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Pathology of Acute Lung Injury and Acute Respiratory Distress Syndrome: A Clinical–Pathological Correlation
Clin Chest Med 27 (2006) 571–578
Pathology of Acute Lung Injury and Acute Respiratory Distress Syndrome: A Clinical–Pathological Correlation Oscar Pen˜uelas, MDa, Jose´ Antonio Aramburu, MDb, Fernando Frutos-Vivar, MDa, Andre´s Esteban, MD, PhDa,* a
Intensive Care Unit and Burn Unit, Hospital Universitario de Getafe, Carretera de Toledo km 12.5, 28905 Getafe, Madrid, Spain b Department of Pathology, Hospital Universitario de Getafe, Carretera de Toledo km 12.5, 28905 Getafe, Madrid, Spain
Acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and colleagues in 1967 [1]. When they first described acute respiratory distress syndrome, they outlined 12 patients with (1) severe dyspnea, (2) tachypnea, (3) cyanosis refractory to oxygen therapy, (4) loss of lung compliance, (5) diffuse alveolar infiltration seen on chest x ray, and (6) no previous history of significant respiratory disease. It is necessary to recognize that this entity does not appear for the first time in the late 1960s and, in fact, there are similar descriptions during the influenza epidemic in 1918 and in experimental studies. The importance of the first description by Ashbaugh and colleagues [1] rests on the fact that that the finding was coincident with the generalization of intensive care units and management of acute respiratory failure with positive pressure ventilation. During the following 2 decades, the syndrome was defined according to Ashbaugh and colleagues’ original description, as adult respiratory distress syndrome for its similarity to the syndrome described in newborns, characterized by presence of hyaline membranes and reduction or absence of surfactant pulmonary. Most experts agree on the theoretical
Funded by Red Gira (G03/063) y Red Respira (C03/11). * Corresponding author. E-mail address: [email protected] (A. Esteban).
concept of ARDS as a disorder or pathophysiologic entity. Review articles of ARDS continue to agree that, at least in its early stages, ARDS represents the pathological state of diffuse alveolar damage (DAD) [2–4]. This state includes alveolar flooding and formation of the characteristic hyaline membranes, as a result of injury to the endothelial and epithelial layers of the alveolarcapillary membrane, with resultant loss of the gas exchange and barrier functions of the lung. Histopathological changes in acute lung injury The pathological state of diffuse alveolar damage was first described by Katzenstein and colleagues in 1976 [5]. Lung morphology in ARDS reflects the rapid evolution from interstitial and alveolar edema to end-stage fibrosis consequent to injury of the alveolocapillary unit. Nevertheless the sequential stages, as shown in Fig. 1, are defined primarily for didactic purpose. Pulmonary lesions correlate with the phase of alveolar damage rather than with its specific cause. The morphologic progression has been subdivided into sequentially occurring exudative, proliferative, and fibrotic phases (Fig. 2). The exudative phase is characterized by the appearance of edema in the alveolocapillary space (Fig. 3), followed by destruction of type 1 pneumocytes that are replaced by a PAS-positive material, called hyaline membranes. These membranes, which are the hallmark of the diffuse alveolar
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572
PEN˜UELAS
et al
Fig. 1. Schematic evolution of the chronology of diffuse alveolar damage.
damage, are made of fibrin and detritus proceeding from the destruction of the type 1 pneumocytes (Fig. 4). Although ARDS frequently culminates in ‘‘interstitial’’ fibrosis, the organization of intraluminal exudate with type 2 cells proliferate with some epithelial cell regeneration and fibroblastic reaction dominates the histologic picture in the proliferative phase (Fig. 5). The late proliferative, or fibrotic, phase of ARDS is the result of cellular proliferation that leads to the deposition of collagen and proteoglycans (Fig. 6A). Extensive fibroblast proliferation with incorporation of the hyaline membranes is a characteristic finding in this stage of ARDS. Involvement of the pulmonary vasculature is an important aspect of ARDS, from the initial phase of edema to the terminal stage of intractable pulmonary hypertension (Fig. 6B). Vascular lesions include thrombotic, fibroproliferative, and obliterative changes, which, like the parenchymal lesions, correlate with the temporal phase of diffuse alveolar damage. An aspect difficult to elucidate is the chronological sequence of these morphological changes. The sequential pulmonary changes occurring in the evolution of ARDS were studied in 35 patients by correlative light, scanning, and transmission electron microscopy [6]. The acute stage in patients surviving 2 to 7 days was characterized by an exudative reaction with a predominance of hyaline membranes. This acute stage merged with and was replaced by a subacute reparative stage in patients surviving 7 to 14 days, which in turn
was replaced by a chronic fibroproliferative stage complicated by interstitial pulmonary fibrosis and a deranged acinar architecture. Correlation of findings by scanning electron microscopy with those by light and transmission electron microscopy provided an added dimension to understanding of the evolving stages of ARDS and demonstrated that type 2 pneumocytes contributed to the fibroproliferative stage through organization of hyaline membranes and reepithelialization of alveoli (Fig. 7). A limitation of this study is that it is possible to see in the same patient lesions in different stages of evolution and the phases previously described can overlap in time (Fig. 2). Obviously, the reconstruction of the chronologic sequence has been performed by means of pulmonary biopsies or samples from autopsies. Usually it is difficult to know when the injury has begun. In an attempt of approach to this issue, we have described the chronological evolution of the lung injury in an animal model of mechanical ventilation with high tidal volumes (tidal volume 35 mL/kg and positive end-expiratory pressure [PEEP] of 0 cm of water) during 45 minutes [7,8]. After the harmful stimulus the animals were extubated and half of them were humanely killed within 6 hours. The rest of the surviving animals were killed at 48 hours, 72 hours, and 7 days after the injury. At 48 hours after injury, the lungs already showed signs of repair. The proliferation of type 2 pneumocytes covering the alveolar surface, to replace type 1 pneumocytes, turns out to
PATHOLOGY OF ALI AND ARDS
573
Fig. 2. Evolution of the histological changes characteristic of diffuse alveolar damage. Black arrows indicate hyaline membrane (exudative phase), and pneumocytes type 2 (proliferative phase).
