key: cord-0036456-glm6ywq8
authors: nan
title: Reticular Diseases
date: 2006
journal: Diffuse Lung Diseases
DOI: 10.1007/88-470-0430-6_3
sha: 868bfa0a0eeba662bcbc4ffc10b132ed3c076171
doc_id: 36456
cord_uid: glm6ywq8

nan

Amyloid is a protein-derived substance which deposits in the extracellular spaces. It appears homogeneous and slightly eosinophilic in hematoxylin and eosin sections, positive to Congo red staining, exhibiting a green birefringence under polarized light and fluorescent after thioflavin staining

In the interstitium of the alveolar and perivascular septa Histopathologic differential diagnoses:

• Fibrosing diseases such as chronic HP, fibrosing NSIP, sarcoidosis, etc. The presence of dense connective tissue of the alveolar septa can simulate amyloid deposits, but it is negative to thioflavin and Congo red staining (beware of artifacts in thick sections!), not birefringent under polarized light, and typically stains as the connective tissue

Deposits of amyloid may be seen in lymphoproliferative lesions (myeloma, monoclonal gammopathy of uncertain significance, low grade B-cell lymphoma, LIP, etc.), collagen vascular diseases and neuroendocrine tumors (carcinoids, small cell carcinomas, etc.)

In the appropriate clinical setting, the association of a reticular-nodular pattern with calcifications on HRCT has a diagnostic accuracy of 95% Utz JP. Pulmonary amyloidosis. The Mayo Clinic experience from 1980 to 1993 . Ann Intern Med 1996 

Diagnosis requires the histologic demonstration of amyloid deposits in the extracellular space and is obtained with fine needle aspiration biopsy from the periumbilical fat or a biopsy of the rectal mucosa or other involved organ, including the lungs. Lung parenchyma for diagnostic purposes can be obtained with fine needle aspiration, transbronchial or surgical biopsy

The few studies available suggest that BAL in amyloidosis is characterized by an increase in lymphocytes and the CD4/CD8 ratio. In addition, paraprotein may be encountered in higher concentration in BAL fluid than in serum in the primary form of the disease 

Asbestosis is a pneumoconiosis caused by the inhalation of asbestos fibers and characterized by a slowly progressive fibrosis up to the end-stage cystic disease ( Asbestosis, advanced)

A toxic effect is thought to be produced by the asbestos fibers on the lung parenchyma with recruitment of inflammatory cells and release of various mediators (reactive oxygen species, cytokines, proteases and growth factors)

The precise epidemiology of the disease is unknown because of its long clinical latency (up to 20-30 years from initial exposure)

Asbestosis affects workers involved in the extraction of the mineral, in the manufacture and installation of products containing asbestos (industrial textiles, insulation, cement-asbestos manufactured goods) and in the repair and removal of the same (naval and railway demolition)

Patients may be asymptomatic for up to 20-30 years from initial exposure. The first symptom is dyspnea on exertion associated at times with a dry cough

Physical examination of the lungs may be normal or characterized by diffuse fine bibasilar rales (32-64%)

The earliest functional changes include reduced D L CO and hypoxemia with exercise. A restrictive pattern is observed in a later stage. The presence of airway obstruction is generally due to cigarette smoking Mossman BT. Asbestos-related diseases. N Engl J Med 1989, 320: 1721

These include interstitial fibrosis, initially around the small airways and alveolar ducts and then involving extensive areas of parenchyma (A), with the possible association of fibrosis of the visceral pleura ( ) and honeycombing. Asbestos bodies may also be present (D)

The diagnosis of asbestosis requires the presence of fibrosis associated with asbestos bodies (at least 1 or 2 according to various authors). The presence of asbestos bodies without fibrosis indicates exposure, but not disease Clinical signs associated with the disease include mucostasis, OP, mild lymphoplasmacellular infiltrate or heavy infiltrate of macrophages with hemosiderin or anthracotic pigment, often intraalveolar, which create DIP-like changes. Multinucleated giant cells elicited by asbestos bodies (asbestos fibers with an iron protein coat) may also be present Initially peribronchiolar and subpleural, then progressively diffuse Histologic grading schemes have been proposed based on the extent of fibrosis. However, rarely is sufficient material available to apply them Histopathologic differential diagnoses: • UIP: prevalently perilobular fibrosis with bronchiolectasis; fibroblastic foci at the interface with normal parenchyma, absence of asbestos bodies • NSIP: diffuse fibrosis of the alveolar septa, non-centrilobular; absence of asbestos bodies • Sarcoidosis: fibrosis with a lymphatic distribution, residual granulomas, absence of asbestos bodies • DIP: dense and diffuse accumulation of intraalveolar macrophages with slight septal fibrosis, absence of asbestos bodies Pleural plaques: these may be bilateral, of varying length, but with a thickness <1 cm and calcified in 10-15% of cases; they are typically absent in the apices and the costophrenic sinuses and tend to be arranged in a spiral pattern extending superoanterior to posteroinferior Rounded atelectasis: these are identifiable as rounded or ellipsoid areas of increased density with a parietal supporting base in correspondence with pleural thickening; the vessels and bronchi around the areas are gently arched with a "comet-tail" appearance. The consolidation is markedly hyperdense following administration of contrast material as it is composed of collapsed parenchyma which is not aerated but rather perfused The signs described may be present in other fibrosing diseases:

• UIP: honeycombing is prevalent with frequent evidence of traction bronchiolectasis • NSIP: ground-glass and bronchiolectasis are prevalent • Collagen vascular diseases: in addition to signs of fibrosis, ground-glass, consolidation and pleural effusion are present • Drug toxicity: ground-glass is often dominant, while progression to fibrosis is rare

