HIVreport.de
03
2012
Syphilis
4
Transmission
5
Prevention
7
Diagnostics
16
aidshilfe.de
History of syphilis
HIVreport 3/2012: Syphilis
Issue No. 03/2012
13/07/2012
SYPHILIS
Dear Readers,
The number of syphilis diagnoses reported
to the RKI has increased. This poster of
Deutsche AIDS-Hilfe [German AIDS Service Organisation] is from the era of the
syphilis wave in 2004/2005.
NEW DIAGNOSES: UPWARD
TENDENCY ............................................. 2
THE DISEASE: A CHAMELEON ............ 3
TRANSMISSION: NOTHING HAPPENS
WITHOUT FRICTION .............................. 4
PREVENTION: THE COMBINATION IS
WHAT MATTERS .................................... 5
DIAGNOSTICS: CONTROVERSY OVER
RAPID TESTS ......................................... 7
Quality assurance for syphilis rapid tests11
Interview with Marcus Behrens ................ 12
THERAPY.............................................. 14
Since then, prevention has made substantial progress. Numerous AIDS service organisations offer syphilis tests in addition to
HIV tests. The rapid tests used in some
projects are highly disputed. We report on
this topic in this issue.
GUILT AND SHAME: HISTORY OF
SYPHILIS .............................................. 15
References ................................................ 18
Further main topics include routes of
transmission, prevention methods as well
as the turbulent history of syphilis.
Imprint ....................................................... 18
Enjoy reading!
Steffen Taubert and Armin Schafberger
1
HIVreport 3/2012: Syphilis
New diagnoses: Upward tendency
In 2011, 21.9% more syphilis cases were reported to the Robert Koch Institute than in the previous
year. It has not yet been sufficiently investigated to what extent the increase in the number of reported cases is attributable to an increase in the number of infections or an intensification of the
test programmes. During the last few years, testing projects of the AIDS service organisations
have expanded their test programmes.
4000
3500
3000
00..14
15..19
20..24
25..29
30..39
40..49
50..59
60..74
75..99
2500
2000
1500
1000
500
0
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
New diagnoses by year and age groups. Source: RKI: SurvStat, as of: 12/07/2012
New syphilis diagnoses
Year
New diagnoses
2001
1,697
2002
2,396
2003
2,931
2004
3,364
2005
3,240
2006
3,165
2007
3,282
2008
3,191
2009
2742
2010
3034
2011
3697
New diagnoses by sex
More than 93% of new
syphilis diagnoses in 2011
occur in men, only 6.4% in
women.
male
female
In Germany, syphilis is a
“men’s disease”. In Eastern
Europe, considerably more
women are affected by the
disease.
New diagnoses by route of infection
unknown
Sex between men is indicated in 60% and heterosexual contacts in 11.5% of
all new diagnoses in 2011.
The route of infection has
not been indicated or is unknown in 28.5% of the cases. When only considering
the new cases where the
route of transmission is
known, 83% of the cases are attributed to sex between
men (MSM) and 16.1% to heterosexual contacts (RKI
2012).
RKI: SurvStat, as of: 12/07/2012
Further literature online:
Epidemiological Bulletin, RKI, 18/06/2012
2
HIVreport 3/2012: Syphilis
The disease: A chameleon
Because of its varying symptoms and courses, syphilis is often confused with other diseases – it is a chameleon of medicine: “The
great imitator”.
When left untreated, syphilis has usually several stages; however, the symptoms listed
below do not always occur.
1st stage
Chameleon. Photo: Kurt F. Domnik_pixelio.de
Ulcer at the point of entry
Usually 3 weeks following the infection,
the so-called primary lesion occurs: At the
point of entry of the bacteria (e.g. on the
glans, foreskin or labium, on the lips, in the
mouth or throat, on the anus or in the rectum,
rarely also on the fingers or at other locations), a miliary papule can form, which extends to become a mostly coin-sized ulcer
with a hard, rolled border (therefore also referred to as hard chancre or Ulcus durum).
On friction or pressure, the usually painless
or low-pain ulcer exudes a clear, highly infectious fluid. After about one to two weeks, the
adjacent lymph nodes also swell. The ulcer
disappears spontaneously within 2-6 weeks.
This stage often remains unnoticed.
This is followed by a resting phase referred to
as latency period, where other disease episodes may occur, which, however, become
increasingly weaker and disappear after 2-3
years at the latest. This may leave the
(wrong) impression that the syphilis has been
completely cured.
Spontaneous healing is indeed possible. After stage 1 or 2, syphilis is likely to heal spontaneously in one-third to half of all cases.
3rd stage
Organ damage
Without treatment or spontaneous healing,
syphilis may pass into a third and fourth stage
after years or decades, where internal organs, predominantly the vessels and the
heart as well as the central nervous system,
may be damaged. A typical symptom is the
formation of hardened, often gum-like nodes
(gummas) occurring everywhere on and in
the body, which destroy the surrounding tissue when bursting.
2nd stage
Malaise, skin rash
The second stage usually begins 4–10
weeks following the infection. During this
phase, the syphilis bacteria spread in the
whole body via the blood and the lymph. Unspecific symptoms occur, e.g. fever accompanied by fatigue, loss of appetite, nightly
sweats and swollen lymph nodes. The patients often feel »kind of sick«.
Neurosyphilis (involvement of the brain and
the nerves) can also occur in earlier stages of
the disease – particularly if an HIV infection is
present. Early symptoms include nightly
headache, later on neuralgia, paralyses and
psychiatric changes (delusion and dementia).
The skin and mucosal lesions are more characteristic: itchy, sometimes scaling, macular
rash, particularly on trunk, palms or soles.
Frequent symptoms also include coated
tongue and oral cavity as well as weeping
verruciform spots on e.g. the genitals or the
anus that resemble condyloma. Loss of hair
occurs in some cases (»moth-eaten alopecia«).
Nowadays, later stages of syphilis occur only
rarely.
sch
Further literature online:
Esser S. and Marcus U.: Syphilis. Epidemiology,
Diagnosis, Therapy. With pictures of syphilitic skin
lesions. In: HIVandMore, 1/2012.
3
HIVreport 3/2012: Syphilis
Furthermore, transmission through smear infections (e.g. sharing of sex toys) and intensive kissing (e.g. if the primary lesion occurs
on the lips) is possible.