be very rapid and effective. Later, the differentiation to type 1 pneumocytes allows the recuperation of the initial structure. Definitions of acute respiratory distress syndrome After the first description of this syndrome by Ashbaugh and colleagues [1], in the subsequent 2 decades ARDS remained very loosely defined, with terms such as a ‘‘worsening picture on analyses of arterial blood gas levels and increasing amounts of bilateral diffuse infiltrates on chest x-ray films’’ being used [9]. Many authors seemed to view ARDS as a gestalt diagnosis, where no specific definition was needed. Indeed only half of 83 articles identified in a systematic review of ARDS incidence specified a definition for ARDS [10]. When ARDS was defined in clinical trials
in the early to mid-1980s, more restrictive definitions tended to be used, for example requiring all of the following to be present: (1) a known risk factor for ARDS, (2) a low static respiratory compliance (generally ! 50 mL/cm H2O), (3) a nonincreased pulmonary artery wedge pressure (generally ! 12-18 mm Hg, and thereby mandating the insertion of a pulmonary artery catheter), (4) diffuse bilateral infiltrates on chest radiograph, and (5) a decreased arterial to alveolar partial pressure of oxygen ratio (variable but generally equivalent to a ratio PaO2 to FIO2 of approximately 150 or less) [10]. In 1988, Murray and coworkers introduced the Lung Injury Score [11]. This score has four domains (chest x ray, hypoxemia, PEEP, and respiratory system compliance) and assigns a score of 0 to 4 to each domain that is available. The
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Fig. 3. (A) Normal alveolar wall with thin alveolar septum (black arrow). (B) Intra-alveolar edema (black arrows) with minimun septal edema. (C, D) Prominent intra-alveolar and interstitial edema (black arrows) (hematoxylin-eosin, original magnification 100.)
individual domain scores are then summed and divided by the number of domains used to give the final Lung Injury Score (LIS). Acute respiratory distress syndrome is defined by an LIS greater than 2.5. Despite the advent of newer definitions, use of the LIS remains in common use. In 1992 the American-European Consensus Conference (AECC) on ARDS was formed to ‘‘bring clarity and uniformity to the definition of acute lung injury and ARDS’’ [12]. The American-European Consensus Conference definition was designed for use in many settings including research, epidemiology, and individual patient care. This definition states that ARDS should be considered present when all of the following conditions are met: (1) timingdacute onset; (2) oxygenationdratio PaO2 to FIO2 % 200 (regardless of PEEP level); (3) chest radiographdbilateral infiltrates seen on frontal chest radiograph; and (4) pulmonary artery wedge pressure (% 18 mm Hg when measured or no clinical evidence of left atrial hypertension). In addition to defining ARDS, this first AECC also defined a clinical entity termed acute lung injury (ALI). ALI is a disorder that encompasses ARDS (comprising a subset of
patients with a severe form of ALI), but that also includes patients with less severe forms of the same pathologic entity. ALI is defined using the same criteria as for ARDS, except for a higher oxygenation threshold, requiring a ratio PaO2 to FIO2 % 300 (regardless of PEEP level).
Validity of the clinical criteria of acute respiratory distress syndrome A way to determine the diagnostic accuracy of clinical definitions for ARDS is to compare these with autopsy finding of diffuse alveolar damage as a reference standard. Recently two studies have been published using this methodology. Esteban and colleagues [13] found that the accuracy of the AECC definition of ARDS was only moderate (Table 1). The definition was more accurate for patients with extrapulmonary risk factor than for patients with pulmonary risk factors. In all patients (N ¼ 382), the sensitivity of the AECC criteria was 75% (95% confidence interval: 66 to 82) and the specificity was 84% (95% confidence interval: 79 to 88). When only patients with
PATHOLOGY OF ALI AND ARDS
Fig. 4. Hyaline membranes. (A) Pink fibrinous material that lines the alveolar ductus. (B) Numerous intraalveolar histiocytes with moderate septal edema (black arrow).