Patients affected by asbestosis are almost always carriers of pleural plaques, which are often calcified; they are also at increased risk of developing cancer, particularly mesothelioma and lung cancer

The disease may progress to respiratory failure (30%), albeit more slowly than in UIP; respiratory failure is the cause of death in about one fifth of patients with asbestosis. Cigarette smoking may accelerate the progression of pulmonary fibrosis The radiological appearance progresses from an early irregular reticular pattern towards cystic honeycombing ( Asbestosis, advanced)

Increased ESR, the presence of antinuclear antibodies and rheumatoid factor are frequently found, but they are not correlated with the disease activity

In the appropriate clinical setting, a detailed history of asbestos exposure and a long period of latency from initial exposure to the onset of clinical signs are diagnostic of asbestosis In 20-30% of patients with a significant history of exposure, symptoms or altered pulmonary function tests, but with a normal radiograph, HRCT allows detection of parenchymal abnormalities. Nonetheless, a normal CT does not exclude the possibility of disease Staples CA. High resolution computed tomography and lung function in asbestos-exposed workers with normal chest radiographs. Am Rev Respir Dis 1989 Dis , 139: 1502 The presence of pleural plaques is a hallmark of asbestos exposure

In doubtful cases a surgical lung biopsy should be performed Asbestos bodies are frequently found in BAL, and their number correlates with those in the tissues. Cell count may reveal an increase in both lymphocytes and polymorphonucleated neutrophils. The lymphocytes show a predominance of CD8+ cells

The number of asbestos bodies increases when BAL is performed in the lower lobes. Asbestos bodies may be present in exposed subjects who do not have asbestosis Karjalainen A. Asbestos bodies in bronchoalveolar lavage in relation to asbestos bodies and asbestos fibres in lung parenchyma. Eur Respir J 1996 Respir J , 9: 1000 Asbestos-induced pneumoconiosis

Collagen vascular diseases are a heterogeneous group of diseases characterized by the presence of circulating autoantibodies which cause inflammatory damage to various organs or tissues. The patterns of lung disease in collagen vascular diseases include fibrosing alveolitis, bronchiolitis, OP, parenchymal nodules, pleuritis, and vasculitis Scleroderma is a collagen vascular disease which will be covered in this chapter as a representative example. The lungs are affected by a diffuse-fibrotic infiltrate, with a reticular radiological appearance in the early stages, although this may progress to cystic disease ( 

The precise pathogenesis of lung involvement is unknown. Experimental data suggest that a fundamental role is played by alveolar macrophages which are thought to produce factors involved in chemotaxis and the activation of fibroblasts such as tumor necrosis factor-alpha, transforming growth factorbeta, fibronectin and insulin-like growth factor-I. Alveolar macrophages are also thought to produce increased amounts of interleukin-8, a powerful chemokine for neutrophils which are regularly found in the BAL of patients with scleroderma Mastocytes and their mediators are also thought to play a role in the pathogenesis of the disease, together with endothelin-1, a factor produced by endothelial cells which directly stimulates the fibroblasts. The "coordinating" cells of these processes are thought to be CD8+ T cells of mostly Tc2 phenotype Scleroderma is a rare disease (12 cases per million/year) which primarily afflicts adults between the age of 30 and 50 years, with women being more commonly affected (3:1). The lung is affected in more than 70% of patients with scleroderma, which makes it the second most frequently affected organ after the esophagus Lung involvement is more common in patients with genetic markers such as HLA-DR3/DR52a, specific autoantibodies (ScL-70, anti-U3RNP, antitopoisomerase I, antihistone) and in African American patients

The most common symptoms in this early phase are dyspnea on exertion and dry cough. Chest pain and hemoptysis are less common Almost 50% of patients present diffuse fine bibasilar rales Reduced D L CO is the earliest functional change and this is present in 70% of patients, including asymptomatic patients with a normal chest X-ray. Another early sign of functional deficit is the alveolar-arterial oxygen gradient during exercise. Lung function is worse in smokers than in non-smokers

The clinical and physiologic features of the fibrosing infiltrative lung disease seen in scleroderma are similar to those in UIP Lamblin C. Interstitial lung diseases in collagen vascular diseases. Eur Respir J Suppl 2001, 32: 69s

In the early phase scleroderma presents with: • Interstitial fibrosis (D) with mainly lymphoplasmacellular infiltrate: this is frequently associated with pleural fibrosis (A) with adhesions • Vascular lesions (independent of fibrosis): medial smooth muscle hypertrophy ( ) and intimal fibrosis of the pulmonary arteries may be seen, while fibrinoid necrosis and plexiform lesions are rarer findings

The pattern of fibrosis in progressive systemic sclerosis is most similar to that of fibrosing NSIP or UIP Diffuse interstitial and subpleural Radiological differential diagnoses are:

• UIP: subpleural honeycombing prevails and the cysts are larger • Asbestosis: ground-glass is less frequent and bronchiolectasis is rare; subpleural lines, parenchymal bands and pleural plaques coexist • Drug-toxicity: ground-glass prevails, while progression towards fibrosis is rare • Collagen vascular diseases: all the described signs (appearance and distribution) may be equally present in the other collagen vascular diseases. Differential elements include: RA: bronchiectasis is isolated and not in the context of consolidation (associated with chronic infections); air-trapping and mosaic perfusion (from bronchiolitis obliterans); centrilobular nodules with hazy margins (from follicular bronchiolitis); cavitating subpleural 

