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Hantavirus pulmonary syndrome, United States, 1993-2009.

In May 1993, a series of cases of an acute illness associated with rapid development of respiratory failure were noted in the Four Corners region of the United States. Surveillance initiated in the area identified 24 cases of compatible illness that had occurred in New Mexico, Arizona, Colorado, and Utah since December 1992; the case-fatality rate was 50%. Preliminary serologic data for case-patients suggested infection with an unknown virus in the family Bunyaviridae and genus Hantavirus (1). This observation was surprising, given that hantaviruses had not been associated with any human diseases in North or South America at that time, and the only known clinical syndrome associated with hantaviruses, hemorrhagic fever with renal syndrome, did not have a predominantly respiratory involvement. However, nucleic acid sequence from a novel hantavirus was rapidly identified in tissue samples of multiple patients, and similarly from deer mice (Peromyscus maniculatus) trapped near the residence of cases, implicating a novel hantavirus as the cause of the disease (2). Additional serologic and molecular data from case-patients and results of trapping studies in the Four Corners region supported these conclusions (3,4).

Since its identification in 1993, hantavirus cardiopulmonary syndrome (HPS) and numerous New World hantavirus species have been described across a wide geographic range of North, Central, and South America (5). In the United States, most HPS cases are likely caused by Sin Nombre virus (6), the virus responsible for the initially identified HPS cases. Other HPS-associated viruses include New York and Monongahela viruses (mice of the genus Peromyscus are reservoirs), associated with HPS in the eastern United States (7-9), Bayou virus, found in the southeastern United States (Oligoryzomys palustris rice rats are reservoirs) (10-12), and Black Creek Canal virus (Sigmodon hispidus cotton rats are reservoirs), which was associated with 1 case of HPS in Florida (13,14).

Hantaviruses are believed to be transmitted by inhalation of rodent secretions and excreta, or possibly through direct contact with an infected rodent. Although clusters of human cases have been identified in the United States, no evidence exists of human-to-human or nosocomial transmission of hantaviruses in North America (15,16) Infrequent but clear instances of human-to-human transmission of Andes virus in Argentina and Chile have been documented (17-19).

The incubation period of HPS is believed to range from 1 to 5 weeks (20). HPS typically begins with a prodromal syndrome, and common symptoms include fever, myalgias, headache, and nausea/vomiting (21,22). After the prodrome, the hallmark of HPS is rapid onset of a severe pulmonary illness, often involving hypoxia, pulmonary edema, and myocardial depression (22-25). Death typically occurs rapidly after hospitalization (21) and often as the result of cardiogenic shock (25). In this report, we evaluate the epidemiologic and clinical characteristics of all known laboratory-confirmed cases of HPS in the United States during 1993-2009.

Materials and Methods

After identification of HPS in 1993, the Viral Special Pathogens Branch at the Centers for Disease Control and Prevention (Atlanta, GA, USA) developed and maintained a registry of confirmed HPS cases in the United States. A clinically confirmed case of HPS is defined as 1) a febrile illness characterized by bilateral diffuse interstitial edema that may radiographically resemble acute respiratory distress syndrome (ARDS), with respiratory compromise requiring supplemental oxygen developing [less than or equal to] 72 hours after hospitalization, and occurring in a previously healthy person, or an unexplained respiratory illness resulting in death, with an autopsy examination demonstrating pulmonary noncardiogenic edema without an identifiable cause; and 2) laboratory evidence of hantavirus infection by detection of hantavirus-specific immunoglobulin M or increasing titers of hantavirus-specific immunoglobulin G, detection of hantavirus-specific RNA sequence by PCR in clinical specimens, or detection of hantavirus antigen by immunohistochemical analysis (26).

