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Hantavirus Pulmonary Syndrome Is Distinguishable From Acute Interstitial Pneumonia.

In the spring and summer of 1993, an outbreak of acute respiratory disease in the southwestern United States was attributed to a novel hantavirus; the disease was subsequently named hantavirus pulmonary syndrome (HPS).[1-9] Hantavirus pulmonary syndrome is a severe respiratory illness with a case fatality rate of 50% to 75%.[3] The case definition for HPS evolved over time and facilitated identification of cases (Table 1).[6-8] Cases fulfilling clinical or autopsy criteria and cases in which no other cause was found were confirmed as HPS by serologic, immunohistochemical, or polymerase chain reaction procedures.[8,9]
Table 1. Case Definition for Hantavirus Pulmonary Syndrome

June 11, 1993[6]

1. ... Radiographic evidence of unexplained bilateral pulmonary
interstitial infiltrates with hypoxemia, or

2. An autopsy finding of unexplained noncardiogenic pulmonary
edema occurring during 1993

June 18, 1993[7]

Confirmed case "... defined as unexplained adult respiratory
distress syndrome (ARDS) or acute bilateral pulmonary interstitial
infiltrates and/or prodromal symptoms in a person who had onset
during 1993 and who has laboratory evidence of recent hantavirus

July 30, 1993[8]

Laboratory confirmation defined as "... any of the following tests
positive: IgM antibodies to hantavirus antigens; fourfold or
greater increase in antibody titers to hantavirus antigen in paired
serum specimens; positive immunohistochemical stain for hantavirus
antigens in tissues; or positive polymerase chain reaction from
tissue specimens."

On autopsy, HPS is marked by a constellation of findings, including large pleural effusions, severe fibrinous pulmonary edema with hyaline membranes, and an immunoblastic proliferation involving the reticuloendothelial system.[5,9] These findings occur in concert with a characteristic hematologic tetrad that includes left-shifted neutrophilic leukocytosis, thrombocytopenia, an increased hematocrit reflective of hemoconcentration, and circulating immunoblastic cells.[5]

Acute interstitial pneumonia (AIP) is an idiopathic, acute lung disease associated with the rapid development of the adult respiratory distress syndrome.[10-13] Most patients with this condition have a prodrome suggestive of a viral infection that rapidly evolves into respiratory failure requiring assisted ventilation. The pathologic findings of AIP are characterized by acute and organizing diffuse alveolar damage. The fatality rate for AIP approaches 50%.[11] Despite the clinical features suggesting viral infection, the cause(s) of AIP have (by definition) not been identified. In the initial clinical evaluation of patients with AIP, HPS is often included in the differential diagnosis. In fact, cases of AIP fulfill the case definition criteria for HPS. Because of this similarity to HPS and because sporadic cases of HPS have been retrospectively identified,[14,15] we have studied 9 cases of AIP, 8 of which occurred prior to the recognition of HPS. We compared these cases with 7 cases of HPS and evaluated the AIP cases for hantaviral antigens by immunohistochemistry.


Paraffin blocks from 9 cases of AIP retrieved from the files of one of the authors (T.V.C.) were selected for study. Eight of these were previously reported as examples of AIP.[11] Clinical findings were obtained from referring physicians and the medical records. Seven fatal cases of HIPS, comprising part of the original series of cases,[5] were selected for comparison, and autopsy reports were reviewed.

The following parameters were assessed semiquantitatively (0-4+) on H&E-stained slides from both groups: interstitial edema; airspace edema and fibrinous exudates; hyaline membranes; hemorrhage; acute inflammation in airspaces; interstitial organization (fibroblast proliferation); airspace organization (intraluminal polyps of fibroblastic proliferation); type 2-cell hyperplasia; alveolar macrophages; interstitial chronic inflammation; alveolar wall atelectasis; cellular inflammation of bronchioles (cellular bronchiolitis); bronchiolar mucosal necrosis and metaplasia; and pleuritis.

Immunohistochemical assays for hantaviral antigens were performed as previously described.[9,11] Briefly, tissue sections were predigested with proteinase-K and then incubated with a cross-reactive hantaviral monoclonal antibody (GB04-BF07). This step was followed by serial application of rabbit anti-mouse link antibody and an alkaline phosphatase-anti-alkaline phosphatase complex (Dako Corporation, Carpinteria, Calif). Hantaviral antigens were then detected by using a naphthol/fast red substrate. Isotype-identical monoclonal antibodies and nonimmune sera were used as negative controls.