About 10% of scleroderma patients develop pulmonary hypertension. Other less common manifestations are pleuritis, aspiration pneumonia, spontaneous pneumothorax, drug-induced pneumonia, tumors, and amyloid deposits

The differential diagnosis of the lung involvement in scleroderma must take into account other possible causes such as drug-associated pneumonia ( Drug toxicity; Drug toxicity); opportunistic infections induced by immunosuppressive drugs; concurrent neoplasm

The disease progresses towards fibrosis and respiratory failure. Lung involvement is the most frequent cause of death in patients with scleroderma

Progression towards fibrosis with the prevalence of honeycombing ( Collagen vascular diseases, advanced) is slower compared to UIP

Antinuclear antibodies are found in most patients. The presence of antitopoisomerase I (topo I or Scl-70) or antihistone is associated with more severe lung fibrosis. Patients with fibrosing alveolitis in the course of scleroderma are reported to have increased serum levels of KL-6, a glycoprotein mainly present in type-II pneumocytes and alveolar macrophages. According to some authors, KL-6 levels are useful in diagnosing and monitoring the disease

In patients with scleroderma, a CT scan exhibiting characteristic features can be considered sufficient for diagnosing fibrosing lung involvement without the need for lung biopsy

Surgical lung biopsy is indicated in the following circumstances: D L CO is notably reduced relative to lung volumes, there is massive pleural involvement, and HRCT is unable to clearly identify a reticular pattern. Transbronchial lung biopsy is only useful for excluding concurrent infections or tumors BAL is characterized by an increase in total cell count and granulocytes, particularly neutrophils and eosinophils. In some cases an increase in lymphocytes and mastocytes is present. BAL plays a part in prognosis, since the presence of persistent alveolitis is associated with more severe lung function deterioration and faster progression of the disease BAL is useful in the diagnosis of complications (aspiration pneumonia, drug-induced pneumonia, concomitant infections or tumors, etc.)

A correlation exists between the BAL findings and the extent of disease seen on HRCT: the number of lymphocytes increases in the still unaffected lung areas, the eosinophils are the first cells to increase detected by HRCT, and neutrophils predominate when at least 50% of the lavaged lobe is affected by disease A number of drugs can cause lung damage, which is expressed by different histopathologic patterns (see the table "Drug-induced lung damage: histopathologic patterns" at the end of this chapter) Methotrexate, a drug which will be covered in this chapter as a representative example, causes chronic interstitial pneumonia, which presents with a reticular HRCT pattern It should nonetheless be noted that the same drug may cause different types of damage in the lung tissue, even in sequence. For example, methotrexate itself may also cause pulmonary edema ( PE, alveolar), OP ( OP) and even diffuse alveolar damage (DAD) typical of AIP ( AIP) and ARDS ( ARDS), although less frequently than chronic interstitial pneumonia Methotrexate-induced lung disease may occur in all those diseases where the drug is administered (lung and breast cancer, osteosarcoma, epidermoid carcinoma of the head-neck, non-Hodgkin's lymphoma, psoriasis and severe rheumatoid arthritis). The incidence of lung damage during treatment with methotrexate, in its various manifestations, varies from 5% to 10%

The following risk factors have been identified in rheumatoid arthritis patients receiving methotrexate: >60 years of age, rheumatoid lung involvement, diabetes mellitus, hypoalbuminemia and the prior use of disease-modifying antirheumatic drugs. No correlation between cumulative dose and lung damage has been observed. Concomitant treatment with drugs which reduce the protein bond of methotrexate (aspirin, chlorambucil, sulfonamide, penicillin, phenylbutazone, barbiturates, NSAIDs) seems to increase the toxicity of methotrexate

Pulmonary toxicity generally arises during treatment and only rarely afterwards. Patients experience subacute fever with a dry cough and dyspnea 3-4 months after beginning treatment. Acute symptoms of fever, chills, cough, dyspnea and chest pain only occur in 5-10% of cases Clinical signs include diffuse fine bibasilar rales, tachypnea and at times cyanosis. A small percentage of patients may present with skin reactions (15%) and signs of pleural effusion 

Treatment with cytotoxic drugs such as methotrexate not only causes direct lung damage, but may also promote the onset of infection (most commonly pneumocystis) or lung cancers (especially non-Hodgkin's lymphomas)

Most patients make a practically complete recovery, with mortality being below 10%. Progression to respiratory failure may also occur, whereas in about 10% the disease progresses towards diffuse pulmonary fibrosis

The lesions described may regress (consolidation and ground-glass) if the drug is discontinued, or in contrast there may be progression towards honeycombing with traction bronchiectasis

Peripheral eosinophilia may be seen (40-65%)

Most cases are diagnosed clinically and only a minority of patients need a lung biopsy. Improvement after discontinuation of the drug and/or response to steroid treatment provide important clues. It is imperative to exclude opportunistic lung infection before treating

Other signs

Maffessanti & Dalpiaz

In the appropriate clinical setting, BAL findings and transbronchial lung biopsy may provide further diagnostic support

Most patients present a high-intensity CD4+ lymphocytic alveolitis, although a prevalence of CD8+ T-cells has been described. Neutrophilia is present in some cases. BAL is particularly useful in ruling out opportunistic infections. The presence in the BAL fluid of atypical epithelial cells may be an early sign of progression towards fibrosis. The table at the end of this chapter entitled "Drug-induced lung damage: BAL findings" summarizes the main features which may be encountered CD4+ lymphocytic alveolitis is not a specific finding in that it may also be seen in sarcoidosis, berylliosis, tuberculosis and rheumatoid arthritis 

