosis, in 50% of CEP cases and is a characteristic feature of Churg-Strauss syndrome; 3. atopy is unusual in eosinophilic pneumonia due to drug toxicity, helminth infestation, and acute eosinophilic pneumonia

Transbronchial lung biopsy and/or BAL, is indicated if the clinical, radiological and laboratory findings are uncharacteristic and in particular, in the absence of peripheral eosinophilia If a biopsy is performed, this should be done under radiological guidance as areas of consolidation may rapidly migrate from one zone to another within the lungs The biopsy should be performed before steroid treatment, since steroids can drastically reduce the number of intraalveolar and interstitial eosinophils

The BAL fluid is characterized by eosinophilia >25-40%. The eosinophils often appear degranulated. The finding of degenerating alveolar macrophages is frequent. Significantly high concentrations of ECP may be found in the supernatant

The highest proportion of eosinophils in BAL fluid are found in association with CEP and Churg-Strauss syndrome 

Systemic vasculitides are diseases characterized by an inflammatory process of the vessel wall. The forms most frequently presenting with pulmonary involvement are Wegener's granulomatosis, Churg-Strauss allergic angiitis and granulomatosis, and microscopic polyangiitis This chapter will deal with Wegener's granulomatosis as a representative example, and in particular with its diffuse lung involvement in the form of diffuse alveolar hemorrhage (DAH) (see the table entitled "Vasculitides syndromes associated with DAH" at the end of the chapter)

Travis WD. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol 1990, 14: 1112

Travis WD. Vasculitis of the lung. Pathology 1996, 4: 23 The anatomical and radiological manifestations of Wegener's granulomatosis are not limited to DAH, but also include large nodules or masses (© Large rounded opacities: Wegener's granulomatosis)

The etiology and pathogenesis are unknown, although various causative agents and pathogenetic mechanisms have been implicated in the development of Wegener's granulomatosis. These include genetic predisposition, infectious agents, autoantibodies, (in particular anti-neutrophil cytoplasmic antibodies C-ANCA), immune complex deposition, and involvement of cell-mediated immunity. The etiology is most likely to be multifactorial

The prevalence is about 1.5-3 cases per 100,000 people. The disease primarily affects adults between 30 and 50 years of age, without sex predilection. DAH is present in approximately 5% of cases at presentation Spring months, pregnancy, silica exposure, allergic syndrome (cutaneous, drug-induced, reaction to insect bites). Advanced age and renal involvement at onset are negative prognostic factors

Onset is usually abrupt with dyspnea, cough, and hemoptysis (which may however be absent in up to one third of patients with DAH). Patients may report symptoms secondary to upper airway involvement (50-75% of cases), as well as symptoms ascribable to involvement of other organs (kidney in 75-85% of cases, polyneuritis in 20-35%, eye in 10-15%, skin in 10-15%, and muscles and joints in 30%)

If DAH is present, physical examination of the chest reveals fine diffuse rales or signs of pulmonary consolidation. There may be physical signs of the underlying systemic vasculitis in other organs DAH causes an increase in D LCO due to the abundance of hemoglobin in the airspaces. Hypoxemia, moderate to severe, is frequent

In the follow-up, D LCO monitoring may reveal disease recurrence DAH in Wegener's granulomatosis needs to be differentiated from other forms of vasculitis with capillaritis (see the table entitled "Vasculitis syndromes associated with DAH" at the end of the chapter) as well as from other conditions responsible for DAH, such as lung damage induced by drugs (penicillamine, nitrofurantoin, propylthiouracil)( Drug toxicity) or toxic inhalation (trimellitic anhydride, cocaine, paraquat, pesticides, isocyanates) • Intraalveolar accumulation of red blood cells and hemosiderin-laden macrophages ( ). This may be associated with capillaritis, consisting of an intense neutrophilic infiltrate around the capillaries of the alveolar septa (A), as well as foci of organizing pneumonia (OP) • In chronic hemorrhage there is also fibrous septal thickening and the presence of hemosiderinladen septal and intraalveolar macrophages

Capillaritis is often a focal and transient process: its presence may therefore depend on the timing of the biopsy

The characteristic lesions of Wegener's granulomatosis should be sought in the interstitium: these may be primary or secondary The primary lesions are necrosis, vasculitis and background granulomatous inflammation. Necrosis may present in the form of both neutrophil microabscesses and extensive patchy ("geographic") basophilic ("blue") areas due to the prevalence of neutrophils. Vasculitis may affect the arteries, veins or capillaries. The lesion is often focal and all types of inflammatory cells are implicated. Granulomatous inflammation may be expressed both by giant cells, sparse or in small groups, and by palisading histiocytes around the necrotic foci Secondary lesions, bronchial or parenchymal, include alveolar hemorrhage, OP, lymphoid hyperplasia, endogenous lipoid pneumonia, acute, chronic and follicular bronchiolitis, tissue eosinophilia. Secondary lesions sometimes dominate the morphological pattern

The finding of "endogenous pneumoconiosis" is frequent during chronic hemorrhage It consists of hemosiderin deposition in the vessel walls with fragmentation of the elastic lamina and consequent giant cell granulomatous reaction (not to be mistaken for Wegener's granulomatous inflammation)

DAH in Wegener's granulomatosis 

The radiological differential diagnoses are: • Other vasculitis syndromes, hemorrhage collagen vascular diseases and immune diseases: the differential diagnosis is based on the clinical and laboratory findings, although the presence of nodules and masses with a tendency to cavitate is less common • PE: pleural effusion (common), widening of the vascular pedicle, possible cardiomegaly, absence of macronodules or masses • Infectious pneumonias: the pattern is often indistinguishable, especially in immunodepressed patients. Ground-glass attenuation in perihilar regions or in the upper lobes prevails in PCP, and thick/thin-walled cysts are possible 

An association with immune-mediated diseases such as Hashimoto's thyroiditis and CREST syndrome has been described

The clinical course of DAH is often dramatic and may be fatal if the disease is not promptly treated. Pulmonary interstitial fibrosis or progressive broncho-obstructive disease have been reported in patients with repeated episodes of DAH Hemorrhagic alveolar consolidations typically evolve rapidly, even within days. During the resolution phase, a reticular pattern may be present which may persist in the case of relapsing hemorrhage

A typical finding is the rapid development of anemia. Non-specific findings include: leukocytosis, thrombocytosis, and elevated ESR. Renal involvement produces changes in renal function indices (azotemia, creatinemia), and in urinalysis (red blood cells, proteinuria, cell casts). More than 90% of patients with active disease and pulmonary-renal involvement have C-ANCA (directed against proteinase) in the serum

The role of C-ANCA in the diagnosis of Wegener's granulomatosis is well-established, and according to some studies, C-ANCA might also be useful in monitoring the disease. However, the possibility of false positives should be kept in mind. These may occur both with other forms of vasculitis and with nonvasculitic diseases (tuberculosis, HIV infection, endocarditis, nasal septal perforation, monoclonal gammopathy, neoplastic disease, drug-toxicity, polyneuritis). A negative C-ANCA test undoubtedly has a strong negative predictive value (90%)

In the appropriate clinical setting, positive serum C-ANCA and anti-proteinase-3 antibodies are considered to be strongly suggestive of Wegener's granulomatosis. Histologic confirmation should nonetheless be sought, with demonstration of necrotizing vasculitis at the affected sites (kidney, lung, skin, etc.)