ARDS risk factors (n ¼ 284) were analyzed the specificity fell to 75% (95% confidence interval: 68 to 81) with a similar sensitivity. Compared with patients with pulmonary risk factors, the sensitivity was significantly higher in patients with an extrapulmonary risk factor (61% versus 85%; P ¼ .009), while the specificity was numerically higher but not statistically significantly different (69% versus 78%; P ¼ .25).
Fig. 5. Extensive proliferation of type 2 pneumocytes along alveolar walls (black arrows) lining the alveolar surface denuded after pneumocytes type 1 necrosis.
575
Fig. 6. Fibroprolifetarive phase of ARDS. (A) Thickening of the alveolar wall by loose organizing connective tissue (black arrow) signs fibrosis. (B) Severe fibrosis with vascular structures engulfing, which contributes to the development of pulmonary hipertension (black arrows).
In the analysis of the discrepancies between clinical criteria and pathological findings, we found that in 43 patients with AECC criteria of ARDS without diffuse alveolar damage (false positives) the diagnoses by pathologists were pneumonia in 32 patients (Fig. 8), pulmonary hemorrhage in 4 patients (Fig. 9), pulmonary hydrostatic edema in 3 patients, pulmonary embolism in 3 patients, and 1 patient with interstitial fibrosis. On the other hand, there were 27 cases of false negatives (absence of clinical criteria of ARDS but presence of diffuse alveolar damage). In these patients the clinical diagnoses were pulmonary edema in 12 patients and pneumonia in 12 patients. In three patients there was no diagnosis of pulmonary pathology. In the other paper [14], Ferguson and colleagues analyzed a subset of these same patients and compared autopsy findings with three different definitions: AECC criteria, LIS, and Delphi definition [15]. In this analysis, definitions were constructed on a daily basis and patients were counted as positive for a definition if they met
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Fig. 7. Electronic microscopy of lung with ARDS. (A) Cellular detritus that constitutes the hyaline membrane (black arrow) and covers the basal membrane detached by the necrosis of the pneumocites type 1. (B) Hyperplasia of pneumocites type 2 (continuous line arrow); pneumocite type 2 in differentiation toward type 1 (discontinuous line arrow).
its criteria on any one day, simulating the process of enrollment into clinical trials. Of the three definitions, the AECC was most sensitive although this did not reach statistical significance. Both the LIS and the Delphi definitions had significantly higher specificities than the AECC definition (Table 1). Thus, while sensitive, the AECC definition may lack specificity, which may be problematic when this definition is used as an entry criterion in some clinical trials. Pulmonary and extrapulmonary acute respiratory distress syndrome The different accuracy of the clinical criteria for pulmonary and extrapulmonary ARDS might raise the hypothesis of two different syndromes [16]. This hypothesis has support in the studies that have reported significant differences in the radiological pattern [17,18], in the respiratory mechanics, and the response to PEEP consistent with a prevalence of consolidation in pulmonary ARDS as opposed to prevalent edema and
et al
alveolar collapse in extrapulmonary ARDS [19] and in the response to prone position [20]. Hoelz and colleagues [21], analyzing biopsy tissues of ARDS patients, described the morphologic differences between pulmonary lesions in ARDS of pulmonary and extrapulmonary origin. They observed a predominance of alveolar collapse, fibrinous exudate, and alveolar wall edema in pulmonary ARDS. The morphologic difference between pulmonary and extrapulmonary ARDS was mainly quantitative in extent and distribution according to the underlying disease. This study has limitations since it was realized with biopsies taken in different moments of the evolution of the disease. To avoid these limitations, this group developed an animal model of ALI of pulmonary and extrapulmonary acute respiratory distress that allows analyzing morphological changes at different times (earlier or later in the course of the disease) [22]. Light microscopy showed similar increments in alveolar collapse and tissue cellularity in pulmonary and extrapulmonary ARDS. However, electron microscopy demonstrated extensive injury of alveolar epithelium, swollen and fragmented type 1 and II cells, intact capillary endothelium, ductal hyperdistention, neutrophil recruitment into the alveolar space, proliferation of fibroblasts into the alveolar septa, the presence of collagen type 3 fiber, and hyaline membranes in pulmonary ARDS, whereas extrapulmonary ARDS showed interstitial edema and intact type 1 and 2 cells. In addition, an increased amount of apoptotic neutrophils was observed in pulmonary ARDS in comparison with extrapulmonary ARDS. Some of those differences between pulmonary and extrapulmonary ARDS may be explained by a different lung architecture remodeling process as a consequence of the two different mechanisms involved in lung injury. Negri and colleagues [23] hypothesized that deposition of extracellular matrix fibers is involved in acute pulmonary remodeling of ARDS and may contribute to understanding the differences reported for lung mechanical properties between pulmonary and extrapulmonary ARDS. To evaluate this hypothesis they analyzed the process of acute pulmonary remodeling, focusing on alterations of fibers of the collagenous and elastic systems in ARDS in the exudative phase according to the etiology of the disease. Histological slides were sampled from the autopsied lungs of 23 patients and the fiber content of the collagenous and elastic systems of the alveolar septum was measured by image
