The Pathologist's Approach to Acute Lung Injury

The Pathologist’s Approach to Acute Lung Injury

Mary Beth Beasley, MD

N Context.—Acute lung injury and acute respiratory distresssyndrome are significant causes of pulmonary morbidity andare frequently fatal. These 2 entities have precise definitionsfrom a clinical standpoint. Histologically, cases from patientswith clinical acute lung injury typically exhibit diffusealveolar damage, but other histologic patterns may occa-sionally be encountered such as acute fibrinous andorganizing pneumonia, acute eosinophilic pneumonia, anddiffuse hemorrhage with capillaritis.Objective.—To review the diagnostic criteria for various

histologic patterns associated with a clinical presentationof acute lung injury and to provide diagnostic aids anddiscuss the differential diagnosis.

Data Sources.—The review is drawn from pertinentpeer-reviewed literature and the author’s personal experi-ence.

Conclusions.—Acute lung injury remains a significantcause of morbidity and mortality. The pathologist shouldbe aware of histologic patterns of lung disease other thandiffuse alveolar damage, which are associated with aclinical presentation of acute lung injury. Identification ofthese alternative histologic findings, as well as identifica-tion of potential etiologic agents, especially infection, mayimpact patient treatment and disease outcome.

(Arch Pathol Lab Med. 2010;134:719–727)

Acute pulmonary injury may occur secondary to anextensive number of direct or indirect pulmonary

insults and often results in acute hypoxemic respiratoryfailure. Most patients with this condition will have acuterespiratory distress syndrome (ARDS) clinically. In 1994,the American-European Consensus Conference on ARDSformally defined ARDS as the presence of acute hypox-emia with (1) a ratio of partial pressure of arterial oxygento the fraction of inspired oxygen (PaO2:FIO2) of 200 mmHg or less, (2) bilateral infiltrates that are consistent withpulmonary edema radiographically, and (3) no clinicalevidence of cardiac failure. A less severe category, termedacute lung injury (ALI), was defined by the same criteriabut with a PaO2 to FIO2 of 300 mm Hg.1 While thedefinitions are not without their critics, they haveprovided a basis for a more uniform approach to thestudy of ALI/ARDS including epidemiology, pathogen-esis, treatment, and clinical trial design. The actualincidence of ALI/ARDS has been difficult to approximatebecause of varying criteria for diagnosis.2,3 A population-based cohort study in King County, Washington,4 exam-ined the incidence and mortality of ALI and ARDS byusing the consensus criteria and found that the incidenceof ALI was 78.9 per 100 000 person-years and the incidenceof ARDS was 58.7 per 100 000 person-years. This samestudy reported an average mortality rate of 41.1% forARDS and 38.5% for ALI. Although the average mortalityrate in the study was lower than the historically reported

mortality rates for ARDS of 50% to 60%, the mortality ratewas found to increase with age and was 60% in personsolder than 85 years. Therefore, in spite of the myriadadvances in understanding the pathogenesis of ALI/ARDS, this entity clearly remains a significant cause ofmorbidity and mortality.

From a pathologic standpoint, most cases of clinical ALIand ARDS will have diffuse alveolar damage (DAD)histologically.5,6 Other histologic patterns encountered in aclinical setting of ALI/ARDS include acute eosinophilicpneumonia (AEP) and the more recently described acutefibrinous and organizing pneumonia (AFOP).7,8 Organiz-ing pneumonia (OP) is often included in the pathologicdifferential of clinical ALI. However, most patients withOP typically present with a subacute, less fulminateclinical course and generally do not meet clinical criteriafor ALI, but OP will be discussed in this article primarilyas part of the differential diagnosis.9,10 Diffuse alveolarhemorrhage may also occasionally present with clinicalALI/ARDS.5 It is important to note that clinicians think ofALI/ARDS in terms of the previously discussed clinicalguidelines, while pathologists tend to use the term acutelung injury in reference to the pathologic findings—particularly in reference to small biopsies, as discussedbelow—when precise classification of findings is notpossible. As such, communication is important to avoidany misinterpretation of the findings. The aim of thisreview is to cover the major features of the commonhistologic patterns seen in association with clinical ALI/ARDS, the differential diagnosis, and an approach tobiopsy specimens.

Given that most biopsy specimens from patients withclinical ALI/ARDS will demonstrate a histologic patternof DAD, some authors have questioned the value ofobtaining a wedge biopsy specimen from patients withALI/ARDS. Patel et al5 examined a series of wedge biopsy

Accepted for publication September 3, 2009.From the Department of Pathology, The Mount Sinai Medical Center,

New York, New York.The author has no relevant financial interest in the products or

companies described in this article.Reprints: Mary Beth Beasley, MD, Department of Pathology, The

Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY10029 (e-mail: [email protected]).

Arch Pathol Lab Med—Vol 134, May 2010 Pathologist’s Approach to Acute Lung Injury—Beasley 719

samples obtained from patients with clinical ALI/ARDSand determined that while most specimens did showDAD, diagnostic findings were found that prompted achange in therapy in nearly one-third of cases. Most ofthese cases involved the discovery of a definitiveinfectious etiology.5 As will be discussed below, evalua-tion for an infectious cause is an important contributionthat the pathologist can make in evaluating a biopsyspecimen from a patient with acute lung injury.

