MMWR: Hantavirus Pulmonary Syndrome

Ruben Donis rdonis at UNLINFO.UNL.EDU
Tue Nov 2 10:10:02 EST 1993


         Update: Hantavirus Pulmonary Syndrome -- United States, 1993
                   SOURCE: MMWR 42(42)   DATE: Oct 29, 1993

     A unique hantavirus has been identified as the cause of the outbreak of
respiratory illness (hantavirus pulmonary syndrome {HPS}) first recognized in
the southwestern United States in May 1993 (1-3). The habitat of the principal
rodent reservoir for this virus, Peromyscus maniculatus (deer mouse), extends
throughout most of the United States except the Southeast (2). Through October
21, 1993, HPS has been confirmed in 42 persons reported to CDC from 12 states
(Figure 1). This report summarizes major clinical, pathologic, and diagnostic
findings in patients with this newly recognized syndrome; addresses the use of
the investigational antiviral drug ribavirin; and presents revised screening
criteria for national surveillance.
     The earliest retrospectively confirmed case of HPS occurred in July 1991;
the two most recently reported case-patients had onsets of illness in
September 1993 (Figure 2). Case-patients' ages have ranged from 12 years to 69
years (median: 32 years); 22 (52%) were male. Overall, 26 (62%) case-patients
have died. Twenty-three (55%) case-patients were American Indians; 15 (36%),
non-Hispanic whites; three (7%), Hispanic; and one (2%), black.
     Clinical findings. Onset of illness has been characterized by a prodrome
consisting of fever, myalgia, and variable respiratory symptoms (e.g., cough)
followed by the abrupt onset of acute respiratory distress. Other symptoms
reported during the early phase of illness have included headache and
gastrointestinal complaints (e.g., abdominal pain, nausea, and/or vomiting).
Among 17 case-patients studied in the four-corners region (New Mexico,
Arizona, Colorado, and Utah), hemoconcentration was noted on admission in 13
(76%) and thrombocytopenia in 12 (71%). In all case- patients reviewed,
bilateral pulmonary infiltrates developed within 2 days of hospitalization.
The hospital course was characterized by fever, hypoxia, and hypotension;
recovery in survivors has been without sequelae.
     Pathologic findings. Postmortem examination has routinely revealed serous
pleural effusions and heavy edematous lungs. Although histopathologic findings
in the lung are characteristic of the illness, the degree of involvement has
varied among patients. Microscopic findings have included interstitial
infiltrates of mononuclear cells in the alveolar septa, congestion, septal and
alveolar edema with or without mononuclear cell exudate, focal hyaline
membranes, and occasional alveolar hemorrhage. Cellular debris and neutrophils
are not prominent. Large mononuclear cells with the appearance of immunoblasts
were found in red and periarteriolar white pulp of the spleen, hepatic portal
triads, and other sites. Hantavirus antigens can be detected by
immunohistochemistry (IHC) in formalin-fixed tissues using specific monoclonal
and polyclonal antibodies. Hantavirus antigens, localized primarily in
endothelial cells, have been detected in most organs, with marked
accumulations in the lungs.
     Virologic diagnosis. Adequate serum specimens were available for antibody
testing in 39 of the 42 confirmed case-patients; 38 had detectable antibodies
against heterologous hantavirus antigens, particularly Prospect Hill virus.
One additional case-patient had antibodies detected only with a recombinant
protein serologic assay (4). Twenty-seven case-patients had polymerase chain
reaction (PCR) evidence of hantavirus ribonucleic acid in frozen lung tissue
and/or positive immunohistochemical staining of formalin-fixed tissue for
hantavirus antigen, in addition to compatible pathologic findings. Each of
three tests -- serology, PCR, and IHC -- were completed for 16 case-patients.
The three tests were concordantly positive for 15 case-patients; antibodies
against heterologous antigens were not detected in the serum of one patient.
In addition, in seven of these patients, PCR testing of peripheral blood
mononuclear cells obtained early in the course of disease was positive.
     Clinical screening criteria. To standardize the investigation and
laboratory assessment of persons with possible HPS in the United States,
clinical screening criteria were developed by CDC in consultation with the
Council of State and Territorial Epidemiologists to detect persons with an
illness similar to that of persons with confirmed hantavirus infection
reported in the initial outbreak in the four-corners region. Cases meeting the
clinical screening criteria (see box) should be reported to CDC through state
health departments. In addition, patients meeting these clinical screening
criteria will need to have laboratory evidence of acute hantavirus infection
before they can be confirmed as having HPS.