Transmission: Nothing happens
without friction
In Germany, the syphilis pathogen (Treponema pallidum) is almost exclusively 1 transmitted through sexual intercourse. A few
bacteria are sufficient to cause an infection,
which are rubbed into small, often invisible injuries in the mucosa (e.g. glans, foreskin, labium, mouth or rectum) or into injured skin
during sex. Statistically, every third sexual
contact with a syphilis-infected person leads
to an infection.
Most syphilitic ulcers are found on the foreskin/glans, on the lips or the tongue, around
or in the anus and in women on the greater
labia and in the vagina, but they can also occur on the skin of the penis, the penis root, on
the fingers or the hands (e.g. after fisting).
Most infectious during sex:
All skin or mucosal lesions, and in the 2nd
stage also the blood, of the infected person are infectious during sexual intercourse.
Treponema pallidum requires friction and
pressure during sex to be transmitted!
Syphilis bacteria are bound in the tissue 2
and need to be “rubbed out” of the ulcer
or the syphilitic skin lesions together with
the tissue fluid.
•
The ulcer (1st stage)
•
Skin
rash
and
mucosal
nd
sions/condylomas (2 stage)
•
Blood (2nd stage)
le-
In spite of the often severe signs of the disease, patients in the third stage are usually
no longer infectious.
“Body fluids” which are relevant to HIV
transmission, such as sperm, vaginal fluid or
the fluid film on the rectal mucosa, are irrelevant 3 for syphilis transmission.
Is a transmission possible in everyday
life?
The simple contact with a syphilitic skin rash
does not seem to involve a relevant transmission risk. Otherwise, people would have refrained from shaking hands during the last
few centuries (syphilitic skin rash on the
palms).
It is not a
scratch card,
but it is transmitted by rubbing:
syphilis
The only known cases where syphilis was
transmitted to doctors’ fingers occurred before the introduction of rubber gloves in medicine (review by Singh 1999). However, these
cases involved clinical examinations (applying pressure!).
Photo:
KFM_pixelio.de
Syphilis can predominantly be transmitted
during anal, vaginal and oral sex, but also
during oral-to-anal contact and fisting – and
whenever blood is involved.
A Chinese study group (Long 2012) has recently published three cases of syphilis
transmission between a nurse and infants.
Sexual abuse seems to have been excluded
with certainty in this case. The transmissions
are explained by the infants grabbing (and
pushing) in the adults’ mouth, kissing/biting
on syphilitic skin lesions as well the adults
chewing food for the infants.
1
Further routes of transmission are not addressed in
this HIVreport. Due to syphilis diagnostics during pregnancy and the low prevalence in heterosexual people,
there are hardly any mother-to-child transmissions in
Germany. Syphilis also does not play a role in blood
transfusions (anymore), since no fresh blood is transfused and blood conserves are subjected to reliable
tests.
Bottom line: A transmission requires intensive contact; mere touching is not sufficient.
2
Treponemas multiply in tissue, e.g. skin, mucosa and
vessel walls.
3
Apart from tissue fluid containing treponema that is
discharged from a syphilitic ulcer or a syphilitic mucous
lesion.
4
HIVreport 3/2012: Syphilis
Prevention: The combination is
what matters
Syphilis is also
transmitted during
oral intercourse.
No matter whether
or not ejaculation
takes place. From
mouth to penis/vulva or from
penis/vulva to
mouth/lips.
Condoms
The most effective protection during vaginal
and anal intercourse is provided by condoms.
However, condoms provide no absolute protection, since sex may also involve pressure
and friction contact with the syphilitic ulcers
and/or skin rash in other areas than the condom-clad penis.
Reducing the number of sexual partners?
Two Australian study groups have calculated
the possible effect of reducing the number of
sexual partners and increasing condom use
on syphilis prevalence in Australian MSM in a
social-scientific study (Gray RT 2011,
McCann PD 2011). The result: A noteworthy
reduction of prevalence would require substantial changes in attitude and a long-term
reduction in the number of partners. At an already high rate of condom use like in Germany, the authors regard such objectives as
unrealistic and recommend other strategies to
counteract the syphilis epidemic in MSM,
above all, more extensive test and treatment
programmes, more intensive information of
partners and syphilis PrEP (McCann 2011).
HIV and syphilis
An existing syphilis infection increases the
probability of an HIV infection in two ways:
•
An existing syphilis infection increases
the HIV viral load of the HIV-positive partner.
•
A primary syphilitic ulcer weakens the
mucosal barrier of the HIV-negative partner.
Syphilis PrEP and mass treatment?
Unlike HIV infections, syphilis infections can
be treated reliably within a short period of
time. It is at all worth making the effort of
long-term
medication-based
prevention
against this background? However, treatment
and PrEP can also be combined in a public
health measure:
Following a syphilis outbreak in heterosexuals between 1997 and 2000, the health authorities in British Columbia (Canada) carried
out mass treatment without prior diagnosis in several thousand persons. Within only
4 weeks, 7,000 tablets of azithromycin were
distributed among persons exposed to high
risk of contracting syphilis. People were also
allowed to pick up tablets for their sexual
partners. This measure was expected to treat
undetected syphilis cases, in addition to the
tablet taking effect as PrEP. One tablet of
azithromycin (with a long half-life) was considered to be sufficient to treat early-stage
When it’s dark, you cannot see the partner’s
syphilitic skin lesions.
5
HIVreport 3/2012: Syphilis
with a great deal of changing partners is
doubtful.
syphilis. Azithromycin is additionally effective
against chlamydia and (not yet resistant)
gonococci.
Proactive treatment of partners
The result: The number of syphilis infections
dropped considerably; however, this success
did not last, which is why the authors advise
against this type of prevention method (Rekart 2000).
When should the partner be treated? Many
specialists recommend “proactive” treatment,
since the primary ulcer is often not diagnosed
and the formation of antibodies can take several weeks.
At present, syphilis PrEP – unlike HIV PrEP –
is not being considered seriously by experts.
Merely a survey on the acceptance of syphilis
PrEP by MSM was conducted in Australia
(Wilson 2011). The medication-based PrEP
discussed there, however, consists of
doxycycline to be taken twice a day over a
yet-to-be-determined period (in syphilis therapy over 14 days). The simpler PrEP with
azithromycin now involves the development
of resistances. Bottom line: Syphilis PrEP is
currently hardly ever considered as an option
in prevention.