Surgical lung biopsy is the method of choice for a definitive diagnosis. Transbronchial lung biopsy does not provide diagnostic material BAL may reveal the presence of DAH in patients without hemoptysis or significant anemia. The BAL fluid is hemorrhagic and the cytological analysis reveals hemosiderin-laden macrophages. C-ANCA may be assayed in the supernatant, but the prognostic significance of the titer is unknown BAL is useful in differentiating disease recurrence from opportunistic infection or drug toxicity in the event that new pulmonary infiltrates appear in the follow-up 

Desquamative interstitial pneumonia (DIP) is a discrete clinical and pathologic entity characterized by abnormal and uniform accumulation of intraalveolar macrophages. A rare disease, it is classified among the idiopathic interstitial pneumonias Alveolar macrophage pneumonia

The general term idiopathic interstitial pneumonias (IIP) includes various diseases, and in particular usual interstitial pneumonia ( UIP, early; UIP, advanced), non-specific interstitial pneumonia ( NSIP), desquamative interstitial pneumonia ( DIP), acute interstitial pneumonia ( AIP), lymphocytic interstitial pneumonia (© LIP) and cryptogenic organizing pneumonia ( OP) 

The etiology and pathogenesis are unknown. Similarities with RB-ILD (© RB-ILD) suggest that the two entities represent the extremes of a spectrum of diseases caused by cigarette smoking. The cells which accumulate in the alveolar spaces are now known to be alveolar macrophages attracted to the site by chemotactic stimuli (probably cigarette smoke antigens) rather than sloughed epithelial cells

The disease tends to affect smokers in their 4th or 5th decades of life, and is more common in men than in women by a ratio of 2:1

Cigarette smoking

DIP develops insidiously with dyspnea (87%) and cough (43%) over a course of weeks or months before diagnosis. Chest pain may be observed, albeit rarely (17%) Bibasilar fine rales may be heard. About 25% of patients have digital clubbing

The earliest functional alteration is reduced D L CO (35%) on a background of a mild restrictive ventilatory defect (30%) Lung volumes may be normal (20%)

Rju JH. Desquamative interstitial pneumonia and respiratory bronchiolitis -associated interstitial lung disease. 

Pulmonary architecture is basically preserved Diffuse intraalveolar Histopathologic differential diagnoses:

• DIP-like reaction: associated with other conditions such as drug-or asbestos-induced disease, eosinophilic pneumonia, infections or simply as a consequence of smoking • RB-ILD: the proliferation is not diffuse but bronchiolocentric with sparing of the alveoli • NSIP: septal thickening due to inflammation and fibrosis are more pronounced and there is less involvement of the alveolar spaces • LCH: centrilobular nodules with stellate margins associated with cysts, and interstitial infiltrate consisting of eosinophils and Langerhans' cells The cysts, which are due to dilatation of the alveolar ducts and respiratory bronchioles, are smaller than those seen in UIP; in addition, there is no fibrotic distortion! Lee KH. The radiologic differential diagnosis of diffuse lung diseases characterized by multiple cysts or cavities. J Comput Assist Tomogr 2002, 26: 5

The main radiological differential diagnoses are: • NSIP: more evident reticular changes, bronchiectasis and traction bronchiolectasis • PCP: acute onset in immunodepressed subjects, frequent localization in the middle-upper regions • HP: the patchy areas of ground-glass attenuation are more randomly distributed. Centrilobular nodules are often associated Heyneman LE. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol 1999, 173: 1617

The disease may be associated with other smoke-induced lung diseases such as respiratory bronchiolitis and centrilobular emphysema 

In smokers with chronic dyspnea, dry cough, restrictive ventilatory pattern and reduced D L CO, the HRCT pattern can raise the suspicion of DIP. The diagnosis, however, requires histological confirmation by surgical lung biopsy. The differential diagnosis will mainly consider the other idiopathic interstitial pneumonias, in particular NSIP ( NSIP) and RB-ILD (© RB-ILD)

Surgical lung biopsy is mandatory for a definite diagnosis. The usefulness of BAL and transbronchial lung biopsy is limited to the exclusion of infectious or neoplastic diseases BAL typically shows increased numbers of alveolar macrophages with yellow, golden, brown or black inclusions (which are also seen in healthy smokers). The absence of these cells makes a diagnosis of DIP highly unlikely. There may be increases in neutrophils, eosinophils and, at times, lymphocytes 

A number of drugs can cause lung injury, which is expressed by different histopathological patterns (see the table "Drug-induced lung injury: histopathologic patterns" at the end of this chapter). This chapter covers amiodarone-induced lung disease as a representative example of drug-induced alveolar damage It should nonetheless be noted that the same drug may cause different types of lung injury, even in sequence. For example, amiodarone itself may also cause OP ( OP) or chronic interstitial pneumonia ( Drug toxicity) or diffuse alveolar damage (DAD) such as AIP ( AIP) and ARDS ( ARDS)

Rosenow EC 3 rd . Drug-induced pulmonary disease. An update. Chest 1992, 102: 239

The lung injury induced by amiodarone is thought to result in part from a direct toxic effect (altered phospholipid turnover, toxic oxygen species) and in part from an immune reaction (hypersensitivity pneumonitis). Inhibition of phospholipid degeneration within the lysosomes is responsible for the characteristic "foamy" appearance of the alveolar macrophages Amiodarone causes pulmonary toxicity in 5-10% of patients treated with the drug A higher risk of pulmonary toxicity is associated with: 1. daily dose (maintenance therapy) ≥400 mg; 2. duration of treatment longer than 2 months: 3. age over 60 years; 4. pre-existing lung disease; 5. surgery (thoracic and non-thoracic); 6. angiographic investigations. There is no correlation between duration of treatment or cumulative dose and the extent of lung damage

The onset of disease is insidious, with dry cough and dyspnea arising within months of starting therapy. Systemic symptoms such as low-grade fever, weight loss and weakness are also common. In one third of patients the onset is acute and mimics a pulmonary infection Patients are tachypneic, and chest auscultation reveals fine diffuse rales and at times pleural rubs. 