Information for the registry, including demographic, geographic, outcome, and (if possible) basic clinical data, is obtained by using a case-report form. Although many laboratory diagnoses are not made at the Centers for Disease Control and Prevention, case-report forms were reviewed to verify hantavirus laboratory diagnostics. Additionally, since 1995, HPS has been a nationally reportable disease in the United States; thus, parallel surveillance for HPS is conducted through the National Notifiable Diseases Surveillance System (26). To ensure completeness of the registry, we attempted to acquire case-report forms for all HPS cases reported to the National Notifiable Diseases Surveillance System. For all cases, we attempted to acquire qualitative data (yes or no) regarding certain clinical signs and symptoms, and laboratory values (fever, thrombocytopenia, increased hematocrit, increased creatinine levels, leukocyte counts, chest radiograph showing unexplained bilateral infiltrates or suggestive of ARDS, requirement of supplemental oxygen, and whether the patient was intubated). For a small number of patients for whom incomplete qualitative data were available, but for whom laboratory values were available, we assigned qualitative values on the basis of described clinical cutoff values (24).


Number of HPS Cases and Demographics

During 1993-2009, we identified 510 laboratory-confirmed cases of HPS in the United States; 31 cases that occurred before 1993 had been retrospectively identified (27-29). HPS is primarily a disease of adults; most cases were in persons 20-50 years of age (mean age 38 years) (Table 1); 7% of cases occurred in children [less than or equal to] 16 years of age. Among HPS cases, 64% occurred in male patients. Most cases occurred in white (78%) or American Indian/ Native American (20%) persons, and 21% of case-patients reported their ethnicity as Hispanic.

Temporal and Geographic Characteristics of Cases

The largest annual number of HPS cases registered (n = 48) occurred in 1993 during the initial investigation. Since that time, annual case counts have varied considerably from year to year (Figure 1); counts have ranged from 11 to 45 cases/year (mean 30 cases/year). No significant trend was observed in increasing or decreasing case counts from after 1993 (p = 0.400, by general linear model). From a population perspective, HPS is rare in the United States; the annual incidence has ranged from 0.04 to 0.19 cases/million persons on the basis of a US Census Bureau estimate of the US population on July 1 of each respective year (www. HPS displayed a strong seasonal distribution; the maximum number of cases occurred in May, June, and July, and the minimum occurred in December, January, and February (Figure 2).

We identified the probable geographic location of rodent exposure (at least to the state level) for 471 cases. Probable exposures occurred in 30 US states; most cases occurred in the western United States To examine trends in HPS occurrence, we grouped states into 4 regions on the basis of geography and hantavirus species present: Southwest (Arizona, California, Colorado, New Mexico, Nevada, Utah); Northwest (Idaho, Montana, Oregon, Washington, and Wyoming); Midwest (Illinois, Indiana, Iowa, Kansas, Louisiana, Minnesota, North Dakota, Nebraska, Oklahoma, South Dakota, Texas, and Wisconsin); and East (Florida, Maryland, North Carolina, New York, Pennsylvania, Virginia, and West Virginia) (Table 2).


We assessed temporal trends in HPS for each of these regions (with the exception of the East because there were only 12 cases) (Figure 3, panel A). Overall case counts were relatively stable across the 17-year period in the Northwest (mean [+ or -] SD 5.9 [+ or -] 2.1 cases/year) and Midwest (mean [+ or -] SD 4.9 [+ or -] 2.8 cases/year). In contrast, case counts in the Southwest tended to fluctuate to a higher degree (mean [+ or -] SD 16.1 [+ or -] 9.8 cases/year). Overall variance in annual case counts was significantly higher in the Southwest than in the Northwest (F-statistic p<0.001) or the Midwest (F-statistic p<0.001). When combined with annual HPS case counts for the entire United States, peaks in HPS case counts in the Southwest corresponded directly with peaks for the entire country. This finding, in conjunction with stable case counts in the Northwest and Midwest, demonstrates that annual variability in HPS in the United States is primarily driven by fluctuations in number of HPS cases in the southwestern United States.

