Technical FAQ

1. There are no known re-infections with the homologous hantavirus; virus neutralizing antibodies are formed. Closely related hantaviruses, such as Seoul and Hantaan viruses, seem to cross-protect against re-infection in experimental animals, and one might expect cross-protection among the hantaviruses derived from sigmodontine rodents.
   • Dr. C. J. Peters, Special Pathogens Branch, CDC.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)
2. For discussion and references, see:
   • Peters CJ. Hantavirus pulmonary syndrome in the Americas. In: Scheld WM, Craig WA, Hughes JM, editors. Emerging Infections II. Washington, D.C.: ASM Press; 1998. p. 17-64.
   • Note: It would be interesting to have observations from areas of the Balkans where Dobrava virus and Puumala virus co-circulate; these two viruses are more distantly related and thus cross-protection might not be seen.

1. Most disease seen in the United States is caused by Sin Nombre virus. The other SNV-related viruses in the United States (New York and Monongahela) seem to cause a very similar disease. Two other viruses in North America, Bayou and Black Creek Canal, cause HPS that fits the surveillance case definition, and the cases were recognized by clinicians as HPS. The few cases that have been evaluatedseem to have more renal failure and higher elevations of serum creatine phosphokinase than the typical SNV infection. In South America, all the recognized cases have been basically HPS, but there are some clusters that seem to have more renal failure, petechiae and bleeding manifestations, and/or involvement of children. In addition, some have had facial flushing, which is not seen with HPS but is seen with hemorrhagic fever with renal syndrome. It must be borne in mind that cases are usually recognized by HPS surveillance or by the dramatic manifestations of HPS, so there is a strong ascertainment bias. Until there is at least a common protocol for evaluating cases in South America, the different manifestations reported by various groups need to be interpreted cautiously.
   • Dr. C. J. Peters, Special Pathogens Branch, CDC.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)
2. For a summary and references to South American publications, see:
   • Kitsutani PT. Acute Non-HPS Sin Nombre Hantavirus Infection in the U.S. Emerg Infect Dis 1999; (in press).

If HPS occurs mostly in rural areas, why are the greatest number of cases affecting white males—up to 76%?

1. That is an interesting question and can best be answered by looking at the way we keep HPS records at CDC. As you noted, most (70%) of U.S. cases occur in rural areas. The most recent statistics show that 61% of cases are male and 75% are white, but only 45% of the cases are white males. While these data seem to show an increased risk for white males, this distribution of cases requires further clarification.
2. In addition to gender, CDC classifies confirmed cases of HPS by race. The U.S. population west of the Mississippi River, where the majority of HPS cases has occurred, is predominantly white, with the following breakdown: white (77%), Asian (7%), black (5%), American Indian (2%), and other (10%).
3. We also record Hispanic ethnicity. Individuals of Hispanic origin make up a large portion of the population of the Southwest, where Sin Nombre virus is endemic. To date, 10% of cases are Hispanic, 9% are white Hispanic, and 5.5% are white Hispanic males.
4. Clearly, there is a statistically significant increased risk associated with being male. Males have a 1.5-fold higher risk for HPS than females. This small increased risk is possibly due to occupational exposure.
   • Dr. James Olson, Special Pathogens Branch, CDC.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)

1. Two or more factors may explain the relative scarcity of HPS cases among children. The first is that children may be less likely to get infected because they do not perform the activities that would put them at risk for infection, such as cleaning in enclosed spaces. Even if they perform these types of activities or have their noses closer to the ground, their total lung exposure to virus may be less than an adult’s; despite the fact that children breathe faster than adults, their minute volume is less. Alternatively, they may just be less likely to get infected due to nonspecific immune mechanisms. The second possibility is that children are as likely to get infected as adults, but less likely to develop HPS, the severest manifestation of infection.
2. There are 20-40 cases of Hantavirus Pulmonary Syndrome (HPS) reported each year in the United States. During May 16th-November 25, 2009, there were reports from the CDC of five pediatric cases of Hantavirus Pulmonary Syndrome (HPS) among children aged 6-14 years from Arizona, California, Colorado, and Washington. All five cases from these states had exposure to rodents and three of the children were <10 years of age. The ages of the children were 6, 9, 13 and 14. Cases of HPS aged <17 years make up fewer than 7% of those cases. Those cases in children < 10 years of age are exceedingly rare. Clinical finding of the five children revealed thrombocytopenia, elevated white blood cell (WBC) count, and pulmonary infiltrates. Three of the five children had elevated hematocrit. Rodents and areas of infestations should be avoided and preventative measures such as rodent control should be encouraged by public health officials.
3. The total picture of HPS infection among children is further complicated by studies in South America. There appear to be proportionately more children infected, more children with asymptomatic or mild infections, and children with hemorrhagic manifestations after infections. Some data suggest Hantavirus transmission via breast-milk. Further research will help answer this question and provide us a clue to the immunology that underlines infection and disease development.
   • Levy, C., Gains, K., Crocco, V., Brown, J., Lawaczeck, E., Ray, W. et al. Hantavirus pulmonary syndrome in five pediatric patients, four states, 2009. Morbidity and Mortality Weekly Report 2009; 58(50):1409-1412.
4. For further information, see:
   • Pini NC, Resa A, Laime GDJ, Lecot G, Ksiazek TG, Levis S, et al. Hantavirus Infection in Children in Argentina. Emerg Infect Dis 1998;4(1):85-7.