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PATHOLOGY OF ALI AND ARDS
Table 1 Diagnostic accuracy of clinical definitions for acute respiratory distress syndrome compared with autopsy finding of diffuse alveolar damage as a reference standard Sensitivity (confidence interval for 95%)
Specificity (confidence interval for 95%)
Positive likelihood ratio (confidence interval for 95%)
Negative likelihood ratio (confidence interval for 95%)
Study
No. of patients
American-European consensus conference criteria Esteban et al [13]
Total (N ¼ 382) Patients with risk factors (n ¼ 284) Patients with direct risk factors (n ¼ 106) Patients with indirect risk factors (n ¼ 178)
75 (66 to 82) 76 (67 to 83)
84 (79 to 88) 75 (68 to 81)
4.7 (3.5 to 6.3) 3 (2.3 to 4.0)
0.3 (0.2 to 0.4) 0.3 (0.2 to 0.5)
61 (47 to 74)
69 (57 to 79)
2.0 (1.3 to 3.1)
0.6 (0.4 to 0.8)
85 (75 to 92)
78 (70 to 85)
3.9 (2.7 to 5.7)
0.2 (0.1 to 0.3)
Total (N ¼ 138)
83 (72 to 95)
51 (41 to 61)
1.7 (1.3 to 2.2)
0.3 (0.2 to 0.7)
Total (N ¼ 138)
74 (61 to 87)
77 (69 to 86)
3.2 (2.1 to 4.8)
0.3 (0.2 to 0.6)
Total (N ¼138)
69 (55 to 83)
82 (75 to 90)
3.9 (2.4 to 6.3)
0.4 (0.2 to 0.6)
American-European consensus conference criteria Ferguson et al [14] Lung injury score O 2.5 Ferguson et al [14] Delphi definition [15] Ferguson et al [14]
analysis. All patients were in the early ARDS phase: 10 patients with pulmonary and 13 patients with extrapulmonary diseases. Collagen content was greater in pulmonary than in extrapulmonary ARDS in the early phase of the disease. Extracellular matrix remodeling occurs early in the development of ALI and appears to depend on the site of initial insult (pulmonary or extrapulmonary).
Fig. 8. Acute pneumonia, with prominent intra-alveolar neutrophilic infiltrates (continuous line arrow) with minimun alveolar edema (discontinuous line arrow), in a patient with clinical criteria of ARDS (diffuse bilateral radiological infiltrate, PaO2/FIO2 ! 200, and sepsis as the possible etiological factor).
Summary Clinical criteria cannot identify all patients who developed ARDS and this might indicate the need to develop new tools that improve reliability and diagnostic accuracy. Nevertheless, being conscious of the limitations of the AECC criteria, these criteria continue being useful in clinical daily practice since patients benefit from treatments such as ventilation with low tidal volumes. This and other management strategies
Fig. 9. Intra-alveolar hemorrhage (black arrows) in a patient with clinical criteria of ARDS (diffuse bilateral radiological infiltrate, PaO2/FIO2 ! 200, and sepsis as the possible etiological factor).
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have been evaluated in patients who, fulfilling the clinical criteria of ARDS, could not have diffuse alveolar damage [24,25].
et al
[14]
References [1] Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967;12: 2(7511):319–23. [2] Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342(18):1334–49. [3] Hudson LD, Steinberg KP. Epidemiology of acute lung injury and ARDS. Chest 1999;116(1 Suppl): 74S–82S. [4] Lesur O, Berthiaume Y, Blaise G, et al. Acute respiratory distress syndrome: 30 years later. Can Resp J 1999;6(1):71–86. [5] Katzenstein AL, Bloor CM, Leibow AA. Diffuse alveolar damage the role of oxygen, shock and related factors. A review. Am J Pathol 1976;85(1):209–28. [6] Anderson WR, Thielen K. Correlative study of adult respiratory distress syndrome by light, scanning, and transmission electron microscopy. Ultrastruct Pathol 1992;16(6):615–28. [7] Nin N, Pen˜uelas O, de Paula M, et al. High tidal volume ventilation in normal rats induces multiorgan dysfunction attenuated by dexametasone. Crit Care Med 2006;34(4):1093–8. [8] Pen˜uelas O, de Paula M, Nin N, et al. Evolucio´n temporal de los efectos pulmonares y siste´micos inducidos por la ventilacio´n meca´nica con volu´menes pulmonares altos. Med Intensiva 2005;29(6): 87. [9] Moss M, Goodman PL, Heinig M, et al. Establishing the relative accuracy of three new definitions of the adult respiratory distress syndrome. Crit Care Med 1995;23(10):1629–37. [10] Garber BG, Hebert PC, Yelle JD, et al. Adult respiratory distress syndrome: a systemic overview of incidence and risk factors. Crit Care Med 1996;24(4): 687–95. [11] Murray JF, Matthay MA, Luce JM, et al. Anexpanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988;138(3):720–3. [12] Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definition mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149(3 Pt 1):818–24. [13] Esteban A, Ferna´ndez-Segoviano P, Frutos-Vivar F, et al. Comparison of clinical criteria for the acute
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[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
