key: cord-1052695-jck799zq authors: Cheung, Oi-Yee; Graziano, Paolo; Smith, Maxwell L. title: 6 Acute Lung Injury date: 2018-12-31 journal: Practical Pulmonary Pathology: A Diagnostic Approach DOI: 10.1016/b978-0-323-44284-8.00006-5 sha: 7ffa0d4867e1d28113ac60ce01734ab6a2939c23 doc_id: 1052695 cord_uid: jck799zq Abstract A wide variety of insults can produce acute lung damage, inclusive of those that injure the lungs directly. The clinical syndrome of acute onset respiratory distress, dyspnea, and bilateral infiltrates is referred to as acute respiratory distress syndrome. The histologic counterpart of acute respiratory distress syndrome is diffuse alveolar damage, classically characterized by hyaline membranes. Other histologic features of acute lung injury include intraalveolar fibrin, organization, interstitial edema, and reactive pneumocytes. Diffuse alveolar damage and other histologic features of acute lung injury are nonspecific as to etiology, and once identified require the pathologist to search the biopsy for further features that may help identify a specific etiology. This chapter reviews the temporal sequence of acute lung injury and explores the large variety of specific etiologic causes with emphasis on helpful histologic features to identify. resultant endothelial and alveolar epithelial cell injury is attended by fluid and cellular exudation. Subsequent reparative fibroblastic proliferation is accompanied by type II pneumocyte hyperplasia. 4, 10 The microscopic appearance depends on the time interval between insult and biopsy and on the severity and extent of the injury. 2 DAD is the usual pathologic manifestation of ARDS and is the best-characterized prototype of acute lung injury. From studies of ARDS, the pathologic changes appear to proceed consistently through discrete but overlapping phases ( Fig. 6 .1)-an early exudative (acute) phase ( Fig. 6.2A and B) , a subacute proliferative (organizing) phase ( Fig. 6.2C) , and a late fibrotic phase ( Fig. 6. 3). 2, 4, 5, 9, 11 The exudative phase is most prominent in the first week of injury. The earliest changes include interstitial and intraalveolar edema with variable amounts of hemorrhage and fibrin deposition ( Fig. 6.4 ). Hyaline membranes (Fig. 6 .5), the histologic hallmark of the exudative phase of ARDS, are most prominent at 3 to 7 days after injury (eSlide 6.1). Minimal interstitial mononuclear inflammatory infiltrates ( Fig. 6.6 ) and fibrin thrombi in small pulmonary arteries (Fig. 6 .7) also are seen. Type II pneumocyte hyperplasia ( Fig. 6.8 ) begins by the end of this phase and persists through the proliferative phase. The reactive type II pneumocytes may demonstrate marked nuclear atypia, with numerous mitotic figures (Fig. 6.9 ). The proliferative phase begins at 1 week after the injury and is characterized by fibroblastic proliferation, seen mainly within the interstitium but also focally in the alveolar spaces ( Fig. 6.10 ). The fibrosis consists of loose aggregates of fibroblasts admixed with scattered inflammatory cells, reminiscent of organizing pneumonia Acute interstitial pneumonia (Hamman- In experimental ARDS, the exact time of injury is known, and the entire lung proceeds through the phases at the same time. In a patient who develops diffuse alveolar damage from any cause, the acute lung injury may begin in different areas at different times, so a biopsy specimen may demonstrate injury at various phases in this sequence. ( In ARDS the inciting event is frequently extrathoracic, and lung injury is therefore superimposed on normal preexisting structure. A B Figure 6 .7 Acute respiratory distress syndrome: fibrin thrombi in arteries. Acute lung injury results in local conditions that lead to arterial thrombosis. Thrombi in various stages of organization may be seen (larger pulmonary artery in part A, smaller pulmonary artery in part B). ( Fig. 6 .11); collagen deposition is minimal. Reactive type II pneumocytes persist. Immature squamous metaplasia may occur ( Fig. 6 .12) in and around terminal bronchioles. The degree of cytologic atypia in this squamous epithelium can be so severe as to mimic malignancy ( Fig. 6 .13). The hyaline membranes are mostly resorbed by the late proliferative stage, but a few remnants may be observed along alveolar septa. Some cases of DAD resolve completely, with few residual morphologic effects, but in other cases, fibrosis may progress to extensive structural remodeling and honeycomb lung. As might be expected, a review of outcomes for 109 survivors of ARDS revealed persistent functional disability at 1 year after discharge from intensive care. 12 By definition, ARDS has a known inciting event. The foregoing description is based on a model of ARDS due to oxygen toxicity, wherein the evolution of histopathologic abnormalities can be studied over a defined time period. 2, 5 In practice, lung biopsy most often is performed in patients without a known cause or specific time of onset of injury. Moreover, with some causes of acute lung injury, the damage evolves over a protracted period of time, or the lung may be injured in repetitive fashion (e.g., with drug toxicity). In such circumstances, the pathologic changes do not necessarily progress sequentially through defined stages as in ARDS, so both acute and organizing phases may be encountered in the same biopsy specimen. The basic histopathologic elements of acute lung injury are presented in Box 6.2. Acute fibrinous and organizing pneumonia (AFOP) is a histologic pattern of acute lung injury with a clinical presentation similar to that of classic DAD, in terms of both potential etiologic disorders and outcome. It differs from DAD in that hyaline membranes are absent. The dominant feature is intraalveolar fibrin balls or aggregates, typically in a patchy distribution. Organizing pneumonia in the form of luminal loose fibroblastic tissue is present surrounding the fibrin (eSlide 6.2). The alveolar septa adjacent to areas of fibrin deposition show a variety of changes similar to those of DAD, such as septal edema, type II pneumocyte hyperplasia, and acute and chronic inflammatory infiltrates. The intervening lung shows minimal histologic changes. AFOP may represent a fibrinous variant of DAD. In some patients, both DAD and AFOP disease patterns may be present simultaneously. 