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Diffuse alveolar damage is the histopathological correlate of the clinical syndrome of ARDS or adult respiratory distress syndrome.


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Diffuse alveolar hemorrhage in allogeneic bone marrow transplantation. A postmortem study.

Agusti C, Ramirez J, Picado C, Xaubet A, Carreras E, Ballester E, Torres A, Battochia C, Rodriguez-Roisin R.

Department of Pathologic Anatomy, University of Barcelona, Spain.

Am J Respir Crit Care Med 1995 Apr;151(4):1006-10 Abstract quote

To define better the syndrome of diffuse alveolar hemorrhage (DAH), we conducted a postmortem study in 77 patients who died of pulmonary complications, distributed into three groups. Group A included 47 patients with hematologic diseases treated with allogeneic bone marrow transplant (BMT); Group B, 20 patients with hematologic diseases treated with conventional chemotherapy; and Group C, 10 patients without hematologic diseases.

The diagnosis of DAH was established when there was blood in at least 30% of the lung tissue evaluated without evidence of infection or any other pathologic change that could account for its presence. The presence of an associated pulmonary complication was considered only when there was normal lung parenchyma between both blood and the specific lesions. Diffuse alveolar hemorrhage was shown in 11 patients in Group A (23%) compared with 1 patient in Group B (5%) (p < 0.05). Of the 11 patients with DAH in Group A, 10 had some associated pulmonary complication: 7 presented with diffuse alveolar damage (DAD), 2 with associated bacterial pneumonia and 1 with invasive aspergillosis, 2 others had an associated cytomegalovirus (CMV) pneumonitis, and the remaining patients had an associated herpes pneumonia.

There were no clinical differences between patients with and without DAH. Of 8 patients with confirmed DAH in Group A, who had been submitted to a bronchoscopic examination within 1 wk of death, 4 had normal BAL fluid; by contrast, 7 of 13 patients without DAH had hemorrhagic BAL fluid.


Idiopathic inflammatory myopathy with diffuse alveolar damage.

Lee CS, Chen TL, Tzen CY, Lin FJ, Peng MJ, Wu CL, Chen PJ.

Mackay Memorial Hospital, Taipei, Taiwan.

Clin Rheumatol 2002 Sep;21(5):391-6 Abstract quote

Interstitial lung disease (ILD) in patients with myositis is defined by the presence of interstitial changes on radiographic examination. The reported prevalence of ILD varies from 0% to nearly 50%. However, only rarely has the pathological pattern of diffuse alveolar damage (DAD) associated with idiopathic inflammatory myopathy (IIM) been reported.

We report five patients with IIM (one with dermatomyositis, one with polymyositis, and three with amyopathic dermatomyositis) and respiratory failure. Four underwent open lung biopsy with pathological proof of diffuse alveolar damage (DAD). Despite intensive immunosuppressive therapy, all of them died. In addition to the case reports, we discuss DAD in patients with IIM.



Alveolar basement membrane breaks down in diffuse alveolar damage: an immunohistochemical study.

Matsubara O, Tamura A, Ohdama S, Mark EJ.

Department of Pathology, School of Medicine, Tokyo Medical and Dental University, Japan

Pathol Int 1995 Jul;45(7):473-82 Abstract quote

Sequential structural changes of the alveoli in diffuse alveolar damage (DAD) were examined by immunohistochemical methods. Lung specimens obtained at autopsy from 52 patients with DAD were stained with antibodies to laminin, 7S collagen (7S) and type IV collagen (type IV) for alveolar basement membrane, to von Willebrand factor, CD-31 and thrombomodulin (TM) for the alveolar capillary endothelial cell, and to epithelial membrane antigen and surfactant apo-protein (PE-10) for the alveolar epithelium.

Forty-two of the patients had the exudative form of DAD; 10 of the patients had the proliferative form of DAD. The results were summarized as follows: (i) laminin was most easily impaired both in the epithelial and capillary basement membrane in the early exudative stage; (ii) following laminin, 7S and type IV in the capillary basement membrane were also injured in the early exudative stage, and recovered in the proliferative stage; (iii) subsequently, 7S and type IV in the epithelial basement membrane were also impaired in the late exudative stage, and remained impaired even in the proliferative stage; and (iv) alveolar epithelium regenerated almost completely in the late exudative stage, but staining for TM in the alveolar capillary recovered in the proliferative stage.

Because the alveolar basement membrane must govern the homeostasis of alveolar tissue architecture, it was concluded that its preservation is necessary to avoid the abnormal remodeling of the alveoli in the reparative stage of DAD, if the patient survives the acute episodes of the disease.