CLINICAL AND PATHOLOGIC OVERVIEW OFHISTOLOGIC PATTERNS ASSOCIATED WITH ALI/ARDS

Diffuse Alveolar Damage

Diffuse alveolar damage is the classic histologic mani-festation of ALI/ARDS. Clinically, patients present withsevere hypoxemia and typically require mechanical venti-lation. The histologic findings will vary depending onwhen a biopsy is obtained during the course of thedisease.11 Radiographically, patients with DAD are classi-cally described as having diffuse bilateral pulmonaryinfiltrates (‘‘white out’’) by conventional chest x-ray.Computed tomography scans, however, often demonstratethat the distribution is actually nonhomogenous and isgreater in the dependent portions of the lung.12,13 Thepathogenesis of DAD has been widely studied, and anextensive review is beyond the scope of this article. Briefly,damage to the capillary endothelium and alveolar epithe-lium result in exudation of edema fluid and cellularbreakdown products, with subsequent pneumocyte hyper-plasia and fibroblastic proliferation as the lung attempts torepair the damage. The entire process is propagated by acomplex and ever-expanding collection of cytokines andother cellular factors. The interested reader is referred toseveral excellent reviews on the pathogenesis of DAD/ARDS.14–18 Additionally, recent work on the genetic factorsinfluencing susceptibility and development of ARDS19,20

has also provided new insights into pathogenesis and hasled to the identification of biomarkers thatmay help predictoutcome as well as serve as potential therapeutic targets.

Histologically, DAD is typically divided into 2 phases:the acute/exudative phase and the organizing/prolifera-tive phase. The acute phase generally occurs during thefirst week following pulmonary insult, with the organiz-ing phase occurring after the first week; however, theprocesses actually represent a continuum and overlappingfeatures may be encountered, particularly late in the firstweek. Some authors additionally include a final fibroticstage. In cases related to a single insult, the diseaseprogresses in a relatively linear fashion. However, in somecases, a patient may experience repeated insults that maylead to variable features within a biopsy specimen.21

The acute/exudative phase is usually easily recogniz-able. The findings are generally diffuse and relativelyuniform, but may occasionally be more focal.22 While theearliest changesmay be seen only ultrastructurally, by day2 intra-alveolar edema and interstitial widening areapparent. Hyaline membranes may be seen at this pointand may reach a peak 4 to 5 days after the initial insult.Hyaline membranes are composed of cellular andproteinaceous debris and appear as dense, glassy eosin-ophilic membranes lining the alveolar ducts and alveolarspaces (Figure 1). Generally, inflammation is relativelysparse unless the DAD is evolving from a preexistingpneumonia. Thrombi may be present and may be quite

extensive (Figure 2).21,23 The formation of thrombi in DADis due to localized alterations in the coagulation pathwayand should not be considered evidence of an underlyingthromboembolic disorder in the patient.24,25

The organizing phase may prove more problematic onbiopsy specimen examination. This phase is characterizedby relatively uniform interstitial fibrosis associated withquite pronounced type 2 pneumocyte hyperplasia (Fig-ure 3). Squamous metaplasia may also be present and insome cases may be quite pronounced (Figure 4). Thehyaline membranes characteristic of the acute phasegradually disappear as they become incorporated intothe alveolar septa; however, residual hyaline membranesmay be identifiable depending on the timing of the biopsyin the course of disease. Cytologic atypia may be quitepronounced in both the type 2 pneumocytes as well assquamous metaplastic areas and should not be confusedwith malignancy. Similarly, mitotic figures may beobserved in the pneumocytes. The fibrosis in DAD tendsto be loose and myxoid and will appear bluish-gray onhematoxylin-eosin sections, in contrast to the collagenousfibrosis typically seen in other disorders such as nonspe-cific interstitial pneumonia and usual interstitial pneumo-nia. Organizing fibroblastic tissue may be observed in airspaces, particularly the alveolar ducts (alveolar ductfibrosis), but this feature is typically not prominent anddoes not constitute the dominant finding as seen in casesof OP.21,26

Following the organizing phase, some cases of DADwill gradually resolve while others may develop contin-ued interstitial fibrosis with architectural remodeling andprogressive respiratory compromise. Among patientswho survive, most experience some degree of residualfunctional impairment.2,21,26

The histologic findings of DAD may result from a largenumber of potential etiologies that include numerousinfectious agents, drug reactions, collagen vascular/immune-mediated diseases, ingestant/inhalant exposure,shock, sepsis, and numerous other agents. Among theinfectious etiologies, viruses (Figure 5), Legionella, Myco-plasma, and Rickettsia are most frequently cited, but it isimportant to note that most any infectious agent canproduce DAD.1,5,21,27 This is of particular importance in theimmunosuppressed patient, a context in which agentssuch as Pneumocystis jiroveci and other fungi are notinfrequently encountered.28

