Le insidie della sifilide: epidemiologia, diagnosi e terapia

Società Italiana di
Medicina Tropicale e
Salute Globale
Le insidie della sifilide:
epidemiologia, diagnosi e terapia
Prof. Francesco Castelli
Cattedra di Malattie Infettive, Università di Brescia
Cattedra UNESCO per la Formazione del personale sanitario nei Paesi a basse risorse
Presidente, Società Italiana di Medicina Tropicale e Salute Internazionale
Delegato del Rettore per la Cooperazione allo Sviluppo
Domain Bacteria
Phylum Spirochaetaltes
Class Spirochaetes
Order Spirochaetales
Family Spirochaetaceae
Genus Treponema  Species T. pallidum
T. pallidum subsp pallidum
“
“
venereal treponematoses
subsp pertenue
“
“
subsp endemicum
“
“
subsp carateum
Yaws (Framboesia)
non-venereal
endemic
Bejel
treponematoses
Pinta
99,8% genomic identity
Farnsworth and Rosen. Clinics in Dermatology (2006) 24, 181–190
In Europa da Americhe (teoria Colombiana)
In Spagna e Portogallo da Africa
Pre-esistente in Europa ma con epidemiologia diversa
A probable case of congenital syphilis from pre-Columbian Austria.
Gaul JS et al. Anthropol Anz. 2015 Sep 30
Treponema pallidum subspec pallidum
Syphilis
Sexual transmission
Transplacental transmission
Direct non-sexual transmission
Blood transfusion/organ transplantation
Sifilide Acquisita
Sifilide primaria: lesione ulcerosa indolente nel
sito di infezione (sifiloma) con adenopatia
satellite, compare nella sede di contatto col
Treponema, di solito è unico.
Sifilide Acquisita
Sifilide secondaria: manifestazioni muco-cutanee
(rash cutaneo, lesioni maculo-papulari palmoplantari) e viscerali (linfoadenopatie, epatite,
poliartrite, irite o iridociclite, meningite
secondaria)
Sifilide Acquisita
Sifilide terziaria: cutanea
(gomme cutaneo-mucose),
manifestazioni ossee,
articolari e muscolari,
cardiovascolari (arteriti e
aneurismi), SNC (paralisi
progressiva, tabe dorsale)
Sifilide Acquisita
Sifilide latente : è totalmente asintomatica, la
diagnosi è unicamente sierologica.
• precoce: da meno di 2 anni
• tardiva: da più di 2 anni
• di durata indeterminata: epoca del contagio
sconosciuta
Cicatrice sierologica: positività di EIA/TPHA con
RPR negativo e storia documentata di
precedente trattamento con penicillina
RISK OF SYPHILIS TRANSMISSION
Sexual
transmission
Vertical
transmission
60 - 30%
100 -
50
-
30
-
10%
Number of primary and secondary syphilis cases among men who have sex with
men, by race/ethnicity — National Notifiable Diseases Surveillance System, 34
states* and the District of Columbia with complete sex partner data, 2009–2012
†
MMWR 2014, 63(18)
SYPHILIS - USA (15): (INDIANA) RISING INCIDENCE, MEN WHO HAVE SEX WITH MEN
**************************************************************************
A ProMED-mail post
ProMED-mail is a program of the International Society for Infectious Diseases
Date: Fri 30 Oct 2015
The Tippecanoe County Health Department is tracking an increase in the number of syphilis cases in the
area. This year [2015], there have been 12 reports of syphilis in Tippecanoe County compared with fewer
than 5 reports in each the of the previous 4 years, the health department said on Friday [30 Oct 2015].
Local and state health departments are partnering to "closely monitor this trend, educate the public and
health care providers about syphilis, and help facilitate proper testing and treatment of affected individuals,"
according to a press release from the department.
