CFIDS/Epstein-Barr virus...HELP!!!
bbredt
bbredt at dnai.com
Sun May 28 19:27:52 EST 1995
CDC has two articles I found on their Viral Diseases Page
(http://www.cdc.gov/diseases/viral.html) that you might find useful.
I'm new at all things Internet, but I'm going to try to attach them to
this. Good Luck.
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Date Last Rev'd: March 9, 1995
CHRONIC FATIGUE SYNDROME
The Centers for Disease Control and Prevention is actively engaged in Chronic
Fatigue Syndrome research. This document reflects current and reliable
information. At this time CDC is not equipped to handle counseling, but
suggests that you call your nearest support group.
GENERAL DESCRIPTION
Chronic Fatigue Syndrome, or CFS, is characterized by persistent and
debilitating fatigue and additional nonspecific symptoms such as sore throat,
headache, tender muscles, joint pains, difficulty thinking and loss of short
term memory. On physical examination, patients may have nonspecific findings
such as low grade fever and redness in the throat, but frequently no
abnormalities are found. No laboratory test or panel of tests is available to
diagnose CFS, so the diagnosis is made solely on clinical grounds. The cause
of CFS is unknown.
In some individuals, CFS appears to develop after an acute illness like
influenza or infectious mononucleosis, both of which usually resolve within a
few months, or after periods of unusual stress. In other persons, however,
CFS appears to develop gradually with no precipitating event. Symptoms are
usually most severe early in the course of illness. Later in the illness,
periods of partial improvement may be followed by relapses or recovery.
While some patients have recovered after several months of illness, others
have remained ill for many years. The average duration and full clinical
picture of CFS over time is unknown. The degree to which CFS patients are
disabled varies widely. Some patients continue to function at home and at
work, although at a reduced level of activity, while others become severely
disabled and cannot perform many of the routine activities of daily living.
CFS affects females and males, and adolescents as well as adults. Most
reported cases, however, have occurred in young to middle aged adults with
females diagnosed more frequently than males. It is unclear to what extent
these demographic characteristics reflect biases among reported cases. CFS
does not appear to be directly transmissible from person to person, and there
is no justification for CFS patients to be isolated. No deaths from CFS have
been reported. Epidemiologic studies of CFS have not documented clear and
consistent risk factors.
The total number of persons with CFS in the United States is unknown. CDC
has conducted surveillance for CFS in four cities across the United States
since 1989. Preliminary analysis of the first three years of data indicates
that in these sites, two to 7 adults out of 100,000 have CFS. These figures,
or prevalence rates, are based upon persons who meet all of the criteria in
the CFS research case definition, which was published in the Annals of
Internal Medicine in 1988. Because this case definition was deliberately
designed to be restrictive for purposes of research, these prevalence rates
probably represent low estimates. They should not be used to estimate the
overall number of CFS patients in the rest of the United States because the
cities chosen for CFS surveillance were not selected randomly.
CASE DEFINITION OF CFS
In 1987, a panel of experts met at CDC in order to define chronic fatigue
syndrome for research purposes. The criteria chosen to define CFS cases were
deliberately selected to be restrictive in order to facilitate research. The
goal of the case definition was to identify CFS patients who were relatively
similar in terms of their illness. The case definition was not designed to
diagnose all persons with CFS or to process CFS associated disability claims.
This research case definition, which was published in March 1988 in the
Annals of Internal Medicine, essentially requires:
1) the presence of new and debilitating persistent or relapsing fatigue for
at least 6 months, and
2) the exclusion, by medical examination and laboratory testing, of other
clinical conditions (including psychiatric disorders) that may also
cause prolonged fatigue, and
3) the presence of a combination of 8 or more symptom and physical sign
criteria during 6 or more months of illness. The symptom criteria are
mild fever, sore throat, painful lymph nodes, generalized muscle
weakness, muscle aches, prolonged fatigue following exercise,
generalized headaches, joint pains, various nervous system complaints,
sleep alterations, and development of the symptom complex over a few
hours to a few days. The physical examination criteria are low grade
fever, an inflamed pharynx without pus, and enlarged lymph nodes.