13, 14 Specific Causes of Acute Lung Injury Infection Infection is one of the most common causes of acute lung injury. If the lung injury pattern is accompanied by a significant increase in neutrophils, areas of necrosis, viral cytopathic effect, and/or granulomas, infection should lead the differential diagnosis. Among infectious organisms, viruses most consistently produce DAD. 2, 5 Occasionally, fungi (e.g., Pneumocystis) and bacteria (e.g., Legionella) also can cause infections manifesting as DAD. Some of the organisms that are well known to cause acute lung injury with characteristic histopathologic changes are discussed next. Considerable structural remodeling may take place after ARDS as these atelectatic spaces fuse to form consolidated areas of lung parenchyma at the microscopic level. Influenza is a common cause of viral pneumonia. The histopathology ranges from mild organizing acute lung injury (resembling organizing pneumonia) in nonfatal cases to severe DAD with necrotizing tracheobronchitis ( Fig. 6 .14) in fatal cases. 15, 16 Specific viral cytopathic effects are not identifiable by light microscopy. On ultrastructural examination, intranuclear fibrillary inclusions may be seen in epithelial and endothelial cells. 17 The Coronavirus responsible for severe acute respiratory syndrome produces the acute lung injury associated with this disorder. 13, [18] [19] [20] Both DAD and AFOP patterns have been identified in affected patients. On ultrastructural examination, involved lung tissue revealed numerous to moderate numbers of cytoplasmic viral particles in pneumocytes, many within membrane-bound vesicles. [21] [22] [23] The virus particles were spherical and enveloped, with spikelike projections on the surface and coarse clumps of electron-dense material in the center. Most had sizes ranging from 60 to 95 nm in diameter, but some were as large as 180 nm. Measles virus produces a mild pneumonia in the normal host but can cause serious pneumonia in immunocompromised children. Adenovirus is an important cause of lower respiratory tract disease in children, 29, 30 although adults (particularly those who are immunocompromised) 31 and military recruits also are occasionally affected. 32 The lung shows necrotizing bronchitis, or bronchiolitis, accompanied by DAD. The pathologic changes are more severe in bronchi, bronchioles, and peribronchiolar regions ( Fig. 6.16A ). Two types of inclusions can be observed in lung epithelial cells: An eosinophilic intranuclear inclusion with a halo usually is less conspicuous than the more readily identifiable "smudge cells" (see Fig. 6 .16B). These latter cells are larger than normal and entirely basophilic, with no defined inclusion or halo evident by light microscopy. 29 On ultrastructural examination, smudge cell inclusions are represented by arrays of hexagonal particles. 33 Herpes simplex virus is mainly a cause of respiratory infection in the immunocompromised host. Two patterns of infection are recognized: airway spread resulting in necrotizing tracheobronchitis ( Fig. 6 .17) and bronchitis and bronchiolitis, and DAD. 24 The characteristic histologic feature is the presence of multinucleated giant cells (Fig. 6 .15A) with characteristic eosinophilic intranuclear and intracytoplasmic inclusions. [24] [25] [26] [27] [28] These cells are found in the alveolar spaces and within alveolar septa (Fig. 6.15B ). Viral inclusions are seen on ultrastructural examination as tightly packed tubules. 28 Interstitial (alveolar septal) edema Fibroblastic proliferation in alveolar septa Alveolar edema Alveolar fibrin and cellular debris, with or without hyaline membranes Reactive type II pneumocytes blood-borne dissemination producing miliary necrotic parenchymal nodules. DAD and hemorrhage can occur in both forms. 34, 35 Characteristic inclusions may be seen in bronchial and alveolar epithelial cells ( Fig. 6 .18). The more obvious type is an intranuclear eosinophilic inclusion surrounded by clear halo (Cowdry A inclusion), and the other is represented by a basophilic to amphophilic ground-glass nucleus (Cowdry B inclusion). Rounded viral particles with double membranes are seen under the electron microscope. 34, 35 Varicella-zoster virus causes disease predominantly in children and is the agent of chickenpox. 36 Pulmonary complications of chickenpox are rare in children with normal immunity (accounting for less than 1% of the cases). By contrast, pneumonia develops in 15% of adults with chickenpox; immunocompetent and immunocompromised persons are equally affected. 32, 36 The histopathologic picture in varicella pneumonia ( Fig. 6.19 ) is similar to that in herpes simplex. Although identical intranuclear inclusions are reported to occur, 32, 36 these can be considerably more difficult to identify in chickenpox pneumonia. Cytomegalovirus is an important cause of symptomatic pneumonia in immunocompromised persons, especially those who have received bone marrow or solid organ transplants, and in patients with human immunodeficiency virus infection. [37] [38] [39] The histopathologic findings range from little or no inflammatory response to hemorrhagic nodules with necrosis ( Fig. 6 .20A) and DAD. 37 The diagnostic histopathologic B A with many organisms (see Fig. 6 .22B). 44, 45 However, in the mildly immunocompromised patient this feature is not observed or the pathologic changes may be subtle. In such cases, several "atypical" manifestations have been described. 43, 45, 46 DAD is the most dramatic of these atypical presentations ( Fig. 6 .23A), with the organisms present within hyaline membranes ( Fig. 6 .23B) and in isolated intraalveolar fibrin deposits. 