Comments Abstract
Acute respiratory distress syndrome (ARDS) is a major clinical problem with high morbidity and mortality. Diffuse alveolar damage (DAD) is considered the histological hallmark for the acute phase of ARDS. DAD is characterized by an acute phase with edema, hyaline membranes, and inflammation, followed by an organizing phase with alveolar septal fibrosis and type II pneumocyte hyperplasia. Given the difficulties in obtaining a biopsy in patients with ARDS, the presence of DAD is not required to make the diagnosis. However, biopsy and autopsy studies suggest that only one-half of patients who meet the clinical definition of ARDS also have DAD. The other half are found to have a group of heterogeneous disorders, including pneumonia. Importantly, the subgroup of patients with ARDS who also have DAD appears to have increased mortality. It is possible that the response of these patients to specific therapies targeting the molecular mechanisms of ARDS may differ from patients without DAD. Therefore, it may be important to develop noninvasive methods to identify DAD. A predictive model for DAD based on noninvasive measurements has been developed in an autopsy cohort but must be validated. It would be ideal to identify biomarkers or imaging techniques that help determine which patients with ARDS have DAD. We conclude that additional studies are needed to determine the effect of DAD on outcomes in ARDS, and whether noninvasive techniques to identify DAD should be developed with the goal of determining whether this population responds differently to specific therapies targeting the molecular mechanisms of ARDS.
Acute respiratory distress syndrome (ARDS) is a major clinical problem in critical care medicine, with an incidence of 78.9 per 100,000 person-years in the United States (1). Furthermore, between 1999 and 2013, approximately 156,000 patients died of ARDS in the United States (2). Survivors suffer from long-term consequences including long-term physiological and cognitive impairment (3). Despite these negative outcomes, there is no specific pharmacological treatment and available treatments are limited to supportive measures such as low-tidal-volume ventilation (4).
ARDS was first described in 1967 by Ashbaugh and colleagues as a clinical entity characterized by severe hypoxemia, decreased lung compliance, and diffuse alveolar infiltrates on chest radiographs (5). Ashbaugh and coauthors performed necropsies in seven patients and found that their lungs showed hyperemia, dilated engorged capillaries, alveolar atelectasis, interstitial and intraalveolar hemorrhage, and fibrosis (5). Notably, the lungs of six patients also had hyaline membranes.
In 1976, Katzenstein and associates proposed the term diffuse alveolar damage (DAD) (Figure 1) to describe a type of lung injury characterized by “endothelial and alveolar lining cell injury which leads to fluid and cellular exudation and in some cases progresses to extensive interstitial fibrosis” (6). At present, DAD is considered the pathological correlate of the clinical syndrome ARDS (7, 8). However, clinical and autopsy studies suggest that only one-half of patients who meet the clinical definition of ARDS have DAD (9–22). This discrepancy leads to several important questions, including the following: Do patients with ARDS who have DAD experience different outcomes than patients with ARDS but without DAD? And if so, should the definition of ARDS be modified to enrich for patients with DAD? Or should we consider ARDS a syndrome with multiple pathological correlates, all of which have similar outcomes?
Figure 1. Examples of histological findings in patients with ARDS: (A) Normal lung with mild alveolar distention. (B) Diffuse alveolar damage (yellow arrows: hyaline membranes). (C) Acute pneumonia (black arrows: neutrophil infiltration). (D) Acute pneumonia with diffuse alveolar damage (black arrows: neutrophil infiltration; yellow arrows: hyaline membranes).
[More] [Minimize]In this review, we first discuss the current definitions of ARDS and DAD; next, we review data concerning the effect of the presence or absence of DAD on ARDS outcome; and finally, we discuss other histological patterns seen in ARDS and their relationship to DAD, with emphasis on pneumonia.
The definition of ARDS was updated by a panel of experts from several countries and societies (the “Berlin definition”) (23, 24). Briefly, ARDS is defined as an acute process developing within 1 week of a known clinical insult or new or worsening respiratory symptoms. The radiographic images should show bilateral opacities not fully explained by effusions, lobar or lung collapse, or nodules. There should be impairment in oxygenation as measured by a PaO2/FiO2 (fraction of inspired oxygen) not exceeding 300 mm Hg in the presence of a positive end-expiratory pressure of at least 5 cm H2O.