DIAGNOSTIC EVALUATION
Severe persistent fatigue and other CFS symptoms can be associated with many
other illnesses. These illnesses include underlying major depression and
anxiety disorders, autoimmune diseases such as systemic lupus erythematosus,
malignancies such as ovarian cancer, lymphoma or leukemia, infectious
diseases such as endocarditis, hepatitis, syphilis, or AIDS, and a variety of
other diseases such as anemia, diabetes, and diseases of the thyroid, heart,
lungs, liver, kidneys, gastrointestinal tract, and endocrine system.
The exclusion of other possible diseases as a cause of CFS symptoms is the
most important part of the diagnostic evaluation. Since many of these
diseases can be treated or managed appropriately following diagnosis, and
since some of these conditions can be progressive or even fatal if untreated,
it is absolutely imperative that a thorough medical evaluation be done before
a diagnosis of CFS is made.
The role of laboratory and radiologic testing in the diagnostic workup of CFS
is to exclude other possible diseases. There are no laboratory tests
currently available, including tests for infections, tests for activation of
the body's natural defenses against infection, or tests for immune function,
that can identify CFS. In particular, tests for Epstein-Barr Virus or EBV,
human T-cell lymphotropic virus type-II or HTLV-II, human spumavirus, and
immunologic abnormalities should not be used to diagnose CFS. Such tests do
not distinguish people with CFS from healthy people and are expensive. Some
physicians have reported finding brain abnormalities in CFS patients using
radiologic tests such as magnetic resonance imaging, known as MRI scans, or
nuclear medicine brain scans such as PET or SPECT scans. The meaning of
these findings is unknown. They are not unique to CFS and are not found in
all CFS patients. Therefore MRI and nuclear medicine scans, which are very
expensive, should not be routinely used to diagnose CFS. These radiologic
scans should only be used, when clinically warranted, to exclude the
possibility of another brain disease.
CDC cannot recommend specific physicians for referral. Our general
recommendation is to contact the county medical society, closest university,
or a local CFS patient support group for a referral to an internist,
infectious disease specialist, or other physician who is knowledgeable about
CFS.
POSSIBLE CAUSES OF CFS
The cause of CFS is unknown. It is also unknown whether or not CFS is a
single illness or a group of different illnesses that share common symptoms.
A number of theories about the underlying cause or causes of CFS have been
proposed. Some theories have focused on possible underlying viral infections,
while others have focused on possible underlying immunologic, hormonal,
neurologic, and psychological dysfunction. Some of the more prominent
theories are discussed in more detail.
Possible Viral Causes
Epstein-Barr virus or EBV, which is the virus that causes mononucleosis, was
widely thought to be responsible for CFS in the 1980s. Later studies,
however, indicated that EBV was not the cause of CFS. Most adults have
antibody to EBV, and a positive test for EBV, even at a high level of
antibody, does not diagnose CFS. In addition to EBV, several other viruses
have been proposed as possible causes of CFS, including cytomegalovirus,
Coxsackie B virus, adenovirus type 1, and human herpesvirus 6 or HHV-6.
Although it is possible that viral infections play a role in causing CFS in
some patients, none of these viruses has been consistently associated with
CFS. More recently, there have been reports suggesting associations between
CFS and human retroviruses. These reports, which suggested that CFS may be
associated with human spumavirus and viruses like human T-cell lymphotropic
virus type-II, received a great deal of attention and generated a great deal
of excitement. Since then, however, three published studies have failed to
verify an association between CFS and any known human retroviruses. At
present there does not appear to be an association between human retroviruses
and CFS. The only role for retroviral testing in the diagnosis of CFS should
be to exclude the possibility of infection with human immunodeficiency virus
or HIV.
Possible Immunologic Causes
Several subtle immunologic abnormalities have been described in some patients
with CFS. Results of immunologic studies as a whole have been confusing, and
the results of some published findings are in conflict. Recently a panel of
distinguished immunologists and virologists from the National Chronic Fatigue
Syndrome Advisory Council issued an official statement regarding immunologic
and virologic aspects of chronic fatigue syndrome. In their statement, the
following points were made:
1) No test is diagnostic for CFS.
2) There is evidence of immune abnormalities in CFS studies,
which suggests a pattern of chronic immune activation. However,
similar findings can be found in other chronic disorders such as
chronic infections, autoimmune disorders, and allergies.