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 organic antigens and chemicals. Clinical presentation may be acute ( HP, acute), subacute ( © HP, subacute) or chronic. This chapter deals with the chronic form Extrinsic Allergic Alveolitis (EAA)

The number of inciting antigens responsible 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 progressive fibrotic changes appear to be linked to a dysregulation of fibroblasts in susceptible subjects

The incidence and prevalence of the disease is difficult to estimate, 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 chronic form appears to be due to continued exposure to low levels of antigens. Non-smokers are more commonly affected

The inciting antigen can be difficult to detect and may remain unknown in some cases. Symptoms of the chronic form are the insidious onset of cough, dyspnea, fatigue and weight loss. Patients may also lack a history of acute episodes Diffuse fine bibasilar rales are often noted on physical examination. Patients may present signs of wasting and digital clubbing Patterns include moderate-to-severe restrictive defect, mixed restrictive and obstructive defect, or rarely an isolated obstructive defect. There is hypoxemia at rest and D L CO is always reduced Patel AM. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol 2001, 108: 661

In the advanced stages, the classic histological triad of HP (mononuclear cell bronchiolitis at times with intraluminal fibroblastic plugs, diffuse chronic inflammatory infiltrates (A), small non-necrotizing granulomas) may be progressively replaced by: • Temporally homogeneous fibrosis, which is more or less extensive and non-specific (D) • 

There is a greater incidence of chronic bronchitis. About one quarter of patients present aspecific bronchial hyperreactivity to methacholine. Pneumothorax or pneumomediastium are rare

The associated chronic bronchitis appears to be linked more to exposure to the inciting antigens than to cigarette smoking Once fibrosis has developed, the disease is irreversible. Its progression can be more or less rapid, leading to chronic respiratory failure with pulmonary hypertension. Removal from exposure results in only partial improvement and chronic steroid therapy is often necessary. Digital clubbing is observed in the advanced stages of the disease and is a sign of poor prognosis Diffuse Lung Diseases

The radiological progression of the lesions depends on the progression of the disease; when the disease worsens, the reticular pattern and honeycombing are more extensive Remy-Jardin M. Subacute and chronic bird breeder hypersensitivity pneumonitis: sequential evaluation with CT and correlation with lung function tests and bronchoalveolar lavage. Radiology 1993, 189: 111 Zompatori M. Chronic hypersensitivity pneumonitis or idiopathic pulmonary fibrosis? Diagnostic role of high resolution Computed Tomography (HRCT). Radiol Med 2003, 106: 135

The presence of serum precipitating antibodies against the offending antigen is a characteristic feature. A slight increase in inflammatory indices (ESR and CRP) as well as a significant increase in quantitative immunoglobulins may be observed

The presence of precipitating IgG and IgM serum antibodies may be considered markers of antigen exposure, although they are not diagnostic, nor does their presence correlate with disease activity

The chronic form is clinically difficult to differentiate from forms of idiopathic interstitial pneumonia such as UIP or NSIP. An accurate occupational and environmental history is needed to ascertain the potential exposure to the offending antigen. There is little agreement regarding the usefulness of inhalation challenge to the offending antigen. HRCT can be useful with a positive predictive value of 80%

At this stage, transbronchial lung biopsy rarely reveals parenchymal regions still affected by small, poorly-formed epithelioid non-caseating granulomas. In cases where the history and transbronchial biopsy are not diagnostic, a surgical lung biopsy is required At this advanced stage, unlike in the acute form where there are high percentages of lymphocytes, the sediment of the lavage is characterized by an increase in neutrophils (>5%) and eosinophils (>5%). Sometimes lymphocytes (10-20%) may still be present This mixed alveolitis with an increase in neutrophils, eosinophils and lymphocytes may also be observed in BAL of OP and NSIP 

In most cases the primary tumor is located in the breast, stomach, pancreas, prostate or in the lung itself

Lymphatic involvement may occur in three ways: hematogenous spread to the pulmonary arterioles followed by invasion of the adjacent interstitium and lymphatics with subsequent spread to the hilum or lung periphery; retrograde dissemination from mediastinal lymph nodes; communication between superior abdominal lymph nodes or lymph nodes of the peritoneal cavity and the lymphatics of the diaphragmatic pleura

Lymphangitic carcinomatosis is a frequent pattern of cancer spread to the lungs (35-55%)

Primary neoplasm

The onset of symptoms is insidious, although disease course is rapid (few months). The most frequent symptom is dyspnea, while a minority of patients present with dry irritative cough (due to involvement of the bronchial submucosa lymphatics). In some patients the symptoms are similar to those of bronchial asthma

There is a restrictive ventilatory defect with reduced compliance and D L CO. A rapid respiratory failure, complicated by tumor emboli, leads to hypoxemia and pulmonary arterial hypertension Radiological differential diagnoses:

• PE: perilymphatic nodules are absent, while ground-glass and consolidation due to associated alveolar edema coexist • Sarcoidosis: signs are bilateral and located in the upper lobes with possible distortion of lobular architecture; the perilymphatic nodular pattern prevails while pleural effusion is absent • Silicosis: centrilobular and subpleural nodules in the upper lobes prevail, associated with masses and distortion of the architecture while pleural effusion is absent • LIP: centrilobular nodules prevail, which may have hazy margins, associated with ground-glass and occasionally cysts

Schaefer-Prokop C. High-resolution CT of diffuse interstitial lung disease: key findings in common disorders. Eur Radiol 2001, 11: 373 