The most common lesion associated with amiodarone-induced pulmonary toxicity is the following: • Chronic interstitial pneumonia with lymphoid hyperplasia and accumulation of foamy macrophages ( ) with finely vacuolated cytoplasm predominantly in the alveolar spaces, but also in the interstitium (A) 

At low magnification the histologic appearance is similar DIP Non-specific inflammatory pleural infiltrate, with or without effusion, may be observed In addition to chronic interstitial pneumonia, amiodarone may occasionally produce OP and DAD patterns with the presence of foamy macrophages

The presence of foamy macrophages is not confined to amiodarone-induced pneumonia, as they can also be observed in other conditions associated with airway obstruction Alveolar and, to a lesser extent, septal Histopathologic differential diagnoses:

• Obstructive pneumonia: there is obstruction of large or small airways • Diffuse panbronchiolitis (DPB) and DPB-like pattern (e.g. associated with idiopathic inflammatory bowel disease): centrilobular lesions with cellular bronchiolitis containing numerous foamy macrophages in the alveolar spaces, but mostly in the pulmonary interstitium • Erdheim-Chester disease: interstitial infiltrate of foamy macrophages along the lymphatic routes associated with fibrosis • TB and mycobacteriosis: presence of numerous mycobacteria in immunodepressed patients • NSIP: interstitial fibrosis and inflammation are more pronounced These findings correspond to NSIP possibly associated with OP: the two patterns may coexist in the same patient. The hyperdensity of the lesions is due to the accumulation of amiodarone (which contains iodine) in the macrophages and type II pneumocytes. In some patients, the consolidation appears as a single pneumonia-like opacity or as a solitary pseudoneoplastic mass The presence of hyperdensities within the areas of consolidation needs to be differentiated from: • Amyloidosis: possible presence of more pronounced hyperdensities due to calcifications within the areas of consolidation and, above all, nodules

The radiological differential diagnoses also include other conditions responsible for consolidation with subacute or acute clinical courses: • Slow-healing infections: the differential diagnosis is made on the basis of the clinical and bronchological findings • CEP: the areas of consolidation are located in the upper lung regions and are always peripheral ("photographic negative" of the butterfly or batwing edema pattern) • OP: the pattern is similar • Churg-Strauss syndrome: the differential diagnosis is challenging. The areas of consolidation may be not only peripheral but also randomly distributed and migratory • BAC and MALToma: the diagnosis is based on bronchoscopy and biopsy Leung AN. Parenchymal opacification in chronic infiltrative lung diseases: CT-pathologic correlation. Radiology. 1993, 188: 209 

Amiodarone is used to treat cardiopathic patients affected by supraventricular arrhythmias unresponsive to conventional therapy Diffuse Lung Diseases

Discontinuation of the drug and administration of corticosteroids have proven to be very effective. Recurrences have been reported following interruption of steroid treatment. Amiodarone-induced lung disease has a mortality rate below 10% which increases to 50% in cases complicated by ARDS The areas of parenchymal consolidation resolve with steroid therapy and only in a small minority of patients do they progress to fibrosis Ellis SJ. Drug-induced lung disease: high-resolution CT findings. AJR Am J Roentgenol 2000, 175: 1019

The laboratory findings are non-specific: leukocytosis, > lactate dehydrogenase (LDH), > ESR. The serum levels of amiodarone are not predictive of lung damage. It has been suggested that serum concentrations of the glycoprotein KL-6 may predict lung damage

Amiodarone-induced lung disease is a diagnosis of exclusion made on the basis of the clinical, radiological and, where possible, BAL findings

In the appropriate clinical setting, surgical lung biopsy is unnecessary, in part because the findings would not be specific. Transbronchial lung biopsy may be useful in identifying OP pattern A common BAL pattern in patients receiving amiodarone, whether or not they have lung disease, is the presence of numerous "foamy" macrophages. In addition to this, patients with lung disease also have an increase in lymphocytes, neutrophils and eosinophils (mixed alveolitis). The lymphocytes are predominantly of the CD8+ subset. These findings may assist in the diagnosis, although they have no prognostic significance The BAL finding of mixed alveolitis in a patient with amiodarone-induced lung damage is similar to that seen in HP, idiopathic OP and at times NSIP. BAL may be of value in ruling out infection or malignancy 

Hypersensitivity pneumonitis (HP) refers to a group of diffuse granulomatous parenchymal lung diseases caused by the repeated inhalation of, and sensitization to, a broad variety of low molecular weight antigens and chemicals. Clinical presentation may be subacute ( © HP, subacute), chronic ( HP, chronic) or more rarely, acute. This chapter deals with the acute form Extrinsic Allergic Alveolitis (EAA)

The number of responsible inciting agents is high (more than 300) and new antigens are constantly being identified. The most commonly known diseases are "Farmer's lung", caused by the inhalation of Faeni rectivirgula present in moldy hay and "Bird fancier's lung", caused by exposure to avian proteins Gell and Coombs type III and type IV immune reactions lie at the basis of the immunopathogenesis of the disease. The acute form seems to be related to heavy exposure to antigens and working conditions (environmental antigen concentration, duration and frequency of exposure, type of work) Little is known about the incidence and prevalence of hypersensitivity pneumonitis, since individual susceptibility, intensity of exposure in different occupational settings, seasons, geographical areas and proximity of industry vary greatly. The prevalence of "Farmer's lung" varies between 2% and 9%, whereas that of "Bird fancier's lung" varies between 6% and 15% The disease is more common in non-smokers

Symptoms of the acute form are cough, dyspnea, fever, chills, malaise and myalgia. A careful clinical history may reveal massive exposure to an inciting antigen and a temporal relationship between exposure and onset of symptoms (4-12 hours) Patients present with tachypnea, and auscultation of the lungs may be normal or reveal fine diffuse rales. Wheezes and stridors are rarely heard Patients typically have a restrictive ventilatory defect with reduced DLCO or, in rare cases, an obstructive pattern. Mild hypoxemia at rest is common Histopathologic differential diagnoses: • NSIP: diffuse rather than bronchiolocentric lesions; granulomas and foci of organizing pneumonia may be present, but they are not characteristic • DAD: the process is diffuse rather than bronchiolocentric, and there is marked hyperplasia of type II pneumocytes • OP: less intense interstitial infiltrate and absence of granulomas 

About one quarter of patients with HP have non-specific bronchial hyperreactivity to methacholine

If the patient avoids exposure to the antigen, single acute episodes may resolve spontaneously within days. The pulmonary function tests and radiological alterations return to normal within weeks: only D L CO takes longer to normalize. The disease may recur with re-exposure. If areas of fibrosis, or honeycombing at HRCT, develop, the disease may become irreversible "Bird fancier's lung" has a worse prognosis than "Farmer's lung"

If exposure continues, the disease progresses to the subacute form (© HP, subacute) and may eventually become chronic ( HP, chronic)

Maffessanti & Dalpiaz

The presence of serum precipitating antibodies against the offending antigen is a characteristic feature. There may also be a slight increase in inflammatory indices (ESR and C-reactive protein -CRP), as well as a significant increase in quantitative immunoglobulins which return to normal once the acute phase is over. Some patients may also test positive for rheumatoid factor and circulating immune complexes

The disease is diagnosed on the basis of a history of exposure to an offending antigen with onset of compatible clinical, radiographical or physiological findings within 4-12 hours. Other diagnostic criteria include clinical improvement after removal from exposure and recurrence on re-exposure. There is little agreement regarding the usefulness of inhalation challenge to the offending antigen

In cases where the inciting antigen cannot be identified or in the presence of conflicting clinical, radiological and functional findings, fiberoptic bronchoscopy with BAL and transbronchial lung biopsy are indicated. Surgical lung biopsy is only required if these prove inconclusive