This definition was constructed on the basis of a conceptual model that describes ARDS from three complementary perspectives: (1) pathobiologically: a type of acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue; (2) clinically: hypoxemia and bilateral radiographic opacities, associated with increased venous admixture, increased physiological dead space, and decreased lung compliance; and (3) morphologically (for the acute phase): DAD (e.g., edema, inflammation, hyaline membranes, and hemorrhage).
It is important to point out that the operative definition of ARDS includes only the clinical variables of the conceptual model; the other characteristics relating to pathobiology and histology were not included in the definition because testing for these variables was considered not clinically feasible (e.g., extravascular lung water, histology, and dead space) (24). In particular, important barriers to operationalizing a pathological diagnosis of DAD include the risks of biopsy, the possibility of biopsy failing to identify DAD because of biopsy location and heterogeneity in the lung tissue itself, and the lack of a clear, minimally invasive tool to identify DAD. At present, the Berlin definition has been adopted by most critical care societies around the world.
DAD is characterized by an initial exudative (acute) phase with edema, hyaline membranes, and interstitial acute inflammation, followed by an organizing (subacute) phase with loose organizing fibrosis mostly within the alveolar septa, and type II pneumocyte hyperplasia (Figure 1). Thrombi are common in small to medium-sized pulmonary arterioles. These findings are present primarily during the acute phase of ARDS, and as shown by Thille and coworkers in a cohort of 159 autopsies from patients with ARDS, with time the histopathology can either resolve to normal lung parenchyma or progress to fibrosis (25).
Of the various pathological manifestations of DAD, most authors suggest that the key finding that defines DAD is the presence of hyaline membranes (Table 1). For example, in the study by Thille and coauthors quoted above, hyaline membranes were used as the definition of DAD (25). Hyaline membranes are characterized by the presence of dense eosinophilic amorphous material plastered along the alveolar septa; these eosinophilic structures are composed of cellular debris, plasma proteins (albumin, fibrinogen, and immunoglobulins), and surfactant components (7, 8, 10, 12, 14, 25, 26).
| First Author (Ref); Cohort Description | Number of Patients (Total/with DAD) | Definition of DAD | Hyaline Membranes as DAD Definition | Definition of Pneumonia |
|---|---|---|---|---|
| Thille (10); autopsies | 356/159 | Presence of hyaline membranes plus at least one of the following: intraalveolar edema, alveolar type I cell necrosis, alveolar type II cell (cuboidal cell) proliferation progressively covering the denuded alveolar–capillary membrane, interstitial proliferation of fibroblasts and myofibroblasts, or organizing interstitial fibrosis | Yes | Presence of intense neutrophilic infiltration in the interstitium and in the intraalveolar spaces, and particularly around terminal bronchioles |
| de Hemptinne (11); autopsies | 64/32 | Not reported | Not reported | Not reported |
| Pinheiro (12); autopsies | 10/5 | Presence of hyaline membranes and at least one of the following findings: necrosis of type I pneumocytes or endothelial cells, edema, organizing interstitial fibrosis and prominent proliferation of type II pneumocytes | Yes | Not reported |
| Sarmiento (13); autopsies | 49/31 | Diffuse distribution, uniform temporal appearance, presence of hyaline membranes, alveolar septal thickening due to organizing fibrosis (usually diffuse) and airspace organization (patchy or diffuse) | Yes | Presence of neutrophil-rich alveolar exudates with variable amounts of fibrin and red cells ± presence of bacteria |
| Sarmiento (14); autopsies | 17/15 | (1) Acute phase (<48 h): interstitial and alveolar edema; (2) subacute phase (Days 3–7): hyaline membranes and fibrin deposit; (3) proliferative phase (>7 d): abundant fibroblasts in the interstitium, fibrosis, and pneumocyte II hyperplasia | Yes (only for the subacute phase) | Not reported |
| Papazian (15); living patients | 36/5 | Not reported | Not reported | Scattered neutrophilic infiltrates localized to terminal bronchioles and surrounding alveoli with evident confluence of infiltrates between adjacent lobules |