A Canadian study group (Singh 1999) recommends that when diagnosed with earlystage syphilis, the partners should receive
proactive treatment if sexual contact took
place during the last 90 days. If the last contact is longer ago, a syphilis serology should
be conducted first (the window period is then
certainly over).
The prevention combination against syphilis
The primary preventive recommendation to
“use condoms” is not sufficient to prevent
syphilis infections, also because syphilis can
be transmitted through oral intercourse and
other sexual practices as well. There is no
vaccination. Syphilis does not leave (sufficient) immunity either – recurrent infections
are thus possible.
Notification of partners
Previous sexual partners should be notified.
But how long should the time span be?
The Robert Koch Institute recommends that
patients suffering from stage-1 syphilis notify
all sexual partners of the last 3 months; in
case of early-stage syphilis (stage 1, stage 2
up to 1 year after infection), all sexual partners of the last 2 years should be notified
(RKI 2007).
Early detection and therapy as well as the notification and (proactive) treatment of partners
are therefore indispensible for prevention.
Since syphilis often produces few symptoms
or its symptoms are misjudged, persons exposed to high risk of contracting syphilis
should have access to low-threshold tests
and counselling. The DAH therefore recommends that gay men with changing partners
take a syphilis test once a year or, if they
have more than 10 partners, twice a year.
The Canadian recommendations do not go
that far: 3 months are also recommended at
stage one; at stage 2, the partners of the last
6 months, and during the latency period (up
to 1 year after the infection), the partners of
the last 12 months should be notified (Singh
1999). Whether this is feasible for persons
The prevention combination
Primary prevention
Condoms
during vaginal and anal intercourse
(for sex workers also during oral intercourse)
Early diagnosis
as prevention
Therapy as prevention
Seek medical care if symptoms are
present!
Routine test in the case of changing
partners (mainly for MSM) once a
year, at > 10 partners twice a year
Antibiotic therapy
prevents new infections
Information and treatment of partners
prevents recurrent and new infections
6
HIVreport 3/2012: Syphilis
Diagnostics: Controversy over
rapid tests
2. Verification
These tests are used to verify the screening
result and additionally make it possible to determine the titre level 6 of the respective antibodies (IgM/IgG).
Direct detection of bacteria
Secretion can be taken out of the primary lesion (stage I) or the skin rash or verrucae
(stage II), and the pathogen can be directly
detected using dark-field microscopy or treponema-PCR (smear). The primary lesion
(mainly in the mouth or anus) is, however, often overlooked.
The following tests are used: FTA-Abs test,
immunoblots (IgG/IgM), IgM-Elisa or 19-SIgM-FTA-abs.
3. Therapy decision test
The presence of early (IgM) or late (IgG) antibodies provides no sufficient insights into
whether the syphilis requires treatment.
Blood tests
Syphilis is usually diagnosed serologically,
i.e. by means of a blood serum test. The specific tests used for this purpose may vary
from laboratory to laboratory.
Examples:
•
Although a high IgM titre level is an indication that an infection is likely to have
occurred in the previous year, but it cannot tell whether or not it is completely
cured or adequately treated.
•
Although an IgG titre level without IgM titre level is an indication of an “older” infection, it provides no insights into
whether or not the syphilis is still active.
1. Screening
Syphilis induces a strong antibody reaction at
an early point. Antibodies can usually already
be detected after 2-3 weeks, and after 2-3
months at the latest.
ELISA, TPPA and TPHA tests as well as rapid tests are used (depending on the laboratory and the test equipment). All of them are
capable of detecting both IgM 4 and IgG 5 antibodies.
The decision “Therapy – yes or no?” is
usually made following the VDRL tests, a
screening for so-called lipoid antibodies. The
titre level (i.e. its concentration) correlates
with the disease and inflammatory activity of
syphilis.
IgM antibodies usually disappear after one
year. IgG antibodies may remain detectable
life-long, which is then referred to as a serum
scar.
After adequate treatment of syphilis, the titre
level normalises again: It should then drop by
at least two activity levels within three
months. The drop of the VDRL titre level is often delayed in HIV-positive patients.
Exceptions:
• When treating syphilis at a very early
stage, the antibody test may be negative
because syphilis has already been treated before a noteworthy number of antibodies formed (e.g. when treating the
partner proactively).
The repeated increase of the VDRL titre level
can hardly allow for distinguishing between
recurrent infection and inadequately treated
syphilis.
• The formation of syphilis antibodies can
be delayed when immunodeficiency is
present (HIV infection).
6
Titre levels are understood to be a dilution series of
the blood serum. The serum used for e.g. the TPPA test
is diluted in a test series (1:80, 1:160, 1:320, 1:640,
etc.), followed by the measurement of antibodies. A
high titre level (e.g. 1:5120) means that the antibody
test is still successful despite the strong dilution, meaning that a high concentration of antibodies is present in
the serum.
4
Immunoglobulins M (IgM) are antibodies that form upon first contact with an antigen (e.g. a bacterium).
5
Immunglobulins G (IgG) are antibodies that form
slightly delayed during the defence period, usually after
approx. 3 weeks. They often remain detectable lifelong. In the case of a recurrent infection, these antibodies form earlier, since the body already “knows” the infection.
7
HIVreport 3/2012: Syphilis
Bottom line:
Rapid tests
The diagnosis is usually easy in persons who
have not been infected with syphilis before.
The antibody screening test for these persons
can easily be performed within the scope of
an anonymous testing project.
In general, the quality of laboratory screening
tests is higher than that of rapid tests.
But is it reasonable to use the syphilis rapid
test as a screening test in certain situations?
This question is answered differently by those
involved in prevention and diagnostics.
For persons who have already had (several)
syphilis infections, it is advantageous to know
the previous findings for a diagnosis in order
to be able to determine whether the concentration of antibodies and lipoid antibodies is
increasing or decreasing. Whether the syphilis infection requires treatment may be difficult
to decide. The “syphilis check” for these persons should be conducted by physicians who
are also familiar with the previous results.
Armin Schafberger
Further literature online:
Hagedorn H-J. (2012): Syphilis Diagnostics. Detailed information on laboratory diagnostics from
the
consultant
laboratory,
Bad
flen. HIVandMore, 1/2012.