46 The Grocott methenamine silver (GMS) method is routinely used to stain the organisms, which typically are seen in small groups and clusters (Figs. 6.22B and 6.23B). 43, 45, 46 Bacterial Infection Common bacterial pneumonias rarely cause DAD; however, this lung injury pattern has been described in legionnaires' disease, Mycoplasma pneumonia, and rickettsial infection. [47] [48] [49] [50] [51] pattern, seen in endothelial cells, macrophages, and epithelial cells, consists of cellular enlargement, a prominent intranuclear inclusion, and an intracytoplasmic basophilic inclusion ( Fig. 6 .20B). 37 Hantavirus is a rare cause of acute lung injury. [40] [41] [42] The infection produces alveolar edema, hyaline membranes, and atypical interstitial mononuclear inflammatory infiltrates (Fig. 6.21 ). [40] [41] [42] Spherical membrane-bound viral particles have been found in the cytoplasm of endothelial cells by electron microscopy. Pneumocystis jiroveci (previously known as Pneumocystis carinii) is the most common fungus to cause DAD. [43] [44] [45] The histopathology of Pneumocystis infection in the setting of profound immunodeficiency is one of frothy intraalveolar exudates ( [AFB] stains or GMS or Warthin-Starry silver stain, etc.) on every lung biopsy specimen exhibiting DAD. Systemic connective tissue disorders are a well-known cause of diffuse lung disease. [52] [53] [54] [55] [56] [57] [58] [59] In some cases, lung involvement may be the first manifestation of the systemic disease, even without identifiable serologic evidence. 57 Histologic clues that suggest the acute lung injury is secondary to connective tissue disease include associated bronchiolitis (especially if it is follicular bronchiolitis), pleuritis, capillaritis, hemorrhage, and Legionella is a fastidious gram-negative bacillus that causes acute respiratory infection in older adults and immunodeficient individuals. 47, 48, 51 The histopathologic pattern is that of a pyogenic necrotizing bronchopneumonia ( Fig. 6 .24A) affecting the respiratory bronchioles, alveolar ducts, and adjacent alveolar spaces. DAD is common. 47, 48, 51 The rod-shaped organisms (Fig. 6 .24B) can be identified by Dieterle silver stain. 51 Of note, in immunocompromised patients, any type of infection can cause DAD, with pneumocystis pneumonia being the most common. 28 For this reason, it is essential to use special stains (acid-fast bacilli and small vessel vasculitis ( Fig. 6 .25B), and pulmonary edema also may be observed. 52, 57, 60 Immunofluorescence studies demonstrate immune complexes in lung parenchyma, and both immune complexes and tubuloreticular inclusions may be seen on ultrastructural examination. 57, 58, 60 Rheumatoid Arthritis A significant percentage of patients with rheumatoid arthritis have lung disease. 53, 54, [61] [62] [63] [64] Many different morphologic patterns of lung disease in rheumatoid arthritis have been described, 54, 57, 59 with the rheumatoid nodule being the most specific. Acute lung injury has been reported ( Fig. 6.26 ), referred to as acute interstitial pneumonia in some publications 65 and as DAD in others. 54 a cellular lymphoplasmacytic infiltrate. Acute lung injury has been reported to occur in the following connective tissue diseases. Pulmonary involvement in systemic lupus erythematosus (SLE) may manifest as pleural disease, acute or chronic diffuse inflammatory lung disease, airway disease, or vascular disease (vasculitis and thromboembolic lesions). Acute lupus pneumonitis (ALP) is a form of fulminant interstitial disease (Fig. 6 .25A) with a high mortality rate. 52 Patients present with severe dyspnea, tachypnea, fever, and arterial hypoxemia. ALP represents the first manifestation of SLE in approximately 50% of affected persons. 52, 58 The most common histopathologic feature of this acute disease is DAD (eSlide 6.3). Alveolar hemorrhage, with capillaritis B A Polymyositis/dermatomyositis, a systemic connective tissue disorder, is well known to be associated with interstitial lung disease. 55, 56 Three main clinical presentations are recognized: (1) acute fulminant respiratory distress resembling the so-called Hamman-Rich syndrome, (2) slowly progressive dyspnea, and (3) an asymptomatic form with abnormalities on radiologic and pulmonary function studies. 59 Three major histopathologic patterns have been observed: DAD (Fig. 6 .27A), organizing pneumonia ( Fig. 6.27B) , and chronic fibrosis (Fig. 6.27C )-the so-called usual interstitial pneumonia (UIP) pattern. 66 The rapidly progressive clinical presentation is associated with a DAD histopathologic pattern on lung biopsy studies and carries the worst prognosis. 56 DAD associated with scleroderma and mixed connective disease also has been described. 57, 67 Many patients with connective tissue disease receive drug therapy during the course of their illness. A large number of drugs, including cytotoxic agents used for immunosuppression, are known to cause DAD. In addition, as a desired result of therapy, patients may be immunosuppressed, making the exclusion of infection a high priority in the case of acute clinical lung disease. Drugs can produce a wide range of pathologic lung manifestations, and the causative agents are numerous. [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] The spectrum of drug-induced lung disease runs the entire gamut from DAD to fibrosis. Between these two extremes, subacute clinical manifestations may include organizing pneumonia, chronic interstitial pneumonia, eosinophilic pneumonia, obliterative bronchiolitis, pulmonary hemorrhage, pulmonary edema, pulmonary hypertension, venoocclusive disease, and granulomatous interstitial pneumonia. 78, 82, 83 DAD is a common and dramatic manifestation of pulmonary drug toxicity. 