Diffuse alveolar damage in which no known causativeetiology can be elucidated is clinically termed acuteinterstitial pneumonia, which also corresponds to caseshistorically referred to as Hamman-Rich syndrome.17,23,29

Transfusion-related acute lung injury (TRALI) deservesmention in the discussion of DAD/ARDS, as TRALI isincreasingly recognized from a clinical standpoint. Trans-fusion-related acute lung injury is a clinical syndromeassociated with transfusion of plasma containing bloodcomponents and is most frequently associated withantibodies to white blood cells in transfused bloodcomponents. Patients may experience a wide range ofrespiratory compromise ranging from mild dyspnea tofulminate respiratory failure, which is fatal in 5% to 10% ofcases, although most patients recover with supportivemeasures. Radiographs demonstrate findings essentiallyidentical to those of ARDS.30–32 As TRALI is typically aclinical diagnosis, reports of pathologic findings are fewand generally restricted to fatal cases. As would be

720 Arch Pathol Lab Med—Vol 134, May 2010 Pathologist’s Approach to Acute Lung Injury—Beasley

expected given the clinical presentation, several casereports33 describe findings identical to those of DAD withclassic hyaline membranes. Other reports describe onlypulmonary edema with neutrophil accumulation withinalveolar capillaries, although neutrophils within alveolarspaces have also been reported. It has been postulated thatthe lack of hyaline membranes in many reported casessuggests a differing pathologic mechanism from DAD,which has warranted further study.32–34

Acute Fibrinous and Organizing Pneumonia

Acute fibrinous and organizing pneumonia (AFOP) is amore recently described histologic pattern associated withacute lung injury in which the alveolar spaces are filledwith organizing fibrin balls, in contrast to the true hyalinemembranes found in DAD. The process may be patchy orrelatively diffuse. The alveolar septa may show mildinterstitial widening or lymphocytic infiltrates, but signif-icant eosinophils or neutrophils should not be seen(Figure 6). Organizing fibroblastic tissue may be presentto varying degrees but is not the dominant finding, andthe fibroblastic tissue may retain a central fibrinous core.8

The differential diagnosis of AFOP is primarily withDAD and eosinophilic pneumonia (EP). Prominent orga-nizing fibrin may be seen in some cases of DAD. Suchcases also contain foci of more typical hyaline membranes,although theymay be relatively focal. Hyaline membranesshould be sought in all cases with prominent organizingfibrin and should be properly classified as DAD and not asAFOP. Eosinophilic pneumonia, described below, mayhave prominent intra-alveolar fibrin and greatly resembleAFOP histologically. Cases of AFOP should not havesignificant eosinophils and should also lack significantmacrophage accumulation. As eosinophils disappearrapidly from tissue following initiation of steroid therapy,partially treated EP may be a consideration if a biopsy isobtained after administration of steroids. Peripheral bloodeosinophilia is not a feature of AFOP and may helpdistinguish these cases on a clinical level. Cases of alveolarhemorrhage may also contain organizing fibrin but thepresence of hemosiderin-laden macrophages and otherfeatures described in the hemorrhage section belowshould point to the correct diagnosis. Similarly, AFOPmay have areas of organizing fibroblastic tissue but this isnot the dominant finding, as seen in cases of OP.8

A diagnosis of AFOP should only be made on a largebiopsy specimen when one can be more certain that thereare not otherwise diagnostic features of DAD or EP.Similarly, abundant fibrin may be encountered in acutebacterial pneumonias and cases with marked neutrophilsshould not be classified as AFOP. Additionally, organiz-ing fibrin can occur as a nonspecific reaction adjacent tolesions such as granulomas, abscesses, or neoplasms ormay occur in subpleural lung parenchyma adjacent toacute pleuritis.8 For these reasons, the finding of organiz-ing alveolar fibrin on a small biopsy specimen should beinterpreted conservatively and carefully correlated withclinical and radiographic information.In the original study of AFOP, the overall mortality rate

was similar to that seen in DAD and it was felt that AFOPlikely represented a histologic variant of DAD. Acutefibrinous and organizing pneumonia was additionallyfound to be associated with a wide range of potentialetiologies similar to those seen in DAD, and some caseswere felt to be idiopathic. Most patients presented with

severe respiratory failure. However, a significant numberof patients with the AFOP pattern presented with asubacute clinical course not requiring mechanical ventila-tion and eventually recovered. Histologic features distin-guishing these 2 prognostic groups were not identified.Therefore, while at least some cases of AFOP appear to berelated to DAD, further study is needed to further definethe significance of this pattern, particularly in regard tothe subacute clinical cases.8 From a practical standpoint atthis time, the primary issue for the practicing pathologistis recognizing the AFOP pattern as being associated withacute lung injury and understanding its spectrum ofpotential clinical associations.