If performed within 2-3 days of the most recent exposure, BAL may reveal an aspecific finding with a predominance of neutrophils. On the other hand, BAL performed after a greater time interval from the most recent exposure to the inciting antigen is characterized by a marked increase in total cell count with a predominance of lymphocytes (often > 50%) and the presence of foamy macrophages and mastocytes (> 1%). The lymphocytes are predominantly CD3+ (T cells) and CD8+ (cytotoxic suppressors). The CD4+/CD8+ ratio is usually decreased to less than 1.0 Similar patterns (CD8+ lymphocytic alveolitis, foamy macrophages, and mastocytes) may also be seen in drug-induced lung disease ( Drug toxicity), in OP ( OP), and in NSIP ( NSIP) 

Pulmonary infections characterized by endobronchial spread may be caused by a variety of pathogens, including mycobacteria other than Mycobacterium (M.) tuberculosis, commonly referred to as nontuberculous mycobacteria (NTM). This chapter will cover these forms. The radiological hallmark of endobronchial spread is known as the tree-in-bud pattern (see the table entitled "Diseases with radiological tree-in-bud pattern" at the end of the chapter)

The main causative agents are M. avium-intracellulare, M. Kansasii, M. fortuitum, and M. chelonei, traditionally classified into 4 groups based on pigment production and growth rate: photochromogens, scotochromogens, nonchromogens and fast-growers. These mycobacteria are ubiquitous and infection generally occurs through environmental contamination rather than human-to-human transmission A North-American surveillance study from the pre-AIDS era (early 1980s) reported that 65% of mycobacterial isolates were M. tuberculosis, 21% were M. avium-intracellulare (MAI) (nonphotochromogen), 6.5% M. fortuitum and M. chelonei (fast-growing), 3.5% M. Kansasii (photochromogen) and 2.3% M. scrofulaceum (scotochromogen). The overall incidence of NTM disease was 1.78 cases per 100,000 with variations due to geographical differences in the mycobacterial habitats The advent of AIDS has brought about an increase in the incidence of M. avium-intracellulare infection. Atypical mycobacteriosis is more common in white males over 50 years of age, and rare in children Immunodepressed states such as AIDS or conditions such as alcoholism, rheumatoid arthritis, gastric resection, organ transplant and diabetes mellitus facilitate infection by atypical mycobacteria. Most patients have co-existing lung diseases such as chronic obstructive bronchitis, bronchiectasis, cystic fibrosis, lung cancer, silicosis, lipoid pneumonia, or a history of tuberculosis A form of diffuse interstitial granulomatous pneumonia has been described in immunocompetent subjects who had inhaled aerosolized water contaminated with MAI (hot tub lung). These cases exhibit small granulomas with or without necrosis that involve the bronchiolar wall and at times the lumen 

The clinical pulmonary manifestations are those of tuberculosis (TB). Immunocompetent subjects with atypical mycobacteriosis due to MAI present with cough, low-grade fever, malaise and, at times, hemoptysis. Systemic symptoms are rare in immunocompetent individuals but frequent in HIV+ subjects, in whom pulmonary involvement is, however, rare

The physical examination is often unremarkable. Bronchiolar crackles may occasionally be heard Mycobacterial infections predominantly affect the upper lobes. Because these have limited functional importance, lung function impairment tends to be mild, and possible alterations should therefore be ascribed to the underlying disease 

In addition to the classic presentation (70%), which strongly resembles that of tuberculosis with endobronchial spread, there is another less frequent presentation (non-classic, 30%) typical of elderly women (80%) and characterized by bronchiectasis and bronchiolectasis, centrilobular nodules and patchy mosaic hypoperfusion (Lady Windermere syndrome). More rarely, mycobacterial infection may give rise to pneumonia-like areas of consolidation or centrilobular nodular ground-glass opacities due to the extrinsic allergic alveolitis produced by the mycobacterial infection The radiological differential diagnoses include:

• Diseases producing a tree-in-bud pattern (see the table at 

Obstructive chronic bronchitis, bronchiectasis, cystic fibrosis, history of tuberculosis, lung cancer, silicosis, lipoid pneumonia If left untreated, NTM infections follow a variable course depending on the underlying lung disease. Even after healing of the parenchymal lesions, an active bronchial infection may persist, which becomes a constant source of infection. The advent of new treatments relying on macrolides and rifabutin has markedly improved the prognosis of these patients If the disease regresses, the opacities will disappear progressively. If it progresses, the bronchiectasis, which are generally more pronounced than in TB, tend to worsen, above all in the forms due to MAI infection

Sputum microbiology and culture can identify the colonizing or pathogenic mycobacterium. The culture, staining and detection techniques used for atypical mycobacteria are very similar to those used for tuberculosis. The advent of genetic probes will enable a faster and more specific diagnosis, whereas laboratory tests are not specific

In immunocompetent individuals, the diagnosis is based on radiological criteria (cavitating lung disease in the absence of other identifiable causes and/or tree-in-bud pattern) and microbiological findings (detection of the mycobacterium in at least 3 sputum samples). The differential diagnosis mainly includes the other forms of infectious necrotizing granulomatosis, such as tuberculosis and fungal infections Isolation of the microorganism (even on repeated occasions) in the absence of pulmonary cavitations indicates colonization rather than infection. These patients should not be treated but instead, closely monitored

Transbronchial lung biopsy can provide material for the direct detection of the microbic agent or for microbiological culture. Surgical lung biopsy to confirm the diagnosis is rarely required BAL may be used in the event that sputum is unavailable. The search for atypical mycobacteria in the BAL fluid must be carried out with extreme care (in particular for M. avium-intracellulare) as often the germs are only present inside the alveolar macrophages. These may have a Gaucher-like appearance due to the massive number of germs distending their cytoplasm

Radiological course

Maffessanti & Dalpiaz

The radiological pattern known as tree-in-bud may be found in different diseases characterized by the presence of distended centrilobular bronchioles with a mucous-or pus-filled lumen and often inflammation of the peribronchiolar airspaces. 

Mucosa-associated lymphatic tissue lymphoma (MALToma) is an extranodal pulmonary B-cell lymphoma with a low grade of malignancy. The cells arise from the marginal zone (centrocyte-like cells) of the normal or hyperplastic bronchus-associated lymphoid tissue (BALT)

MALT lymphoma, BALT lymphoma, marginal zone B-cell lymphoma

These tumors express CD19, 20, 22 and 79a, are negative for CD5, CD 23 and CD10 and do not present bcl-1 and bcl-2 gene rearrangements

The etiology and pathogenesis of the disease are unknown. It is thought, however, that certain stimuli (cigarette smoking, infections, asbestos exposure, various collagen vascular diseases) are capable of provoking BALT hyperplasia with subsequent malignant transformation

In contrast to other pulmonary lymphomas, no association with Epstein-Barr virus has been described for MALToma

MALToma primarily affects adults in their fifth decade of life, without gender predilection. It is the most common primary pulmonary lymphoma (60-80%)

Collagen vascular diseases such as RA, Sjögren's syndrome and SLE. Hepatitis C virus infection

Half of the patients are asymptomatic. When present, the most common symptoms are cough and dyspnea, whereas pleural pain and hemoptysis are rare. Systemic symptoms such as fever, night sweats or weight loss are encountered in 20-40% of cases

In the presence of a large lymphomatous mass, physical examination may reveal lung consolidation. 