3) Among the most frequently identified abnormalities are the
following: chronic activation of T-cells, decreased function of
natural killer cells, reduction of subsets of CD8 positive
suppressor cells, and increased levels of antibody to Epstein- Barr
virus early antigen.
4) Other immune abnormalities have been inconsistently reported.
These include: failure to respond to skin tests, deficiencies of
immunoglobulin subclasses, and abnormal CD4 and CD8 numbers and
ratios.
Recently researchers at the National Institutes of Health reported finding
slightly lower percentages of naive CD4 T-cells circulating in the blood of
CFS patients than in controls.
The significance of these reported immunologic abnormalities is uncertain,
but to keep these reports in perspective, the following points should be kept
in mind. While it is possible that immunologic abnormalities may be part of
the process that causes CFS, these abnormalities may also represent
nonspecific immune changes that occur as part of many chronic diseases. It is
clear, however, that severe suppression of the immune system such as that
seen in AIDS, does not occur in CFS. The opportunistic infections common to
AIDS are not seen in CFS.
Possible Psychological Causes
The role of psychological factors and psychiatric diseases in causing CFS is
highly controversial and particularly difficult to study. It is clear that
psychiatric disease, and especially depression, is frequently found in
individuals with persistent fatigue and among patients referred for
evaluation for CFS. Approximately half of the individuals referred to the
CDC's CFS surveillance system have evidence of psychiatric illness, which was
present before the start of their CFS symptoms. It is also clear that CFS
patients commonly experience depression or anxiety sometime during the course
of their illness.
These kinds of findings have led some researchers to conclude that CFS is one
specific manifestation of underlying psychiatric illness. Other researchers,
however, point out that many patients who develop CFS do not have evidence of
prior psychiatric disease, and that the depression or anxiety that develops
after the start of CFS symptoms may be a part of the CFS disease process or
simply a natural reaction to any chronic illness.
TREATMENT
Treatment for CFS should be initiated only after the possibility of another
disease has been excluded as thoroughly as possible. No medication has been
shown to be effective for curing CFS in well conducted clinical trials. The
current standard of treatment is to treat the symptoms of CFS.
Most experts begin by recommending a regimen of adequate rest, balanced diet,
and physical conditioning. Moderate exercise is generally helpful to
minimize loss of physical conditioning, but patients should take care to
avoid over exertion since this can lead to relapses of severe fatigue and
other symptoms. Non-steroidal anti-inflammatory medications can be useful
for treating headaches, and muscle and joint pains. Since all medications
can have side effects, a physician should be consulted for specific
recommendations regarding drugs.
Among the numerous medications claimed to be effective for treating CFS are a
variety of antiviral and immune system modulating drugs, vitamins, and
holistic remedies. While some of these treatments may be of benefit to some
patients, other treatments are expensive, are of no proven use, and are
potentially harmful to the patient. If you are in doubt about a specific
therapy, one or more reputable physicians in your area should be consulted.
Acyclovir and gamma globulin are two medications that have undergone rigorous
clinical testing in CFS patients. Acyclovir, which is usually used to treat
herpes infections, was shown to be no more effective than a placebo in
treating CFS patients. Gamma globulin, which is composed of antibodies pooled
from many individuals, was tested in two trials. One trial conducted in the
U.S. showed no benefit. The other trial conducted in Australia showed minimal
benefit, but this benefit was lost after the trial ended. Currently, two
other medications, cortisol and ampligen are undergoing controlled trials.
FOR FURTHER INFORMATION
There are several national and local non-profit support groups for persons
with chronic fatigue syndrome. These groups publish periodic newsletters,
provide lists of interested physicians, and facilitate contact between
affected persons. The CDC does not endorse these organizations or their
published information but provides the names and addresses of the two largest
national organizations for further information. These are:
1) The National CFS Association, 919 Scott Avenue, Kansas City,
KS. 66105. Tel. (913) 321-2278.
2) The CFIDS Association, Community Health Services, P.O. Box
220398, Charlotte, NC. 28222-0398. Tel. (704) 362-2343
CENTERS FOR DISEASE CONTROL AND PREVENTION
Date Last Rev'd: March 9, 1995
EPSTEIN-BARR VIRUS
DISEASE INFORMATION
The Epstein-Barr virus frequently refereed to as EBV, is one of the most
common human viruses, and it occurs world-wide. The Epstein-Barr virus is in
the herpes family of viruses, and most people will become infected with EBV
sometime during their lives. In the United States, as many as 95% of adults
between 35 and 40 years of age have been infected. Infants become
susceptible to EBV as soon as the maternal protection present at birth
disappears. Many children are infected, with EBV and these infections
usually cause no symptoms or are indistinguishable from the other mild, brief
illnesses of childhood.
