Moderators: Dr. Dani Zander, Dr. David Hwang and Dr. Osamu Matsubara
Section 3 -
SARS: Lung Pathology and the Histologic Differential of Diffuse Alveolar Damage
Teri J. Franks
Chairman, Department of Pulmonary and Mediastinal Pathology
Armed Forces Institute of Pathology
Lung Pathology of SARS
Severe acute respiratory syndrome (SARS) emerged from Guangdong Province, China, in mid-November 2002
and swept around the globe via routes of international air travel. By its end in July 2003, the initial
outbreak affected more than 8,000 people in 28 countries and regions with a mortality rate of 9.6%.
While sporadic cases, primarily in laboratory workers, subsequently occurred, no new cases of SARS have
been reported since 2004. Although the causative agent, SARS-associated coronavirus (SARS-CoV), a new
member in the family Coronaviridae, has been identified and its viral genome
sequenced, many questions regarding how SARS-CoV causes disease remain.
Clinically, SARS is dominated by respiratory involvement. Histologically, the predominant pattern of
lung injury is diffuse alveolar damage (DAD), and the histology varies according to duration of illness.
Patients with illnesses of 10 or fewer days duration demonstrate acute phase DAD, while those with
illnesses greater than 10 days show organizing phase DAD. Acute phase DAD is characterized by hyaline
membranes, interstitial and intraalveolar edema, mild/minimal interstitial infiltrates of inflammatory
cells, and vascular congestion. Bronchiolar injury is evidenced by collections of fibrin within lumens
that are associated with loss of cilia, bronchiole epithelial denudation, and focal deposition of fibrin
on exposed basement membranes.
Organizing phase DAD, characterized by interstitial and airspace fibroblast proliferation, is
accompanied by repair in the form of type II pneumocyte hyperplasia and squamous metaplasia. Hyperplasic
type II pneumocytes may show marked cytologic changes including cytomegaly, nucleomegaly, clearing of
nuclear chromatin, and prominent nucleoli. Alveolar spaces contain a combination of macrophages (CD68
positive) and desquamated pneumocytes (pancytokeratin/TTF-1 positive), including multinucleated forms of
both. Occasional pneumocytes and macrophages demonstrate fine cytoplasmic vacuoles, however,
vacuolization is not a striking feature in SARS. The numbers of macrophages within alveolar spaces is
not significantly different from the numbers typically seen in non-SARS organizing DAD. Fibrin thrombi,
common in DAD, are also present in SARS.
Some viruses can be identified in histologic sections by their characteristic tissue response and
cytopathic changes. For example, the combination of bronchiolar necrosis and smudge cells is virtually
diagnostic of adenovirus pneumonia. While the cytologic changes described in the prior paragraph may
well be viral induced, the changes are not unique for SARS-CoV infection. Ding et al (2003) described
intracytoplasmic inclusions, however, this has not been our experience and is also not reported in other
series. Although severe, the cytologic changes in SARS are within the spectrum of epithelial changes
seen in non-SARS cases of DAD. In the absence of ancillary studies, the lack of a unique tissue response
and cytopathic effect makes the diagnosis of SARS difficult at the light microscopic level. SARS-CoV can
be detected in pneumocytes by in situ hybridization (ISH) and
immunohistochemistry (IHC) utilizing paraffin-embedded tissue.
Employing ISH and IHC, Nicholls et al (2006) demonstrated viral replication in autopsy lung samples
from SARS patients who died within two weeks after onset of symptoms, in patients who died more than two
weeks after onset of symptoms, virus was not demonstrable. They further showed that positive staining by
ISH and IHC was localized mainly to pneumocytes with only scattered positive cells in bronchiolar
epithelium and no staining in bronchial epithelium. Staining was also present in alveolar macrophages,
although staining was of lower intensity than in pneumocytes. From this, the authors concluded that
pneumocytes rather than alveolar macrophages are the primary target cells of the virus and that
macrophage involvement represented either phagocytosis or low-level viral replication.