Heterogeneous expression of cell adhesion molecules by endothelial cells in ARDS.

Muller AM, Cronen C, Muller KM, Kirkpatrick CJ.

Institute of Pathology, University Clinic Bergmannsheil, Ruhr-University Bochum, Germany.

J Pathol 2002 Oct;198(2):270-5 Abstract quote

ARDS (acute respiratory distress syndrome) can be associated with septic shock and multiple organ failure caused by an uncontrolled systemic inflammatory response to Gram-negative bacterial infection. While in animal models the key role of the endothelial adhesion molecules ICAM-1, E-selectin, and VCAM in ARDS has been extensively studied, there are scarcely any corresponding pathomorphological studies of human lung tissue. Hence, little is known about whether there is a comparable, or even heterogeneous, expression pattern of these molecules in the human pulmonary vasculature.

This study was therefore undertaken to investigate the immunohistochemical expression of the constitutively expressed PECAM (CD31) and the inducible molecules ICAM-1, E-selectin, and VCAM in ARDS lungs from patients who had died in septic shock induced by Gram-negative bacteria. While in all specimens (ARDS and normal lungs) there was homogeneous strong expression of PECAM in all vessels, ICAM-1 was clearly up-regulated in ARDS lungs. E-selectin and VCAM were not expressed by endothelial cells (ECs) in normal lungs, but in ARDS lungs there was strong expression of both molecules in larger vessels, while in the capillaries there was only mosaic-like weak expression of a few ECs.

This immunohistochemical investigation demonstrates the induction and up-regulation of adhesion molecules in human ARDS lungs, comparable to that described in animal models. There is also markedly heterogeneous expression of E-selectin and VCAM, indicating toporegional differences in the function of pulmonary ECs.

Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury.

Fligiel SE, Standiford T, Fligiel HM, Tashkin D, Strieter RM, Warner RL, Johnson KJ, Varani J.

Department of Pathology, The University of Michigan, Ann Arbor, 48109, USA.

Hum Pathol. 2006 Apr;37(4):422-30. Abstract quote  

The objective of this study was to assess matrix metalloproteinase (MMP) and MMP inhibitor expression in the airspace of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and to determine the prognostic significance of MMP expression in this patient population.

Twenty-eight patients with ALI or ARDS were prospectively enrolled in this study; bronchoalveolar lavage (BAL) fluid obtained from these patients was examined for expression of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-8 (neutrophil collagenase), and MMP-9 (gelatinase B). Levels of MMP inhibitors (ie, tissue inhibitor of metalloproteinases-1 and -2 [TIMP-1 and TIMP-2]) were examined in parallel. Expression of MMPs was correlated with relevant clinical outcomes in patients with ALI/ARDS. In nearly all specimens obtained from patients with ALI/ARDS, there were high levels of MMP-2, MMP-8, MMP-9, and TIMP-1, but in only a small subset of patients (6/28) were there detectable levels of MMP-1 and/or MMP-3. In the patients with elevated MMP-1 and/or MMP-3, the mortality rate was higher (83%) than in the group without detectable levels of these enzymes (32%). Likewise, the overall severity of disease as indicated by Acute Physiology and Chronic Health Evaluation III scores was higher in this group (98 +/- 30) than in the group without detectable MMP-1 or MMP-3 (78 +/- 28).

The percentage of individuals in whom lung disease was complicated by multiorgan failure was also higher in the group with detectable MMP-1 and/or MMP-3 (83%) than in the group without (64%), as was the number of organs that failed. In contrast, there was no correlation between MMP-1 and/or MMP-3 expression and impairment in gas exchange, as determined by the ratio of partial pressure of oxygen to fraction of inspired oxygen (Pao(2)/Fio(2)) on the day of BAL sample.

Based on these findings, we conclude that elevated MMP-2, MMP-8, and MMP-9 in BAL fluid is a marker of acute lung injury (and, perhaps, a contributor to ALI) but is not necessarily an indicator of a poor outcome. On the other hand, the presence of detectable MMP-1 and/or MMP-3 is an indicator of more ominous disease progression.




Diagnostic imaging of idiopathic adult respiratory distress syndrome (ARDS)/diffuse alveolar damage (DAD) histopathological correlation with radiological imaging.

Kobayashi H, Itoh T, Sasaki Y, Konishi J.