In the United States and in other developed countries, many persons are not
infected with EBV in their childhood years. In these people infection with
Epstein-Barr virus during adolescence or young adulthood commonly causes
infectious mononucleosis.
Symptoms of infectious mononucleosis are fever, sore throat, and swollen
lymph glands. Sometimes there is also a swollen spleen or liver infection.
Heart problems or involvement of the central nervous system occur only
rarely, and infectious mononucleosis is almost never fatal. There are no
known associations between active Epstein-Barr virus infection and problems
during pregnancy, such as miscarriages or birth defects. Although the
symptoms of infectious mononucleosis usually resolve in one or two months,
the Epstein-Barr virus remains dormant in cells in the throat and blood for
the rest of the person's life. Periodically, the virus can reactivate and
can be found in the saliva of infected persons. This reactivation usually
occurs without symptoms of illness.
EBV also establishes a lifelong dormant infection in some cells of the body's
immune system. A late event in a very few viral carriers is the emergence of
Burkitt's lymphoma and nasopharyngeal carcinoma, two rare cancers that are
not normally found in the United States. EBV appears to play an important
role in these malignancies, but is probably not the sole cause of disease.
Most individuals exposed to people with infectious mononucleosis have
previously been infected with EBV and are not at risk of developing
infectious mononucleosis. In addition, transmission of EBV requires contact
with the saliva (found in the mouth) of an infected person. Transmission of
this virus through the air or blood does not normally occur. The incubation
period, or the time from infection to appearance of symptoms, ranges from 4
to 6 weeks. Thus persons with infectious mononucleosis may be able to spread
the infection to others for a period of time. However, no special
precautions or isolation procedures are recommended since the virus is also
found frequently in the saliva of healthy people. In fact, many healthy
people can carry and spread the virus intermittently for life. These people
are usually the primary reservoir for person-to-person transmission. For
this reason, transmission of the virus is almost impossible to prevent.
The diagnosis of infectious mononucleosis is suggested on the basis of the
clinical symptoms of fever, sore throat, swollen lymph glands, and the age of
the patient. Usually, laboratory tests are needed for confirmation.
Blood findings with infectious mononucleosis include an elevated white blood
cell count, an increased percentage of certain white blood cells, and a
positive reaction to a "mono spot test."
There is no specific treatment for infectious mononucleosis, other than
treating the symptoms. No antiviral drugs or vaccines are available. Some
physicians have prescribed a five day course of steroids to control the
swelling of the tonsils. The use of steroids has also been reported to
decrease the overall length and severity of illness, but these reports have
not been published.
*** Please note: Symptoms related to infectious mononucleosis due to EBV, as
confirmed in the laboratory seldom last for more than 3 or 4 months. When
such an illness lasts more than 6 months, it is frequently called chronic EBV
infection. However, valid evidence for continued active EBV infection is
found very seldom in these patients, and their illness is usually more
appropriately described as chronic fatigue syndrome, or CFS.
LABORATORY TESTS USED FOR EBV DIAGNOSIS
Recent advances in laboratory tests have given physicians new tools for
diagnosing illnesses, but these tests are not always foolproof. Tests can
fail in two ways. First the can indicate that a condition exists, when in
fact it does not; this is called a false positive result. Second, the test
can miss the detection of a condition that does exist; this is called a false
negative result. For a variety of reasons false positive and false negative
results can occur for almost all laboratory tests. Some of the reasons for
incorrect laboratory results are:
1) Despite improvements some tests lack the sensitivity needed to detect a
condition.
2) Sometimes infection with another virus may cause a nonspecific, or
accidental response in the test.
3) The testing process is complex and many events can prevent accurate
results. These include: (1)incorrect shipping, handling, and storage of
the item to be tested; (2) incorrectly performing the test itself; or (3)
misinterpreting the results.