The neoplastic population is composed of different cell types in varying proportions: 1. small lymphocytes with round nuclei; 2. "monocytoid" lymphocytes with slightly larger and more irregular nuclei and abundant, pale cytoplasm; 3. lymphocytes with plasmocytoid appearance and plasma cells; 4. occasional large "transformed" lymphocytes, with round vesicular nucleolated nuclei and abundant cytoplasm. This pattern is often associated with a non-neoplastic (polyclonal) reactive lymphoplasmacellular infiltrate and, in 70% of cases, with numerous germinal centers. Amyloid deposits, bands of dense fibrosis and granulomas may also be present. Although non-specific, lymphoepithelial complexes are a characteristic feature of MALT lymphomas. Infiltration of the pleura and bronchial cartilage is rare but, when present, is strongly suggestive of lymphoma Many cases now interpreted as MALT lymphomas were previously classified as pseudolymphomas or LIP (© LIP) depending on whether the lesions were localized or diffuse Along the lymphatics. In macronodular lesions, lung architecture is effaced in the center of the nodule and lymphatic distribution can therefore only be identified at the periphery Histopathologic differential diagnoses:

• LIP, diffuse lymphoid hyperplasia, pseudolymphoma: the lymphocyte population is heterogeneous and polyclonal. Absence of dense monotypic lymphocytic infiltrate around the germinal centers and in the septa, which is typical of lymphomas. Infiltration of the pleura and the bronchial cartilage is rare, as is the presence of lymphoepithelial complexes • Chronic lymphocitic leukemia: although neoplastic infiltrates which are histologically indistinguishable from those of MALToma, may be present along the lymphatics lymphoepithelial complexes rare 

Basic radiological signs: • Parenchymal consolidation (60%) with air bronchogram ( )(50-90%); the bronchi appear stretched and narrowed • Masses with variable diameter up to several centimeters (A) • Nodules with hazy margins (D) due to airspace filling (60%)

The above HRCT signs are frequently seen in combination Frequently bilateral (60%), but also unilateral, diffuse, or patchy with involvement of extensive areas (80%) Radiological differential diagnoses:

• OP: the consolidations are basal and peripheral, at times migratory, and respond readily to steroid treatment • BAC: the differential diagnosis is histological; however, the form with endobronchial spread tends to progress more rapidly • Metastases: consolidation is present in a limited number of cases (hemorrhagic metastases, or metastases from angiosarcoma or choriocarcinoma) • Angioinvasive mycosis: associated nodules or masses with a tendency to cavitate • Lymphomatoid granulomatosis: nodules or masses without air bronchogram and with a tendency to coalesce; consolidation is rare

Other signs

Cryptogenic organizing pneumonia (COP) is a disease entity classified among the idiopathic interstitial pneumonias, which presents clinically with pneumonia-like features

The general term idiopathic interstitial pneumonias (IIP) include various diseases, in particular, usual interstitial pneumonia ( UIP, early; UIP, advanced), non-specific interstitial pneumonia ( NSIP), desquamative interstitial pneumonia ( DIP), acute interstitial pneumonia ( AIP), lymphocytic interstitial pneumonia (© LIP) and cryptogenic organizing pneumonia ( OP) An identical histological and radiological pattern (BOOP-reaction pattern) may be seen in a number of diseases where the lung responds non-specifically to different noxae (see the table entitled "BOOPreaction pattern" at the end of this chapter)

Katzenstein AL. Katzenstein and Askin's surgical pathology of non-neoplastic lung disease. WB Saunders, 1997

The etiology and pathogenesis of idiopathic COP is unknown. The disease is thought to result from alveolar epithelium injury due to an unknown cause, capable of triggering angiogenesis and exaggerated reparative response by the fibroblasts Mean age at onset varies from 50 to 60 years. The two sexes are equally affected, with a prevalence in non-smokers (2:1). The incidence of COP on hospital admissions is 6-7 per 100,000

There are no known specific risk factors

At the time of diagnosis, 75% of patients report symptoms of less than 2 months duration. The most common presentation is that of a community-acquired pneumonia, at times preceded by a flu-like illness. The most frequent symptoms are cough and dyspnea upon exertion at times associated with mucous production. Systemic symptoms are also frequent and include weight loss (57%), chills, sweats, intermittent fever and myalgia Localized or diffuse fine rales are noted in 74% of patients. Digital clubbing is absent

The most common findings are a restrictive ventilatory defect (mild to moderate) and reduced D L CO. An obstructive ventilatory defect is present in a minority of patients (20%), usually smokers. More than 80% of affected individuals have mild resting hypoxemia The disease process involves multiple temporally uniform foci (the connective tissue is young and at the same stage of maturation throughout). Lung architecture is preserved On hematoxylin-and-eosin stain, the "polyps" appear as pale serpiginous plugs reproducing the shape of the airways in which they form. These plugs consist of fibroblasts arranged parallel to one another and immersed in a mucopolysaccharide-rich matrix containing inflammatory cells As the disease progresses the "polyps" become covered by bronchiolar or alveolar epithelium and incorporated within the septa, resulting in the healing of the lesions Bronchiolar and peribronchiolar Histopathologic differential diagnoses:

• Infections: suppurative or granulomatous inflammation, presence of necrosis. Identification of the infectious agent • Obstructive pneumonia: predominance of foamy macrophages in the inflammatory infiltrate • Organizing DAD: the process is diffuse rather than patchy, the fibrosis is interstitial with uniformly distended and edematous septa. The septal infiltrate is less intense and hyperplasia of type II pneumocytes is more pronounced. In addition, a bronchiolar component is absent • Wegener's granulomatosis (BOOP-like variant): vasculitis and necrosis with an infiltrate often rich in eosinophils are present • HP: poorly-formed granulomas, very intense inflammatory infiltrate • CEP: intense eosinophilic infiltrate in the interstitium and alveoli • UIP: subpleural fibrosis with fibroblastic foci at the edges of the fibrotic areas; temporal heterogeneity and remodeling with honeycombing. There is no bronchiolar involvement The differential diagnoses of the typical pattern (patchy consolidation and ground-glass attenuation) include: • Slow-resolving bacterial infections: clinical history and regression of the opacities at follow-up are the key to the diagnosis • BAC: the radiological pattern may be similar • TB: the differential diagnosis is based on bronchological studies especially in elderly, diabetic, debilitated or mildly immunodepressed patients • Sarcoidosis: associated subpleural nodules, hilar and mediastinal adenopathy • CEP: consolidation predominates in the upper lung fields and has strictly subpleural distribution In contrast, the differential diagnosis of the pattern seen in immunodepressed patients (ground-glass opacities and nodules) includes:

• Opportunistic infections: the differential diagnosis is based on the biopsy 

The various diseases that result in the development of a BOOP-like pattern (see the table "BOOP-reaction pattern" at the end of this chapter)

Two thirds of subjects treated with corticosteroids make a full recovery: most patients recover within several weeks or months and some respond dramatically with improvements appearing even within 1 or 2 weeks. Only a minority of patients, however, experience spontaneous remission and about half of those treated relapse when treatment is reduced or discontinued One third of patients have persistent disease which rarely, however, progresses to respiratory failure or death. On the other hand, rare hyperacute forms are possible which rapidly lead to death (accelerated BOOP)

The opacities may resolve spontaneously and then form elsewhere, usually more cranially and at times in the contralateral lung (migratory opacities). Left untreated, the disease may progress to permanent damage with fibrosis and bronchiectasis

Common findings include elevated ESR, often more than 100 mm in one hour (70-80%), and raised CRP. Leukocytosis is present in 50% of cases. Autoantibodies are usually absent or the titer is low

A definitive diagnosis cannot be made on the basis of the clinical features alone. The HRCT findings will enable the correct diagnosis to be included among the first three in 50% of cases and, in the appropriate clinical setting, can provide the diagnosis in 80% of cases BOOP-pattern should be considered in patients with areas of parenchymal consolidation labeled as pneumonia, which persist or migrate after antibiotic therapy

In the presence of a characteristic clinical-radiological setting, transbronchial lung biopsy alone may be sufficient for histological confirmation, with BAL providing further support for the diagnosis. The diagnosis of COP is, however, a diagnosis of exclusion made only after ruling out all the other conditions characterized by a BOOP-reaction pattern Cryptogenic Organizing Pneumonia (COP)

Clinical course

If biopsy is needed, it should be performed under radiological guidance since the areas of consolidation may rapidly migrate from one zone to another within the lungs

The BAL fluid is characterized by elevated total cell count, with a reduction in the percentage of macrophages and an increase in lymphocytes (>40%), neutrophils and eosinophils (mixed alveolitis pattern). The CD4/CD8 ratio is reduced. Foamy macrophages are typically present and mast cells and plasma cells are increased A mixed alveolitis pattern (increased CD8+ lymphocytes, neutrophils and at times eosinophils) is not specific to COP, and may also be observed in HP ( HP, acute), NSIP ( NSIP) and drug-induced lung disease ( Drug toxicity) 

The etiology of the disease is unknown, although similar histopathologic findings have been reported in acute silicosis, exposure to dusts containing aluminium, titanium or silicon, Pneumocystis carinii (jiroveci) infection, hematologic malignancies and immunosuppressive disorders. The pathogenesis of the disease is related to changes in the production or degradation of surfactant resulting from altered macrophage function and/or diminished production or inhibition (neutralizing antibodies) of the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF)

The disease is rare and its incidence is unknown. It primarily affects subjects aged 20 to 50 years, with a predominance of males (2:1), without racial or geographic predilection Exposure to mineral dusts and cigarette smoking

Approximately one third of patients are asymptomatic. The main symptoms at onset are progressive exertional dyspnea, and less frequently productive cough with expectoration of gelatinous material, low-grade fever, fatigue, hemoptysis, chest pain and weight loss Breath sounds are often normal, although fine rales may be heard in about 50% of patients. Digital clubbing is rare, as is cyanosis

The most common physiologic alteration is a restrictive ventilatory defect associated with a reduction in D L CO. Hypoxemia at rest is present in only one third of patients, whereas oxygen desaturation with exercise is seen in over half The lesions are more numerous in the peripheral and subpleural regions, but may also affect the peribronchial airspaces. These features often make it possible to diagnose the disease with transbronchial biopsy In alveolar proteinosis secondary to infection and in long-standing disease, marked interstitial alterations may be seen, which are due to intense inflammatory infiltrate and septal fibrosis, respectively Histopathologic differential diagnoses:

• PE: the material is neither granular, nor PAS-positive; macrophages and cholesterol clefts are lacking • Infections: demonstration of the infectious agent in PCP • DAD: in the exudative phase, presence of fibrin in the form of hyaline membranes associated with hyperplasia of type II pneumocytes; in the proliferative phase, foci of fibroblastic organization Pulmonary Alveolar Proteinosis

Pneumocystis carinii (recently renamed Pneumocystis jiroveci) pneumonia (PCP) is a clinically significant lung infection, found only in immunosuppressed subjects Pneumocystosis

The mode of transmission of the infectious agent is unknown. Some studies have suggested an exogenous infection transmitted through inhalation, whereas others have implicated a reactivation of a latent infection acquired during childhood Infection is undoubtedly favored by the subject's immunosuppressed state and in particular by CD4+ T-cell deficiency (circulating CD4+ count below 200/mm 3 ) and impairment of the bactericide action of alveolar macrophages and neutrophils Prior to advent of highly active antiretroviral therapy (HAART), 15% of HIV+ patients receiving prophylactic treatment and 45% of those not on prophylaxis developed PCP. PCP is decreasing in frequency due to use of prophylaxis and HAART Immunodeficiency: HIV+, post-transplant immunosuppression, lymphatic system malignancies, and immunosuppressive treatments

Onset is generally insidious. In patients with full-blown AIDS, however, the disease may manifest abruptly with fever and hypoxemia. The most common symptom is dyspnea (95%) often associated with dry cough (90%). Less frequent symptoms include chills, malaise, weight loss and chest pain. Sputum production may be present in 25% of patients, whereas hemoptysis is unusual. About 7% of patients are asymptomatic Patients have fever (84%) and tachypnea (62%). The most common finding on chest auscultation is fine rales heterogeneously distributed throughout the lung fields. At times ronchi and wheezes are heard. Chest examination is normal in 50% of cases. Patients may have splenomegaly and skin lesions. Digital clubbing is rare Most patients have reduced DLCO (<70% of the predicted value) with increased alveolar-arterial oxygen gradient. A finding of normal D L CO and alveolar-arterial oxygen gradient has a strong negative predictive value for PCP Santamauro JT. Pneumocystis carinii pneumonia. Med Clin North Am 1997, 81: 299

The histopathologic features are the following: • Colonies of Pneumocystis carinii consisting of intraalveolar eosinophilic masses with a foamy appearance as they are made up of tiny cysts approximately the size of a red blood cell (D). At the center of these cysts is a small gray-blue spot that is poorly appreciable upon hematoxylin-andeosin stain but clearly evident with silver stains (methenamine silver). 