| Patel (16); living patients | 57/23 | Not reported | Not reported | Not reported |
| Baumann (17); living patients | 27/2 | Not reported | Not reported | Not reported |
| Charbonney (18); living patients | 19/9 | Not reported | Not reported | Not reported |
| Nussbaum (19); living patients | 7/3 | Hyaline membranes | Yes | Not reported |
| Willetts (20); living patients | 20/9 | Not reported | Not reported | Not reported |
| Kao (21); living patients | 101/57 | Presence of pulmonary inflammatory infiltrates, hyaline membranes, and at least one of the following: intraalveolar edema, alveolar type I cell necrosis, alveolar type II cell proliferation progressively covering the denuded alveolar–capillary membrane, interstitial proliferation of fibroblasts and myofibroblasts, or organizing interstitial fibrosis | Yes | Severe neutrophil infiltration in the interstitium and intraalveolar spaces, particularly around terminal bronchioles |
| Guerin (22); living patients | 83/48 | Exudative phase: presence of edema, hyaline membrane lining alveoli, and interstitial acute inflammation. Proliferative phase: presence of organizing fibrosis, usually diffuse, mostly within the alveolar septa or DAD with an airspace organization and type II pneumocyte hyperplasia or honeycomb fibrosis | Yes (only for the acute phase) | Presence of scattered neutrophilic infiltrates localized to terminal bronchioles and surrounding alveoli with evident confluence of infiltrates between adjacent lobules |
From an operative point of view, the presence of hyaline membranes can be considered the required criterion for DAD diagnosis, and the remaining pathological features can be used to determine the evolutionary stage of DAD (25).
One of the idiopathic interstitial pneumonitides is acute interstitial pneumonia (AIP) (7, 8). AIP is characterized by the sudden development of bilateral pulmonary infiltrates and acute hypoxemic respiratory failure. Histologically, the lungs of patients with AIP show an acute and/or organizing form of DAD that is indistinguishable from the histological patterns found in ARDS. Despite their similarities, the two entities differ in one key point: AIP develops without any known precipitating factor (7, 8). In contrast, ARDS, as defined by the Berlin definition, appears after a known clinical insult (23). In addition, although large clinical trials are lacking, AIP may respond to high-dose corticosteroid therapy during the acute phase, whereas corticosteroids are not recommended in the acute phase of ARDS (9, 27, 28).
Other lung processes that feature DAD on histology are acute exacerbations of idiopathic pulmonary fibrosis and primary graft dysfunction in recipients of a lung transplant. Again, both of these processes manifest as acute hypoxemic respiratory failure with bilateral infiltrates and DAD on biopsy, but they differ from ARDS by the underlying diagnosis of idiopathic pulmonary fibrosis (acute exacerbations) or by a recent lung transplant (primary graft dysfunction).
Despite the fact that, as mentioned above, DAD is considered the pathological correlate of ARDS (23), most studies performed using open lung biopsies or autopsies have found that only approximately one-half of the patients with ARDS also have DAD (Table 1). For example, one meta-analysis, which included 350 patients who had undergone open lung biopsies because of nonresolving ARDS, found that only 156 patients had DAD, yielding a proportion of 0.48 (95% confidence interval [CI], 0.42–0.53) (9). The other one-half of patients is a group with heterogeneous histological diagnoses other than DAD (Table 2). However, it is important to exert caution, because studies based on open lung biopsies or autopsies are subject to selection bias, as only selected patients can undergo a lung biopsy and only subjects who die are subjected to autopsy.
| • Infections (e.g., bacterial, including leptospirosis; viral; fungal, including Pneumocystis jirovecii; etc.) |
| • Diffuse alveolar hemorrhage |
| • Acute eosinophilic pneumonia |
| • Drugs (e.g., methotrexate) |
| • Pulmonary mycotoxicosis |
| • Idiopathic pneumonia syndrome |
The finding that only some patients with ARDS also have DAD leads to an important question: Does the presence of DAD identify a subset of patients with ARDS with different outcomes, or is the presence (or absence) of DAD irrelevant? If the presence of DAD matters for the clinical phenotype of ARDS as a syndrome, the current clinical definition should be improved to enrich for the presence of DAD (27, 28).