1. For those who frequently handle or are frequently exposed to rodents in rural areas (such as mammalogists and pest control workers), CDC recommends wearing either a half-mask air-purifying (or negative-pressure) respirator or a powered air-purifying respirator (PAPR) with N-100 filters.
2. CDC does not recommend routine use of respirators by farmers and homeowners in rural areas. CDC guidelines (MMWR 1993; 42, RR-11) address specific risk-reduction measures for rural residents (rodentproofing, environmental management, and trapping) and precautions to be taken during activities that may pose increased risk of hantavirus infection (cleanup of rodent infested areas). Cleanup of very heavy rodent infestations or of homes associated with known cases of HPS are special instances for which we do recommend respiratory protection, and these tasks are best left to pest control or public health professionals. There is no evidence that farmers operating farm machinery in open fields (even though rodents may be crushed in the machinery) are at increased risk. Under these conditions, the natural circulation of air and virucidal properties of natural UV light make inhalation of infectious aerosols less likely. The possibility of human exposure is greater in indoor closed spaces, such as barns and sheds, that may be infested with rodents. It is important that outbuildings be rodent-proofed to the greatest extent possible. When effective rodentproofing is not possible, snap traps (and, if necessary, rodenticides) should be used continuously, and recommended precautions (concerning airing out and cleanup of infestations) should be followed when entering such buildings after periods of non-use.
   • Dr. James Mills, Special Pathogens Branch, CDC.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)

1. Ultraviolet (UV) light is a very effective way to kill viruses under certain circumstances. Sunlight produces high intensities of UV and finely dispersed aerosols of the kind that infect humans are readily penetrated by the light. Virus inactivation has never been measured under those circumstances, but it must be very rapid.
2. However, the UV light must penetrate to the virus particle. One reason why the interior of structures may be dangerous is that the reflected white light from outside will not contain sufficient UV. Similarly, solids or liquids provide a challenge to UV penetration.
3. We also don’t recommend UV lights for disinfection because of the considerations above, the difficulties in assuring continued strength of the radiation at the site for disinfection, and possible health effects.
   • Dr. C. J. Peters, Special Pathogens Branch, CDC.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)

1. Studies on Hantaan virus have shown that the virus infectivity cannot be recovered after 2 days upon desiccation. Studies with Sin Nombre virus are pending.
2. Dr. C.J. Peters, Special Pathogens Branch, CDC.
   Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)
3. Thrombocytopenia, left shift of the myeloid series, and appearance of immunoblasts are consistent findings in almost all HPS patients. The total white cell count is quite variable, ranging from as low as 2,800 during prodrome, to over 100,000 /mm-3 in some severe HPS cases. The elevation of the WBC is not an accurate indicator of severity. The hematocrit is significantly elevated (>50 in men, >48 in women) in only approximately 50% of cases, and is a function of preceding existence of anemia, as well as severity of the capillary leak syndrome.
   • Dr. Frederick Koster, University of New Mexico, School of Medicine.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)

1. A search for correlates to severity of HPS has not revealed any relationships to gender or ethnicity. Individuals under the age of 15 years appear to have milder disease. Preliminary data using HLA typing have suggested that individuals bearing one particular B-locus allele, B*35, appear to be at higher risk for severe disease than all other B alleles. No associations have yet been found for alleles in other HLA genes. Other than supporting the notion that T cells are critically involved in mediating the lung and/or cardiac injury in HPS, the significance of these immunogenetic data is not yet known.
   • Dr. Frederick Koster, University of New Mexico, School of Medicine.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)