Current standards and recommendations of
DAH for tests and rapid tests in the testing
projects. Order online
The Alere Determine syphilis test is considered to be the most reliable product in the
market. Its sensitivity and specificity have
been investigated in direct comparison with
other tests in several studies (Siedner 2004,
Herring 2006, Li 2009, Mabey 2006).
With approx. 77.1% and 81.9% (Li 2009) or
88% (Siedner 2004), its sensitivity with capillary or whole blood is too low for a purposeful application of the test.
With 97.2% (Herring 2006), 100% (Li 2009)
and, according to a 4-country study (Mabey
2006), with 91.2% in Tanzania, 88.5% in Brazil, 100% in China and 100% in Haiti, its sensitivity with serum, however, nearly reaches
the reliability of laboratory screening tests.
Syphilis rapid tests are only capable of detecting antibodies. Just like laboratory screen8
HIVreport 3/2012: Syphilis
The specificity amounted to 99%, i.e. the
test result was false-positive in one out of
hundred samples.
ing tests, they are not capable of distinguishing between “old” cured syphilis infections
and syphilis infections requiring treatment
when the result is positive.
So far so good!?
Its use is thus not reasonable for all those
who have already had a syphilis infection in
their case history. However, most patients in
the testing projects know whether they have
previously had a syphilis infection.
No, because the study has found that the
positive result was delayed in a total of 7
tests. According to the manufacturer, the test
can be read off within a period of 15 minutes
to 24 hours.
•
Three of these 7 tests did not show a positive result until the next morning. More
accurate data on when these tests became positive is not available.
•
The time sequence of the reactions was
documented for four additional tests.
Three of the four samples became positive after 30 minutes and all four after 4560 minutes.
Controversy over rapid tests
In a statement with the Robert Koch Institute
and the Paul Ehrlich Institute in March 2012,
the German STI Society advised against the
application of syphilis rapid tests (Bremer
2012). The German AIDS Service Organisation criticised the statement in the HIVreport
01/2012.
Six of the seven tests with a delayed reaction
concerned clinically irrelevant serum scars of
previous infections.
Study reviews syphilis rapid test
Prof. Dr. Hans-Jörg Hagedorn and Dr. Dr. Dieter Münstermann from the Krone Syphilis
Reference Laboratory in Salzuflen have now
conducted a publicly funded study to determine the sensitivity and specificity of the
Alere-Determine syphilis rapid test (Hagedorn
2012). The study results have been available
since early April 2012 and were presented in
excerpts at the German STI Congress on 15
June. Unfortunately, the study has so far not
been published in its entirety.
There was only one case where a syphilis infection requiring treatment would have not
been recognised (read off after 15 minutes).
In this case, the reaction on the test strip was
on the borderline after 45 minutes and was
clearly visible only after 60 minutes. This
case concerns a 35-year-old HIV-positive patient in the primary stage of syphilis.
However, it is generally the case with primary-stage infections that antibodies often cannot be detected – the patients are therefore
expressly informed about the “window period”
in testing projects. Furthermore, the patient
was HIV positive. HIV-positive patients
should be examined for syphilis by HIV specialists and not within the scope of testing
projects, since we know that the antibody
formation can be delayed if there is an existing immunodeficiency.
Method: The Determine syphilis rapid test by
the company Alere has been tested on the
basis of a total of 1,000 serum samples and
compared with the results of laboratory diagnostics. 818 of these serums were routine
samples from a large clinic; 178 samples with
a known positive syphilis antibody result were
additionally examined.
Result: The syphilis rapid test detected 205
out of 210 positive samples. The resulting
sensitivity of 97.6% corresponds to the results of other studies. All 5 samples that had
not been recognised concerned so-called serum scars 7“, i.e. the detection of clinically irrelevant residual antibodies following a
previous cured syphilis infection.
Another result of the study (which was, however, not presented at the STI congress) is
that the laboratory screening test read off as
prescribed also failed to detect a case of
syphilis requiring treatment. It also concerned
a patient in the primary stage of the disease.
The rapid test showed a positive result in this
case.
Limitations of the study: The selection of the
sample serums only partly corresponded to
the real-life conditions in the testing projects
in which the rapid test is used. In the study,
nearly one-quarter (50 out of 201) of the
7
Serum scar: Antibodies remain detectable in blood serum for a long time or even life-long. Syphilis has left a
“scar” here, but it is completely cured and thus no longer requires treatment.
9
HIVreport 3/2012: Syphilis
Reading off the result after more than one
hour is usually not possible in low-threshold
testing projects. The patients are not likely to
wait for their results that long. The rapid test
would become a slowcoach.
syphilis-positive samples were provided by
HIV patients, in addition to a great number of
samples from patients with a cured infection
(serum scars). Most of these patients are,
however, identified within the scope of counselling and should not be subjected to a rapid
test. The former because they are required by
the European guideline to undergo annual
syphilis screenings in specialist HIV practices, the latter because their screening results
can already be predicted based on the case
history, making the application of a rapid test
redundant.
For everyday practice, it is decisive whether
the cases requiring treatment (i.e. persons
with an active syphilis infection) are reliably
recognised – and in this respect, the rapid
test performed on par with the laboratory test.
Both of them would not have recognised one
case of primary infection – and the fact that
the detection of antibodies may be difficult at
this stage is well-known and the patients are
informed about it within the scope of counselling.
The “classic” client for the syphilis rapid test
is HIV-negative, has not yet had a syphilis infection (or is not aware of an infection) and
comes to take an HIV and syphilis test.
Under certain conditions (case history and
exclusion of previous syphilis infections,
high prevalence in the tested population,
exclusive use of serum), Deutsche AIDSHilfe still considers the application of the
Alere-Determine tests to be reasonable if
this helps provide advice and tests to
more persons exposed to high risk of contracting syphilis.
It’s often the case with science: The results
are available and the conclusions drawn from
them are different:
Conclusions of the authors:
•
The 4-eyes principle should be applied
when reading off the test results, since
some tests only show unclear test results.
•
The syphilis test should only be conducted with serum or plasma samples.
•
What’s next?