During the course of the disease, episodes of tumor embolism with acute cor pulmonale may arise, and associated pleural effusion is not uncommon

The clinical picture rapidly deteriorates up to the onset of severe pulmonary arterial hypertension. Half of all patients die within three months of diagnosis and only 15% survive longer than six months

The radiological picture may progress towards the presence of numerous metastatic rounded opacities (© Large rounded opacities: Metastases) arising from hematogenous spread of the primary tumor

The spread of the primary tumor to other organs and the bone marrow may cause microangiopathic hemolytic anemia, thrombocytopenia and lead to the presence of immature granulocytes and nucleated red blood cells in the circulation

The clinical-radiological picture of the lung is characteristic and in the presence of a known primary tumor may be considered diagnostic, with an HRCT accuracy of 92%

Other signs

Maffessanti & Dalpiaz

In the presence of an unknown primary tumor, the diagnosis is based on cytologic (BAL, bronchial washing, pulmonary artery blood sampling, transthoracic needle aspirate, pleural fluid) or pathologic specimens (transbronchial or surgical lung biopsy) Bronchoalveolar lavage fluid often reveals cancer cells (65-70%) and a non-specific increase in lymphocytes

The reactive type II pneumocytes seen in the BAL fluid during various idiopathic interstitial pneumonias and in the organizing phase of diffuse alveolar damage may appear so atypical as to be confused with cancer cells Lymphangitic Carcinomatosis

Non-specific interstitial pneumonia (NSIP) is one of the idiopathic interstitial pneumonias which in certain aspects is similar to UIP ( UIP, early), although it often has a more favorable prognosis 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)

Although the etiology is unknown, the temporal appearance of the histologic changes regardless of the stage of disease suggests a single triggering event

The mean age at onset is 40-50 years, although children may also be affected. The disease equally affects males and females. NSIP is less common than UIP, but much more common than the other idiopathic interstitial pneumonias. There is no correlation between the disease and cigarette smoking

None are known

Onset is mainly subacute. The duration of symptoms to the moment of diagnosis varies from 18 to 31 months. The most common symptoms are exertional dyspnea, cough and fatigue, while half of patients report weight loss and one third fever Physical examination is characterized by fine bibasilar crackles and in some cases inspiratory squeaks. Clubbing has been reported in 10 to 35 percent of cases All patients have reduced D L CO, and there is a concurrent restrictive defect in 90 percent of cases. A minority of patients also have a mild obstructive syndrome, whereas two thirds show exertional hypoxemia

Histologic features are fibrosis and inflammation of the alveolar interstitium to varying degrees. The distribution of the lesions is uniform (spatial homogeneity) and the disease appears in the same phase (temporal homogeneity), with rare or absent fibroblastic foci. Two types of disease can be identified according to whether fibrosis or inflammation is prevalent: • Cellular NSIP (D): the inflammatory infiltrate, composed of lymphocytes and plasma cells, is moderately intense and prevails over the fibrosis • Fibrosing NSIP (A): dense or loose fibrosis predominates and expands the alveolar septa, while the inflammatory infiltrate, composed of lymphocytes and rare plasma cells, is mild 

Although NSIP may also present with a patchy distribution, with a relatively normal intercurring parenchyma, in contrast to UIP the appearance within each individual focus is characteristically uniform

In the fibrosing form, if the fibrosis has an irregular and subpleural distribution, the lack of fibroblastic foci is critically important. In contrast to UIP, such foci are neither common nor situated at the interface between normal parenchyma and fibrotic areas Histopathologic differential diagnoses:

• UIP: spatial and temporal heterogeneity with fibroblastic foci at the interface between normal parenchyma and fibrotic areas. The fibrosis is prevalent in subpleural regions • HP: intense lymphoplasmacellular infiltrate, poorly-formed interstitial granulomas, centrilobular lesions • Organizing diffuse alveolar damage (DAD): loose fibrosis and septal thickening; marked type II pneumocyte hyperplasia • Well-differentiated lymphocytic lymphoma: dense and diffuse neoplastic lymphoid infiltrate composed mainly of small lymphocytes with frequent pleural infiltration; lymphoepithelial complexes in BALT • DIP: The alveoli are filled with pigmented macrophages; inflammatory infiltrate and interstitial fibrosis are mild Radiological differential diagnoses:

• UIP: clearly peripheral reticular pattern, even in the upper lung regions; ground-glass is limited and honeycombing is more common • DIP: ground-glass is dominant and the reticular pattern is limited or absent • OP: consolidations prevail and tend to be peripheral but also bronchocentric • HP: clear predominance of the reticular pattern over ground-glass Polverosi R. Idiopathic interstitial pneumonias. Radiol Med 2003, 105: 403 

It should be noted that an NSIP histopathologic pattern may be present in association with other clinical conditions such as collagen vascular diseases ( Collagen vascular diseases, early), hypersensitivity pneumonitis ( HP, chronic), drug-induced pneumonia ( Drug toxicity), radiation, infections and immunodeficiencies including HIV+ status. NSIP in these cases is a pattern of lung reaction to different stimuli

The prognosis of NSIP is more favorable than that of UIP ( UIP, early) and appears to be correlated with the extent of fibrosis present at surgical biopsy. Although there have been no reported cases of spontaneous remission, the literature does report cases of stabilization, improvement and even complete recovery in up to 75% of treated cases, even though relapse is possible if treatment is discontinued. Only in a minority of cases does the disease progress, leading to death from respiratory failure Diffuse Lung Diseases