78 Many drugs are known to cause DAD. 82 A few of the more common ones are discussed next. (Drug-related lung disease is also discussed in Chapter 8.) As a generalization, marked cytologic atypia and numerous foamy macrophages in the airspaces are histologic harbingers of possible drug reaction. DAD frequently is caused by cytotoxic drugs, and the commonly implicated ones include bleomycin (Fig. 6 .28), busulfan ( Fig. 6.29) , and carmustine. 5, 78, 82 Patients usually present with dyspnea, cough, and diffuse pulmonary infiltrates. [84] [85] [86] [87] [88] The histologic pattern most commonly is one of nonspecific acute lung injury with hyaline membranes, but some changes may be present to at least suggest a causative agent. For example, the presence of acute lung injury with associated atypical type II pneumocytes with markedly enlarged pleomorphic nuclei 89 and prominent nucleoli (see Fig. 6 .29) is characteristic for busulfan-induced pulmonary toxicity, and, on ultrastructural examination, intranuclear tubular structures have been found in type II pneumocytes in association with administration of busulfan and bleomycin. [89] [90] [91] [92] In most cases, the possibility that a drug is the cause of DAD can only be inferred from the clinical history. Considerations in the differential diagnosis typically include other treatment-related injury or complication of therapy (e.g., concomitant irradiation or infection). For example, oxygen therapy is a well-recognized cause of DAD (Fig. 6 .30) and also may exacerbate bleomycin-induced lung injury. 93 Methotrexate (Fig. 6 .31) is another commonly used cytotoxic drug that can cause acute and organizing DAD. 94 Methotrexate also produces other distinctive patterns, such as granulomatous interstitial pneumonia (see Chapter 8) that is seldom seen in association with other commonly used chemotherapeutic agents. To complicate matters further, methotrexate also is used in the treatment of rheumatoid arthritis, a disease known to produce DAD independently as one of its pulmonary manifestations. 57, 62 Epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be associated with DAD. 95, 96 The increasing use of targeted therapy drugs in cancer patients warrants a notice of this category as a potential cause. Amiodarone is a highly effective antiarrhythmic drug that is increasingly recognized as a cause of pulmonary toxicity. 77,97-101 Because patients taking amiodarone have known cardiac disease, the clinical presentation often is complicated, with several superimposed processes potentially affecting the lungs in various ways. Clinical and radiologic considerations typically include congestive heart failure, pulmonary emboli, and acute lung injury from other causes. 77, 101 Distinctive features may be present on chest computed tomography scans. 77 The lung biopsy commonly shows acute and organizing lung injury (Fig. 6 .32A and eSlide 6.4). Other patterns include chronic interstitial pneumonitis with fibrosis and organizing pneumonia. 99 Characteristically, type II pneumocytes and alveolar macrophages show finely vacuolated cytoplasm in response to amiodarone therapy (see Fig. 6 .32B), but these changes alone are not evidence of toxicity because they also may be seen in patients taking amiodarone who do not have evidence of lung toxicity. 97 Methotrexate and gold, common agents for treatment of rheumatoid arthritis, are frequently implicated in lung toxicity. Methotrexate is discussed earlier in this chapter. Organizing DAD (Fig. 6.33 ) and chronic interstitial pneumonia are commonly described pulmonary manifestations of so-called gold toxicity. 74, 76, 102 Acute Eosinophilic Pneumonia Acute eosinophilic pneumonia was first described in 1989 103 and is characterized by acute respiratory failure, fever of days' to weeks' duration, diffuse pulmonary infiltrates on radiologic studies, and eosinophilia in bronchoalveolar lavage fluid or lung biopsy specimens in the absence of infection, atopy, and asthma. 104 Peripheral eosinophilia frequently is described but is not a consistent finding at initial presentation. 103, 105 Acute eosinophilic pneumonia is easily confused with acute interstitial pneumonia because both manifest as acute respiratory distress without an obvious underlying cause. 104 Histologically, the disease is characterized by acute and organizing lung injury showing classic features (Fig. 6.34 ) of (1) alveolar septal edema, (2) eosinophilic airspace macrophages, (3) tissue and airspace eosinophils in variable numbers, and (4) marked reactive atypia of alveolar type II cells (eSlide 6.5). Intraalveolar fibroblastic proliferation (patchy organizing pneumonia) and inflammatory cells are present to a variable degree. Hyaline membranes and organizing intraalveolar fibrin also may be present (Fig. 6.35) . The most significant feature is the presence of interstitial and alveolar eosinophils. Infiltration of small blood vessels by eosinophils also may be seen. It is important of special stains applied to tissue sections or cytologic preparations (e.g., AFB, GMS, or Warthin-Starry silver stain) also is essential to rule out infectious organisms in this setting. So-called pulmonary hemorrhage syndromes may feature the histopathologic changes of acute lung injury, 112 in addition to the characteristic alveolar hemorrhage and hemosiderin-laden macrophages. In some patients, DAD may be the dominant histopathologic pattern. 113 In a study by Lombard et al. in patients with Goodpasture syndrome, all showed acute lung injury ranging in distribution from focal to diffuse lung involvement. 113 Histopathologic examination demonstrated typical acute and organizing DAD, with widened and edematous alveolar septa, fibroblastic proliferation, reactive type II pneumocytes, and, rarely, even hyaline membranes (Figs. 6.37 and 6.38). Alveolar hemorrhage, either focal or diffuse, was present in all cases. Capillaritis, an important finding indicating true alveolar hemorrhage, 112 also was seen, as evidenced by marked septal neutrophilic infiltration. Capillaritis was absent in one case for which DAD was the dominant histopathologic pattern. Microscopic polyangiitis can manifest as an acute interstitial pneumonia both clinically and histopathologically. Affected patients have vasculitis as the known cause of acute lung injury. 