Eosinophilic Pneumonia

Eosinophilic pneumoniamost commonly presents with asubacute clinical course but occasional cases present withfulminate respiratory failure, often associated with fever.Such cases, termed acute eosinophilic pneumonia (AEP), maynot be associated with the peripheral blood eosinophiliatypical of chronic eosinophilic pneumonia.7 Both AEP andEP may be associated with underlying etiologies such astoxic inhalation, drug reaction, or infection, particularlywith parasites or fungus, or may be idiopathic.35–38

Interestingly, AEP has also been reported in patients afterrecent initiation of cigarette smoking.39,40

Eosinophilic pneumonia in general is characterized byintra-alveolar fibrin and macrophages in variable propor-tions, admixed with numerous eosinophils. Eosinophilsmay also be present in the interstitial tissue andeosinophilic microabscess formation may be observed. Insome cases, eosinophils may infiltrate blood vesselwalls.41,42 In AEP, these features may be present to varyingdegrees with the additional finding of hyaline membraneformation identical to that seen in the acute phase of DAD(Figure 7).7 The histologic differential of EP/AEP isprimarily with DAD and AFOP, as described in the 2previous sections. Churg-Strauss syndrome does nottypically present with clinical ALI/ARDS but may arisein the histologic differential of EP. The finding ofnecrotizing vasculitis and granulomas should distinguishcases of Churg-Strauss syndrome from EP, along withclinical findings of systemic vasculitis.

The presence of eosinophils should be sought in allcases with histologic findings of DAD. The importance ofthis finding lies in the fact that AEP is exquisitely sensitiveto steroid therapy, with most patients making a dramaticrecovery when appropriate therapy is instituted.7,35,36,38

Diffuse Alveolar Hemorrhage With Capillaritis

Occasionally, diffuse alveolar hemorrhage (DAH) withcapillaritis will present with fulminate respiratory fail-ure.5,43 Such cases demonstrate diffuse intra-alveolar bloodadmixed with hemosiderin-laden macrophages contain-ing coarse hemosiderin granules. Capillaritis is evidencedby neutrophils within the alveolar septa with resultantvascular necrosis (Figure 8). Neutrophilic cellular debrisor fibrin thrombi may also be observed. Capillary necrosismay be difficult to visualize but the histologic finding ofsignificant neutrophilic infiltrates within the alveolarsepta with minimal or absent involvement of the airspaces should strongly suggest capillaritis. Organizingfibroblastic tissue may be present and form ‘‘dumbbell’’shapes crossing the alveolar septa (Figure 9). This featureevolves as capillaritis resolves. Some cases of DAH with


Figure 1. Diffuse alveolar damage, acute/exudative phase. Alveolar septa show edematous widening and sparse inflammation and are lined byprominent hyaline membranes (hematoxylin-eosin, original magnification 3200).

Figure 2. Thrombi may be observed in cases of diffuse alveolar damage and are secondary to localized alterations in the coagulation pathway.Such findings should not be misinterpreted as pulmonary emboli (hematoxylin-eosin, original magnification 3200).

Figure 3. Diffuse alveolar damage, organizing phase. The alveolar septa are expanded by myxoid-appearing fibrous tissue and pneumocytehyperplasia is prominent. A residual hyaline membrane is still visible (hematoxylin-eosin, original magnification 3200).

Figure 4. Organizing diffuse alveolar damage (DAD) with an unusually large amount of squamous metaplasia. The finding of more typical featuresof DAD elsewhere in the biopsy specimen, the distribution of the squamous epithelium along air spaces, and the lack of overt cytologic features ofmalignancy should help avoid misdiagnosis as carcinoma (hematoxylin-eosin, original magnification 3100).


capillaritis will also have hyaline membranes, which mayoccasionally be the dominant histologic component.44–46

The primary challenge upon encountering hemorrhagein a biopsy specimen is to determine if the hemorrhage isof pathologic significance or if it is related to traumasecondary to the biopsy procedure. Hemosiderin-ladenmacrophages are an important finding, which points totrue alveolar hemorrhage. The hemosiderin in thesemacrophages is characteristically coarsely granular andgolden brown, in contrast to the finely granular brownpigment encountered in the lungs of cigarette smokers(Figure 10, A and B). Iron stains may highlight the coarsenature of true hemosiderin, but one should keep in mindthat pigmented ‘‘smoker’s type’’ macrophages may alsocontain stainable iron; therefore, morphologic featuresshould take precedence over the finding of stainable ironalone. Hemosiderin-laden macrophages begin to developas soon as 2 days after a bleeding episode and may persistfor as long as several months. As such, the mere finding ofhemosiderin-laden macrophages may not be indicative ofacute or active hemorrhage. Other histologic findings thatpoint towards active hemorrhage include cellular reactivechanges in the adjacent alveolar septa and focal areas of airspace organization.44–46 When hemorrhage is determinedto be potentially significant from a histologic standpoint,the finding must be evaluated in the appropriate clinicalcontext. From a clinical standpoint, significant alveolarhemorrhage is almost always associated with hemoptysis.While the focus of the article is on ALI, in a broader scopehemorrhage may be localized or diffuse, and localizedhemorrhage in particular may occur secondary to a widerange of etiologies, particularly bronchiectasis or throm-boembolism among others. A diagnosis of DAH should beentertained only when a patient presents with diffusealveolar infiltrates. Diffuse alveolar hemorrhage mayoccur with or without associated capillaritis; however, itis typically the cases with capillaritis that may presentwith clinical manifestations of ALI.5 Diffuse alveolarhemorrhage with capillaritis most commonly occurs inassociation with immune-mediated disorders. The prima-ry considerations include collagen vascular diseases (mostcommonly systemic lupus) and microscopic polyangiitis.Goodpasture syndrome (anti–glomerular basement mem-brane antibody syndrome) may present with DAHwith orwithout associated capillaritis, and Wegener granuloma-tosis may occasionally present with a primary pattern ofhemorrhage and capillaritis. Other entities that have beenreported in association with DAH include primary anti-phospholipid antibody syndrome, mixed cryoglobulin-emia, Behcet syndrome, and Henoch-Schonlein purpuraalong with some drug reactions and some infections(human immunodeficiency virus, listeriosis).44–47 As mostof the potential causes of DAH are immune mediated,specific patterns of immunoglobulin deposition may beobserved by immunofluorescence, particularly Goodpas-ture syndrome. While interesting, in reality, such studiesare rarely necessary in establishing a diagnosis from a