Maffessanti & Dalpiaz

The areas of ground-glass and consolidation may decrease with cortisone treatment (>80% of cases), whereas in cases of disease progression the irregular reticular opacities may develop into fibrosis with honeycombing Akira M. Non-specific interstitial pneumonia: findings on sequential CT scans of nine patients. Thorax 2000, 55: 854 Nishiyama O. Serial high resolution CT findings in nonspecific interstitial pneumonia/fibrosis. J Comput Assist Tomogr 2000, 24: 41

ESR is elevated and about half of patients also have increased CRP and fibrinogen. Some patients may have low-titer antinuclear antibody positivity

In a patient with suspected idiopathic interstitial pneumonia, the presence of patchy or subpleural groundglass opacities and limited reticulation is strongly suggestive of NSIP, whereas if honeycombing is predominant on HRCT, the most likely diagnosis is UIP. In contrast to other diseases, however, lung biopsy is essential given the possible association of the two conditions in different lobes or even in the same lobe, a feature which influences prognosis and treatment options 

Diagnostic confirmation can only be provided by surgical lung biopsy. Transbronchial lung biopsy is of no use About 50% of patients present with increased lymphocytes and reduced CD4:CD8 ratio (cellular NSIP), whereas another 50% of cases present with increased neutrophils and eosinophils (fibrosing NSIP). These two patterns may also be present simultaneously. BAL is unable to distinguish between UIP and fibrosing NSIP Nagai S. Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP. Eur Respir J 1998 Respir J , 12: 1010 Veeraraghavan S. BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia. Eur Respir J 2003, 22: 239 Non-Specific Interstitial Pneumonia

Pulmonary edema refers to the accumulation of fluid in the interstitium and in more severe cases in the alveoli ( PE, alveolar)

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 pulmonary edema is cardiogenic (left ventricular systolic or diastolic dysfunction, left atrial outflow impairment). Less common causes result from a reduction in capillary osmotic pressure (renal disease, liver cirrhosis, fluid overload), neurogenic alterations (head injury, increase in intracranial pressure, non-hemorrhagic stroke) and diseases of the pulmonary veins (idiopathic veno-occlusive disease, fibrosing mediastinitis)

Pulmonary edema is a frequent cause of admission to the hospital These include diseases affecting the function of the left atrium and ventricle, liver cirrhosis and kidney failure

In this stage of the disease (interstitial edema) the onset of symptoms is gradual and insidious. At times the main symptoms of dry cough and dyspnea are only present on exertion. Orthopnea and paroxysmal nocturnal dyspnea are relatively rare Physical examination of the lung is often negative, although wheezes may be heard. Auscultation may reveal a gallop rhythm in cases of valvular dysfunction. Some patients present hepatojugular reflux without peripheral edema

In interstitial edema, the only functional deficits observed are reduced compliance and increased lung resistance. Some patients present bronchial hyperreactivity, while mild hypoxemia with normal-hypocapnia may also be present

In these patients the most common differentials are bronchial asthma and chronic obstructive lung disease Interlobular, perivascular, peribronchial and subpleural interstitium Other characteristics:

• Patchy ground-glass ( ) • Acinar-sized hazy nodules • Pleural effusion, which is often bilateral • Increased diameter of pulmonary vessels and enlargement of left heart

The main radiological differential diagnosis is: • LC: changes with less uniform distribution, while the reticular pattern is more commonly nodular with well-defined margins

Schaefer-Prokop C. High-resolution CT of diffuse interstitial lung disease: key findings in common disorders. Eur Radiol 2001, 11: 373 

In the presence of suspected pulmonary edema, the function of the various organs (heart, kidneys, etc.) involved in the pathogenesis of edema should be investigated Interstitial pulmonary edema may progress towards alveolar pulmonary edema and acute respiratory failure ( PE, alveolar). The progression from chronic pulmonary edema to mild interstitial fibrosis has also been reported Interstitial edema may regress or progress towards the alveolar stage ( PE, alveolar); in the latter case, the interstitial signs become increasingly masked by alveolar signs

Basic lab studies may be performed, although they are not indispensable for the diagnosis or for planning treatment. Nonetheless, they may be useful for excluding possible precipitating factors, such as concurrent infections or anemia Cardiac enzyme levels are important for excluding the presence of myocardial infarction, just as altered creatinin may reveal underlying renal failure. Measurement of plasma brain natriuretic peptide (BNP) may be useful to distinguish heart failure from lung disease as a cause of dyspnea Diffuse Lung Diseases

Maffessanti & Dalpiaz

Other signs

Sarcoidosis is a multisystemic granulomatous disorder of unknown etiology characterized by noncaseating epithelioid granulomas in involved organs. As a result the disease tends to present an HRCT nodular pattern (© Sarcoidosis, granulomatous), although it may occasionally have a fibrosing reticular appearance. The latter of these two forms will be covered in this chapter

The mechanism which causes the progression towards fibrosis is thought to be a shift of pulmonary T cells towards the production of Th2-type cytokines with a consequent fibroproliferative response with extracellular matrix deposition Fewer than 10% of lung sarcoidosis cases progress to the fibrosing form

The disease is 3-4 times more common and more severe among Afro-Americans than whites. Negative prognostic factors include lupus pernio, chronic uveitis, hypercalcemia, nephrocalcinosis, cystic bone lesions and nervous system involvement

