Is there any information on re-infection with
hantaviruses, for example, in areas of South America where there
is high prevalence of antibodies indicating widespread exposure?
Have any correlates of protective immunity been identified in epidemiologic
studies?
Answer
Are the findings for HPS in
South America the same as those in the United States? Is it the
same disease?
Answer
If HPS occurs mostly in rural areas,
why are the greatest number of cases affecting white males -- up
to 76%?
Answer
Why is HPS uncommon in children
in the United States?
Answer
What types of respirators or masks can
farmers and homeowners in rural areas use for protection against
hantavirus?
Answer
Is exposure to sunlight an effective means
of disinfecting materials contaminated with hantavirus? If so, how
long of an exposure is recommended?
Answer
If Sin Nombre is an enveloped virus, why
is it not destroyed by desiccation? Also, do you have data on how
long the virus is infective in dried feces, urine, and other excreta
of rodents?
Answer
You discussed the platelet count and the
blood smear in the diagnosis of HPS. What about the white blood
cell count (WBC) and hematocrit. Are they helpful?
Answer
Is there evidence to correlate immunologic
or immunogenetic characteristics (such as HLA type, immunosuppression)
with the severity of the disease?
Answer
Are there specific cytokine-blocking agents
or antibiotics that would be helpful in the treatment of acute HPS
cases?
Answer
What is known about virus attachment
and entry into host cells? Can this information be used to design
treatment strategies?
Answer
HPS patients seem to recover quite promptly
after their acute insult. Do they have residua, either from the
time on the ventilator or from their disease process?
Answer
What percent of the population in disease-endemic
areas have HPS antibody but have not presented with symptoms of
disease?
Answer
We recently had a Sin Nombre false-positive
result with a report from a commercial laboratory. The patient was
in ICU and ARDS was part of her clinical presentation: IgM was 1:80
and the IgG was 1:512 with > 1:80 being positive. When we tested
the patient's blood at our laboratory, it was negative, and another
diagnosis was clinically relevant to the patient. The commercial
laboratory is representing that they do Sin Nombre testing now --
not other related hantaviruses. Most of our hospitals know to send
all samples here, but the occasional mistake with a new employee
may occur. Do you know what test they have developed and its sensitivity
and specificity?
Answer
Is
there any information on re-infection with hantaviruses, for example,
in areas of South America where there is high prevalence of antibodies
indicating widespread exposure? Have any correlates of protective
immunity been identified in epidemiologic studies?
Answer:
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 .
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.
Back to questions
Are
the findings for HPS in South America the same as those in the United
States? Is it the same disease?
Answer:
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 evaluated
seem 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
For a summary and
references to South American publications, 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.
For a discussion
of milder SNV infections, see:
Kitsutani PT. Acute Non-HPS Sin Nombre Hantavirus Infection
in the U.S. Emerg Infect Dis 1999; (in press).
Back to questions
If
HPS occurs mostly in rural areas, why are the greatest number of
cases affecting white males -- up to 76%?
Answer:
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.
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%).
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.
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.
Back to questions
Why
is HPS uncommon in children in the United States?
Answer:
As of June 1, 1999, 217 cases of HPS have been reported in
the United States. Thirteen (6%) were 16 years of age or younger,
although this age group represents 24.2% of the US population. The
youngest reported patient was 10 years of age.
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. We would not generally know of these mild infections,
but are aware of a 4-year-old boy who had a very mild illness and
did not develop the severe cardiac and pulmonary syndrome. We know
that HPS is a disease that reflects your immune response to the
virus, so it is possible that children respond differently than
adults.
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.
Dr. Ali Khan, Special Pathogens Branch, CDC.
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.
Back to questions
What
types of respirators or masks can farmers and homeowners in rural
areas use for protection against hantavirus?
Answer:
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.
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.
Back to questions
Is
exposure to sunlight an effective means of disinfecting materials
contaminated with hantavirus? If so, how long of an exposure is
recommended?
Answer:
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.
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.
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.
Back to questions
If
Sin Nombre is an enveloped virus, why is it not destroyed by desiccation?
Also, do you have data on how long the virus is infective in dried
feces, urine, and other excreta of rodents?
Answer:
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.
Dr. C. J. Peters, Special Pathogens Branch, CDC.
Back to questions
You discussed the platelet
count and the blood smear in the diagnosis of HPS. What about the
white blood cell count (WBC) count and hematocrit. Are they helpful?
Answer:
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.
Back to questions
Is
there evidence to correlate immunologic or immunogenetic characteristics
(such as HLA type, immunosuppression) with the severity of the disease?
Answer:
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.
Back to questions
Are
there specific cytokine-blocking agents or antibiotics that would
be helpful in the treatment of acute HPS cases?
Answer:
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.
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.
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.
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.
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. Simpson, University of Kansas Medical Center, School of
Medicine.
Back to questions
What
is known about virus attachment and entry into host cells? Can this
information be used to design treatment strategies?
Answer:
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 .
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.
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.
Back to questions
HPS patients seem to recover quite promptly after their acute insult.
Do they have residua, either from the time on the ventilator or
from their disease process?
Answer:
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.
Back to questions
What
percent of the population in disease-endemic areas have HPS antibody
but have not presented with symptoms of disease?
Answer:
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 health 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.
Dr. James Olson, Special Pathogens Branch, CDC.
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.
Back to questions
We
recently had a Sin Nombre false-positive result with a laboratory
report from a commercial laboratory. The patient was in ICU and
ARDS was part of her clinical presentation: IgM was 1:80 and the
IgG was 1:512 with > 1:80 being positive. When we tested the
patient's blood at our laboratory, it was negative, and another
diagnosis was clinically relevant to the patient. The commercial
laboratory is representing that they do Sin Nombre testing now --
not other related hantaviruses. Most of our hospitals know to send
all samples here, but the occasional mistake with a new employee
may occur. Do you know what test they have developed and its sensitivity
and specificity?
Answer:
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.
Dr. James Olson, Special Pathogens Branch, CDC.
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.
Back to questions
|