1. The simple answer to this question is that there have been no studies of any cytokine blocking agents in HPS, so they should not be tried empirically. Such agents should only be used on an experimental protocol. However, the simple answer begs the question of whether an anti-cytokine protocol should be implemented.
2. There is evidence that certain cytokines are involved in the pathogenesis of HPS. Tumor necrosis factor (TNF) alpha or beta and interleukin 2 (IL-2) seem especially important. When direct measurements of these cytokines were made in acutely ill HPS patients, the serum levels were found to be not statistically different from those of normal volunteers or from critically ill control patients. However, evaluation of soluble receptors for TNF and IL-2 demonstrated that they were strikingly elevated in HPS patients, as compared with controls. Additionally, the levels of these soluble receptors were highest in severely ill patients, as compared with patients who had mild HPS. In patients who survived the acute illness, the levels of soluble cytokine receptors for TNF and IL-2 decreased during the convalescent period.
3. Administration of TNF or IL-2 to animals causes syndromes that are quite similar to HPS. Both cytokines can cause myocardial depression, as is seen in HPS, via activation of intracellular nitric oxide in cardiac myocytes. IL-2 causes pulmonary edema and hypotension when it is given to humans as cancer chemotherapy. A plausible explanation for the cytokine findings in HPS is that TNF alpha or beta and IL-2 levels may have been strikingly increased in the period leading up to the acute illness, or that a surge of one or another or all of these cytokines led to rapid onset of pulmonary edema and shock. By the time of hospital admission and blood collection, the cytokine levels had either decreased to normal or were masked by binding to high levels of circulating soluble receptors. However, alternative explanations for the cytokine findings should not be ignored. For example, both forms of soluble TNF receptor (55 kd and 75 kd) and the soluble IL-2 receptor can be released from activated mononuclear cells, even in the absence of binding of the respective cytokine. Presumably, this release of soluble receptors represents a mechanism of slowing or modulating inflammation.
4. So, a more circumspect answer to the question may be that there is as yet insufficient evidence to attempt a therapeutic trial that hinges on blocking the actions of one of these cytokines. There are currently no agents available for blocking the action of IL-2. However, several anti-TNF agents have been developed, including a humanized murine monoclonal antibody to TNF alpha and a fusion protein of recombinant 75 kd receptor and the Fc portion of human IgG. These agents have failed to prove useful in sepsis resulting from microorganisms other than hantaviruses. Other agents that are potentially useful include the anti-inflammatory cytokines IL-10 and TGF-beta. Before trials with anti-cytokine agents are designed, a more definite association must be made between increased cytokine levels and the development of shock and pulmonary edema in patients with HPS. This will probably require earlier evaluation of cytokine profiles in patients who have not yet developed pulmonary edema.
5. As to the use of antibiotics in HPS, it is clear that no antibacterial is likely to be an effective therapy. Nevertheless, patients should be placed on broad spectrum antibiotics until the diagnosis of HPS is well established, since bacterial shock is far more common than hantaviral shock. The antiviral agent ribavirin is effective in improving survival and shortening the length of illness in another hantaviral illness, hemorrhagic fever with renal syndrome caused by Hantaan virus. An open label trial of ribavirin in 1993-94 did not demonstrate the drug to be effective in HPS. However, most patients who received the drug were critically ill at the time, and it is difficult to postulate that inhibition of the virus reverses shock. An NIH-sponsored, double-blinded, placebo-controlled trial of ribavirin administered earlier in the syndrome is currently under way, but ribavirin should not be regarded as the standard of care.
   • Steven Q. Simposon, University of Kansas Medical Center, School of Medicine.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)