At this stage patients present with dyspnea on exertion and dry cough Physical examination may be normal, although at times fine localized rales may be present. Clubbing is not frequently found in chronic fibrosing sarcoidosis. In the more severe cases, chronic cor pulmonale (jugular turgor, peripheral edema, hepatomegaly, systolic ejection murmur at the pulmonary foci, etc.) may be observed A more or less serious restrictive syndrome may be present in relation to the extent of fibrosis, and reduction in D L CO. Patients present with hypoxemia on exertion and in the more severe cases even at rest In cases of extensive fibrosis, the underlying disease can be identified by the presence of residual granulomas Along the lymphatic routes in the early stages (along the bronchovascular bundles, in the interlobular septa and subpleural) and diffuse in the advanced stages Histopathologic differential diagnoses:

• NSIP: alveolar septa are uniformly thickened without a prevalently lymphatic distribution, while granulomas are rare The interstitial inflammatory infiltrate is more abundant • HP: lesions are centrilobular, there is intense lymphoplasmacellular inflammation, and granulomas are poorly formed • UIP: fibrosis tends to be distributed in the subpleural regions and along the interlobular septa Fibroblastic foci are present at the interface with normal parenchyma; granulomas are absent Radiological differential diagnoses:

• HP: alterations are predominantly subpleural with a patchy distribution, whereas perilymphatic nodules are absent • Radiation-induced lung injury: fibrosis selectively affects the irradiated site • UIP: alterations are prevalently located in the peripheral regions and lung bases, with a predominance of honeycombing

In this stage superinfection of the cystic spaces created by the fibrosis may be seen, particularly by aspergillus, whereas pneumothorax is relatively rare

The presence of hemoptysis is sufficient cause for suspecting aspergillus superinfection Spontaneous resolution of the disease in this stage has never been documented. The fibrosis may gradually lead to respiratory failure and chronic cor pulmonale

Conglomerates of the bronchi and vessels may be seen within the opacities, with possible cavitations and mycetomas

The increase in ESR and serum ACE is less pronounced in the fibrosing form than in the nodular form (© Sarcoidosis, granulomatous). In two thirds of patients the Mantoux skin test is negative

The diagnosis is based on a compatible clinico-radiological setting and the definite exclusion of other granulomatous diseases

Other signs

Usual interstitial pneumonia (UIP) is the histopathologic pattern of idiopathic pulmonary fibrosis (IPF), a chronic fibrosing interstitial lung disease of unknown etiology. The term UIP has become so well known as to often be used as a substitute of IPF even in clinical practice. If studied in the early stage, the condition exhibits a predominantly reticular pattern Idiopathic Pulmonary Fibrosis (IPF), Cryptogenic Fibrosing Alveolitis (CFA)

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 of IPF is unknown. There are two prevailing theories regarding pathogenesis: 1. Inflammatory theory. In the early stage of disease, chronic interstitial and alveolar inflammation (macrophages, neutrophils, eosinophils) damages the lung structure and increases production of fibrogenic cytokines with a consequent exaggerated reparative response leading to end-stage fibrotic disease 2. Fibroblast dysregulation. Following an unknown insult, an exaggerated reparative response characterized by the migration and proliferation of fibroblasts, reduced apoptosis of the fibroblasts themselves and increased response to fibrogenic cytokines takes place. This situation is associated with an absence of re-epithelization of the alveolar structures and inappropriate remodeling of the extracellular matrix A prevalence rate of 20.2 cases per 100,000 for males and 13.2 cases for females has been reported. Mean age at diagnosis is 66 years, and the incidence increases with age. The disease has no geographical or racial predilection, although familial cases have been reported

These are thought to include antidepressant drugs, chronic gastroesophageal reflux, inhalation of metal and wood dust, and smoking (1.6-2.3 times), although their importance in the pathogenesis of the disease is unknown

The onset of symptoms is insidious; in most patients symptoms are present for > 6 months before diagnosis. The most common symptoms are breathlessness with exertion and dry cough. Constitutional symptoms are rare and include weight loss and fatigue. Joint and muscle pain may also be present Most patients present with tachypnea. In the early stages, fine diffuse bilateral rales are detected in the posterior lung bases. With progression of the disease the rales extend throughout the lungs. Clubbing occurs in 25-50% of cases Lung function tests reveal a mild-to-moderate restrictive defect, reduced D LCO and mild hypoxemia at rest which worsens on exertion. Smokers may also exhibit an obstructive defect. Although rare, normal pulmonary function tests have been reported at diagnosis Other radiological characteristics: • Reactive enlargement of mediastinal lymph nodes (70-90%) (A) • Ground-glass (limited) • Honeycombing (D)(limited in this phase of the disease)

The ground-glass may be linked not only to the presence of areas of alveolitis and active fibroblast proliferation, but also to the intralobular septal thickening caused by mild fibrosis

The presence of irregular dilatation within the ground-glass areas is a sign of irreversible fibrosis, as is a cystic pattern, which indicates progression from reticular alterations towards honeycombing Bergin C. Mediastinal lymph node enlargement on CT scans in patients with usual interstitial pneumonitis. AJR Am J Roentgenol 1990, 154: 251 Lee JS. Fibrosing alveolitis: prognostic implication of ground-glass attenuation at high-resolution CT. Radiology 1992, 184: 451 Diffuse Lung Diseases

In subjects above 65 years of age, severely obese with severe respiratory failure or severe and chronic co-existing diseases of other organs, surgical lung biopsy is considered high-risk

Surgical lung biopsy is the most definitive method of establishing diagnosis (UIP pattern) and is always performed when the above mentioned criteria have not been met. Transbronchial lung biopsy cannot be used to diagnose IPF but is useful in excluding alternative specific diagnosis (fourth clinical major criteria)