respiratory distress syndrome with autopsy findings. Ann Intern Med 2004;141(6):440–5. Ferguson ND, Frutos-Vivar F, Esteban A, et al. Acute respiratory distress syndrome: underrecognition by clinicians and diagnostic accuracy of three clinical definitions. Crit Care Med 2005;33(10): 2228–34. Ferguson ND, Davis AM, Slutsky AS, et al. Development of a clinical definition for acute respiratory distress syndrome using the Delphi technique. J Crit Care 2005;20(2):147–54. Rocco PR, Zin WA. Pulmonary and extrapulmonary acute respiratory distress syndrome: are they different? Curr Opin Crit Care 2005;11(1):10–7. Goodman LR, Fumagalli R, Tagliabue P, et al. Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: CT clinical and functional correlations. Radiology 1999;213(2): 545–52. Desai SR, Wells AU, Suntharalingam G, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative CT study. Radiology 2001;218(3):689–93. Gattinoni L, Pelosi P, Suter PM, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med 1998;158(1):3–11. Lim CM, Kim EK, Lee JS, et al. Comparison of the response to the prone position between pulmonary and extrapulmonary acute respiratory distress syndrome. Intensive Care Med 2001;27(3):477–85. Hoelz C, Negri EM, Lichtenfels AJ, et al. Morphometric differences in pulmonary lesions in primary and secondary ARDS: a preliminary study in autopsies. Pathol Res Pract 2001;197(8):521–30. Menezes SL, Bozza PT, Neto HC, et al. Pulmonary and extrapulmonary acute lung injury: inflammatory and ultrastructural analyses. J Appl Physiol 2005;98(5):1777–83. Negri EM, Hoelz C, Barbas CS, et al. Acute remodeling of parenchyma in pulmonary and extrapulmonary ARDS. An autopsy study of collagen-elastic system fibers. Pathol Res Pract 2002;198(5): 355–61. Dı´ az-Guzma´n Zavala E, Arroliga AC. Validez de los criterios clı´ nicos en el diagno´stico del sı´ ndrome de distre´s respiratorio agudo. Med Intensiva 2005; 29(5):305–7. Luce J. The imperfect diagnosis of acute respiratory distress syndrome. Crit Care Med 2005;33(10): 2419–20.
Pathology of Acute Lung Injury and Acute Respiratory Distress Syndrome: A Clinical–Pathological Correlation Oscar Pen˜uelas, MDa, Jose´ Antonio Aramburu, MDb, Fernando Frutos-Vivar, MDa, Andre´s Esteban, MD, PhDa,* a
Intensive Care Unit and Burn Unit, Hospital Universitario de Getafe, Carretera de Toledo km 12.5, 28905 Getafe, Madrid, Spain b Department of Pathology, Hospital Universitario de Getafe, Carretera de Toledo km 12.5, 28905 Getafe, Madrid, Spain
Acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and colleagues in 1967 [1]. When they first described acute respiratory distress syndrome, they outlined 12 patients with (1) severe dyspnea, (2) tachypnea, (3) cyanosis refractory to oxygen therapy, (4) loss of lung compliance, (5) diffuse alveolar infiltration seen on chest x ray, and (6) no previous history of significant respiratory disease. It is necessary to recognize that this entity does not appear for the first time in the late 1960s and, in fact, there are similar descriptions during the influenza epidemic in 1918 and in experimental studies. The importance of the first description by Ashbaugh and colleagues [1] rests on the fact that that the finding was coincident with the generalization of intensive care units and management of acute respiratory failure with positive pressure ventilation. During the following 2 decades, the syndrome was defined according to Ashbaugh and colleagues’ original description, as adult respiratory distress syndrome for its similarity to the syndrome described in newborns, characterized by presence of hyaline membranes and reduction or absence of surfactant pulmonary. Most experts agree on the theoretical
Funded by Red Gira (G03/063) y Red Respira (C03/11). * Corresponding author. E-mail address: [email protected] (A. Esteban).
concept of ARDS as a disorder or pathophysiologic entity. Review articles of ARDS continue to agree that, at least in its early stages, ARDS represents the pathological state of diffuse alveolar damage (DAD) [2–4]. This state includes alveolar flooding and formation of the characteristic hyaline membranes, as a result of injury to the endothelial and epithelial layers of the alveolarcapillary membrane, with resultant loss of the gas exchange and barrier functions of the lung. Histopathological changes in acute lung injury The pathological state of diffuse alveolar damage was first described by Katzenstein and colleagues in 1976 [5]. Lung morphology in ARDS reflects the rapid evolution from interstitial and alveolar edema to end-stage fibrosis consequent to injury of the alveolocapillary unit. Nevertheless the sequential stages, as shown in Fig. 1, are defined primarily for didactic purpose. Pulmonary lesions correlate with the phase of alveolar damage rather than with its specific cause. The morphologic progression has been subdivided into sequentially occurring exudative, proliferative, and fibrotic phases (Fig. 2). The exudative phase is characterized by the appearance of edema in the alveolocapillary space (Fig. 3), followed by destruction of type 1 pneumocytes that are replaced by a PAS-positive material, called hyaline membranes. These membranes, which are the hallmark of the diffuse alveolar
0272-5231/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2006.07.003
chestmed.theclinics.com
572
PEN˜UELAS
et al
Fig. 1. Schematic evolution of the chronology of diffuse alveolar damage.