We assessed seasonality of HPS by geographic region (Figure 3, panel B). Similar to aggregate trends for the entire United States, HPS displayed a clear seasonal trend in the Midwest, Northwest, and Southwest. In contrast to the Midwest and Northwest, in which the highest proportion of cases occurred in May and decreased in the summer months, HPS cases peaked 2 months later (in July) in the Southwest.

Clinical Characteristics and Case-Fatality Rates

The overall case-fatality rate was 35%. Deaths varied noticeably from year to year (Figure 1); however, no temporal trend in deaths was observed (p = 0.307, by Cochran-Armitage trend test). Additionally, case-fatality rates were similar across demographic characteristics; no differences in case-fatality rates were noted for age groups, or by sex, race, or ethnicity (Table 1). Similarly, from a geographic standpoint, case-fatality rates did not differ between geographic regions (p = 0.773, by x2 test) (Table 2). The mean time from onset of symptoms to death was 6.4 days (median 5 days).


As described (21,22), HPS case-patients had a severe respiratory illness (most persons had chest radiographs showing unexplained bilateral infiltrates or suggestive of ARDS, and required supplemental oxygen) and thrombocytopenia (Table 3). Other common findings included fever >101[degrees]F and increased hematocrits, creatinine levels, and leukocyte counts. Increased hematocrits, creatinine levels, and leukocyte counts; requirement for supplemental oxygen; and necessity for intubation were all associated with death of a patient. Additionally, although nearly all HPS case-patients had thrombocytopenia, platelet counts (lowest measured value during illness) were significantly lower among patients who died than among patients who survived (median platelet count in persons who died 33,500 cells/mL vs. median in persons who survived 51,500 cells/mL; p<0.001 by Wilcoxon rank-sum test), for 278 persons for whom data were available.


In 1996, Khan et al. published a description of the first 100 cases of HPS identified in the United States (21). Some aspects of the epidemiology of HPS in the United States have since been discussed in the peer-reviewed literature. However, no studies have provided a comprehensive evaluation of the epidemiology of HPS in the United States. By maintaining a registry and obtaining information in standardized manner, we were able to evaluate the epidemiologic characteristics of HPS in >500 cases over 17 years of data collection. Although HPS is a nationally reportable disease in the United States, maintenance of our registry has enabled us to obtain more detailed and standardized information on HPS than otherwise possible through other national surveillance mechanisms.

HPS is often characterized as an emerging infectious disease. The discovery of a novel clinical syndrome and associated virus might constitute emergence from a public health perspective. However, several lines of evidence indicate the epidemiology of HPS constitutes that of an endemic or sporadic disease. First, although overall numbers clearly vary from year to year, our data demonstrate continual occurrence of HPS since 1993 without a trend toward an increasing or decreasing number of cases. Additionally, HPS cases before 1993 in the United States (27-29), possibly as far back as 1959 (30), and rodents infected with hantaviruses (6,31) have been identified retrospectively. Similarly, the evolutionary history of hantavirus species in the United States appears to have been closely linked with that of their primary rodent host species and to persist over time among these host species (32), consistent with the notion that hantaviruses are not newly emergent in the United States. Finally, HPS and wide distribution of associated hantavirus species across most of the New World do not support recent emergence of a novel pathogenic virus.


The distribution of rodent reservoirs of pathogenic hantaviruses covers the entire mainland United States (33). During 1993-2009, HPS cases were associated with probable rodent exposures in 30 US states. However, in contrast to the wide distribution of rodent reservoirs, HPS is clearly more common in the western United States; only a small proportion (<3%) of cases are associated with exposures in the eastern United States. Although the virus species responsible for HPS is not typically assessed in diagnostic testing, it is likely that most cases of HPS in the United States are caused by Sin Nombre virus because of the western distribution of the reservoir host of this virus, the deer mouse, in comparison with reservoir hosts of other pathogenic hantavirus species, which are found primarily in the central and eastern United States.