Other possible histopathologic patterns include: 1. DAD with hyaline membranes; 2. non-specific cellular, granulomatous or desquamative interstitial pneumonia; 3. intraalveolar hemorrhage; 4. fibrosis and microcalcification; 5. alveolar proteinosis-like pattern. Colonies of Pneumocystis may also be found in the context of a normal lung Intraalveolar Histopathologic differential diagnoses:

• Intraalveolar fibrin or edema: the intraalveolar material is not foamy and is negative upon PAS and silver stainings • PAP: the intraalveolar material is not foamy and is negative upon silver stainings. Although PAS may be positive, it does not selectively stain the microcyst walls 

Other radiological signs: • Cysts ( ) within the ground-glass opacities (35% of cases) • Reticular opacities ( ) due to smooth interlobular septal thickening possibly associated with ground-glass density with resulting crazy paving pattern • Small diffuse or parahilar nodules with ill-defined borders (due to granulomatous reaction); more rarely large nodules or true masses (pneumocystomas) may be seen • Mediastinal or hilar adenopathy • Pleural effusion (about 5% of cases) • At times signs of infectious bronchiolitis with tree-in-bud pattern, bronchial wall thickening, and bronchiectasis

The cysts, which are often arranged in clusters in the upper lobes, have thick walls and bizarre shapes. At times the cysts are septated and may become very large A reticular pattern associated with ground-glass attenuation is often seen in the subacute phase of the disease. This is the result of interstitial organization of the intraalveolar exudate Moskovic E. High resolution computed tomography of Pneumocystis carinii pneumonia in AIDS. Clin Radiol 1990, 42: 239 The differential diagnosis includes other diseases characterized by acute alveolar pattern:

• Viral infections: the radiological patterns may be similar, but the cysts are absent • DAH: the longitudinal distribution is variable. In Wegener's disease large round cavitating opacities may be present • PE: predominantly basal distribution, and frequent cardiomegaly and pleural effusion

Infections in other organs, in particular due to Cytomegalovirus, or neoplastic disease (Kaposi's sarcoma or lymphomas). Pneumothorax due to rupture of a cyst into the pleural space in 5-10% of cases

The appearance of severe dyspnea in a patient with PCP should raise the suspicion of pneumothorax Feurestein IM. Thin-walled cavities, cysts, and pneumothorax in Pneumocystis carinii pneumonia: further observations with histopathologic correlation. Radiology 1990, 174: 697 Diffuse Lung Diseases

Maffessanti & Dalpiaz PCP is a severe infection which may be fatal if overlooked. If promptly treated, on the other hand, it has a favorable prognosis (50-95% survival). In 50-75% of AIDS patients, the disease will relapse unless appropriate chemoprophylaxis has been instituted If treatment is effective the radiological consolidative changes may resolve completely. A minority of cases show persistence of mild fibrosis in the form of retracting strands. The cysts may even persist for weeks or months after the pneumonia has resolved, and in this case they have thin walls In cases not responding to therapy, the consolidative changes may progress to a clinical and radiological pattern of ARDS ( ARDS) Chow C. Lung cysts associated with Pneumocystis carinii pneumonia: radiographic characteristics, natural history, and complications. AJR Am J Roentgenol 1993, 161: 527

Most patients have moderate leukocytosis with lymphopenia. In 50% of cases, the CD4/CD8 ratio is reduced (often the absolute count of CD4+ T-cells is <200/mm 3 ). Elevated serum levels of LDH are common (90%), as are high serum levels of angiotensin-converting enzyme (ACE). Recent studies showed undetectable plasma levels of S-adenosylmethionine in PCP patients

The finding of elevated LDH levels is a negative prognostic factor LDH has been suggested to be an index of pneumonia extension more than a marker of PCP infection

Although the clinical and radiological setting may often be strongly suggestive of PCP, the presence of Pneumocystis carinii (jiroveci) in the respiratory specimens should always be demonstrated (first in induced sputum) The sensitivity of HRCT is close to 100% and its specificity is greater than 80%, with good interobserver agreement

The negative predictive value of HRCT is so high that a negative scan allows a diagnosis of PCP to be confidently ruled out. HRCT has replaced gallium scintigraphy

Given the high diagnostic yield of induced sputum and BAL, histological confirmation, which is mostly obtained by transbronchial lung biopsy, is rarely required. When performing a biopsy, the high risk of postbiopsy bleeding due to the typical thrombocytopenia found in HIV+ subjects should be borne in mind BAL is recommended if sputum induction is non-diagnostic. A characteristic BAL finding is "foamy exudate": the "foamy" effect is due to the presence of empty cysts within the pathological secretions. This exudate, which can be seen with May-Grunwald-Giemsa or Papanicolau stains, is diagnostic of PCP even without special stains. Sporozoites may be observed inside, and free trophozoites outside the cysts The diagnostic yield of BAL in HIV+ subjects in 97-100%, which drops to 62% in those on pentamidine prophylaxis. Increased levels of interleukin-8 or the presence of cysts in the BAL fluid have been reported to be negative prognostic factors Golden JA. Bronchoalveolar lavage as the exclusive diagnostic modality for Pneumocystis carinii pneumonia. A prospective study among patients with acquired immunodeficiency syndrome. Chest 1986, 90: 18 Pneumocystis Carinii Pneumonia

Maffessanti & Dalpiaz

Pulmonary edema (PE) refers to the accumulation of extravascular fluid in the alveoli Cardiogenic, hemodynamic edema

The volume of water and the movement of proteins in the lung depend on the equilibrium achieved between the hydrostatic and intra-and extravascular osmotic pressures and the permeability of the alveolar-capillary membrane. An increase in hydrostatic pressure produces an increase in the transudation of excess fluid (edema) from the microcirculation to the extravascular compartment, with an accumulation initially in the pulmonary interstitium and then in the alveolar spaces

The most common cause of PE is cardiogenic (left ventricular systolic or diastolic dysfunction, left atrial flow impairment). Less common causes result from a reduction in capillary osmotic pressure (renal disease, liver cirrhosis, fluid overload), neurogenic alterations (head injury, increased intracranial pressure, non-hemorrhagic stroke) and diseases of the pulmonary veins (idiopathic veno-occlusive disease, fibrosing mediastinitis) PE is a frequent cause of admission to hospital These include liver cirrhosis, kidney failure, heart disease, valvulopathy

The onset of symptoms is often acute and dramatic. Patients present with orthopnea and are in an obvious state of respiratory distress (use of accessory respiratory muscles). Peripheral and central cyanosis, tachycardia, pallor, cold clammy skin, anxiety and often elevated systemic pressure are all common findings. In the more severe cases, the patients have productive cough with expectoration of pink frothy sputum up to frank hemoptysis. Patients often have a long history of orthopnea and/or paroxysmal nocturnal dyspnea

The physical examination reveals indirect signs of increased venous return such as jugular venous distention, tender hepatosplenomegaly and peripheral edema. Examination of the lung is characterized by fine diffuse inspiratory rales and expiratory wheezees. In patients with valvular dysfunction, a gallop rhythm may be noted on cardiac auscultation. In the end stages of disease, loss of consciousness and cardiocirculatory failure occur Lung function testing is rarely performed in patients with full-blown PE. Nonetheless, the findings will include a reduction in compliance, vital capacity and total lung capacity, and an acute increase in pulmonary resistance and closing volume Bronchial hyperreactivity has been reported in some patients. Severe hypoxemia and normocapnia or hypercapnia are also encountered

The differential diagnosis of PE includes fulminant pneumonia, acute asthma, acute exacerbation of COPD and acute hemorrhagic alveolitis 