Reported by: S Allen, R Feddersen, K Foucar, MD, B Hjelle, MD, D James, S
Jenison, MD, F Koster, MD, H Levy, MD, G Mertz, MD, S Simpson, J Williams,
Dept of Pathology, and Dept of Medicine, Univ of New Mexico School of
Medicine, Albuquerque; K Nolte, MD, New Mexico Office of Medical
Investigations; CM Sewell, DrPH, State Epidemiologist, New Mexico Dept of
Health. L Sands, DO, State Epidemiologist, Arizona Dept of Health Svcs. GW
Rutherford, III, MD, State Epidemiologist, California Dept of Health Svcs. RE
Hoffman, MD, State Epidemiologist, Colorado Dept of Health. FR Dixon, MD,
State Epidemiologist, Div of Health, Idaho Dept of Health and Welfare. L
McFarland, DrPH, State Epidemiologist, Office of Public Health, Louisiana Dept
of Health and Hospitals. TA Damrow, PhD, State Epidemiologist, Montana State
Dept of Health and Environmental Sciences. A DiSalvo, MD, State Health
Laboratory, Div of Health, Nevada State Dept of Human Resources. LA Shireley,
MPH, State Epidemiologist, North Dakota State Dept of Health and Consolidated
Laboratories. D Fleming, MD, State Epidemiologist, State Health Div, Oregon
Dept of Human Resources. KA Senger, State Epidemiologist, South Dakota State
Dept of Health. DM Simpson, MD, State Epidemiologist, Texas Dept of Health. CR
Nichols, MPA, State Epidemiologist, Utah Dept of Health. Div of Viral and
Rickettsial Diseases, National Center for Infectious Diseases, CDC.

Editorial Note: Clinical syndromes previously associated with hantavirus
infections have been characterized by hemorrhagic features and by renal
involvement (5). In comparison, the clinical manifestations of hantavirus
infection in the United States have been distinguished by the predominance of
respiratory symptoms and only limited renal involvement (6,7).
     No defined set of symptoms and signs reliably distinguishes HPS at the
time of presentation from other forms of noncardiogenic pulmonary edema or
adult respiratory distress syndrome. In addition to thrombocytopenia and
hemoconcentration, other abnormalities have included leukocytosis, increased
band forms on differential, hypoalbuminemia, and lactic acidosis. Efforts are
ongoing both to identify clinical and laboratory features that distinguish HPS
from other infections with similar manifestations and to develop improved
diagnostic tests for rapid early diagnosis (7). Serologic tests in combination
with PCR and IHC should be used in confirming the diagnosis of acute
hantavirus infection.
     The prognosis is poorest in case-patients with shock and with severe
lactic acidosis. Anecdotal reports suggest that periods of severe hypoxia or
hypotension before stabilization in the intensive-care setting adversely
affect survival. Supportive measures are the basis for therapy; severe hypoxia
and overhydration should be avoided or prevented. Pressors or cardiotonic
drugs should be employed to maintain perfusion without excessive fluid
administration. Testing for alternative diagnoses should be done, and
appropriate treatment to cover infections mimicking HPS should be administered
     Observed racial/ethnic differences and the age distribution of cases may
reflect differences in activities that facilitate exposure to the rodent
reservoir for this virus, usually in rural settings. For example, persons
participating in agricultural activities near habitats of infected rodents may
be at greater risk for infection.
     Previously isolated hantaviruses have demonstrated in vitro sensitivity
to the investigational antiviral drug ribavirin. Based on this finding and
evidence of activity of intravenous ribavirin therapy against Hantaan virus
infection (8), intravenous ribavirin has been made available as an
investigational agent through a CDC-sponsored open label protocol for patients
with HPS. Whether treatment with ribavirin has had any beneficial effect on
the course of HPS is unknown. Further plans for study of ribavirin are under
consideration by a collaborative working group sponsored by the National
Institute for Allergy and Infectious Diseases, National Institutes of Health.
     Physicians who want to enroll patients should contact the CDC Ribavirin
Officer of the Day (telephone {404} 639-1510 weekdays or {404} 639-2888
evenings and weekends). Alternatively, physicians in the four-corners area may
contact the enrolling coinvestigator in their state. Physicians must report
patients meeting the screening criteria for HPS and submit appropriate
clinical samples to state health departments to confirm the diagnosis.


1. CDC. Outbreak of acute illness -- southwestern United States, 1993. MMWR

2. CDC. Update: outbreak of hantavirus infection -- southwestern United
States, 1993. MMWR 1993;42:441-3.

3. CDC. Update: outbreak of hantavirus infection -- southwestern United
States, 1993. MMWR 1993;42:477-9.

4. CDC. Progress in the development of hantavirus diagnostic assays -- United
States. MMWR 1993;42:770-1.

5. World Health Organization. Haemorrhagic fever with renal syndrome:
memorandum from a WHO meeting. Bull WHO 1983;61:269-75.

6. Kim D. Clinical analysis of 111 fatal cases of epidemic hemorrhagic fever.
Amer J Med 1965;39:218-20.

7. Tsai TF. Hemorrhagic fever with renal syndrome: clinical aspects. Lab Anim
Sci 1987;37:419-27.

8. Huggins JW, Hsiang CM, Cosgriff TM, et al. Prospective, double-blind,
concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy
of hemorrhagic fever with renal syndrome. J Infect Dis 1991;164:1119-27.

Dr. Ruben Donis                                                 
Dept. of Veterinary and Biomedical Sciences      
202 VBS                                                                    
University of Nebraska,                                                  
Lincoln, NE 68583-0905                                   
Phone: 402-472-6063                                     
FAX to 402-472-9690                                     

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