Our examination of the epidemiology of HPS on the basis of geographic region has obvious limitations. For instance, state boundaries do not necessarily represent boundaries of ecosystems or distribution of reservoirs of different pathogenic hantavirus species. We noted major conclusions from this approach. First, we examined the hypothesis that hantavirus species may differ in their pathogenic potential. Although the overall number of HPS cases in the eastern United States was small (n = 12) and infections were potentially caused by multiple hantavirus species in the East and Midwest regions, our data do not suggest a difference in pathogenicity between hantavirus species endemic to the United States. Furthermore, systematic viral genotyping is needed to conclusively address the hypothesis that hantaviruses in the United States may differ in their pathogenic potential in humans. Second, annual numbers of HPS cases in the Northwest and Midwest were relatively consistent, whereas annual HPS case counts in the Southwest were significantly more variable, and peak years of HPS in the Southwest corresponded with high overall case-count years in the United States. These findings suggest greater potential for increases in HPS in the southwestern United States than in other regions of the country.

The HPS case-fatality rate in the United States was 35% during 1993-2009. No antiviral treatment is available for HPS, and we did not observe a trend in the case-fatality rate for HPS over time. No demographic factors were associated with deaths caused by HPS outcomes. The apparent rarity of HPS in younger persons is notable. However, similar case-fatality rates for HPS across age groups and results of case studies of HPS in children (34,35) indicate that severity of HPS is likely similar in adults and younger persons. We have limited data about the relationship between concurrent conditions and HPS outcome. However, similar case-fatality rates for HPS across age groups (particularly that the case-fatality rate remains similar in older persons) does not support the notion that underlying health conditions are the primary determinant of disease outcome. The actual level of virus exposure at the time of infection may also be a major determinant of disease severity. A recent study reported smoking as a significant risk factor for Puumala virus (genera Hantavirus) infection in Finland (36). We believe this finding warrants a study in the United States to determine whether smoking might increase the likelihood of development or the overall severity of HPS.

HPS is characterized by the rapid onset of a severe respiratory disease. Virtually all patients with laboratory-confirmed HPS in our registry for whom clinical data were available required supplemental oxygen (96%) and had a chest radiograph showing unexplained bilateral infiltrates or suggestive of ARDS (96%). Although thrombocytopenia is a common symptom of HPS, lowest platelet counts were lower in fatal HPS cases. Similarly, increased hematocrits, creatinine levels, and leukocyte counts occurred in a higher proportion in HPS case-patients who died. Although similar clinical findings have been reported for smaller case studies (21-24,37), our data demonstrate the role of these factors in predicting the outcome of HPS. We also noted similar associations between outcomes in patients who died and the requirement for supplementary oxygen and intubation. These 2 variables represent clinical procedures and thus would be expected to be more common in severe HPS cases. Although we do not have any data about the proportion of case-patients who received extracorpeal membrane oxygenation, some studies suggest that this procedure might improve the prognosis for severe HPS (38,39).

Because of the centralized and passive nature of data collection, our methods have some limitations. Data collection was limited to a short, standardized case investigation form; thus, we were unable to collect detailed clinical information and verify clinical information (such as radiographic findings). In addition, clinical aspects of our surveillance data were limited to a small number of specific criteria. Other investigators have reported signs, symptoms, radiographic characteristics, and pathologic features of HPS in greater detail (21-24,40). Studies have also demonstrated cardiopulmonary depression, and resulting cardiogenic shock, as a major pathologic aspect of HPS, particularly in patients who died (25). In addition, because of the passive nature of HPS surveillance, we may have missed some HPS cases in the United States. However, through continued outreach with state health departments and the ability to cross-check HPS cases with those reported through the National Notifiable Diseases Surveillance System, we have attempted to minimize the number of HPS cases that might go unregistered. However, frequently updated HPS case counts and geographic data are available (

Despite its rarity, HPS continues to occur in the United States. With a case-fatality rate of 35%, HPS remains 1 of the most severe infectious diseases endemic to the United States.