The BAL fluid shows an increase in total cells and polymorphonucleated neutrophils (>5%) which correlate with the extension of the reticular lesions seen at CT. Polymorphonucleated eosinophils may also be increased (>5%). This pattern is much the same as most idiopathic interstitial pneumonias or other fibrosing lung conditions. The number and type of cells found in the BAL fluid have no prognostic value and therefore serial BAL for monitoring disease progression or response to treatment are not advised A lone increase in eosinophils (>20%) is suggestive of eosinophilic pneumonia just as a lone increase in lymphocytes (>15%) is uncommon in IPF. A mixed alveolitis (an increase in lymphocytes, neutrophils and eosinophils) is suggestive of a non-specific interstitial pneumonia (NSIP) or a cryptogenic organizing pneumonia (COP)

Haslam PL. Bronchoalveolar lavage fluid cell counts in cryptogenic fibrosing alveolitis and their relation to therapy. Thorax 1980, 35: 328 Veeraraghavan S. BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia. Eur Respir J 2003, 22: 239 

exhibiting an increase in total cells, lymphocytes (smaller than the nodular form) and neutrophils (>3%). An increase in CD8+ T-cells and mastocytes (>1%) has been documented

The value of bronchoalveolar lavage in the diagnosis and prognosis of sarcoidosis

Sarcoidosis Bronchoalveolar lavage A characteristic feature of the disease is the subversion of the lobular architecture produced by the fibrosis

Idiopathic interstitial pneumonias: high-resolution CT and histologic findings

Bilateral, patchy, interspersed between more-or-less extensive areas of unaffected parenchyma in relation to which the pathological zones are clearly defined Preferentially peripheral (subpleural), predominantly dorsal From the apices to the bases along the entire subpleura

Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia

Idiopathic interstitial pneumonias

Lung volume is normal or only slightly reduced in this phase

The alphabet soup revisited: the chronic interstitial pneumonias in the 1990s

Idiopathic interstitial pneumonias: diagnostic accuracy of thin-section CT in 129 patients

ground-glass prevails and the lesions are less noticeably peripheral. Involvement of upper subpleural zones is rare, as is honeycombing • Asbestosis: subpleural branching or dotlike opacities, subpleural lines and parenchymal bands • Collagen vascular diseases: ground-glass and consolidations containing bronchiectasis and bronchiolectasis • Drug toxicity: ground-glass and consolidations prevail

Diagnosis is often achieved on the basis of clinical and radiological settings. Clinical suspicion may be confirmed by non-invasive instrumental investigations such as BNP plasma levels, electrocardiogram and echocardiography HRCT is performed when there is a discrepancy between clinical history and radiological progression

Pulmonary edema is not an indication to perform BAL, which even if performed would reveal a pattern similar to that of diffuse hemorrhagic alveolitis ( DAH), associated with an increased number of red blood cells, siderophages and neutrophils

The lesions in early UIP are:• Small fibrotic areas starting in the subpleural regions (D) or in the interlobular septa ( ), and less commonly along the bronchovascular bundles. The lung architecture is slightly modified • Extensive areas of normal parenchyma between pathological areas • Characteristic fibroblastic foci (A) at the interface between normal lung and fibrotic areas Spatial heterogeneity (areas of fibrosis alternating with areas of normal parenchyma) and temporal heterogeneity ("old" fibrosis alternating with areas with "young" fibroblastic foci) are characteristic Subpleural and paraseptal Histopathologic differential diagnoses:• NSIP: lesions are spatially and temporally homogeneous, lacking fibroblastic foci • HP: peribronchiolar distribution, presence of granulomas and a more intense inflammatory interstitial infiltrate • LCH: centrilobular stellate nodules containing a mixed infiltrate with Langerhans' cells and often eosinophils • Asbestosis: fibrosis is centrilobular, at least in the early stages, and asbestos bodies are present

The HRCT pattern commonly shows irregular reticulation:• Intralobular (more evident)(D) • Interlobular (less evident)(A)

Usual Interstitial Pneumonia

Subjects with idiopathic pulmonary fibrosis tend to have an increased incidence of lung carcinoma, both adenocarcinoma and squamous cell carcinoma 

Non-specific increases in ESR, quantitative immunoglobulins and LDH levels may be seen. In 10-20% of patients low titer-positive antinuclear antibodies or rheumatoid factor may be slightly increasedThe presence of a titer-positive antinuclear antibodies higher than 1:160 should suggest a collagen vascular disease. Indeed, some collagen vascular diseases (particularly scleroderma) may present with lung involvement similar to that of IPF which may even precede by months or years the more typical systemic manifestations

In an immunocompetent adult the presence of all of the following major diagnostic criteria as well as at least three of the four minor criteria is considered suggestive of IPF in the absence of a surgical lung biopsyMajor criteria: 1) exclusion of other known causes of diffuse infiltrative lung disease such as drug toxicities, environmental exposures and connective tissue diseases; 2) Abnormal pulmonary function studies that include evidence of restriction (reduced vital capacity often with an increased FEV1/FVC ratio) and impaired gas exchange (decreased D L CO or increased alveolar-arterial oxygen gradient); 3) bibasilar reticular abnormalities with minimal ground-glass opacities at HRCT scans; 4) transbronchial lung biopsy or BAL showing no features support an alternative diagnosis Minor criteria: 1) age > 50 years; 2) insidious onset of otherwise unexplained dyspnea on exertion; 3) duration of illness > 3 months; 4) bibasilar, inspiratory crackles (Velcro-like)Usual Interstitial Pneumonia

Clinical course Differentials