clinical standpoint. A diagnosis of ‘‘alveolar hemorrhage’’with a comment regarding the presence or absence ofcapillaritis is typically sufficient and the etiology isconfirmed via clinical and serologic findings.

From a histologic standpoint, it should be noted thatsome cases of conventional DAD may present with fairlyconsiderable intra-alveolar hemorrhage, which is morecommonly fresh blood and seen in the acute phase. Thepresence of coarse hemosiderin, neutrophilic interstitialinfiltrates, and capillaritis should raise the possibility of animmune-mediated lung injury.

Organizing Pneumonia

As stated previously, OP generally presents with asubacute clinical course without fulminate respiratoryfailure and is not generally encountered in patients withclinical ALI/ARDS. Indeed, the clinical finding of fulmi-nate respiratory failure requiring mechanical ventilationmilitates against a diagnosis of OP. However, OP isfrequently included in the pathologic differential diagno-sis of ALI and, most importantly, is often a considerationin the differential diagnosis of the other histologic patternsassociated with ALI.

The histologic pattern of OP, as defined in the currentAmerican Thoracic Society/European Respiratory Societyconsensus classification of interstitial lung disease, corre-sponds to the entity formerly termed bronchiolitis obliteransorganizing pneumonia. The clinical term for idiopathic OP iscryptogenic organizing pneumonia (COP). The OP patternmay also be seen in association with a number of potentialunderlying etiologies such as infection, collagen vasculardisease, and drug reactions, which must be excludedclinically before a clinical diagnosis of COP is made.29

The OP pattern is characterized by patchy accumulationof intra-alveolar organizing fibroblastic tissue, which isprimarily centered around bronchioles. Intra-bronchiolarfibroblastic tissue (bronchiolitis obliterans) may or maynot be present. The alveolar septa in involved areasgenerally exhibit mild chronic inflammation. Significantfibrosis should not be present, and the intervening lungtissue should be relatively normal (Figure 11).9,10,29

Organizing pneumonia is typically readily distinguishedfrom DAD histologically. Some cases of organizing DADmay, however, contain comparatively prominent intra-alveolar or alveolar duct fibrosis and therefore, OP mayarise in the histologic differential diagnosis. OrganizingDAD is typically much more diffuse and, even whenrelatively prominent air space fibrosis is present, thedominant finding remains the diffuse interstitial expan-sion/myxoid fibrosis with marked pneumocyte hyperpla-sia. In OP, the air space organization is the primary findingand the interstitial changes are relativelymild, consisting oflymphocytic interstitial inflammation without significantinterstitial fibrosis. Pneumocyte hyperplasia is similarly notas prominent. Organizing pneumonia is additionally apatchy, bronchiolocentric process with the intervening lungparenchyma appearing relatively normal.

r

Figure 5. Diffuse alveolar damage (DAD) with cytopathic changes of adenovirus infection (arrows). Infectious etiologies should be sought in allcases of DAD (hematoxylin-eosin, original magnification 3400).

Figure 6. Acute fibrinous and organizing pneumonia is characterized by intra-alveolar fibrin balls in contrast to classic hyaline membranes(hematoxylin-eosin, original magnification 3100).


Figure 7. Acute eosinophilic pneumonia. Hyaline membranes, essentially identical to those seen in diffuse alveolar damage, are present butcontain numerous eosinophils on closer inspection (hematoxylin-eosin, original magnification 3400).

Figure 8. Neutrophilic capillaritis is characterized by prominent neutrophils within the alveolar septa. Necrosis of the capillary may be difficult tovisualize, but neutrophilic debris, as seen here, or fibrin thrombi suggest underlying vascular damage (hematoxylin-eosin, original magnification3400).

Figure 9. Healing capillaritis is characterized by organizing fibroblastic tissue. Often the organizing tissue bridges the previously damaged alveolarsepta in a ‘‘dumbbell’’ fashion, as seen here (hematoxylin-eosin, original magnification 3100).