The laboratory tests associated with Epstein-Barr virus (EBV) are for the
most part accurate and specific. They can measure a number of different
antibodies specific to EBV. Antibodies are those substances which the body
produces to fight invading bacteria and viruses. If an antibody is present,
then an infection with that agent has occurred at some time in the past. If
no antibodies to a virus are found, then the virus has probably not entered
that person's body.
The fact that a person has antibodies to EBV does not automatically indicate
that a recent infection has occurred. Since 95% of adults have been infected
with EBV, most adults will show antibodies to EBV from infection years
earlier.
The body produces a number of specific antibodies to EBV that are present at
different stages of infection. Some types of EBV antibodies are present only
during active infection. Other specific EBV antibodies are present for years
after past infection, and still other antibodies are present during
reactivated infection with EBV. Therefore, by measuring the type and amount
of a specific antibody that is present, laboratory tests can determine the
presence of current infection, past infection, or reinfection.
Finally, even when EBV antibody tests, such as the early antigen test,
suggest that reactivated infection is present, this result does not
necessarily indicate that a patient's current medical condition is caused by
EBV. A number of normal people with no symptoms have antibodies to the EBV
early antigen for years after their initial EBV infection.
Therefore, interpretation of laboratory results is complex and difficult, and
should be left to physicians who are familiar with EBV testing and who have
access to the entire clinical picture of a person. Thus, to determine if EBV
infection is associated with the current illness, consult with a trained
physician.
ADDITIONAL INFO ABOUT EBV ANTIBODY TESTS AND INTERPRETATION
Antibody tests for Epstein-Barr virus measure the presence and/or the
concentration of specific EBV antibodies. Different laboratory tests can
measure six specific EBV antibodies. Some of these tests can be performed on
a single sample of blood, while others compare different samples of blood
over a period of time. These tests over time are called paired antibody
tests, and they are used to evaluate changes in antibody levels. The rise or
fall in antibody levels, called titers, indicates specific facts about
infection. By evaluating the results of these different tests, the stage of
EBV infection can be determined. However, these tests are expensive and not
usually needed for the diagnosis of infectious mononucleosis.
Four distinctive EBV antibodies are used to provide a comprehensive picture
of EBV infection: these are IgM-viral capsid antibody, IgG-viral capsid
antibody, IgG-antibody to early antigen, and EBV nuclear antibody (EBNA).
Accurate interpretation of EBV infection will be based on the results from
all these antibodies, and usually will not rely on single test results for a
diagnosis.
It is not appropriate for CDC to interpret test results or to handle
counseling for the general public. We suggest that questions be directed to
a local physician who is familiar with the patient's history and laboratory
test results.
In addition, CDC cannot recommend specific physicians for referral. Our
general recommendation is for the patient to consult an infectious disease
specialist, or the infectious disease department in a university affiliated
medical center in your area, or to ask your county medical society for a
referral.
CHRONIC EPSTEIN-BARR VIRUS AND ITS RELATIONSHIP WITH CHRONIC FATIGUE SYNDROME
During the mid 1980's, several studies described a prolonged illness that was
associated with chronic infection with Epstein-Barr virus (EBV). This illness
was characterized by extreme fatigue and a group of other related symptoms,
including headache, sore throat, low grade fever, muscle and joint aches,
memory loss, and difficulty in concentrating. Further studies have been
unable to link EBV directly with this illness. These studies reported that
patients were no more likely than healthy persons to have antibodies to EBV.
Although some patients had a higher than normal level of antibodies to EBV,
they also had higher-than-normal levels of antibody to other viruses. Thus,
EBV testing was of no value in determining the diagnosis or the status of
illness in individual patients. Since 1988, investigators have used the term
chronic fatigue syndrome, or CFS, to describe this illness. In most cases,
persons diagnosed as having a chronic EBV infection are more appropriately
classified as having chronic fatigue syndrome.
Please note: Documented infectious mononucleosis due to EBV may have been
present initially in some patients with prolonged illnesses. However,
infectious mononucleosis-like symptoms lasting over 6 months are very seldom
due to continued EBV infection and are more appropriately described as
chronic fatigue syndrome.