1. The cellular receptor for pathogenic hantaviruses has been recently identified as the b3 integrins. The b3 integrins have been characterized as the receptors for many other viruses, such as adenovirus, foot-and-mouth disease virus, coxsackievirus, and papillomavirus. Antibodies to the b3 integrins can partially inhibit hantavirus entry into cells in tissue culture experiments. Based on these results, a therapeutic potential to anti-b3 antibodies has been suggested, but it is too early in the hantavirus studies to know their real application. More information is needed on the cause of the vascular leakage and on hantavirus pathogenesis in general. In addition, the above studies are hampered by the lack of any animal model for diseases caused by the hantaviruses.
   • Dr. Christina Spiropoulou, Special Pathogens Branch, CDC.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)
2. For more information on receptor studies, see:
   • Gavrilovskaya IN, Brown EJ, Ginsberg MH, and Mackow ER. Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by b3 integrins. J Virol 1999; 73:3951-59.
   • Gavrilovskaya IN, Shepley M, Shaw R, Ginsberg MH, and Mackow ER. B3 integrins mediate the cellular entry of hantaviruses that cause respiratory failure. Proc Natl Acad Sci USA 1998;95:7074-79.
3. Additional information on these outbreaks can be found in:
   • Chapparo J, Vega J, Terry W, Barra B, Meyer R, Peters CJ, et al. Assessment of person-to-person transmission of hantavirus pulmonary syndrome in a Chilean hospital setting. J Hosp Inf 1998;40:281-5.
   • Padula PJ, Edelstein A, Miguel SD, Lopez NM Rossi CM, Rabinovich RD. Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology 1998; 241(2):323-30.
   • Parisi MDN, Enria DA, Pini NC, sabattini MS. Retrospective detection of clinical infections caused by hantavirus in Argentina. Medicina (Buenos Aires) 1996; 56(1):113.
   • Toro J, Vega JD, Khan AS, Mills JN, Padula P, Terry W, et al. An outbreak of hantavirus pulmonary syndrome, Chile, 1997. Emerg Infect Dis, 1998;4:687-94.
   • Wells RM, Sosa Estani S, Yadon ZE, et al. An unusual hantavirus outbreak in southern Argentina: Person-to-person transmission? Emerg Infect Dis 1997;3:171-4.
   • Wells RM, Sosa Estani S, Yadon ZE, Enria D, Padula P, Pini NC, et al. Seroprevalence of antibodies to hantavirus in health care workers and other residents of southern Argentina. Clin Inf Dis 1998;27:895-6.
   • Wells RM, Young J, Williams RJ, Armstrong LR, Busico K, Khan AS, et al. Hantavirus transmission in the United States. Emerg Infect Dis 1997;3:361-5.

1. Following recovery from HPS, patients often experience fatigue and exercise intolerance for several months. Almost all patients, including those not requiring mechanical ventilation, have evidence for a modest degree of small airways obstruction, which persists for more than one year after recovery. Evidence for decreased diffusion capacity in the lung resolves after 3 to 6 months. A few patients have mild proteinuria and mild pulmonary hypertension, but the number of patients studied is too small to draw conclusions on the significance of these findings.
   • Dr. Frederick Koster, University of New Mexico, School of Medicine.
     Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)

1. Studies in the United States suggest that most people who are infected with Sin Nombre virus (SNV) develop HPS. The prevalence of antibody to SNV among healthy people residing in the disease-endemic area is extremely low (0.3%). On the other hand, the prevalence of antibodies to South American hantaviruses among healthy populations in disease-endemic areas of South America may be considerably higher, suggesting that there are inapparent infections or that the disease is mild and unrecognized following infection with some hantaviruses.
2. Dr. James Olson, Special Pathogens Branch, CDC.
   Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)
3. For further information, see:
   • Williams RJ, Bryan RT, Mills JN, Palma E, Vera I, de Velasquez F, et al. An outbreak of hantavirus pulmonary syndrome in western Paraguay.Am J Trop Med Hyg 1997;57:274-82.

1. There are at least three tests we are aware of that are being done for diagnosis. One, developed at the University of New Mexico, is a strip that is treated with serum and then the resulting bands are analyzed. This method has been compared to the ELISA and seems to give very similar results in testing human diagnostic sera. The other two have not been compared. One of these is an ELISA similar to the one in use at CDC, but does not use the same controls and we would not be surprised if it gave false-positives from time to time. None of the tests for SNV are licensed by the FDA for diagnostic use with human sera.
2. Dr. James Olson, Special Pathogens Branch, CDC.
   Hantavirus Pulmonary Syndrome Clinical Update, 1999 Satellite Conference (A CDC/Public Health Training Network Satellite Broadcast, May 27, 1999)
3. For further information, see:
   • Ksiazek TG, Peters CJ, Rollin PE, Zaki S, Nichol ST Spiropoulou CF, et al. Identification of a new North American hantavirus that causes acute pulmonary insufficiency. Am J Trop Med Hyg 1995; 52(2):1017-23.