We thank state health and local health department personnel for assisting in collection of data in the HPS registry; coordinators, laboratorians, epidemiologists, and Epidemic Intelligence Service Officers at the Viral Special Pathogens Branch, Centers for Disease Control and Prevention, for helping to maintain this registry since 1993; Arie Manangan for assisting in geographic classification of cases and development of map-based graphics; Timothy Fliestra for statistical assistance; James N. Mills for helpful discussions; and Stuart T. Nichol for support.

This study was supported by the Centers for Disease Control and Prevention.

Dr MacNeil is an epidemiologist with Viral Special Pathogens Branch, Centers for Disease Control and Prevention. His research interests include the epidemiology of emerging and zoonotic viral diseases.


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Address for correspondence: Adam MacNeil, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop G14, Atlanta, GA 30333, USA; email:

Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (A. MacNeil, T.G. Ksiazek, P.E. Rollin); and University of Texas Medical Branch, Galveston, Texas, USA (T.G. Ksiazek)

DOI: 10.3201/eid1707.101306

CME Questions

1. You are seeing a 50-year-old woman with a 2-day history of headache, myalgia, and fever to 39.5[degrees]C. While your differential diagnosis remains broad for this patient, what should you consider regarding the epidemiology of infection with hantavirus?

A. The majority of hantavirus pulmonary syndrome (HPS) cases in the United States are caused by the Sin Nombre virus

B. Hantavirus is primarily transmitted via droplet secretions from human to human

C. The incubation period of HPS is usually less than 48 hours

D. Human fecal-oral transmission is the principal source of hantavirus

2. The prevalence of HPS is highest and most variable over time in which region of the United States?

A. Eastern region

B. Southern region

C. Midwest region

D. Southwest region

3. The patient from Question #1 develops HPS. What does the current study suggest regarding her prognosis?

A. The case-fatality rate was 35%

B. Older age predicted a higher fatality rate

C. Patients in the Southwest were most likely to die from HPS

D. The mean time from symptom onset to death was 3.5 weeks

4. Based on the results of the current study, which of the following laboratory findings is associated with the most significant risk for mortality due to HPS?

A. Any thrombocytopenia

B. Reduced hematocrit

C. Elevated serum creatinine

D. Reduced serum albumin
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Author affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Table 1. Demographic characteristics of HPS case-patients,
United States, 1993-2009 *

                                No. (%)         Outcome
Characteristic                   cases     CFR, %   p value ([dagger])

Age, y, n = 508                                           0.992
    <10                          5 (1)       20
    10-19                       56 (11)      36
    20-29                       116 (23)     36
    30-39                       105 (21)     37
    40-49                       101 (20)     33
    50-59                       69 (14)      35
    60-69                        48 (9)      33
    >70                          8 (2)       38

Sex, n = 510                                              0.180
    M                           324 (64)     33
    F                           186 (36)     39

Race, n = 492                                             0.284
    White                       383 (78)     33
    American Indian or          96 (20)      43
    Native American
    Black                        8 (2)       38
    Asian or Pacific Islander    5 (1)       60

Ethnicity, n = 393                                        0.637
    Non-Hispanic                312 (79)     37
    Hispanic                    81 (21)      40

* HPS, hantavirus pulmonary syndrome; CFR, case-fatality rate.

([dagger]) [Chi sqaure] p value for testing the difference in
proportion of HPS case-patients who died between categories for
each demographic characteristic.