Follow-up study: The Hagedorn study is to
be followed by another, more extensive study
before the end of this year, which is to document the time sequence of the test results
more accurately (15, 30, 45 minutes, etc.), in
addition to investigating the syphilis rapid test
under real-life conditions within the scope of a
Cologne-based testing project.
The test result should only be read off “after at least half an hour or even after a
whole night in order to achieve the maximum test sensitivity”. The final recommendation prescribes that the result be
read off “after two hours, however, no
earlier than after one hour”, alongside a
“final assessment of initially negative results after 24 hours”.
Quality assurance: Since the discussion
about the consequences obtained from the
study has led to substantial uncertainties in
the testing projects, Deutsche AIDS-Hilfe is
introducing an external quality assurance
method for the syphilis rapid test (see below).
Conclusions of DAH:
•
The 4-eyes principle has so far been applied in all DAH testing projects anyway.
•
The performance of the tests with serum
or plasma samples instead of whole blood
has also been the standard procedure in
all DAH testing projects since the introduction of syphilis rapid tests.
•
We still (DAH 2012) recommend – unlike
the authors of the syphilis study – that the
test be read off only after 30 minutes instead of 15 minutes. This would have
made it possible to recognise three of the
four delayed cases documented over the
course of time.
10
HIVreport 3/2012: Syphilis
DAH bears the costs of the quality assurance
and documents the measure taken. Interim
evaluations are performed; the final evaluation will take place in summer 2013.
Quality assurance for syphilis rapid
tests
According to current legislation, HIV and
hepatitis rapid tests are reviewed by the Paul
Ehrlich Institute, while syphilis rapid tests
(and other rapid tests) are not; in these cases, the manufacturer is solely responsible for
quality assurance.
The pilot phase ends on 1 July 2013. The
manufacturers of the rapid tests should offer
quality assurance procedures at this point in
time at the latest.
A guideline of the German Medical Association adopted in 2011 prescribes external
quality assurance procedures for qualitative
laboratory tests as from 1 July 2013. This covers all rapid tests (besides syphilis tests, also HIV and hepatitis tests).
sch/tau
The manufacturers of rapid tests will then be
expected to provide test reagents for interlaboratory tests 8. Users of rapid tests would
then probably examine such external samples and send the results to a central body
twice a year.
Deutsche AIDS-Hilfe will introduce an external quality assurance method for syphilis rapid tests as early as August 2012.
DAH testing projects can participate on a voluntary basis.
Procedure: The syphilis rapid test involves
the taking and centrifugation of blood samples, which is why the serum is available anyway.
Determine syphilis rapid test. Left test strip without
protective foil. The serum is applied at the bottom
(arrows); the control line, and, if the result is positive, also the patient line appears in the top white
fields after several minutes. The latter also indicates the presence of antibodies. photo: sch.
The serum tube of every tenth syphilis
rapid test is sent to a central laboratory,
along with the information whether or not
the rapid test was positive.
The laboratory conducts a screening test. In
case of positive rapid test result and/or positive laboratory test result, further laboratory
tests are conducted with the serum sample in
order to ascertain whether it is caused by a
serum scar or a syphilis infection requiring
treatment.
The results are sent to both the testing project and the medical department of DAH.
8
Interlaboratory tests are a tried and tested method of
external quality assurance in laboratory medicine. A
central body sends blood serums with a defined concentration of antibodies or other substances to be tested to several laboratories (or test facilities). The
laboratories conduct measurements and return the results. In case of deviations from the value to be measured, the respective laboratory needs to make the
necessary corrections.
11
HIVreport 3/2012: Syphilis
Are there any situations where you recommend that your clients should rather have a
conventional laboratory test performed – by a
registered physician?
Interview with Marcus Behrens
Marcus Behrens, qualified psychologist
and technical manager of Mann-O-Meter,
Berlin’s gay information and counselling
centre talks about the use of rapid tests in
Berlin
Yes, if clinical symptoms are present, e.g. if
the client reports about small ulcers while the
test shows a negative result, or if someone
tells us that his boyfriend has syphilis and
they’ve had sex together. Then I would recommend a laboratory test straightaway. The
probability of an infection is just very high in
these cases.
How do you offer the syphilis rapid test?
We offer the syphilis rapid test as a standard
and also somewhat proactively, as we also
want to raise awareness among the men
here.
How often have you conducted the syphilis
rapid test this year?
Since the beginning of the year, we have
conducted 363 syphilis rapid tests. By comparison, we have performed 417 HIV tests.
Twelve syphilis rapid tests, i.e. 3.3%, were
positive.
Do you also have false-positive or falsenegative results?
We have so far not been reported any falsepositive or false-negative results, but we are
currently checking whether the syphilis rapid
test practice should be slightly changed, allowing for the test result to be read off half an
hour or an hour later to increase its reliability.
In this respect, we would like to take account
of the current study results of Professor
Hagedorn.
Markus Behrens, Mann-O-Meter, Berlin
What practical experience have you had with
the rapid test: Is it technically well-feasible or
a bit complicated?
What has changed for Mann-O-Meter since
you have been offering extensive STI diagnostics?
I should mention in advance: We use the
Alere Determine Syphilis TP, which can be a
little messy because you only have a test
strip instead of such a stylish test cassette
like the HIV test, but we use an extra plate for
all test equipment. All in all, the test is fairly
easy to perform with a bit of practice.
There are altogether more men visiting us
than before. Nowadays, few gays come to us
just to get information. After all, most of them
are aware of the basics of safer sex. I don’t
need to tell a 39-year-old gay man, who has
been having gay sex for decades, to use
condoms. Nevertheless, there are also situations where even these men have questions
about infection risks and residual risks, and
simple prevention messages are not helpful.
The test setting, where it is always also about
the individual assessment of infection risks,
allows for in-depth counselling. These men
12
HIVreport 3/2012: Syphilis
would have never had the idea to make use
of our counselling services if we didn’t offer
testing.
And such counselling services are accepted,
although they are somewhat forced?
Yes, the men are usually very grateful to be
able to talk about their sexual lives and risktaking attitude. It’s something new for many
of them. Most men don’t really like going to a
psychologist. During counselling, we also
have the opportunity to ask specifically what it
means when someone says he has “mostly”
safer sex. Not from the standpoint of right or
wrong, but to initiate a thinking process. Then
we also ask questions like: How satisfied are
you with your sexual life? How satisfied are
you with your safer sex management? These
are questions to start a conversation, often
involving topics about which the person has
never worried before in more detail.