114 Alveolar hemorrhage with arteritis, capillaritis ( Fig. 6.38) , and venulitis may be seen in some cases. 114 Polyarteritis nodosa and vasculitis associated with systemic connective tissue disease (notably SLE and rheumatoid arthritis) can also show acute lung injury with alveolar hemorrhage as the dominant histopathologic finding. 57, 115 Cryoglobulinemia is a rare cause of acute lung injury and alveolar hemorrhage. [116] [117] [118] Radiation can produce both acute and chronic damage to the lung, manifesting as acute radiation pneumonitis and chronic progressive fibrosis, respectively. 119 The effect is dependent on radiation dosage, total time of irradiation, and tissue volume irradiated. Concomitant chemotherapy and infections, which in themselves are causes of DAD, may potentiate the effect of radiation injury. 5, 79, 120, 121 Acute radiation pneumonitis manifests 1 to 2 months after radiation therapy. 5, 121 With traditional external beam radiation the pneumonitis is typically confined to the radiation field. However, more diffuse radiation pneumonitis can be seen following yttrium 90-impregnated microsphere chemoembolization for nonoperable hepatic tumors. 122 Clinical findings include dyspnea, cough, pleuritic pain, fever, and chest infiltrates. The lung biopsy specimen shows acute and organizing DAD. 119, 121 Markedly atypical type II pneumocytes with enlarged hyperchromatic nuclei and vacuolated cytoplasm constitute a hallmark of the disease (Fig. 6.39A) , and increased numbers of alveolar macrophages are seen. Foamy cells are present in the intima and media of pulmonary blood vessels in some cases, and thrombosis ( Fig. 6.39B) , with or without transmural fibrinoid necrosis, is common. 79, [123] [124] [125] Disease Presenting as Classic Acute Respiratory Distress Syndrome By definition, ARDS must be associated with an identifiable inciting event. The histopathologic pattern is that of classic DAD. The histopathologic changes should be consistent with those expected for the time interval from the onset of clinical disease (see later). In many cases the ARDS may be caused by a combination of factors, each potentiating the other. 4 For the purposes of illustration, a few thoroughly studied causes are discussed next. to distinguish acute eosinophilic pneumonia from other causes of DAD because patients typically benefit from systemic corticosteroid treatment, with prompt recovery. However, before initiation of immunosuppressive therapy, infection should be rigorously excluded by culture and special stains because parasitic and fungal infections also can manifest as tissue eosinophilia. Treatment with steroids prior to the biopsy can make the number of eosinophils less impressive. Acute interstitial pneumonia, also commonly referred to as Hamman-Rich syndrome, is a fulminant lung disease of unknown etiology occurring in previously healthy patients. [107] [108] [109] Acute interstitial pneumonia is one of the major idiopathic interstitial pneumonias included in the most recent classification scheme for diffuse interstitial pneumonia. 110 Patients usually report a prodromal illness simulating viral infection of the upper respiratory tract, followed by rapidly progressive respiratory failure. The mortality rate is high, with death occurring weeks or months after the acute onset. 107, 109 The classic histopathologic pattern is that of acute and organizing DAD, 107,109 with septal edema and hyaline membranes in the early phase and septal fibroblastic proliferation with reactive type II pneumocytes prominent in the organizing phase. In practice, a combination of acute and organizing changes ( Fig. 6 .36) often is seen in the lung at the time of biopsy. 111 A variable degree of airspace organization, mononuclear inflammatory infiltrates, thrombi in small pulmonary arteries, and reparative peribronchiolar squamous metaplasia also are seen in most cases. Because acute interstitial pneumonia is idiopathic, other specific causes of acute lung injury must be excluded before making this diagnosis. Considerations in the differential diagnosis include infection, connective tissue disease, acute exacerbation of idiopathic pulmonary fibrosis (IPF), drug effect, and other causes of DAD. 111 Most cases of DAD are not acute interstitial pneumonia, and detailed clinical information, radiologic findings (localized vs. diffuse disease), serologic data, and microbiologic results will often point to or rule out a specific etiologic condition. Use Figure 6 .36 Acute interstitial pneumonia (AIP). Idiopathic AIP may take the form of every possible morphologic manifestation of acute respiratory distress syndrome, depending on the timing of biopsy relative to the onset of symptoms. Here, a classic pattern of diffuse alveolar damage (DAD) with hyaline membranes of variable cellularity is seen (midproliferative phase). Interstitial fibroblastic proliferation may be more or less prominent from case to case and should not serve as a qualifying morphologic finding for the diagnosis. AIP is nothing more than DAD of unknown causation. Oxygen is a well-known cause of ARDS and a useful model for all types of DAD. 4, 126, 127 Oxygen toxicity also is important in that it is widely used in the care of patients, often in the setting of other injuries that can potentially cause ARDS, such as sepsis, shock, and trauma. Exposure to high concentrations of oxygen for prolonged periods can lead to characteristic pulmonary damage. In 1958 Pratt first noted pulmonary changes due to high concentrations of inspired oxygen. 128 In 1967 Nash et al. described the sequential histopathologic changes of this injury, 126 later reemphasized by Pratt. 