Figure 10. Hemosiderin secondary to alveolar hemorrhage typically consists of large, coarse granules (A) in contrast to the finely granular pigmentassociated with cigarette smoking (B) (hematoxylin-eosin, original magnifications 3400).

Figure 11. Organizing pneumonia is characterized by patchy intra-alveolar organizing fibroblastic tissue. The surrounding alveolar septa containmild lymphocytic infiltrates (hematoxylin-eosin, original magnification 3100).


As with AFOP, a diagnosis of OP/COP shouldgenerally only be made on a large biopsy specimen, andonly when the histologic pattern described above ispresent. Organizing fibroblastic tissue may occur as acomponent of a number of pathologic processes, such ashypersensitivity pneumonitis and Wegener granulomato-sis, or it may occur as a nonspecific reaction adjacent to anunrelated lesion. That being said, the opinion that OPshould only be diagnosed with certainty on a large biopsyspecimen is controversial. Certainly, there are instanceswhen a small biopsy specimen with organizing fibroblas-tic tissue may be considered consistent with OP/COPwith careful clinical and radiographic correlation.29,48

APPROACH TO BIOPSY SPECIMENS IN PATIENTS WITHCLINICAL ALI/ARDS

As with any lung biopsy, when evaluating a biopsyspecimen from a patient with clinical acute lung injury, itis important to have as much clinical information aspossible. Information regarding disease onset and pro-gression, suspected underlying etiologies, radiographicinformation, and whether or not the patient is on

mechanical ventilation are important to support or refutepossible differential diagnoses.

With the exception of diffuse alveolar hemorrhage withcapillaritis, which most commonly occurs in a relativelynarrow range of immune-mediated settings, all of theabove histologic manifestations of ALI, and DAD inparticular, may be associated with myriad potentialunderlying etiologic agents, or they may be idiopathic.29,48

In many cases the etiology will not be apparent from thehistologic findings alone. While the role of the pathologistis limited in elucidating the etiology, the one thing that canand should be done in every case is careful evaluation forpotential infectious etiologies. Special stains for microor-ganisms, namely an acid-fast stain, a Gomori methena-mine-silver or similar silver stain, and a bacterial stainsuch as Brown-Brenn or Brown-Hopps should be ob-tained, and cases should also be carefully scrutinized forviral cytopathic changes. This should be done in all casesbut is of particular importance in cases of DAD andAFOP,which may harbor fungal, pneumocystis, mycobacterial,or bacterial infections that may affect the clinical treatment(Figure 12, A and B).

Figure 12. A, In this case of acute fibrinous and organizing pneumonia, numerous fungal organisms compatible with Aspergillus were present(Gomori methenamine-silver, original magnification 3200). B, These organisms were surprisingly not visible on the corresponding hematoxylin-eosin section, thus emphasizing the importance of obtaining microorganism stains in such cases (original magnification 3200).

Figure 13. A, Panoramic view of a small biopsy specimen from a patient with clinical features suggestive of eosinophilic pneumonia. B, On closerinspection, abundant eosinophils are supportive of the diagnosis (hematoxylin-eosin, original magnifications 340 [A] and 3400 [B]).


The entities discussed herein are diagnosed withgreatest certainty on a wedge biopsy specimen, and aspreviously stated, a definitive diagnosis of AFOP or OPshould generally be made on a large biopsy specimen. Inpractice, however, one is more frequently presented witha small biopsy specimen, particularly in the initial stagesof the clinical workup. In some cases, one may befortunate and hyaline membranes may be detectable,enabling a diagnosis of DAD, or one may be able toidentify features of eosinophilic pneumonia (Figure 13, Aand B) or capillaritis. More frequently, a precise diagnosismay not be possible. Important features to evaluateinclude (1) presence of intra-alveolar edema and/ormyxoid interstitial fibrosis, (2) presence of markedpneumocyte hyperplasia, especially with bizarre cytologicfeatures, and (3) presence of alveolar fibrin or debris. Ifsuch features are present, particularly in a patient withknown respiratory failure, it is appropriate to provide adescriptive diagnosis with a comment that the findings aresuggestive of, or consistent with, acute lung injury(Figure 14). When a diagnosis of acute lung injury issuspected, additional features to assess include evaluationfor the presence of (1) microorganisms and viral inclu-sions, (2) eosinophils, suggesting the possibility of AEP,and (3) coarse hemosiderin and capillaritis, suggesting animmune-mediated vasculitis.

It cannot be emphasized enough that clinical correlationand communication with the clinician are critical to avoidoverinterpretation of findings in small biopsy specimens,and it is generally better to be conservative, especially ifcorrelative information is not available. While the abovefeatures may point to acute lung injury in the properclinical setting, they are not specific taken alone and out ofcontext.