damage, are made of fibrin and detritus proceeding from the destruction of the type 1 pneumocytes (Fig. 4). Although ARDS frequently culminates in ‘‘interstitial’’ fibrosis, the organization of intraluminal exudate with type 2 cells proliferate with some epithelial cell regeneration and fibroblastic reaction dominates the histologic picture in the proliferative phase (Fig. 5). The late proliferative, or fibrotic, phase of ARDS is the result of cellular proliferation that leads to the deposition of collagen and proteoglycans (Fig. 6A). Extensive fibroblast proliferation with incorporation of the hyaline membranes is a characteristic finding in this stage of ARDS. Involvement of the pulmonary vasculature is an important aspect of ARDS, from the initial phase of edema to the terminal stage of intractable pulmonary hypertension (Fig. 6B). Vascular lesions include thrombotic, fibroproliferative, and obliterative changes, which, like the parenchymal lesions, correlate with the temporal phase of diffuse alveolar damage. An aspect difficult to elucidate is the chronological sequence of these morphological changes. The sequential pulmonary changes occurring in the evolution of ARDS were studied in 35 patients by correlative light, scanning, and transmission electron microscopy [6]. The acute stage in patients surviving 2 to 7 days was characterized by an exudative reaction with a predominance of hyaline membranes. This acute stage merged with and was replaced by a subacute reparative stage in patients surviving 7 to 14 days, which in turn
was replaced by a chronic fibroproliferative stage complicated by interstitial pulmonary fibrosis and a deranged acinar architecture. Correlation of findings by scanning electron microscopy with those by light and transmission electron microscopy provided an added dimension to understanding of the evolving stages of ARDS and demonstrated that type 2 pneumocytes contributed to the fibroproliferative stage through organization of hyaline membranes and reepithelialization of alveoli (Fig. 7). A limitation of this study is that it is possible to see in the same patient lesions in different stages of evolution and the phases previously described can overlap in time (Fig. 2). Obviously, the reconstruction of the chronologic sequence has been performed by means of pulmonary biopsies or samples from autopsies. Usually it is difficult to know when the injury has begun. In an attempt of approach to this issue, we have described the chronological evolution of the lung injury in an animal model of mechanical ventilation with high tidal volumes (tidal volume 35 mL/kg and positive end-expiratory pressure [PEEP] of 0 cm of water) during 45 minutes [7,8]. After the harmful stimulus the animals were extubated and half of them were humanely killed within 6 hours. The rest of the surviving animals were killed at 48 hours, 72 hours, and 7 days after the injury. At 48 hours after injury, the lungs already showed signs of repair. The proliferation of type 2 pneumocytes covering the alveolar surface, to replace type 1 pneumocytes, turns out to
PATHOLOGY OF ALI AND ARDS
573
Fig. 2. Evolution of the histological changes characteristic of diffuse alveolar damage. Black arrows indicate hyaline membrane (exudative phase), and pneumocytes type 2 (proliferative phase).
be very rapid and effective. Later, the differentiation to type 1 pneumocytes allows the recuperation of the initial structure. Definitions of acute respiratory distress syndrome After the first description of this syndrome by Ashbaugh and colleagues [1], in the subsequent 2 decades ARDS remained very loosely defined, with terms such as a ‘‘worsening picture on analyses of arterial blood gas levels and increasing amounts of bilateral diffuse infiltrates on chest x-ray films’’ being used [9]. Many authors seemed to view ARDS as a gestalt diagnosis, where no specific definition was needed. Indeed only half of 83 articles identified in a systematic review of ARDS incidence specified a definition for ARDS [10]. When ARDS was defined in clinical trials
in the early to mid-1980s, more restrictive definitions tended to be used, for example requiring all of the following to be present: (1) a known risk factor for ARDS, (2) a low static respiratory compliance (generally ! 50 mL/cm H2O), (3) a nonincreased pulmonary artery wedge pressure (generally ! 12-18 mm Hg, and thereby mandating the insertion of a pulmonary artery catheter), (4) diffuse bilateral infiltrates on chest radiograph, and (5) a decreased arterial to alveolar partial pressure of oxygen ratio (variable but generally equivalent to a ratio PaO2 to FIO2 of approximately 150 or less) [10]. In 1988, Murray and coworkers introduced the Lung Injury Score [11]. This score has four domains (chest x ray, hypoxemia, PEEP, and respiratory system compliance) and assigns a score of 0 to 4 to each domain that is available. The
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et al
Fig. 3. (A) Normal alveolar wall with thin alveolar septum (black arrow). (B) Intra-alveolar edema (black arrows) with minimun septal edema. (C, D) Prominent intra-alveolar and interstitial edema (black arrows) (hematoxylin-eosin, original magnification 100.)