Jeremy Adler, the county department's health officer, said anecdotal reports suggest those contracting the
infection are engaged in risky sexual behavior with multiple partners. Adler said that smartphone apps such
as Tinder that facilitate random sexual encounters, could be contributing to the issue. He noted the disease is
spread through sexual contact and not through drug use, such as sharing needles. "Syphilis is often viewed
as a disease that happened a long time ago that was a problem in the old days," Adler said. "But clearly, this
shows that it still can be a big problem, and it's something that we have to really be aware of and educate the
public about."
Statewide, Indiana is following the same trend. More than 350 cases of syphilis were reported between 10
Jan-3 Oct of this year [2015], representing a 53 per cent increase from last year, according to a press release
from the Indiana State Department of Health. "This is an alarming increase in the number of people being
diagnosed with a preventable and curable disease," state health commissioner Jerome Adams said in the
release.
Most cases have occurred in men who have had sexual contact with other men, although some heterosexual
cases have been reported, according to the state's information.
Syphilis is a sexually contracted infection and in certain stages can cause symptoms including sores, fever,
muscle aches and weight loss. For more information, visit the Centers for Disease Control website at <
http://www.cdc.gov/std/syphilis> or call the county health department's nursing division at 765-423-9221.
Incidenza di sifilide in Europa, 2003-12
ECDCD Annual epidemiological report 2014 – STIs
Notiziario ISS 2014; 27 (4)
♂ hetero
♂
♂ MSM
♀
Diagnosi di sifilide
DIAGNOSI SIEROLOGICA
1.
Test non treponemici: valutano l’attività
della malattia e la risposta terapeutica
dopo trattamento (VDRL, RPR)
2.
Test treponemici: basati sulla ricerca di
anticorpi diretti contro antigeni specifici
(TPHA, TPPA, FTA-ABS)
Tre differenti algoritmi per la sierodiagnosi
di sifilide
Congenital syphilis
Sifilide congenita
Rischio di trasmissione verticale
(nelle donne non trattate)
•
•
•
•
Sifilide primaria: 70-100%
Sifilide secondaria: 67%
Sifilide latente precoce: 40-83%
Sifilide latente tardiva: 2,5-10%
Sifilide congenita
Probabilità di trasmissione
 Il rischio aumenta col progredire dell’epoca di gestazione
 Il trattamento tempestivo abolisce il rischio di
trasmissione verticale
 Trasmissione possibile se intervallo tra terapia e parto
inferiore a 4 settimane
Screening e diagnosi precoce
Lesioni ulcerative
Hutchinson teeth
Fronte olimpica
Pregnant women with
active syphilis
1,360,485 (1,160,195-1,560,776)
With ANC
1,085,637 (79.8%)
Stillbirths or fetal deaths
285,702
Neonatal deaths
122,444
Premature or LBW
81,629
Infected newborns
217,678
Newman L et al. PLoS Med 2013
Syphilis seropositivity among antenatal care
attendees, 2008 or 2009
Newman L et al. (2013) Global Estimates of Syphilis in Pregnancy and Associated Adverse Outcomes: Analysis of
Multinational Antenatal Surveillance Data. PLoS Med 10(2): e1001396. doi:10.1371/journal.pmed.1001396
SYPHILIS - AUSTRALIA (02): (NORTHERN TERRITORY, WESTERN AUSTRALIA)
INCREASE, INDIGENOUS PEOPLE, CONGENITAL
**********************************************************************************************************
Date: Sun 1 Nov 2015
Health authorities are scrambling to contain an outbreak of syphilis that is believed to have claimed the lives of 10 babies
across northern Australia.
Professor Basil Donovan, of the Sydney-based Kirby Institute, said while instances of the sexually transmitted infection
(STI) were in decline, an outbreak that started in northern Queensland in 2011 had swept across the Top End. "We got a
large outbreak amongst very young people in the Gulf country in Queensland, and since that time it's turned up in the
Katherine area of the Northern Territory and then swept across the Kimberley [Western Australia]," he said. "We worry
because if pregnant women catch syphilis, the result is very frequently disastrous. It leads to loss of pregnancy, stillbirths,
[births] of very disabled babies." Professor Donovan said 10 babies had died as a result of congenital syphilis since the
outbreak began. "A rich country like Australia, shouldn't really be seeing any deaths," he said.