Counselling and testing services in Berlin. Soon to
include gonococcal and chlamydial smears?
What are the future prospects? Are you intending to expand your programme?
What are the main counselling topics?
Yes, indeed, we are intending to also offer
chlamydia and gonorrhoea tests in the future
to detect hidden infections, as these undetected infections also have an effect on HIV
transmission. Whether we will manage to do
so is mainly a matter of funds. In this regard,
we would be happy to get more support from
policymakers instead of repeated budget cutbacks.
Even if they have been more or less openly
gay for many years, many gay men have
considerable problems with their homosexuality. But topics that are only addressed secretly are often put under taboo. When you’re
a member of the gay community, you can’t
have a problem with it and must have accepted that you’re gay. Occasionally, these
men experience their own homosexuality as
being something harassing, sometimes as
“dirty sexuality”, for example when they have
sex in a dark room but they actually disapprove of it because it doesn’t match their
moral concept. This certainly doesn’t apply to
all men visiting us, but it’s a frequent topic in
consultations.
tau
Do you only have one-off consultations on
account of the test programme or do the men
visit you repeatedly?
We have about 80% repeat testers, so counselling sessions can often pick up where a
previous one left off.
13
HIVreport 3/2012: Syphilis
Therapy
Neurosyphilis
The most effective substance, penicillin, has
been available since 1943. Early-stage syphilis (< 1 year following the infection) requires
less intensive treatment. Early detection is
worthwhile!
If the cranial meninges and the brain are affected, the preferred therapy is the intravenous
administration
of
penicillin
or
ceftriaxone. The therapy should last for at
least 14 days.
Therapy of early-stage syphilis
Herxheimer reaction
In some patients, what is referred to as the
“Jarisch-Herxheimer reaction” occurs in the
first 2 days after starting the therapy. The disintegration of the pathogens causes the excretion of toxic substances, resulting in a flulike feeling of malaise, accompanied by shivers, articular pain and skin rash.
There are various approaches and attitudes
to (proactive) therapy:
1st choice: Penicillin. One injection of benzathine-pencillin given into each buttock is
the optimum treatment of early-stage syphilis
(<1 year following the infection).
1. A cortisone therapy PRIOR to administering penicillin prevents or reduces the
Herxheimer reaction quite reliably.
2nd choice: Less effective alternatives (e.g. if
a penicillin allergy is present) include ceftriaxone injected intravenously over 10 days, or
doxycycline or erythromycin taken orally
over 14 days.
2. The patient is given cortisone (sometimes
also paracetamol) to take away; this only
treats the symptoms already present. In
addition, paracetamol is not capable of
controlling the Herxheimer reaction but
can only alleviate its symptoms.
Last choice: A single dose of azithromycin
taken orally. Azithromycin has been “popular”
with physicians and patients because one
tablet taken as a single dose is sufficient.
However, this antibiotic increasingly involves
resistances, which is why its use should be
avoided.
3. “The patient will get in touch when he’s
feeling worse.” The cortisone therapy
comes too late when following this strategy.
A single dose of cortisone involves no side effects.
sch
Therapy of late syphilis
Late syphilis (existing for more than one year)
and syphilis of unknown duration require
longer treatment.
Further literature online:
H. Schöfer: Syphilis. In: Schöfer H, Baur-Beger S
(ed.) 2010, Derma-Net-Online
German STI Society. Syphilis. Guideline 2008
Deutsche Society of Neurology: Neurosyphilis.
Guidelines, 2008. AWMF online The only syphilis
9
guideline currently listed with AWMF
German STI Society. Brief information on syphilis.
1st choice: Penicillin. One injection of benzathine-penicillin given into each buttock over
three weeks (day 1, 8, 15).
2nd and 3rd choice: Ceftriaxone injected intravenously over 14 days, or doxycycline or
erythromycin taken orally over 28 days.
9
AWMF=Association of Scientific Medical Societies.
Publish and promote quality-tested and evidence-based
guidelines.
14
HIVreport 3/2012: Syphilis
Guilt and shame: History of syphilis
Out of the blue
logical theories (e.g. constellation of Saturn
and Jupiter on 25/11/1484), especially the
theological view established itself: The disease was seen as God’s punishment for “obscene” behaviour. In this connection, the
origin of the name “syphilis” is also interesting: Syphilus seems to be the Latin equivalent of the Ancient Greek name Sýphilos,
literally meaning “loving pigs”. Syphilis as a
disease caused by “filthy sexuality”?
The disease hit Europe suddenly: In 1495,
the armies of King Charles VIII of France and
King Ferdinand I of Naples were facing each
other. Ferdinand I was also supported by soldiers who has returned with Christopher Columbus from the New World two years ago –
carrying the syphilis pathogen from there to
Naples. The conditions were ideal for the disease to spread: After several weeks of siege,
the armies formed an alliance with each other
and celebrated for several weeks – with thousands of sutlers and prostitutes travelling
along in the baggage train of the army of
Charles VIII.
This worked, and partly still works, that well
because it picks up the thread of old Christian
threats, as demonstrated by an example from
the Old Testament: “But if you will not obey
the Lord your God by diligently observing all
his commandments and decrees, which I am
commanding you today, then all these curses
shall come upon you and overtake you: […]
The Lord will afflict you with the boils of
Egypt, with ulcers, scurvy, and itch, of
which you cannot be healed.” (Deuteronomy
28, 15, 27)
The disease of the others
When the armies returned to their home
countries, syphilis spread all over Europe. Its
nomenclature more or less followed the way
of the syphilis epidemic:
The explanatory model of syphilis as a punishment was not only advocated by the
church but also by physicians.
In France, syphilis is called the Italian disease
(according to its origin, Naples), in Italy the
French (according to the origin of the army of
Charles VIII), in Germany and Spain the
French, in Russia the Polish, in England the
French or Spanish and in Norway the Scottish disease. The Italian physician and poet
Girolamo Fracastoro called the disease with
the many names “syphilis” for the first time in
a didactic poem published in 1530.
A disease changes sexuality
Syphilis succeeded in what the Catholic
Church had not been able to accomplish until
that point: It terminated the lack of inhibition
in the sexual morale of the Late Middle Ages.