Statistical comparison between the 2 groups was performed with the Wilcoxon rank sum test.


The clinical features of the 2 groups are compared in Table 2. Differences in the length of prodrome and the time to tissue evaluation were statistically significant between the 2 groups (P = .002 and P = .008, respectively).
Table 2. Clinical Findings(*)

 Time to
 Age, y Sex Prodrome, d Evaluation, d Follow-up

AIP Cases
 1 24 F 60 66 Survived
 2 60 M 7 55 Survived
 3 71 F 30 34 Died
 4 54 M 14 16 Died
 5 56 F 7 16 NA
 6 29 F 7 10 NA
 7 72 M 5 6 NA
 8 42 F 7 8 NA
 9 34 F 14 21 Survived

 Mean 49.1 16.8 25.8
 Median 54 7 16

HPS Cases
 1 22 F 1 2 Died
 2 64 F 2 4 Died
 3 38 M 2 3 Died
 4 14 M 2 3 Died
 5 22 M 4 6 Died
 6 49 F 3 19 Died
 7 35 M 7 9 Died

 Mean 34.9 3.0 6.6
 Median 35 2 4

(*) AIP indicates acute interstitial pneumonia; HPS, hantavirus pulmonary syndrome; F, female; M, male; and NA, not available.

In all 7 cases of HPS, viral antigens were detected immunohistochemically in lung tissue. There was widespread staining of hantaviral antigens primarily within endothelial cells of the pulmonary microvasculature. None of the cases of AIP showed positivity for hantaviral antigens. Representative histologic findings of both entities are shown in Figures 1 and 2. Comparison of the histologic parameters as assessed by 3 observers (T.V.C., R.M.F., and K.B.N.) is shown in Table 3.


Table 3. Histologic Comparison of Hantavirus Pulmonary Syndrome and Acute Interstitial Pneumonia(*)
Histologic Feature([dagger]) (n = 9) (n = 7) P

Interstitial edema/lymphatic dilatation 0.9 1.8 NS
Airspace edema/fibrinous exudate 0.8 1.3 .04
Hyaline membranes 1.8 1.2 NS
Hemorrhage 1.01 1.0 NS
Acute inflammation (neutrophils) 0.8 1.2 NS
Interstitial organization
 (fibroblast proliferation) 3.3 0.3 <.001
Airspace organization([double dagger]) 1.61 0.2 .002
Type 2-cell metaplasia/hyperplasia 3.3 0.3 <.001
Alveolar macrophages 2.11 1.7 NS
Interstitial chronic inflammation 1.81 1.7 NS
Intravascular immature lympboid cells 0.4 1.7 .002
Alveolar wall atelectasis 2.9 0.7 <.001
Cellular broncbiolitis 0.8 1.1 NS
Bronchiolar mucosal necrosis/metaplasia 0.81 0.5 NS
Acute pleuritis 0.5 0.1 NS

(*) AIP indicates acute interstitial pneumonia; HPS, hantavirus pulmonary syndrome; and NS, not significant.

([dagger]) Assessed on a scale of 0-4+.

([double dagger]) Pattern of bronchiolitis obliterans with organizing pneumonia (BOOP pattern).


The clinical characteristics and pulmonary histologic findings in our cases of HPS and AIP are distinct. Not surprisingly, none of the cases of AIP studied showed any hantaviral antigens by immunohistochemistry. Hantavirus pulmonary syndrome tends to be of shorter duration and shows disproportionately more pulmonary edema than AIP. Organization and type 2-cell proliferation are characteristic of AIP and are rarely seen in HPS cases. Intravascular immature lymphoid cells (that correlate with the distinctive hematologic tetrad described previously) were common in HPS and unusual in AIP; furthermore, microatelectasis, one of the most characteristic features of AIP, was rarely seen in HPS cases. In addition, the pleural effusions, immunoblastic proliferation in the reticuloendothelial system, and hematologic tetrad seen in HPS are not present in cases of AIP.[5,11] These differences, combined with immunohistochemical staining for hantaviral antigens, should allow pathologic distinction between the 2 conditions.