The Kirby Institute's national surveillance system showed 2000 new cases were diagnosed in 2014. As of [30 Oct 2015],
another 1972 cases had been recorded in 2015, making it the most severe Australian outbreak in 30 years. The only other
group affected outside of northern Aboriginal communities are urban gay communities. Professor Donovan said in cities
like Melbourne, Sydney, and Perth, the STI was almost entirely limited to gay men.
Syphilis can cause dementia, blindness, [and] brain damage. Syphilis can be cured with a simple course of antibiotics, but
if left untreated the STI can have serious health impacts, including dementia, blindness, and permanent damage to the
heart and brain.
The northern outbreak crossed the NT border into WA last year [2014] and health authorities in the Kimberley are trying to
contain its spread. Broome-based sexual health nurse Katy Crawford said for the 2 years to June 2014, the region had
been syphilis-free. But since then, more than 40 people had been infected, and dozens more may be carrying it without
realising. "It is a significant health concern for the region, and we expect this outbreak to continue for a number of months
to years," he said. "It will be difficult to contain unless we get more people tested, and more people practising safe sex.“
Another challenge was finding materials suitable to Indigenous teenagers with often limited English and no understanding
of sexual health. "A lot of resources that we have available are created in a metro area where there's very high literacy, so
we're trying to create locally appropriate resources," Ms Sibosado said. "One campaign we've started is around the rodeo
round that happens up here in the Kimberley, encouraging people to have safe sex, and letting them know where to get
more information." The campaign includes condom wallets and posters featuring a rugged looking Aboriginal rodeo rider
looking for love
Syphilis seroprevalence in pregnant women
in European Countries
Country
Seroprevalence (%) year
source
UK
0.44
2007
Giraudon. Euro Surveill 2009; 14: 8-12
Italy
0.49
2007
Marangoni. Clin Microbiol Infect 2008; 14
(11): 1065-8
Poland
0.16
2003
Rudnick. Euro Surveill 2005;
10:E050519.3
Czech Rep.
0.16
2001
Zakoucka. Euro Surveill 2004; 9:18-20
Congenital syphilis in Italy: a multicentre study
Newborns with
CS (n. 25)
N (%)
Newborns without
CS (n. 182)
N (%)
RR (IC 95%)
Foreign born mother
19 (76)
142 (78)
0.90 (0.4-2.1) 0.82
Mother < 20 yrs old
7 (28)
14 (7.7)
3.44 (1.6-7.3) 0.005
No antenatal screening 8 (32)
21 (11.5)
3.1 (1.4-6.6)
0.003
Inadequate antenatal
treatment
45 (24.7)
15.3 (5.2-47)
0.0001
22 (88)
P-value
Tridapalli et al. For the Italian Society of Neonatology. Arch Dis Child Fetal Neonatal Ed. 2012 May;97(3):F2113. doi: 10.1136/adc.2010.183863. Epub 2010 Sep 24
Diagnosi di sifilide congenita
ISOLAMENTO
T.PALLIDUM DA
LESIONE
SIEROLOGICO
IgM
+
TITOLO TPHA/RPR
CLINICO
CERTAMENTE
INFETTO
SEGNI/SINTOMI
COMPATIBILI
ASINTOMATICO
> 4VV
˂ 4VV
ALTA
PROBABILITÀ
DI INFEZIONE
BASSA
PROBABILITÀ
DI INFEZIONE
Syphilis and HIV
The High Risk of an HIV
Diagnosis Following a
Diagnosis of Syphilis: A
Population-level Analysis
of New York City Men
1 in 30 diagnosed with
HIV within a year of
syphilis infection.