The histopathologic features of PE are the following: • Accumulation of intraalveolar fluid (D): the lungs are heavier than normal, with frothy fluid oozing out of the cut surface of the lung and bronchi, either spontaneously or following compression • The alveolar spaces appear overdistended and often optically empty (A) as their content is easily lost during tissue processing • Less frequently, slightly eosinophilic granular and proteinaceous material may be seen within the alveolar spaces ( ) • Interstitial edema associated with congested capillaries in the intraalveolar septa ( ) 

The edema may be unilateral, as in patients in protracted lateral decubitus, or asymmetric and bizarreshaped, as in patients with regional emphysema (because edema does not form in the affected area)

In patients with acute pulmonary thromboembolism, hemodynamic edema due to hyperperfusion may develop in the otherwise unaffected areas Predominantly subpleural and gravitational, although also diffuse Peripheral edema is more characteristic of cardiogenic edema because the movement of the fluid towards the hilum (mediated by the lymphatics) is hindered by the elevated central venous pressure. Instead, a hilar distribution is more typical of hypervolemic edema since the central pressures are relatively normal The differential diagnoses include the various causes of acute parenchymal consolidation: • ARDS: patchy opacities with air bronchogram without clear gravitational predominance. There is no reticular pattern or pleural effusion, and the vascular pedicle and heart volume are normal • AIP: there are no cardiovascular signs of hemodynamic edema • Acute eosinophilic pneumonia: the appearance is similar to lesional edema (AIP associated with DAD or ARDS) • HP: patchy distribution, with associated hazy centrilobular nodules, and mosaic pattern with air-trapping • DAH: "butterfly" or "batwing" pattern with perihilar distribution and sparing of the subpleural regions. Cardiomegaly is absent • PCP: crazy paving, thick-walled cysts, and distribution in the middle-upper lung regions Diffuse Lung Diseases

Maffessanti & Dalpiaz

Diffuse ( ) or focal (D) areas of parenchymal consolidation

Parenchymal consolidation may be caused both by the underlying disease and by supervening opportunistic infection. The latter is suspected when the consolidation is focal Godwin JD. Pulmonary alveolar proteinosis: CT findings

Lesion distribution is asymmetrical, often peripheral and basal, and pleural effusion and adenopathy may be present • Slow-resolving bacterial pneumonia: frank areas of consolidation predominate and crazy paving is rare • Lipoid pneumonia: negative density at CT • CEP: peripheral distribution in the middle and upper regions. Crazy paving is not a constant feature and, when present, has limited extension

Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings

Italian COURSE and COMPLICATIONS

Secondary alveolar proteinosis has also been described in AIDS, dermatomyositis and pulmonary tuberculosis Left untreated, the disease proves fatal in about 25% of patients with death due to respiratory failure or pulmonary superinfections. Spontaneous recovery may occur in 20-30% of cases, whereas progression to fibrosis is rare

In patients treated with repeated therapeutic bronchial lavage, follow-up radiology demonstrates regression or improvement of the opacities, which may, however, recur. Progression to fibrosis is rare

865 diagnoses: • Normal parenchyma: normal lung weight and optically empty alveoli

Pulmonary histology for the surgical pathologist

Acute respiratory distress syndrome: imaging of the injured lung

Diffuse pulmonary hemorrhage: clinical, pathologic, and imaging features

It is almost impossible to distinguish between tuberculous and non-tuberculous mycobacteria on the basis of morphology alone: the differential diagnosis requires special stains (PAS), and cultures or molecular biology assays Histopathologic differential diagnoses:• Sarcoidosis: small non-necrotizing granulomas. The search for mycobacteria by any method, is negative • Fungal infections: presence of mycetes • Wegener's granulomatosis (endobronchial): necrosis is patchy ("geographic") and "blue" as it is rich in neutrophilic debris. The infiltrate is more intense and granulomas are not associated with marked fibrosis • HP: poorly-formed granulomas associated with intense interstitial lymphoplasmacellular infiltrate. Presence of giant cells containing needle-shaped clefts, and absence of necrosis Fujita J. Pathological and radiological changes in resected lung specimens in Mycobacterium avium intracellulare complex disease. Eur Respir J 1999, 13: 535

Mycobacteriosis, classic form (70% of cases): • Poorly-defined centrilobular nodules, often clustered into "rosettes" (A) • Branching opacities with tree-in-bud appearance • Bronchial wall thickening (D) with or without bronchiectasis • Multiple areas of consolidation of acinar or lobular size; cavitation is common

Atypical mycobacteriosis

Pleural effusion (10%), lymphadenopathy (5%). In some subjects, the disease may manifest with signs and symptoms in other regions, such as the upper respiratory tract or the stomach (33%). The signs of lung involvement may appear later. Besides the above-mentioned elements, an association with LCH and sarcoidosis has been described in a small number of instances If appropriately treated, patients with low-grade pulmonary B-cell lymphoma have a good prognosis (84% survival at 5 years). Progression of the disease into a high-grade lymphoma is rareProgression of the lesions is very slow: they can initially appear months, or even years, before diagnosis

If plasmcytoid differentiation develops, monoclonal gammopathy, usually IgM, may be detected in the peripheral blood. Free light chains may be detected in the urine, including Bence-Jones protein. The leucocyte count is generally normal, although lymphocytosis can be detected in a small number of cases.In the case of pleural effusion, the exudate will contain predominantly B lymphocytes

Normally, diagnosis neccesitates invasive techniques

Diagnosis can be based on histologic-immunohistochemical analysis of pulmonary tissue obtained by transbronchial biopsy or surgery, or, more rarely, based upon typification of lymphocytes in the BAL or pleural fluidThe BAL results are pathognomonic where cytofluorometry demonstrates an increase in the B lymphocyte population (>5%) with monoclonal aspects (k or λ light chains). In this case, use of the polymerase chain reaction (PCR), can allow analysis of the gene re-arrangement of the tumor cells The histological pattern known as "BOOP-reaction pattern" occurs when the lung responds non-specifically to different noxae. As a result, it is seen in varying extents and severity in a number of diseases BOOP as a disease: 

Various valvular and non-valvular heart diseases may also be present Alveolar PE is a dramatic condition that may become life-threatening if not treated promptly Acute onset and rapid regression with treatment are characteristic features of this form of edema, and may assist in the differential diagnosisThere may be a time lag between the regression of edema and pleural effusion and the return to normal of the pulmonary capillary wedge pressure

Laboratory findings are useful for ruling out infection or anemia which may act as precipitating factors. Normal cardiac enzymes allow exclusion of an underlying myocardial infarction, and renal function indices enable detection of concurrent renal failure Brain natriuretic peptide (BNP) levels are increased in PE and therefore can be helpful in differentiating between cardiogenic and lesional PE

The diagnosis is clinical and may be aided by instrumental investigations such as BNP serum levels, chest radiographs, electrocardiogram and echocardiography

There is no indication to perform BAL in PE. The small amount of data available in the literature suggests that the BAL findings are similar to those seen in hemorrhagic alveolitis