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Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies

https://doi.org/10.1016/S2213-2600(13)70053-5Get rights and content

Summary

Background

Diffuse alveolar damage is the histological hallmark of acute respiratory distress syndrome (ARDS). However, the chronology of histological lesions is not well established. We aimed to determine the time to onset of exudative or proliferative changes and end-stage fibrosis in ARDS.

Methods

We analysed all patients who died between Jan 1, 1991, and Dec 31, 2010, in the intensive-care unit at the Hospital Universitario de Getafe, Madrid, Spain, and who had a clinical autopsy. Patients had to have clinical criteria for ARDS at time of death and histological features of diffuse alveolar damage at autopsy examination. Capillary congestion and intra-alveolar oedema characterised the exudative phase whereas proliferation of alveolar cell type 2 or fibroblasts, or fibrosis characterised the proliferative phase.

Findings

We analysed 159 patients. The prevalence of exudative changes decreased over time, being reported in 74 (90%) of 82 patients with ARDS of less than 1 week duration, 40 (74%) of 54 patients with disease of 1–3 week duration, and only four (17%) of 23 patients with disease of longer than 3 weeks' duration (p<0·0001). The incidence of proliferative changes increased over time, and was reported in 44 (54%) of 82 patients with ARDS of less than 1-week duration, 42 (78%) of 54 patients with disease duration of 1–3 weeks, and 23 (100%) of 23 patients with disease duration longer than 3 weeks (p<0·0001). Fibrosis was noted in three (4%) of 82 patients with disease of less than 1 week duration, 13 (24%) of 54 patients with disease of 1–3-weeks' duration, and 14 (61%) of 23 patients with disease longer than 3-week duration (p<0·0001). Fibrosis was more frequent in ARDS of pulmonary origin than in that of extrapulmonary origin.

Interpretation

Histological features of the lungs were related to duration of ARDS. Within the first week of evolution, exudative changes were predominant and fibrosis was rarely noted. Beyond the third week of evolution, proliferative changes were noted in all patients and fibrosis in two-thirds of them. Treatments with a potential effect on inflammation or fibrosis, or both, should probably focus on the first week after the onset of ARDS.

Funding

None.

Introduction

Acute respiratory distress syndrome (ARDS) is a clinical syndrome described for the first time by Ashbaugh and colleagues in 1967.1 However, it was not until 1994 that an international American-European Consensus Conference laid the foundations for the definition of the disorder.2 The clinical diagnostic criteria for ARDS have been recently revised and modified in the so-called Berlin definition.3, 4 This clinical insult triggering ARDS can be either a pulmonary disease (direct injury) such as pneumonia, aspiration, or chest trauma, or an extra-pulmonary disease (indirect injury) such as pancreatitis and haemorrhagic or septic shock.

Whatever the origin of ARDS, diffuse alveolar damage consisting of changes such as the presence of hyaline membranes, interstitial oedema, cell necrosis and proliferation, or fibrosis, is the histological hallmark of ARDS as was described by Katzenstein and colleagues in 1976.5 Since then, these changes have been generally assumed to evolve over time in well defined phases (exudative, proliferative, and fibrosis) classified by specific histological changes.5, 6 The exudative phase is defined by capillary congestion and intra-alveolar oedema, and is maximum during the first week after the onset of ARDS. The second phase, proliferative, is a phase of repair marked by intense cellular proliferation, especially of alveolar type-2 cells and fibroblasts. This phase, which is maximum during the second and third week, could result in normal tissue resolution or progress toward fibrosis if lung injury is persistent. These proposed sequential changes might overlap, and fibrosis might occur from the 10th day while the proliferative phase is fading, and become maximum with a chronic appearance after 2 or 3 weeks of evolution.5

The description of the different histological stages was based on observations that predated the first clinical definition for ARDS.5 The chronology of histological lesions attributed to the clinical syndrome was then extrapolated from these pooled observations to the proposed time course of histological changes in the disorder. However, the time dependency of the histological changes was never validated in patients who met clinical criteria for the diagnosis of ARDS. The accurate identification of the chronology of appearance of histological lesions and especially, the time to onset of the proliferative phase and fibrosis in the disorder is clinically relevant because it might influence the effectiveness of treatments. For example, steroid therapy might be effective only at the early-stage of the disorder by attenuating inflammation during the exudative phase,7 whereas it could be ineffective when fibrosis is already present.8 Also, potential for alveolar recruitment induced by positive end-expiratory pressure (PEEP) could be lower in late stage of ARDS when the presence of fibrosis leads to lung consolidation and lung stiffness.9, 10

Therefore, our main objective was to identify the chronology of appearance of histological lesions in ARDS by analysing clinical autopsy samples and focusing on the subgroup of patients with ARDS and diffuse alveolar damage from our database.11, 12 We also specifically assessed the effect of duration, severity, and origin of ARDS on the presence of fibrosis.

Section snippets

Study design and patients

We analysed all patients who died between Jan 1, 1991, and Dec 31, 2010, in the 18-bed intensive care unit (ICU) at the Hospital Universitario de Getafe, Madrid, Spain, and who had a clinical autopsy. No ethics approval was needed since we systematically requested informed consent from patient's relatives for both clinical autopsy and potential use of tissue samples in research or teaching purposes. Our usual practice is to systematically request consent for autopsy from relatives of all

Results

We analysed 159 autopsies from patients who presented with histological findings of diffuse alveolar damage at autopsy examination and met clinical criteria for the diagnosis of ARDS at time of death. ARDS was caused by a pulmonary disease in 71 (45%) patients and by an extra-pulmonary disease in 88 (55%) patients. According to the Berlin definition, 97 (61%) patients were deemed to have severe ARDS, 56 (35%) patients to have moderate ARDS and six (4%) patients to have mild ARDS. The median

Discussion

In a large population of patients who met clinical criteria for ARDS and who had diffuse alveolar damage at autopsy examination, histological findings were closely correlated to the duration of evolution of ARDS. Although exudative changes were predominant during the first week (90% of patients), proliferative changes occurred early in the course of ARDS and were noted in 54% of patients with ARDS of less than a week of evolution. After 3 weeks of evolution, only 17% of patients had exudative

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