All HPS cases were fatal and autopsy tissue was evaluated, whereas open lung biopsy tissue was evaluated in all of the AIP cases. Ideally, either biopsies in both conditions or autopsies in both conditions would be compared, but as yet, this has not been possible. The extremely rapid evolution and early mortality of HPS has precluded biopsy in most cases. This clinical pattern in itself is one of the most important differences between HPS and AIP. It is possible that HPS may manifest a very early phase of severe diffuse alveolar damage and in the few cases when patients survived in the hospital for 2 days or more, the histologic changes may more closely resemble those of AIP.[9] No such cases were available for inclusion in this study. While HPS may be a very early phase of diffuse alveolar damage, there is insufficient time for most cases to develop the reparative changes (such as organization and type 2-cell metaplasia) that are seen in cases of AIP.

The authors gratefully acknowledge Jane Sweeney for technical help and V. Shane Pankratz, PhD, for statistical help.


[1.] Duchin JS, Koster FT, Peters CJ, et al. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. N Engl J Med. 1994;330:949-955.

[2.] Foucar K, Nolte KB, Feddersen RM, et al. Outbreak of Hantavirus pulmonary syndrome in the southwestern United States. Am J Clin Pathol. 1994;101(suppl 1):S1-S5.

[3.] Khan AS, Ksiazek TG, Peters CJ. Hantavirus pulmonary syndrome. Lancet. 1996;347:739-741.

[4.] Levy H, Simpson SQ. Hantavirus pulmonary syndrome. Am J Respir Crit Care Med. 1994;149:1710-1713.

[5.] Nolte KB, Feddersen RM, Foucar K, et al. Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent. Hum Pathol. 1995;26:110-120.

[6.] Centers for Disease Control. Outbreak of acute illness--southwestern United States, 1993. MMWR Morb Mortal Wkly Rep. 1993;42:421-424.

[7.] Centers for Disease Control. Update: outbreak of hantavirus infection--southwestern United States, 1993. MMWR Morb Mortal Wkly Rep. 1993;42:441-443.

[8.] Centers for Disease Control. Update: hantavirus pulmonary syndrome--United States, 1993. MMWR Morb Mortal Wkly Rep. 1993;42:816-820.

[9.] Zaki SR, Greer PW, Coffield LM, et al. Hantavirus pulmonary syndrome: pathogenesis of an emerging infectious disease. Am J Pathol. 1995;146:552-579.

[10.] Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia: a clinical pathologic, ultrastructural and cell kinetic study. Am J Surg Pathol. 1986;10: 256-267.

[11.] Olson J, Colby TV, Elliott CG. Hamman-Rich syndrome revisited. Mayo Clin Proc. 1990;65:1538-1548.

[12.] Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998;157:1301-1315.

[13.] Polychonopulous V, Bouros D, Stirling R, Conron M, Nicholson A, du Bois R. Acute interstitial pneumonia (AIP): clinical features and treated course in 13 cases [abstract]. Eur Respir J. 1999;14:139s.

[14.] Zaki SR, Khan AS, Goodman RA, et al. Retrospective diagnosis of hantavirus pulmonary syndrome, 1978-1993. Arch Pathol Lab Med. 1996;120:134-139.

[15.] Khan AS, Gaviria M, Rollin PE, et al. Hantavirus pulmonary syndrome in Florida: association with the newly identified Black Creek Canal virus. Am J Med. 1996;100:46-48.

Accepted for publication March 23, 2000.

From the Department of Pathology and Laboratory Medicine, Mayo Clinic Scottsdale, Scottsdale, Ariz (Dr Colby); the Infectious Disease Pathology Activity, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga (Drs Zaki and Nolte); and the Department of Pathology (Drs Feddersen and Nolte) and the Office of the Medical Investigator (Dr Nolte), University of New Mexico School of Medicine, Albuquerque, NM.

Reprints: Thomas V. Colby, MD, Department of Pathology, Mayo Clinic, 13400 East Shea Blvd, Scottsdale, AZ 85259.
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Author:Colby, Thomas V.; Zaki, Sherif R.; Feddersen, Richard M.; Nolte, Kurt B.
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2000
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