individual domain scores are then summed and divided by the number of domains used to give the final Lung Injury Score (LIS). Acute respiratory distress syndrome is defined by an LIS greater than 2.5. Despite the advent of newer definitions, use of the LIS remains in common use. In 1992 the American-European Consensus Conference (AECC) on ARDS was formed to ‘‘bring clarity and uniformity to the definition of acute lung injury and ARDS’’ [12]. The American-European Consensus Conference definition was designed for use in many settings including research, epidemiology, and individual patient care. This definition states that ARDS should be considered present when all of the following conditions are met: (1) timingdacute onset; (2) oxygenationdratio PaO2 to FIO2 % 200 (regardless of PEEP level); (3) chest radiographdbilateral infiltrates seen on frontal chest radiograph; and (4) pulmonary artery wedge pressure (% 18 mm Hg when measured or no clinical evidence of left atrial hypertension). In addition to defining ARDS, this first AECC also defined a clinical entity termed acute lung injury (ALI). ALI is a disorder that encompasses ARDS (comprising a subset of
patients with a severe form of ALI), but that also includes patients with less severe forms of the same pathologic entity. ALI is defined using the same criteria as for ARDS, except for a higher oxygenation threshold, requiring a ratio PaO2 to FIO2 % 300 (regardless of PEEP level).
Validity of the clinical criteria of acute respiratory distress syndrome A way to determine the diagnostic accuracy of clinical definitions for ARDS is to compare these with autopsy finding of diffuse alveolar damage as a reference standard. Recently two studies have been published using this methodology. Esteban and colleagues [13] found that the accuracy of the AECC definition of ARDS was only moderate (Table 1). The definition was more accurate for patients with extrapulmonary risk factor than for patients with pulmonary risk factors. In all patients (N ¼ 382), the sensitivity of the AECC criteria was 75% (95% confidence interval: 66 to 82) and the specificity was 84% (95% confidence interval: 79 to 88). When only patients with
PATHOLOGY OF ALI AND ARDS
Fig. 4. Hyaline membranes. (A) Pink fibrinous material that lines the alveolar ductus. (B) Numerous intraalveolar histiocytes with moderate septal edema (black arrow).
ARDS risk factors (n ¼ 284) were analyzed the specificity fell to 75% (95% confidence interval: 68 to 81) with a similar sensitivity. Compared with patients with pulmonary risk factors, the sensitivity was significantly higher in patients with an extrapulmonary risk factor (61% versus 85%; P ¼ .009), while the specificity was numerically higher but not statistically significantly different (69% versus 78%; P ¼ .25).
Fig. 5. Extensive proliferation of type 2 pneumocytes along alveolar walls (black arrows) lining the alveolar surface denuded after pneumocytes type 1 necrosis.
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Fig. 6. Fibroprolifetarive phase of ARDS. (A) Thickening of the alveolar wall by loose organizing connective tissue (black arrow) signs fibrosis. (B) Severe fibrosis with vascular structures engulfing, which contributes to the development of pulmonary hipertension (black arrows).
In the analysis of the discrepancies between clinical criteria and pathological findings, we found that in 43 patients with AECC criteria of ARDS without diffuse alveolar damage (false positives) the diagnoses by pathologists were pneumonia in 32 patients (Fig. 8), pulmonary hemorrhage in 4 patients (Fig. 9), pulmonary hydrostatic edema in 3 patients, pulmonary embolism in 3 patients, and 1 patient with interstitial fibrosis. On the other hand, there were 27 cases of false negatives (absence of clinical criteria of ARDS but presence of diffuse alveolar damage). In these patients the clinical diagnoses were pulmonary edema in 12 patients and pneumonia in 12 patients. In three patients there was no diagnosis of pulmonary pathology. In the other paper [14], Ferguson and colleagues analyzed a subset of these same patients and compared autopsy findings with three different definitions: AECC criteria, LIS, and Delphi definition [15]. In this analysis, definitions were constructed on a daily basis and patients were counted as positive for a definition if they met
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PEN˜UELAS
Fig. 7. Electronic microscopy of lung with ARDS. (A) Cellular detritus that constitutes the hyaline membrane (black arrow) and covers the basal membrane detached by the necrosis of the pneumocites type 1. (B) Hyperplasia of pneumocites type 2 (continuous line arrow); pneumocite type 2 in differentiation toward type 1 (discontinuous line arrow).