Imai and Kuba, provide the first genetic proof that angiotensin converting enzyme 2 (ACE2) is a SARS
receptor in vivo. Examing DAD in a mouse model, Imai et al, showed that angiotensin converting enzyme 2
(ACE2) in the renin-angiotensin system protects against lung injury. In a subsequent article from the
same group, Kuba et al, demonstrated that ACE2 is downregulated in mice infected with SARS-CoV
contributing to lung injury in this disease. These findings provide a molecular explanation for why SARS
infections cause severe lung injury and suggest a rational therapy for SARS and potentially other lung
injuries that cause DAD.
Histologic Differential of DAD
In our consultation practice, DAD, particularly the organizing phase is frequently confused with
several other histologic patterns of injury; usual interstitial pneumonia (UIP), organizing pneumonia
(OP, previously termed BOOP) and non-specific interstitial pneumonia (NSIP). Separation of these
patterns is difficult in part because they are rare conditions and few pathologists have substantial
experience with their diagnosis and because most of the lesions are varying combinations of inflammation
and fibrosis. In addition to the histologic details, knowledge of the clinical history, particularly the
duration of illness before presentation, and the radiologic findings can be important clues to narrowing
the histologic and etiologic differential diagnosis. High-resolution computed tomography (HRCT) is the
most important radiologic method for evaluating patients with diffuse pulmonary lung disease. The
following are brief clinical and radiologic descriptions utilizing the American Thoracic Society/European
Respiratory Society Classification of the idiopathic interstitial pneumonias.
Acute Interstitial Pneumonia (AIP)
AIP is a rapidly progressive interstitial pneumonia that is associated with the histologic pattern of
DAD. DAD has a wide variety of causes, and the clinical term AIP is reserved for cases of unknown
etiology. Patients typically present with severe exertional dyspnea that develops over a few days with
rapid progression to respiratory failure usually requiring mechanical ventilation. HRCT varies with the
phase of disease. In the acute phase, bilateral areas of ground glass and consolidation involving the
majority of the lung are admixed with focal areas of sparing. The organizing phase is characterized by
ground glass and airway distortion with traction bronchiectasis; the latter two findings reflecting
effects of contracting fibrous tissue.
Idiopathic Interstitial Pneumonia (IPF)
IPF is a chronic fibrosing interstitial pneumonia of unknown cause associated with a surgical lung
biopsy showing a histologic pattern of UIP. In the presence of a surgical lung biopsy showing UIP, the
clinical diagnosis of IPF requires: exclusion of other known causes of interstitial lung disease
including drug toxicities, environmental exposure and collagen vascular disease, characteristic chest
radiograph or HRCT findings and abnormal pulmonary functions. Patients are typically over 50 years of
age, and there is a slight male predominance. The onset of symptoms is gradual, in most patients
symptoms are present for more than 6 months before presentation. The clinical course is one of gradual
deterioration with median survival of 2.5 to 3.5 years from time of diagnosis. HRCT is characteristic in
approximately 50% of patients with IPF and demonstrates bibasilar peripheral reticular opacities with
Cryptogenic Organizing Pneumonia (COP)
COP is the same entity termed BOOP/idiopathic BOOP that is associated with the histologic pattern of
organizing pneumonia (OP). OP also has a wide variety of causes but infection is the most common. The
clinical term COP is reserved for cases of unknown etiology and is preferred to avoid confusion with the
term constrictive bronchiolitis obliterans. On HRCT, uni- or bilateral areas of consolidation are
present in 90% of patients.
Non-specific Interstitial Pneumonia (NSIP)
NSIP represents a heterogeneous group of disorders including: collagen vascular disease,
hypersensitivity pneumonitis, drug reaction, infection, slowly resolving acute lung injury and
inadequately sampled UIP. Unlike UIP, NSIP can occur in children. The onset of symptoms is gradual and
varies from 6 months to 3 years. Prognosis varies with degree of fibrosis and the underlying condition.
NSIP displays a wide variety of CT patterns but in its most characteristic form shows lower lobe,
peribronchiolar reticulation and airway distortion with subpleural sparing.
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