Hemorrhagic small biopsy samples may also beproblematic. Fresh hemorrhage secondary to the biopsyprocedure is very common, and blood and associatedfibrin within air spaces should not be overinterpreted as

hyaline membranes. Fibrin associated with proceduraleffect is generally loose and wispy. Only well-formedhyaline membranes with a dense, glassy eosinophilicquality should be taken as evidence of DAD. Similarly,procedural-related hemorrhage should not be overinter-preted as a chronic hemorrhage syndrome. Features ofchronic hemorrhage such as macrophages with coarsehemosiderin granules and associated reactive pneumo-cytes, or definitive evidence of capillaritis, should bepresent before suggesting this diagnosis.In summary, ALI and ARDS clinically represent a

significant cause of pulmonary morbidity and mortality.Most patients with these conditions will have a histologicpattern of DAD, but AFOP, AEP, and DAH withcapillaritis may also be encountered and constituteimportant considerations in the differential diagnosis.Determination of potential infectious etiologies is impor-tant from the pathologic perspective, and caution shouldbe used in interpreting small biopsy specimens.

References

1. Bernard GR, Artigas A, Brigham KL, et al. The American-EuropeanConsensus Conference on ARDS: definitions, mechanisms, relevant outcomes,and clinical trial coordination. Am J Respir Crit Care Med. 1994;149(3, pt 1):818–824.2. Avecillas JF, Freire AX, Arroliga AC. Clinical epidemiology of acute lung

injury and acute respiratory distress syndrome: incidence, diagnosis, andoutcomes. Clin Chest Med. 2006;27(4):549–557.3. Bernard GR. Acute respiratory distress syndrome: a historical perspective.

Am J Respir Crit Care Med. 2005;172(7):798–806.4. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of

acute lung injury. N Engl J Med. 2005;353(16):1685–1693.5. Patel SR, Karmpaliotis D, Ayas NT, et al. The role of open-lung biopsy in

ARDS. Chest. 2004;125(1):197–202.6. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J

Med. 2000;342(18):1334–1349.7. Tazelaar HD, Linz LJ, Colby TV, Myers JL, Limper AH. Acute eosinophilic

pneumonia: histopathologic findings in nine patients. Am J Respir Crit Care Med.1997;155(1):296–302.8. Beasley MB, Franks TJ, Galvin JR, Gochuico B, Travis WD. Acute fibrinous

and organizing pneumonia: a histological pattern of lung injury and possiblevariant of diffuse alveolar damage. Arch Pathol Lab Med. 2002;126(9):1064–1070.9. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis

obliterans organizing pneumonia. N Engl J Med. 1985;312(3):152–158.10. Epler GR. Bronchiolitis obliterans organizing pneumonia: definition and

clinical features. Chest. 1992;102(suppl 1):2S–6S.11. Tomashefski JF Jr. Pulmonary pathology of acute respiratory distress

syndrome. Clin Chest Med. 2000;21(3):435–466.12. Caironi P, Carlesso E, Gattinoni L. Radiological imaging in acute lung

injury and acute respiratory distress syndrome. Semin Respir Crit Care Med.2006;27(4):404–415.13. Gattinoni L, Caironi P, Valenza F, Carlesso E. The role of CT-scan studies

for the diagnosis and therapy of acute respiratory distress syndrome. Clin ChestMed. 2006;27(4):559–570.14. Ware LB. Pathophysiology of acute lung injury and the acute respiratory

distress syndrome. Semin Respir Crit Care Med. 2006;27(4):337–349.15. Suratt BT, Parsons PE. Mechanisms of acute lung injury/acute respiratory

distress syndrome. Clin Chest Med. 2006;27(4):579–589.16. Parsons PE. Mediators and mechanisms of acute lung injury. Clin Chest

Med. 2000;21(3):467–476.17. 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):209–228.18. Belperio JA, Keane MP, Lynch JP III, Strieter RM. The role of cytokines

during the pathogenesis of ventilator-associated and ventilator-induced lunginjury. Semin Respir Crit Care Med. 2006;27(4):350–364.19. Gong MN. Genetic epidemiology of acute respiratory distress syndrome:

implications for future prevention and treatment. Clin Chest Med. 2006;27(4):705–724.20. Frank JA, Parsons PE, Matthay MA. Pathogenetic significance of biological

markers of ventilator-associated lung injury in experimental and clinical studies.Chest. 2006;130(6):1906–1914.21. Tomashefski JF Jr. Pulmonary pathology of acute respiratory distress

syndrome. Clin Chest Med. 2000;21(3):435–466.22. Yazdy AM, Tomashefski JF Jr, Yagan R, Kleinerman J. Regional alveolar

damage (RAD): a localized counterpart of diffuse alveolar damage. Am J ClinPathol. 1989;92(1):10–15.

Figure 14. This small biopsy specimen contains intra-alveolar fibrinwith mild expansion of the alveolar septa and pneumocyte hyperplasia.Taken in isolation the findings are not specific, but in the appropriateclinical setting of a patient with diffuse pulmonary infiltrates andrespiratory compromise, the findings can be interpreted as beingconsistent with acute lung injury (hematoxylin-eosin, original magni-fication 3100).


23. Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia: aclinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol. 1986;10(4):256–267.24. Tomashefski JF Jr, Davies P, Boggis C, Greene R, Zapol WM, Reid LM. The

pulmonary vascular lesions of the adult respiratory distress syndrome. Am JPathol. 1983;112(1):112–126.25. Sapru A, Wiemels JL, Witte JS, Ware LB, Matthay MA. Acute lung injury

and the coagulation pathway: potential role of gene polymorphisms in the proteinC and fibrinolytic pathways. Intensive Care Med. 2006;32(9):1293–1303.26. Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress

syndrome. Clin Chest Med. 1990;11(4):593–619.27. Travis WD. Surgical pathology of pulmonary infections. Semin Thorac

Cardiovasc Surg. 1995;7(2):62–69.28. Travis WD, Pittaluga S, Lipschik GY, et al. Atypical pathologic

manifestations of Pneumocystis carinii pneumonia in the acquired immunedeficiency syndrome: review of 123 lung biopsies from 76 patients with emphasison cysts, vascular invasion, vasculitis, and granulomas. Am J Surg Pathol. 1990;14(7):615–625.29. Travis W. American Thoracic Society/European Respiratory Society

International Multidisciplinary Consensus Classification of the IdiopathicInterstitial Pneumonias: this joint statement of the American Thoracic Society(ATS), and the European Respiratory Society (ERS) was adopted by the ATS boardof directors, June 2001 and by the ERS Executive Committee, June 2001. Am JRespir Crit Care Med. 2002;165(2):277–304.30. Swanson K, Dwyre DM, Krochmal J, Raife TJ. Transfusion-related acute

lung injury (TRALI): current clinical and pathophysiologic considerations. Lung.2006;184(3):177–185.31. Looney MR. Newly recognized causes of acute lung injury: transfusion of

blood products, severe acute respiratory syndrome, and avian influenza. ClinChest Med. 2006;27(4):591–600.32. Toy P, Popovsky MA, Abraham E, et al. Transfusion-related acute lung

injury: definition and review. Crit Care Med. 2005;33(4):721–726.33. Kopko PM, Popovsky MA. Pulmonary injury from transfusion-related acute

lung injury. Clin Chest Med. 2004;25(1):105–111.34. Danielson C, Benjamin RJ, Mangano MM, Mills CJ, Waxman DA.

Pulmonary pathology of rapidly fatal transfusion-related acute lung injury revealsminimal evidence of diffuse alveolar damage or alveolar granulocyte infiltration.Transfusion. 2008;48(11):2401–2408.

35. Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia asa reversible cause of noninfectious respiratory failure. N Engl J Med. 1989;321(9):569–574.36. King MA, Pope-Harman AL, Allen JN, Christoforidis GA, Christoforidis AJ.

Acute eosinophilic pneumonia: radiologic and clinical features. Radiology. 1997;203(3):715–719.37. Philit F, Etienne-Mastroianni B, Parrot A, Guerin C, Robert D, Cordier JF.

Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir CritCare Med. 2002;166(9):1235–1239.38. Pope-Harman AL, Davis WB, Allen ED, Christoforidis AJ, Allen JN. Acute

eosinophilic pneumonia: a summary of 15 cases and review of the literature.Medicine (Baltimore). 1996;75(6):334–342.39. Shintani H, Fujimura M, Yasui M, et al. Acute eosinophilic pneumonia

caused by cigarette smoking. Intern Med. 2000;39(1):66–68.40. Shintani H, Fujimura M, Ishiura Y, Noto M. A case of cigarette smoking-

induced acute eosinophilic pneumonia showing tolerance. Chest. 2000;117(1):277–279.41. Carrington CB. Eosinophilic reactions in the lung. N Engl J Med. 1969;

281(1):51.42. Liebow AA, Carrington CB. The eosinophilic pneumonias. Medicine

(Baltimore). 1969;48(4):251–285.43. Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol.

2001;13(1):12–17.44. Colby TV, Fukuoka J, Ewaskow SP, Helmers R, Leslie KO. Pathologic

approach to pulmonary hemorrhage. Ann Diagn Pathol. 2001;5(5):309–319.45. Franks TJ, Koss MN. Pulmonary capillaritis. Curr Opin Pulm Med. 2000;

6(5):430–435.46. Travis WD. Pathology of pulmonary vasculitis. Semin Respir Crit Care

Med. 2004;25(5):475–482.47. Travis W. Vasculitis. In: Tomashefski JF Jr, Cagle PT, Farver CF, Fraire A,

eds. Dail and Hammar’s Pulmonary Pathology. 3rd ed. New York, NY: Springer;2008:1088–1138.48. Travis W, Colby TV, Koss MN, Rosado-de-Christenson ML, Muller NL,

King TE Jr. Idiopathic interstitial pneumonia and other diffuse parenchymal lungdiseases. In: Non-Neoplastic Disorders of the Lower Respiratory Tract.Washington, DC: American Registry of Pathology and Armed Forces Institute ofPathology; 2002:49–231. Atlas of Nontumor Pathology; 2nd series.


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The Pathologist's Approach to Acute Lung Injury