Until that point in time, the suppression of
sexuality was considered to cause diseases
and visits to brothels were normal; men and
women bathed naked together in public
baths. Syphilis put an end to these practices;
many brothels and public baths fell into disrepair; the way of life changed (Winau 2002).
The punishment of God
In his poem, Fracastoro tells the story of a
shepherd named Syphilus, who falls away
from the cult of the sun god, guides his nation
to a new religion and gets horribly punished
for that: “Their bodies covered with hideous
taints, deploying their youth destroyed in its
bloom, and have cursed the gods and threatened the sky! Unfortunates! Night which
pours sweet repose upon all nature has no
more charms for them, for sleep has fled from
their eyes. Then, this terrible disease known
since then among us by the name of Syphilis
– does not take long to spread in our entire
nation, not even sparing our King himself!”
A disease changes faces
When it first occurred in Europe, syphilis was
not the same disease as it is known today: It
had a considerably more severe course and
was fatal in numerous cases. The diseased
persons were covered with ulcers and skin
rash. Due to its massive presence, as many
as ten medical publications on the new disease were published between 1495 and
1500. The epidemic reached its climax in Europe in 1530; the first publication from Japan
dates back to 1512. The pathogen attenuated
Humankind was seeking an explanation for
the new plague. It was soon recognised that it
is transmitted through sex. Alongside astro15
HIVreport 3/2012: Syphilis
within just a few years: Because not the most
dangerous treponema have the best opportunities of spreading further but those which
let their host live (and experience sexuality)
longer and without stigmatising skin lesions.
The attenuation of the disease had an effect
on diagnostics. Whereas infected persons
were clearly marked in the first few years, the
course of the disease is less severe today.
The painless ulcer in the first stage is often
overlooked and the skin rash in the second
stage is often attributed to other reasons; after this, syphilis seems to “disappear”. Therefore, it is important today to also test
asymptomatic persons exposed to a syphilis
risk.
The wig helped hide syphilitic ulcers on the head
and loss of hair. Powder was used for the face. Photo: Dieter Schütz/pixelio.de
Initial behavioural and structural preventionThe primary route of transmission was already known in 1497: It was recommended
avoiding sexual intercourse with “pustulous
persons” or women “who previously lay with a
pustulous person”. It was also recommended
to wash the penis after cohabitation. Linen
cloths soaked in tinctures wrapped around
the penis prior to sexual intercourse are the
precursors of linen and silk condoms introduced in the middle of the 16th century. But
also cinnabar fumigations after sex were expected to prevent the disease.
Syphilis was initially treated like a skin disease by applying mercury-based ointments
and administering the heavy metal orally. The
signs of poisoning caused by following this
“treatment regimen” for up to 40 days – aching and loose teeth and hypersalivation –
were considered to be the signs of recovery.
Mercury cures and fumigations with cinnabar 10 claimed many victims. Syphilis patients were virtually poisoned with mercury
treatments and the disease remained incurable well into the 20th century.
The first hygiene and structural prevention
measures date back to circa 1496 in Nuremberg. Surgical devices used to treat syphilis
patients were not reused and syphilis patients
were no longer admitted to public baths. Attempts to contain the epidemic by isolating or
expelling syphilis patients from the cities
failed.
«A night in the arms of Venus leads to a
lifetime on Mercury.»
The situation did not change until 1909, when
Paul Ehrlich developed an arsenical drug,
which made it possible to cure the disease.
Since 1910, this has also been reflected in
the drug’s name: Salvarsan is a composition
of “salvare” (= to heal), arsenic and “sanus”
(= healthy), thus meaning “remedial arsenic”.
Arsenic is, however, extremely toxic. These
substances were used to eliminate unpleasant fellow human beings not only in the comedy “Arsenic and Old Lace”. Salvarsan
treatment also involved application problems
for the staff and many side effects for the patients.
Martial therapy: Until the teeth got loose
Syphilis patients had no effective therapeutic
option at their disposal for four centuries.
Consequently, no one was safe from the disease.
«We are democratised and venerealised.»
(Baudelaire, 1848)
In 1943, Salvarsan was superseded by penicillin, an effective drug involving fewer side
effects. Even today, almost 70 years later,
10
Cinnabar: Mineral with a quantity ratio of 1:1 of sulphur and metal.
16
HIVreport 3/2012: Syphilis
ment and initial successes with substances
involving a great deal of side effects: All this
shows parallels to HIV infection, except that
the development regarding HIV proceeded
within a considerably shorter period of time.
this active substance is still the number one
therapeutic option.
Inhuman medicine
1. The Tuskegee Study
If any, we can draw the following lesson from
the way syphilis used to be handled: The exclusion of diseased persons or metaphors involving guilt and punishment do not help in
overcoming an epidemic. It was only the scientific research of therapeutic and protective
options that made it possible for us to deal
with the disease and the persons affected in
a more reasonable manner. Full destigmatisation has nevertheless not been
achieved. Even today, many people feel embarrassed to have contracted syphilis. This
may be attributed to the fact that STIs are associated with a promiscuous, sinful sex life.
Anyone who suffers from an STI is thought to
have either been “unfaithful” or have even
acquired venal love. This is how the idea of
faithfulness in a partnership and “what it
takes for a good and appropriate sexual attitude” merge with the stance on a bacterial
disease.
Between 1932 and 1972, unethical syphilis
experiments were performed on people in the
small town of Tuskegee in the US state of Alabama. The goal was to gain insights into the
natural course of the disease, because although syphilis had already been know for
centuries, there were (and still are) some
open questions. Formerly, syphilis was far too
often confused with other diseases – or involved co-infections.
The course of the disease was documented
in roughly 400 African-American farm workers. They themselves had not been informed
or they were provided incorrect information:
They were told that they were suffering from
“bad blood”, were treated and received money to travel to the study centre. The experiment was not stopped even when an effective
remedy, penicillin, became available in 1943.
The scandal did not become public and the
study was not stopped until 1972.
How about HIV? HIV research is currently focussed on healing the disease. This is the
right approach and there should be more
funding for this purpose. What will happen if
the disease becomes curable? Will the stigmatisation and exclusion of HIV-positive people come to an end? Experience with syphilis
has shown that not “everything is going to be
alright” then. Our society seems to be far
away from understanding STIs as common
infectious diseases. There is another lesson
we can learn from syphilis: Even if it can be
reliably cured, the disease is still far from being defeated!
