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 <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).

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 31 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 (www.cdc.gov/hantavirus).

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.