Department of Radiology and Nuclear Medicine, Kyoto University, Japan

Clin Imaging 1996 Jan-Mar;20(1):1-7 Abstract quote

In ten patients with idiopathic adult respiratory distress syndrome (ARDS) who had histopathologically diffuse alveolar damage (DAD), and who did not have specific underlying diseases, we compared the histopathological findings with their radiographic images in order to study the detail analysis of radiographic images and the clinical courses.

These patients were roughly classified as having the interstitial pneumonia dominant type (type IP) of idiopathic ARDS, in which alveolar septal thickening, alveolitis, or both were the predominant histological findings and images showed increasing attenuation of lung fields with small honeycomb lung, or the organizing pneumonia dominant type (type OP), in which organizing exudate predominantly filled the alveoli histologically and images showed consolidation shadows with some air. Hyaline membrane was seen very frequently in patients with a short clinical course, and in accordance with a longer clinical course, widespread fibrosis and honeycomb lung covered by organizing hyaline membrane was seen with both types.

Patients with type OP in whom collapse of the normal pulmonary structure was less and for whom changes on radiographic images were larger seemed to respond relatively favorably to steroid treatment, as judged from pulmonary function and radiographic images.


Diffuse alveolar damage and recurrent respiratory failure: Report of 6 cases

Dana Savici, MD
Anna-Luise A. Katzenstein, MD

Hum Pathol 2002;32:1398-1402. Abstract quote

We report 6 patients in whom diffuse alveolar damage (DAD) was found on 1 or more lung biopsy specimens and who experienced recurrent episodes of acute respiratory failure.

The patients ranged in age from 43 to 55 years. Two to five episodes of respiratory failure occurred in each over a period of 4 months to 2 years. One patient developed evidence of chronic lung disease; while the others remained well between episodes. Lung biopsies showed the acute stage of DAD in 3, overlapping acute and organizing stages in 3, and the organizing stage in 2. A definite cause was not identifiable in any. However, 4 had been treated with narcotics for chronic pain before the first episode, and 1 received this treatment before the recurrent episode. Three also were receiving psychotropic drugs for anxiety and depression. Five patients had evidence of gastroesophageal reflux disease (GERD) and/or hiatal hernia, 2 of whom underwent Nissen fundoplication in hopes of preventing future recurrences.

Although a definite cause of the recurrent DAD was not identified, the findings suggest the possibility of a reaction to narcotics and/or psychotropic drugs in some patients, with a possible additional effect of GERD. A drug history should be carefully elicited in patients with recurrent DAD, and all potentially toxic drugs should be stopped.


Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage.

Beasley MB, Franks TJ, Galvin JR, Gochuico B, Travis WD.

Department of Pulmonary, Armed Forces Institute of Pathology, Washington, DC 20306, USA.

Arch Pathol Lab Med 2002 Sep;126(9):1064-70 Abstract quote

CONTEXT: The histologic patterns of diffuse alveolar damage (DAD), bronchiolitis obliterans with organizing pneumonia (BOOP), and eosinophilic pneumonia (EP) are well-recognized histologic patterns of lung injury associated with an acute or subacute clinical presentation. We have recognized acute fibrinous and organizing pneumonia (AFOP) as a histologic pattern, which also occurs in this clinical setting but does not meet the classic histologic criteria for DAD, BOOP, or EP and may represent an underreported variant.

OBJECTIVE: To investigate the clinical significance of the AFOP histologic pattern and to explore its possible relationship to other disorders, including DAD and BOOP.

DESIGN: Open lung biopsy specimens and autopsy specimens were selected from the consultation files of the Armed Forces Institute of Pathology, which showed a dominant histologic pattern of intra-alveolar fibrin and organizing pneumonia. Varying amounts of organizing pneumonia, type 2 pneumocyte hyperplasia, edema, acute and chronic inflammation, and interstitial widening were seen. Cases with histologic patterns of classic DAD, BOOP, abscess formation, or eosinophilic pneumonia were excluded. To determine the clinical behavior of patients with this histologic finding, clinical and radiographic information and follow-up information were obtained. Statistical analysis was performed using Kaplan-Meier and chi(2) analysis.

RESULTS: Seventeen patients (10 men, 7 women) with a mean age of 62 years (range, 33-78 years) had acute-onset symptoms of dyspnea (11), fever (6), cough (3), and hemoptysis (2). Associations believed to be clinically related to the lung disease included definitive or probable collagen vascular disease (3), amiodarone (1), sputum culture positive for Haemophilus influenza (1), lung culture positive for Acinetobacter sp. (1), lymphoma (1), hairspray (1), construction work (1), coal mining (1), and zoological work (1). Six patients had no identifiable origin or association. Follow-up revealed 2 clinical patterns of disease progression: a fulminate illness with rapid progression to death (n = 9; mean survival, 0.1 year) and a more subacute illness, with recovery (n = 8). Histologic analysis and initial symptoms did not correlate with eventual outcome, but 5 of the 5 patients who required mechanical ventilation died (P =.007).