The benefits of incorporating the presence of DAD in the ARDS definition are that it would allow the identification of a subpopulation of patients with a uniform histological diagnosis and worse prognosis that would represent a more homogeneous target for potential specific therapies targeting the cellular and molecular mechanisms of DAD. This might possibly bridge the gap between positive results obtained in animal models and negative results obtained in clinical studies (29–31).
However, there are significant hurdles associated with incorporating DAD into the ARDS definition. First and foremost, a noninvasive, widely implementable method of identifying DAD will need to be developed, either using biomarkers or novel imaging techniques. Second, it will be important that clinicians not limit the use of lung-protective ventilation to patients with ARDS and DAD, as it has been clearly shown that lung-protective ventilation is effective across all of the ARDS severity groups.
Evidence suggests that the presence of DAD may identify a subset of patients with different outcomes in ARDS. For example, one study investigated a cohort of 149 autopsied patients who had been invasively mechanically ventilated and met the criteria for ARDS within 14 days of death (32). The main finding was that ARDS associated with DAD differed from ARDS without DAD in several variables: younger age (64 [55–73] vs. 70 [62–79] yr; P < 0.01), higher proportion of alcoholism (30.6 vs. 15.0%; P < 0.01), lower dynamic respiratory system compliance (Cdyn) (20 [16–28] vs. 26 [18–34] ml/cm; P < 0.01), lower PaO2/FiO2 ratio on the day of ARDS diagnosis (110 [87–161] vs. 172 [123–214]; P < 0.01), and higher Sequential Organ Failure Assessment (SOFA) score during their time course, respectively. Moreover, the main reason for death differed in both groups (see below).
The authors reported a predictive model for DAD that included (odds ratio [95% CI]) the PaO2/FiO2 ratio (0.988 [0.981–0.995]), Cdyn (0.937 [0.892–0.984]), and age (0.972 [0.946–0.999]). Characteristics of this model (95% CI) were as follows: sensitivity, 0.45 (0.31–0.59); specificity, 0.82 (0.74–0.90); positive likelihood ratio, 2.49 (1.48–4.20); and negative likelihood ratio, 0.67 (0.51–0.88). The area under the receiver operating characteristic curve (95% CI) for the prediction model of DAD was significantly greater than for the Berlin definition (0.74 [0.65–0.82] vs. 0.64 [0.55–0.72], respectively) (P = 0.03). In the validation cohort (n = 21 with DAD, n = 36 without DAD), the area under the receiver operating characteristic curve was also larger for the new model (0.73 [0.56–0.90]) than for the Berlin definition (0.67 [0.54–0.81]).
Thus, it is possible to devise models that predict the presence of DAD in ARDS; but is this important? Perhaps the most relevant finding in the quoted study was the relationship between DAD and the cause of death (32). Whereas numerous studies have found that severe sepsis and shock are the main causes of death in patients with ARDS (33), the study found that patients with DAD were about five times as likely to die of refractory hypoxemia than patients without DAD (32). In contrast, patients without DAD were about twice as likely to die of shock than patients with DAD.
Another study supporting an effect of DAD on outcomes in patients with ARDS was performed by Guerin and colleagues (22). They studied a cohort of 83 patients with ARDS and open lung biopsy and found that on the day the biopsy was performed, patients with DAD (n = 48) were associated with a lower PaO2/FiO2 ratio and higher plateau pressures for similar positive end-expiratory pressure (PEEP) and tidal volumes than were patients without DAD. In addition, they found that mortality in patients with DAD was 10% higher than in the non-DAD group. Similarly, Kao and associates found in a cohort of 101 patients with nonresolving ARDS and open lung biopsy that DAD (n = 57) was an independent risk factor for mortality (OR, 3.55; CI 95%, 1.38–9.12) (21). Finally, a meta-analysis including 350 patients with ARDS who had undergone open lung biopsy found that 156 had DAD, and DAD was associated with an increase in mortality (OR, 1.81; CI 95%, 1.14–2.86). Importantly, all of the other variables studied (age, days between ARDS and open lung biopsy, SOFA score, and PaO2/FiO2) were similar in patients with DAD and those without DAD.