127 In neonates receiving oxygen for hyaline membrane disease, bronchopulmonary dysplasia was reported to occur. 129 As might be expected, the features of hyaline membrane disease in neonates and oxygen-induced DAD in adults are indistinguishable (see Fig. 6 .30). Other inhalants such as chlorine gas, mercury vapor, carbon dioxide in high concentrations, and nitrogen mustard all have been reported to cause ARDS. 2,4,5 Massive extrapulmonary trauma and shock first became recognized as causes of unexplained respiratory failure during the wars of the second half of the 20th century. A variety of names were assigned to this wartime condition, including shock lung, congestive atelectasis, traumatic wet lung, Da Nang lung, respiratory insufficiency syndrome, posttraumatic pulmonary insufficiency, and progressive pulmonary consolidation. 2 It which can be performed even on autopsy specimens. Other ingested toxins (e.g., kerosene, rapeseed oil) also have been reported to cause ARDS. 5 Pathologist Approach to the Differential Diagnosis of Acute Lung Injury The histologic spectrum encountered in acute lung injury is broad. Very early cases may look nearly normal with only mild interstitial and alveolar edema. Other more advanced cases are clearly abnormal with fibrin, inflammation, and organization. The basic elements of the acute injury pattern include interstitial edema, alveolar edema, fibrin, hyaline membranes, reactive pneumocytes, and organization (see Box 6.2). Acute lung injury is a pathologic pattern and by itself is a nonspecific finding. From a practical perspective, after an acute lung injury pattern is became clear that shock of any cause (e.g., hypovolemia due to hemorrhage, cardiogenic shock, sepsis) could cause ARDS, and that in most cases, a number of factors come into play. In the typical presentation, dyspnea of rapid onset is accompanied by development of diffuse chest infiltrates several hours to days after an episode of shock. After ARDS begins, the mortality rate is high. 1,2,130 Paraquat is a potent herbicide that causes the release of hydrogen peroxide and superoxide free radicals, resulting in damage to cell membranes. [131] [132] [133] Oropharyngitis is the initial sign of poisoning, followed by impaired renal and liver function. Approximately 5 days later, ARDS develops. The histopathologic pattern in most cases is one of organizing DAD (Fig. 6.40 ). The diagnosis is confirmed by tissue analysis for paraquat, B A raise consideration of immunologically mediated pulmonary hemorrhage. 112 Care must be taken not to interpret the pigmented macrophages seen in the lungs of cigarette smokers as evidence of hemorrhage. 135 The hemosiderin in macrophages related to true hemorrhage in the lung (from any cause) is globular, often slightly refractile, and golden-brown in color. 57, [112] [113] [114] Presence of atypical cells. Viral infections often produce cytopathic effects, including intracellular inclusions (see Chapter 7) . Examples of intracellular inclusions are the Cowdry A and B inclusions seen in herpesvirus infection, cytomegaly with intranuclear and intracytoplasmic inclusions of cytomegalovirus, the multinucleated giant cells of measles virus and respiratory syncytial virus, and the smudged cells of adenovirus infection. 33, 37, 38, 136, 137 Chemotherapeutic drugs such as busulfan and bleomycin often are associated with markedly atypical type II pneumocytes, which may have enlarged pleomorphic nuclei and prominent nucleoli. 90, 91 Markedly atypical type II pneumocytes that may be suggestive of a viropathic effect also are seen in radiation pneumonitis. 79, 124, 125 Presence of foamy cells. Alveolar lining cells with vacuolated cytoplasm accompanied by intraalveolar foamy macrophages are characteristic features seen in patients taking amiodarone, and amiodarone toxicity may lead to acute lung injury changes. [97] [98] [99] 101 In some cases of radiation pneumonitis, foam cells are seen in the intima and media of blood vessels. 79, 125 Presence of foreign material. Foreign material in the spaces in the form of vegetable matter or other food elements is indicative of aspiration. Massive aspiration events may cause DAD. Other foreign material, such as radiation impregnated beads may also be encountered. Presence of advanced interstitial fibrosis. Clinical IPF is associated with the changes of UIP on pathologic examination (see Chapter 8), with advanced lung remodeling. Of interest, IPF undergoes episodic exacerbation, and on occasion such exacerbation may be overwhelming, with resultant DAD. 138 It is prudent to examine lung biopsy sections for the presence of dense fibrosis with structural remodeling (microscopic honeycombing) in cases of DAD, to identify the rare case of IPF that manifests for the first time as an acute episode of exacerbation. Because the morphologic manifestations of acute diffuse lung disease may be relatively stereotypical, clinicopathologic correlation is often helpful in arriving at a specific diagnosis. A summary of the more important history and laboratory data pertinent to this correlation is presented in Box 6.3. identified, careful search for the following additional features often help to narrow the list of possible causes (summarized in Immune status Acuity of onset Radiologic distribution and character of abnormalities History of inciting event (e.g., shock) History of lung disease (e.g., usual interstitial pneumonia with current acute exacerbation) History of systemic disease (e.g., connective tissue disease, heart disease) History of medication use or drug abuse History of other recent treatment (e.g., radiotherapy for malignancy) Results of serologic studies: erythrocyte sedimentation rate determination, assays for autoimmune antibodies (e.g., ANA, RF, ANCA, Scl-70, Jo-1) Results of microbiology studies One of the first questions to be addressed is whether or not a known inciting event was identified