Table 2. HPS case-patients by geographic region, United
States, 1993-2009 *

Region                    States ([dagger])

Southwest    Arizona, California, Colorado, New Mexico,
                            Nevada, Utah
Northwest    Idaho, Montana, Oregon, Washington, Wyoming

Midwest      Illinois, Indiana, Iowa, Kansas, Louisiana,
            Minnesota, North Dakota, Nebraska, Oklahoma,
                   South Dakota, Texas, Wisconsin

East        Florida, Maryland, North Carolina, New York,
                Pennsylvania, Virginia, West Virginia

                    Hantavirus species present in
Region                         region

Southwest                 Sin Nombre virus

Northwest                 Sin Nombre virus

Midwest             Sin Nombre virus, Bayou virus

East                 New York virus, Monongahela
                   virus, Black Creek Canal virus

                     No. case-patients who died/
                       total no. case-patients
Region               (CFR, %) ([double dagger])

Southwest                    92/273 (34)

Northwest                    35/101 (35)

Midwest                      33/84 (39)

East                          5/12 (43)

* HPS, hantavirus pulmonary syndrome; CFR, case-fatality rate.

([dagger]) Only states with >1 probable rodent exposure-related
HPS case are shown.

([double dagger]) There were no significant differences in
case-fatality rates between geographic regions (p = 0.773 by
[Chi square] test).

Table 3. Clinical characteristics of HPS case-patients,
United States, 1993-2009 *

                                                  No. patients reporting
                                                  no. patients for whom
                                                  data were available
                                                      for that
                                                    characteristic (%)

Characteristic                                           All

Fever                                                 356/397 (90)
Thrombocytopenia ([double dagger])                    405/418 (97)
Increased hematocrit ([double dagger])                261/389 (67)
Increased creatinine level ([double dagger])          120/286 (42)
Increased leukocyte count ([double dagger])           169/234 (72)
Chest radiograph showing unexplained bilateral        390/406 (96)
infiltrates or suggestive of ARDS
Need for supplemental oxygen                          390/405 (96)
Intubation of patient                                 265/430 (62)

                                                  No. patients reporting
                                                  no. patients for whom
                                                  data were available
                                                       for that
                                                   characteristic (%)

Characteristic                                             Died

Fever                                                 116/132 (88)
Thrombocytopenia ([double dagger])                    131/134 (98)
Increased hematocrit ([double dagger])                103/130 (79)
Increased creatinine level ([double dagger])           54/93 (58)
Increased leukocyte count ([double dagger])            72/83 (87)
Chest radiograph showing unexplained bilateral        135/141 (96)
infiltrates or suggestive of ARDS
Need for supplemental oxygen                          134/135 (99)
Intubation of patient                                 129/139 (93)

                                                  No. patients reporting
                                                  no. patients for whom
                                                  data were available
                                                      for that
                                                    characteristic (%)

Characteristic                                       Survived

Fever                                             239/264 (91)
Thrombocytopenia ([double dagger])                273/283 (96)
Increased hematocrit ([double dagger])            157/258 (61)
Increased creatinine level ([double dagger])      66/193 (34)
Increased leukocyte count ([double dagger])       96/150 (64)
Chest radiograph showing unexplained bilateral          0.812
infiltrates or suggestive of ARDS
Need for supplemental oxygen
Intubation of patient

Characteristic                                    p value ([dagger])

Fever                                                0.414
Thrombocytopenia ([double dagger])                   0.477
Increased hematocrit ([double dagger])              <0.001
Increased creatinine level ([double dagger])        <0.001
Increased leukocyte count ([double dagger])         <0.001
Chest radiograph showing unexplained bilateral
infiltrates or suggestive of ARDS
Need for supplemental oxygen
Intubation of patient

* HPS, hantavirus pulmonary syndrome; ARDS, acute respiratory
distress syndrome.

(dagger]) By [Chi square] test for difference in the proportion
of HPS case-patients with a clinical characteristic who died and
those who survived.

([double dagger]) Based on qualitative data (yes or no) regarding
clinical characteristic from case investigation form. For a small
number of case-patients for whom qualitativ incomplete, but for
whom laboratory values were available, qualitative values were
assigned on the basis of described clinical cutoff values (24).
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Title Annotation:RESEARCH
Author:MacNeil, Adam; Ksiazek, Thomas G.; Rollin, Pierre E.
Publication:Emerging Infectious Diseases
Article Type:Report
Geographic Code:1USA
Date:Jul 1, 2011
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