2. The Guatemala Experiment
In the 1940s, the effect of penicillin was tested in Guatemala on 1,500 persons. In this effort, prostitutes were infected with syphilis
and gonorrhoea and were encouraged to
have unsafe sex with clients; later on, soldiers, mental patients and prison inmates
were also infected. Only the authority, but not
the persons affected, were asked for their
consent and were informed. This dark chapter of syphilis experiments did not become
public until 2010; President Obama thereupon apologised to the Guatemalan president.
Deutsche AIDS-Hilfe still considers it important to counteract taboos and selfrighteousness regarding the issues of sexuality and STIs and to exert an influence on
bacterial or viral infections being discussed
from a medical instead of a moral point of
view.
Can we still learn something from syphilis?
The sudden occurrence of a previously unknown disease, the rapid recognition of the
primary route of transmission, the attribution
of the disease to “others”, futile attempts of
exclusion and segregation, the designation of
the disease as the punishment of God, the
changes in both sexual attitude and social
circumstances, desperate attempts of treat-
sch/tau
Further literature online:
Spiegel online: Guatemala. Obama apologises
for syphilis experiments. 02/10/2010
Wikipedia: Tuskegee Syphilis Study
Rolf Winau: Since Cupid’s quiver also shoots
poison arrows. The spread of syphilis in Europe.
17
HIVreport 3/2012: Syphilis
References
Imprint
Bremer V, Brockmeyer N, Hagedorn H-J, Marcus U,
Meyer T, Nitschke H, Nick S, Ross S, Straube E
(2012): Schnelltests in der Diagnostik sexuell
übertragbarer Infektionen; Gemeinsame Stellungnahme
des RKI, PEI und der DSTIG. Epidemiologisches
Bulletin des RKI, 06.02.2012 (Nr. 5).
Publisher
Deutsche AIDS-Hilfe e.V., Wilhelmstr. 138
10963 Berlin
Tel: (030) 69 00 87- 0
Fax: (030) 69 00 87- 42
www.aidshilfe.de
Deutsche AIDS-Hilfe 2012: HIV- und STI-Tests: Informationen und Standards 2012/2013. 3. Auflage, Bestellnummer 116001, als PDF online.
Responsible in the sense of the German
"Pressegesetz" (law on publishing/news):
Steffen Taubert (tau)
Armin Schafberger (sch)
Gray RT et al. (2011): Will Changes in Gay Men`s
Sexual Behaviour Reduce Syphilis Rates? Sexually
Transmitted Diseases, Vol. 38, Number 12, December
2011
Editorial staff
Armin Schafberger, Uli Sporleder, Steffen Taubert
[email protected]
Hagedorn
H-J,
(2012):
Syphilis-Schnelltest;
Präsentation am 15.06.2012 auf dem Kongress der
Deutschen STI-Gesellschaft in Berlin
Hagedorn H-J, Münstermann D (2012): SyphilisSchnelltest – orientierende Studie zur Spezifität und
Sensitivität. 03.04.2012 unveröffentlicht.
Texts
Armin Schafberger, Physician, MPH
Steffen Taubert, Qualified Psychologist
Herring et al. (2006): A mulit-center evaluation of nine
rapid, point-of-care syphilis tests using archived sera.
Sex Transm Inf 82, Suppl V: v7–v12.
German-English Translation: Macfarlane International Business Services GmbH & Co. KG
Li J, Zheng HY et al. (2009): Clinical evaluation of four
recombinant Treponema pallidum antigen-based rapid
diagnostic tests for syphilis. J Eur Acad Dermatol
Venereol 23: 648–650.
Order new and download older
sues: www.hivreport.de
Long FQ et al. (2012): Acquired Secondary Syphilis in
Prescool Children by Nonsexual Close Contact.
Sexually Transmitted Diseases, online ahead of print
(Stand Juli 2012)
Donations account of Deutsche AIDS-Hilfe e.V
Account no. 220 220 220
Berliner Sparkasse
Sort code 100 500 00
Mabey D et al. (2006): Prospective, multi-centre clinicbased evaluation of four rapid diagnostic tests for
syphilis. Sex Transm Infect 2006;82(Suppl V):v13–v16.
doi: 10.1136/sti.2006.022467
Notice
The procedures, medication, constituents and generic drugs are communicated regardless of the
existing patent situation. Protected product names
(trademarks) are not always marked as such;
however, this must not give rise to the assumption
that the designations used are non-proprietary
names.
Deutsche AIDS-Hilfe accepts no liability for the
correctness of the information provided as well as
for any damage caused by possible errors. We
recommend that our readers refer to the manufacturers’ summary of product characteristics and
package inserts.
McCann PD et al. (2011): Would Gay Men Change
Their Sexual Behaviour to Reduce Syphilis Rates?
Sexually Transmitted Diseases, Vol. 38, Number 12,
December 2011
Rekart M et al. (2000): Mass treatment/prophylaxis
during an outbreak of infectious syphilis in Vancouver,
British Columbia. Can Commun Dis Rep. 2000 Jun
15;26(12):101-5.
RKI (2007): Syphilis. Ratgeber für Ärzte. online
RKI (2012): Erneuter Anstieg der Syphilis-Meldungen in
2011. Epidemiologisches Bulletin, 18. Juni 2012
Schmidt AJ (2011): Alles auf GUM; Warum wir in Europas Metropolen Zentren für schwule Gesundheit
brauchen. Vortrag auf dem Deutsch-Österreichischen
AIDS-Kongress, Hannover, Juni 2011.
The translation of this issue was made possible by the support of
Siedner M et al. (2004): Performance of rapid syphilis
test in venous and fingerstick whole blood specimens.
Sex Transm Dis 31: 557–560.
Singh AE und Romanowski B (1999): Syphilis:
Review with some Emphasis on Clinical, Epidemiologic
and some Biologic Features. Clinical Microbiology
Reviews, Apr. 1999, p. 187-209
Winau R (2002) : Seit Amors Köcher auch vergiftete
Pfeile führt. FU Berlin, Wissenschaftsmagazin, online
18
HIVreport 3/2012: Syphilis
19