clinically (i.e., Is this ARDS?). Next, the results of any sampling procedures to identify infection should be checked, along with application of special stains to the tissue sections, to exclude infection. Finally, data regarding related disease, such as infection, autoimmune disease, underlying lung disease, are needed. For example, if the patient is immunosuppressed, infection should always be the leading consideration in the differential diagnosis. Another point to keep in mind is that patients with certain diseases may be taking medications with the potential to cause DAD (e.g., amiodarone for cardiac arrhythmia). Moreover, laboratory studies may reveal antibodies related to connective tissue disease (e.g., antineutrophil antibody, rheumatoid factor, Jo-1, Scl-70, antifibrillarin, anti-Mpp10, SS-A, SS-B). Regarding the pathologist's role and responsibility in biopsy cases of acute lung injury, use of special stains for organisms (at a minimum, methenamine silver and acid-fast stains) is indicated. Additional stains (auramine-rhodamine, Dieterle or Warthin-Starry silver stain, immunohistochemical stains for specific organisms, or molecular probes) may be used, especially in patients known to be immunocompromised from any cause. The pathology in immunocompromised patients may not show necrosis, neutrophils, or granulomas, all features favoring an infectious etiology. Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com. Acute and fibrinous organizing pneumonia (eSlide 6.2) a. History-A 55-year-old female presented with acute onset dyspnea. Her past medical history was significant for rheumatoid arthritis for which she had recently begun methotrexate. Imaging studies show bilateral ground-glass infiltrates in upper and lower lobes. A surgical lung biopsy was performed. b. Pathologic findings-From scanning magnification, the lung architecture appears preserved without significant fibrosis. At higher power there is an extensive airspace filling process. Many airspaces are filled with fibrin and scattered inflammatory cells. In other areas there is light pink material suggestive of edema. Finally, some early fibroblastic polyps of organization are present. The interstitium shows Diffuse alveolar damage with hyaline membranes (eSlide 6.1) a. History-A 49-year-old male without significant past medical history presented to the emergency room with acute shortness of breath and cough. A week prior he participated in a half marathon without difficulty. He was taking no medications and had no exposures. His oxygen saturation was 82% on room air. He progressed to respiratory failure after being admitted to the intensive care unit. A surgical lung biopsy was performed. b. Pathologic findings-From scanning magnification the biopsy shows preserved lung parenchyma without significant scarring. However, there is a diffuse process that gives the biopsy a "pink" appearance from low power. At higher power, the histologic features of diffuse alveolar damage (DAD) are recognized including alveolar wall edema, reactive type-II pneumocytes, and hyaline membranes. A few foci of organization are also present. A significant inflammatory cell infiltrate is not recognized. There is no pleuritis, hemosiderosis, granulomas, or necrosis. c. Diagnosis-Diffuse alveolar damage. d. Discussion-Features of acute lung injury are readily apparent, and the numerous hyaline membranes support a diagnosis of diffuse alveolar hemorrhage. The biopsy is negative for numerous eosinophils, foamy macrophages, alveolar hemorrhage, foreign material, neutrophils, necrosis, and granulomas. Therefore the histology does not suggest a particular etiology on this case. Acid-fast and fungal stains were negative. Extensive serologic screening studies were negative, and cultures are negative to date. Because the additional work-up is negative, this case is best categorized as acute respiratory distress syndrome. 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Refers to an increased number of alveoli relative to the corresponding conducting airways Which of the following is NOT in the macroscopic differential diagnosis of cystic lung lesions in children? A. Adenomatoid malformation B. Intralobar sequestration C. Congenital lobar overinflation D. Lymphangioleiomyomatosis E. Pneumatocele ANSWER: D 3. Pulmonary sequestration is characterized by: A. Communication with second-order bronchial lumina B. Solely systemic vascular supply C. Exclusive extralobar localization D. Densely apposed, atelectatic airspaces E. Multifocal aggregates of eosinophils ANSWER: B 4. Extralobar pulmonary sequestrations may occasionally contain which ONE of the following heterotopic tissues? A. Bone B. Glial nodules C. Hepatoid anlage D. Striated muscle E. Enteric-type epithelium ANSWER: D 5. Congenital malformations of the pulmonary airways: A. Are most often seen in stillborns or newborns B. Represent malformations of each bronchopulmonary segment C. May be difficult to subclassify in fetal lungs D. Must be distinguished from pleuropulmonary blastoma E. All of the above ANSWER: E 6. Which ONE of the following tissues may have implications for future lung pathology, if it is present in a congenital malformation of the pulmonary airways? A. Striated muscle B. Cartilage C. Mucinous epithelium D. Embryonic-type mesenchymal tissue E. Lymphoid aggregates ANSWER: C 146.e2 19. Which ONE of the following storage disorders does NOT usually involve the lung parenchyma? A. Niemann-Pick disease B. Gaucher disease C Obliterative bronchiolitis in children can be associated with all of the following EXCEPT: A. Adenovirus B. Influenza C. Stevens-Johnson syndrome D. Paragonimiasis E. Graft-versus-host disease ANSWER: D Acute eosinophilic pneumonia (eSlide 6.5) a. History-A previously healthy 29-year-old female presented to the emergency room with acute-onset shortness of breath and cough. She was initially evaluated and admitted to the medicine floor for presumed