CONCLUSIONS: Acute fibrinous and organizing pneumonia is a histologic pattern associated with a clinical picture of acute lung injury that differs from the classic histologic patterns of DAD, BOOP, or EP. Similar to these patterns of acute lung injury, the AFOP pattern can occur in an idiopathic setting or with a spectrum of clinical associations. The overall mortality rate is similar to DAD and therefore may represent a histologic variant; however, AFOP appears to have 2 distinct patterns of disease progression and outcome. The need for mechanical ventilation was the only parameter that correlated with prognosis. None of the patients with a subacute clinical course required mechanical ventilation.


Regional alveolar damage (RAD). A localized counterpart of diffuse alveolar damage.

Yazdy AM, Tomashefski JF Jr, Yagan R, Kleinerman J.

Department of Pathology, Cleveland Metropolitan General Hospital, Ohio 44109

Am J Clin Pathol 1989 Jul;92(1):10-5 Abstract quote

Diffuse alveolar damage (DAD) is usually considered a generalized lung process. During five years the authors observed 83 patients with generalized DAD in 827 adult autopsies (10.1%) and 10 patients with identical, but localized, lesions.

The authors propose the term regional alveolar damage (RAD) to designate localized "DAD." RAD was unilateral in six patients and most frequently involved the upper lobe. All ten patients had chronic systemic diseases and presented with life-threatening illnesses. The probable causes of RAD were multifactorial and included hypotensive shock, septicemia, pneumonia, hyperoxia, and pancreatitis. All patients developed respiratory failure, requiring supplemental oxygen and, in nine patients, mechanical ventilation. Chest roentgenograms revealed alveolar or combined alveolar and interstitial infiltrates that corresponded to the lesions found at autopsy.

The reasons for localization of RAD within the lung are unclear, but the presence of proliferative lesions and frequent involvement of the upper lobe suggests that RAD is not simply an early phase of DAD and implicates additional pathogenetic factors.


Extensive squamous metaplasia with cytologic atypia in diffuse alveolar damage mimicking squamous cell carcinoma: a report of 2 cases.

Ogino S, Franks TJ, Yong M, Koss MN.

Department of Pathology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Hum Pathol 2002 Oct;33(10):1052-4 Abstract quote

Squamous metaplasia in the setting of diffuse alveolar damage, a form of acute lung injury, in rare cases can be very extensive with cytologic atypia, mimicking squamous cell carcinoma.

We describe 2 such cases that posed diagnostic difficulty in the evaluation of biopsy specimens.

These cases demonstrate that histologic findings must be correlated with clinical and radiologic information to avoid a misdiagnosis of malignancy.




Is outcome from ARDS related to the severity of respiratory failure?

Ferring M, Vincent JL.

Dept of Intensive Care, Erasme University Hospital, Free University of Brussels, Belgium.

Eur Respir J 1997 Jun;10(6):1297-300 Abstract quote

The characteristics and outcome of acute respiratory distress syndrome (ARDS) may have changed with time. Some studies have reported that mortality is more commonly related to the development of sepsis/multiple organ failure (MOF), and others that it is related to the severity of acute respiratory failure (ARF).

The present study evaluates the relative importance of the two phenomena in a large series of patients. The clinical and biological data of all patients who developed ARDS during a 26 month period (January 1993 until February 1995) in our intensive care unit (ICU) were reviewed retrospectively. A total of 129 patients developed ARDS during the study period, representing an incidence of 2.4% of all ICU admissions. The mortality rate was 52%. The primary cause of death was sepsis/MOF (49%), followed by respiratory failure (16%), cardiac failure or arrhythmias (15%), neurological failure (10%), and other causes (8%). The mortality rate was related to age and degree of organ failure. MOF was not always a cause of late death, since half the deaths occurred within 5 days after admission. In addition, mortality was higher in septic than in nonseptic patients, and lower in trauma and surgical than in medical patients.

We conclude that sepsis/multiple organ failure is still the most common cause of death in acute respiratory distress syndrome. Improvements in outcome of acute respiratory distress syndrome may depend more on treatment of sepsis and multiple organ failure than on oxygenation measures.

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