DIAGNOSIS OF EBV INFECTIONS
In most cases of infectious mononucleosis, the clinical diagnosis can be made
from the characteristic triad of fever, pharyngitis, and lymphadenopathy
lasting for 1 to 4 weeks. Blood findings in infectious mononucleosis
include, a normal to moderately elevated white blood cell count, an increased
total number of lymphocytes, greater than 10% atypical lymphocytes, and a
positive reaction to a "mono spot" test. In patients with symptoms
compatible with infectious mononucleosis, a positive Paul-Bunnell heterophile
antibody test result is diagnostic, and no further testing is necessary.
Moderate-to-high levels of heterophile antibodies are seen during the first
month of illness and decrease rapidly after week four. False-positive
results may be found in 3% of the cases, and there are 10% to 15%
false-negative results, primarily in children younger than 10 years of age.
True outbreaks of infectious mononucleosis are extremely rare. A substantial
number of pseudo-outbreaks have been linked to laboratory error, as reported
in the MMWR on August 16, 1991.
When "mono spot" or heterophile test results are negative, additional
laboratory testing may be needed to differentiate EBV infections from a
mononucleosis induced by cytomegalovirus, adenovirus, or Toxoplasma gondii.
Direct detection of EBV in lymphoid tissues is a research tool and not
practical for routine diagnosis. Instead, serologic testing is the method of
choice for diagnosing primary infection.
Because the humoral response in primary EBV infection appears to be quite
rapid, in most cases testing paired sera will not demonstrate significant
antibody changes. Effective laboratory diagnosis can be made on a single
acute-phase serum sample by testing for antibodies to several EBV-associated
antigens simultaneously. In most cases, distinction can be made as to
whether a person is susceptible to EBV, has had a recent infection, has had
infection in the past, or has a reactivated EBV infection.
Antibodies to several antigen complexes may be measured. These antigens are
the viral capsid antigen (VCA), the early antigen (EA), and the EBV nuclear
antigen ("EBNA"). In addition, differentiation of immunoglobulin G and M
subclasses to the viral capsid antigen can often be helpful for confirmation.
When the mono spot is negative, the optimal combination of EBV serologic
testing consists of the antibody titration of four markers: IgM to the viral
capsid antigen, IgG to the viral capsid antigen, IgG to the early antigen,
and antibody to EBNA.
IgM to the viral capsid antigen appears early in infection and disappears
within 4 to 6 weeks. IgG-viral capsid antigen appears in the acute phase,
peaks at 2 to 4 weeks after onset, declines slowly, and then persists for
life.
IgG to the early antigen appears in the acute phase, and generally falls to
undetectable levels after 3 to 6 months. In most people, detection is a sign
of active infection, but 20% of healthy people may have this antibody for
years.
Antibody to the EBV Nuclear Antigen or EBNA is not seen in the acute phase,
but slowly appears 2 to 4 months after onset, and persists for life. This is
true for the standard immunofluorescent EBNA test, but is not true for the
new EBNA enzyme immunoassay.
SUMMARY OF INTERPRETATION
The diagnosis of EBV infection is summarized as follows:
Susceptibility
If antibodies to the viral capsid antigen are not detected the patient is
susceptible to EBV infection.
Primary Infection
Primary EBV infection is indicated if IgM antibody to the viral capsid
antigen is present and antibody to EBV Nuclear Antigen or EBNA is absent. A
rising or high IgG antibody to the viral capsid antigen and negative antibody
to EBNA after at least 4 weeks of illness is also strongly suggestive of
primary infection. In addition, 80% of patients with active EBV infection
produce antibody to early antigen.
Past Infection
If antibodies to both the viral capsid antigen and EBNA are present, then
past infection is indicated.
Reactivation
In the presence of antibodies to EBNA, an elevation of antibodies to early
antigen suggests reactivation. However, when EBV antibody to the early
antigen test is present, this does not automatically indicate that a
patient's current medical condition is caused by EBV. A number of healthy
people with no symptoms have antibodies to the EBV early antigen for years
after their initial EBV infection. Many times reactivation occurs
subclinically.
Symptoms related to infectious mononucleosis caused by EBV seldom last for
more than 3 or 4 months. When such an illness lasts more than 6 months it is
frequently been called chronic EBV infection. Valid evidence for continued
active EBV infection is found very seldom in these patients. Their illness
is usually more appropriately described as chronic fatigue syndrome or CFS,
assuming other causes of chronic illness or fatigue have been ruled out.
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