pneumonia. However, she quickly deteriorated and was transferred to the medical intensive care unit and required intubation. Imaging studies showed bilateral ground-glass opacities without lobar distribution. Additional history obtained from the patient's roommate revealed the patient was recently treated with sulfamethoxazole and trimethoprim for a urinary tract infection. b. Pathologic findings-The overall architecture of the lung appears intact, but there is a diffuse acute lung injury pattern including alveolar wall edema, airspace fibrin, organization, and scattered hyaline membranes. Pneumocytes show marked reactive atypia. There are numerous eosinophils in the airspaces, embedded within the fibrin, and within the interstitium. Numerous airspace macrophages are also present. No necrosis or granulomas are identified. c. Diagnosis-Acute eosinophilic pneumonia. d. There are four key histologic features in acute eosinophilic pneumonia, all of which are satisfied in this case. i. Alveolar septal edema ii. Eosinophilic airspace macrophages iii. Tissue and airspace eosinophils iv. Reactive atypia of type-II pneumocytes There is a differential diagnosis for the acute eosinophilic pneumonia pattern of injury including drug reaction, infection, connective tissue disease, smoking related, and idiopathic. Rigorous exclusion of infection is imperative and requires both infectious stains on the tissue blocks and culture studies. Recognition of this injury pattern is of particular importance as these patients typically respond dramatically to high-dose steroids and have a better prognosis than that of diffuse alveolar damage. In this patient the exposure to a sulfa drug in the days prior to presentation was the likely etiology. She was treated with steroids, dramatically improved, and was discharged in 4 days. Amiodarone-induced diffuse alveolar damage (eSlide 6.4) a. History-A 71-year-old male presented to the emergency room with acute shortness of breath first noted the evening prior. His past history was significant for a deceased donor renal transplant 10 days prior to presentation for end-stage renal disease secondary to diabetes. He also had a history of hypertension and atrial fibrillation. Imaging studies showed bilateral ground-glass opacities in the upper and lower lobes. b. Pathologic findings-From scanning magnification there is preserved architecture without significant fibrosis. There is diffuse alveolar wall thickening, mostly by edema. Overlying pneumocytes show reactive epithelial changes. Numerous hyaline membranes and focal fibrin in airspaces are present. Some airspaces are filled with numerous macrophages showing finely vacuolated cytoplasm. Some Acute lupus pneumonitis (eSlide 6.3)a. History-A 34-year-old African-American female presented with the emergency room with cough and shortness of breath. Upon further questioning, she reported some blood-tinged sputum. The patient was febrile, and chest imaging studies showed bilateral ground-glass infiltrates without lobar distribution. Serologic studies revealed an elevated erythrocyte sedimentation rate and C-reactive protein and positive antinuclear antibodies and anti-double-stranded DNA antibodies. A surgical lung biopsy was performed. b. Pathologic findings-The biopsy shows preserved lung architecture with a diffuse abnormality from scanning magnification. There is extensive alveolar wall edema with numerous foci of hyaline membranes. Patchy organization is present, along with a relatively diffuse lymphoplasmacytic interstitial infiltrate. c. Diagnosis-Acute lupus pneumonitis. d. Discussion-Based on the histologic features alone, this biopsy is diagnostic of diffuse alveolar damage. However, the clinical history is required to arrive are a more specific diagnosis of acute lupus pneumonitis. The biopsy does show a mild increase in lymphoplasmacytic interstitial inflammation that would be unusual for most cases of idiopathic acute respiratory distress syndrome.edema and a mixed lymphoplasmacytic infiltrate. No hemorrhage, necrosis, or hyaline membranes are present. c. Diagnosis-Acute fibrinous and organizing pneumonia (AFOP). d. Discussion-AFOP presents in the same fashion as diffuse alveolar damage (DAD) and the differential diagnosis for AFOP and DAD is the same, including drug reaction, toxin exposure, connective tissue disease, infection, and as an idiopathic reaction. They both represent forms of acute lung injury. In this case the degree of lymphoplasmacytic inflammation in the interstitium raises the possibility of a background connective tissue disease. Additional history revealed she had recently cut her methotrexate dose in half to save money. She had also recently experienced inflammatory flares in her joints. All of these factors support a diagnosis of AFOP related to rheumatoid arthritis. A definitive etiology for AFOP is identified in a minority of patients.pneumocytes show similar cytoplasmic vacuolization. There is no necrosis, neutrophils, or hemorrhage. c. Diagnosis-Diffuse alveolar damage (DAD) with foamy macrophages.A drug reaction leads the differential diagnosis. d. Discussion-Based on the presence of the patchy but marked cytoplasmic vacuolization in the macrophages and pneumocytes, a drug reaction is the most likely etiology for the DAD pattern. In particular, amiodarone is a commonly used drug that causes this cytoplasmic vacuolization, even in the absence of associated lung injury. This was communicated to the clinical services who identified the patient was indeed taking amiodarone, even on the day of transplant. Amiodarone-induced lung injury is associated with prolonged use of the drug and with an inciting event (such as a major operation). This patient had been on amiodarone for several years. Following clinicopathologic correlation, this case is best diagnosed as amiodarone-induced DAD. The patient was treated with pulse high-dose steroids and eventually had a full recovery.