Thus, the available data suggest that identifying the subgroup of patients with ARDS who also have DAD could potentially help determine a subpopulation at high risk for death from respiratory failure that might particularly benefit from lung-targeted therapeutic strategies. Because of the limitations associated with performing an invasive procedure such as a lung biopsy in patients with ARDS, we strongly recommend that future research investigate noninvasive methods to diagnose DAD, either by biomarkers or by imaging techniques.
Early investigations suggest a possible association of pro-collagen III with DAD (34), but these studies are preliminary and require validation. The potential use of positron emission tomography to diagnose DAD is also of interest, but the main limitation is identifying a radiotracer specific for DAD. It has been suggested that annexin V, which labels apoptotic cells, could be such a radiotracer, but apoptosis is not unique to DAD and further studies are required (35). Unfortunately, neither of these methods has yet reached a stage where they can be used clinically to identify DAD in living patients.
Pneumonia is the second most frequent histological pattern found in open lung biopsies and postmortem studies performed in patients with ARDS. Therefore, determining whether there are clinical and pathophysiological differences between pneumonia and DAD in patients with ARDS is of relevance for studies on biomarkers and for the development of new therapies.
There is evidence suggesting that DAD and pneumonia constitute two independent entities that often coexist in patients with ARDS. The pathology of pneumonia and DAD differ (Table 1 and Figure 1), and DAD and pneumonia can be diagnosed independently of each other. Furthermore, DAD and pneumonia have different microbiological isolation rates. Sarmiento and colleagues performed an autopsy study on 49 patients with ARDS secondary to clinical pneumonia and found positive lung microbiology results in 23 of 25 patients (92%) with histological pneumonia and DAD; 7 of 11 patients (64%) with histological pneumonia but without DAD; 2 of 6 patients (33%) without histological pneumonia but with DAD; and 3 of 7 patients (43%) without histological pneumonia or DAD (13).
Importantly, the clinical evolution of pneumonia and DAD is different. In one study, patients with ARDS and DAD were younger and had a higher SOFA score, a greater peach inspiratory pressure–PEEP difference, and a lower PaO2/FiO2 ratio and Cdyn than did patients with ARDS and histological pneumonia (32). Although differences in the cause of death did not reach statistical significance, the group with ARDS with DAD showed a higher proportion of patients dying of hypoxemia, whereas patients with ARDS and histological pneumonia were more likely to die of shock.
Finally, the mortality of patients with ARDS and DAD is different from that of patients with ARDS and histological pneumonia. Using open lung biopsy, Kao and coworkers found that the hospital mortality rate in patients with ARDS and DAD (33 of 46; 72%) was higher than that of patients with ARDS and histological pneumonia with and without DAD (10 of 21; 48%) (21). When the group of patients with ARDS and histological pneumonia was clustered according to the presence or absence of DAD, the mortality in the group with histological pneumonia and DAD (8 of 11; 73%) was higher than that of patients with histological pneumonia without DAD (2 of 10; 20%) (21).
Thus it seems the patients with ARDS and pneumonia as the histological finding (not DAD) have a different clinical profile than those with ARDS and DAD, supporting the hypothesis that the search for a biomarker specific for DAD could be of interest.
In summary, DAD is considered the pathological correlate of ARDS, but not all patients with ARDS have DAD and not all patients with DAD have ARDS. This is important because patients who meet the clinical definition of ARDS and have DAD appear to have worse outcomes than patients with ARDS but without DAD. In conclusion, additional studies are needed to determine the effect of DAD on outcomes in ARDS. If it is confirmed that DAD is associated with worse outcomes, then efforts should be made to develop biomarkers or imaging techniques that identify DAD in live patients.
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Supported by Merit Award Number i01 BX002914 from the U.S. Department of Veterans Affairs Biomedical Laboratory R&D (BLRD) Service and by the Instituto de Salud Carlos III (FIS 15/1492), Spain.
Author Contributions: Review concept, design, and writing of the manuscript: P.C.-F., J.A.L., A.B.-B., G.M.-B.
Author disclosures are available with the text of this article at www.atsjournals.org.