its criteria on any one day, simulating the process of enrollment into clinical trials. Of the three definitions, the AECC was most sensitive although this did not reach statistical significance. Both the LIS and the Delphi definitions had significantly higher specificities than the AECC definition (Table 1). Thus, while sensitive, the AECC definition may lack specificity, which may be problematic when this definition is used as an entry criterion in some clinical trials. Pulmonary and extrapulmonary acute respiratory distress syndrome The different accuracy of the clinical criteria for pulmonary and extrapulmonary ARDS might raise the hypothesis of two different syndromes [16]. This hypothesis has support in the studies that have reported significant differences in the radiological pattern [17,18], in the respiratory mechanics, and the response to PEEP consistent with a prevalence of consolidation in pulmonary ARDS as opposed to prevalent edema and
et al
alveolar collapse in extrapulmonary ARDS [19] and in the response to prone position [20]. Hoelz and colleagues [21], analyzing biopsy tissues of ARDS patients, described the morphologic differences between pulmonary lesions in ARDS of pulmonary and extrapulmonary origin. They observed a predominance of alveolar collapse, fibrinous exudate, and alveolar wall edema in pulmonary ARDS. The morphologic difference between pulmonary and extrapulmonary ARDS was mainly quantitative in extent and distribution according to the underlying disease. This study has limitations since it was realized with biopsies taken in different moments of the evolution of the disease. To avoid these limitations, this group developed an animal model of ALI of pulmonary and extrapulmonary acute respiratory distress that allows analyzing morphological changes at different times (earlier or later in the course of the disease) [22]. Light microscopy showed similar increments in alveolar collapse and tissue cellularity in pulmonary and extrapulmonary ARDS. However, electron microscopy demonstrated extensive injury of alveolar epithelium, swollen and fragmented type 1 and II cells, intact capillary endothelium, ductal hyperdistention, neutrophil recruitment into the alveolar space, proliferation of fibroblasts into the alveolar septa, the presence of collagen type 3 fiber, and hyaline membranes in pulmonary ARDS, whereas extrapulmonary ARDS showed interstitial edema and intact type 1 and 2 cells. In addition, an increased amount of apoptotic neutrophils was observed in pulmonary ARDS in comparison with extrapulmonary ARDS. Some of those differences between pulmonary and extrapulmonary ARDS may be explained by a different lung architecture remodeling process as a consequence of the two different mechanisms involved in lung injury. Negri and colleagues [23] hypothesized that deposition of extracellular matrix fibers is involved in acute pulmonary remodeling of ARDS and may contribute to understanding the differences reported for lung mechanical properties between pulmonary and extrapulmonary ARDS. To evaluate this hypothesis they analyzed the process of acute pulmonary remodeling, focusing on alterations of fibers of the collagenous and elastic systems in ARDS in the exudative phase according to the etiology of the disease. Histological slides were sampled from the autopsied lungs of 23 patients and the fiber content of the collagenous and elastic systems of the alveolar septum was measured by image
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PATHOLOGY OF ALI AND ARDS
Table 1 Diagnostic accuracy of clinical definitions for acute respiratory distress syndrome compared with autopsy finding of diffuse alveolar damage as a reference standard Sensitivity (confidence interval for 95%)
Specificity (confidence interval for 95%)
Positive likelihood ratio (confidence interval for 95%)
Negative likelihood ratio (confidence interval for 95%)
Study
No. of patients
American-European consensus conference criteria Esteban et al [13]
Total (N ¼ 382) Patients with risk factors (n ¼ 284) Patients with direct risk factors (n ¼ 106) Patients with indirect risk factors (n ¼ 178)
75 (66 to 82) 76 (67 to 83)
84 (79 to 88) 75 (68 to 81)
4.7 (3.5 to 6.3) 3 (2.3 to 4.0)
0.3 (0.2 to 0.4) 0.3 (0.2 to 0.5)
61 (47 to 74)
69 (57 to 79)
2.0 (1.3 to 3.1)
0.6 (0.4 to 0.8)
85 (75 to 92)
78 (70 to 85)
3.9 (2.7 to 5.7)
0.2 (0.1 to 0.3)
Total (N ¼ 138)
83 (72 to 95)
51 (41 to 61)
1.7 (1.3 to 2.2)
0.3 (0.2 to 0.7)
Total (N ¼ 138)
74 (61 to 87)
77 (69 to 86)
3.2 (2.1 to 4.8)
0.3 (0.2 to 0.6)
Total (N ¼138)
69 (55 to 83)
82 (75 to 90)
3.9 (2.4 to 6.3)
0.4 (0.2 to 0.6)
American-European consensus conference criteria Ferguson et al [14] Lung injury score O 2.5 Ferguson et al [14] Delphi definition [15] Ferguson et al [14]
analysis. All patients were in the early ARDS phase: 10 patients with pulmonary and 13 patients with extrapulmonary diseases. Collagen content was greater in pulmonary than in extrapulmonary ARDS in the early phase of the disease. Extracellular matrix remodeling occurs early in the development of ALI and appears to depend on the site of initial insult (pulmonary or extrapulmonary).
Fig. 8. Acute pneumonia, with prominent intra-alveolar neutrophilic infiltrates (continuous line arrow) with minimun alveolar edema (discontinuous line arrow), in a patient with clinical criteria of ARDS (diffuse bilateral radiological infiltrate, PaO2/FIO2 ! 200, and sepsis as the possible etiological factor).
Summary Clinical criteria cannot identify all patients who developed ARDS and this might indicate the need to develop new tools that improve reliability and diagnostic accuracy. Nevertheless, being conscious of the limitations of the AECC criteria, these criteria continue being useful in clinical daily practice since patients benefit from treatments such as ventilation with low tidal volumes. This and other management strategies
Fig. 9. Intra-alveolar hemorrhage (black arrows) in a patient with clinical criteria of ARDS (diffuse bilateral radiological infiltrate, PaO2/FIO2 ! 200, and sepsis as the possible etiological factor).
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PEN˜UELAS
have been evaluated in patients who, fulfilling the clinical criteria of ARDS, could not have diffuse alveolar damage [24,25].
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[14]
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