Time trends in the incidence rates of STIs in
HIV patients, Taiwan, 2000-2010
Chen YC. J AIDS 2015
Sifilide e HIV: epidemiologia
AUTOCTONI :
Prevalenza HIV nei
pazienti con sifilide
MIGRANTI:
ECDC technical report 2014: Assessing the burden of key infectious diseases affecting migrant populations in the EU/EEA
Sifilide e HIV: epidemiologia
M.C. Salfa, V. Regine, M. Ferri et al. Not Ist Super Sanità 2013;26(6):3-9
Prevalenza ed incidenza di sifilide in persone
con infezione da HIV – Brescia
Popolazione: 1905 soggetti HIV+
Periodo in studio: gennaio 2001 - luglio 2007
Prevalenza di sifilide*: 18,6% (238/1280 soggetti).
Incidenza di sifilide**: 43,8 casi/1000 persone/anno
* TPHA positivo all’ingresso nella coorte
** Conversione TPHA nel periodo di follow up
Matteelli A. et al. ECCMID 2008
Analisi univariata dei fattori di rischio associati ad un
incremento del rischio di sieroconversione per sifilide
Parametro
OR
Sesso (M)
5.2
Età (≥35 vs <35)
0.9
Nazionalità (Italia vs altro)
0.7
Trasmissione (sex vs altro)
2.8
Trasmissione (omo-bisex vs altre) 6.2
IC (95%)
p
1.8 – 14.8
0.5 – 1.7
0.3 – 1.4
1.2 – 6.7
3.3 - 11.7
0.001
0.822
0.368
0.020
<0.005
La modalità di trasmissione omo-bisessuale è risultata
indipendentemente associata al rischio di sieroconversione per
sifilide (HR 4.4, IC 95% 2.3 - 8.3, p< 0,005).
Matteelli A. et al. ECCMID 2008
Incidenza di sifilide in persone con infezione
da HIV. Coorte ICONA
Popolazione: 1744 soggetti
Tempo di analisi: 1997- 2006
Incidenza di sifilide: 23,4 casi/1000 persone/anno
Incremento dell’incidenza negli anni:
 11,3 casi/1000 persone/anno nel 1997
 21,3 casi/1000 persone/anno nel 1998-2000
 27,2 casi/1000 persone/anno dal 2000-2006
Cicconi P. et al. Infection 2008; 36: 46
Sifilide e HIV: diagnosi
Salute sessuale e riproduttiva:
La prevenzione, la diagnosi periodica e la
cura di tutte le IST dell’assistito e/o infezioni
che abbiano a che fare comunque con la
sfera sessuale, quindi intese nel senso più
ampio del termine. Lo screening deve
essere eseguito a tutte le persone con HIV
al momento della diagnosi e con
periodicità almeno annuale [AI].
Tale tempistica è da ridefinirsi [BIII]:
• Secondo lo stile di vita della persona, in
accordo con il curante;
• Nel caso vengano riportate o riscontrate
sintomatologie riguardanti le IST;
• Quando la persona con HIV appartiene a
popolazioni ‘epidemiologicamente’ più a
rischio per IST
Impatto della sifilide su HIV
Nicola M. Zetola and Jeffrey D. Klausner Syphilis and HIV Infection: An Update Clinical Infectious Diseases 2007; 44:1222–8
Sifilide e HIV: reciproca influenza
Sifilide e HIV: terapia
Regimi terapeutici di seconda linea NON adeguatamente studiati nei pz HIV+: necessario tentativo
di desensibilizzazione in caso di allergie alla penicillina
E’ necessario UNO STRETTO FOLLOW UP sierologico (test quantitativi non treponemici) a 3, 6, 9, 12
e 24 mesi dopo la terapia per valutare eventuali fallimenti terapeutici
Nicola M. Zetola and Jeffrey D. Klausner Syphilis and HIV Infection: An Update Clinical Infectious Diseases 2007; 44:1222–8
Klausner JD, Kohn RP, Kent CK. Azithromycin versus penicillin for early syphilis. N Engl J Med 2006; 354:203–5;
Neurosifilide e HIV: terapia
Marra CM, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in
human immunodeficiency virus–infected individuals. Clin Infect Dis 2000; 30: 540–4.
Neurosifilide: storia naturale
Esposizione
10-90
giorni
Sifilide primaria
4-10
settimane
Neurosifilide precoce
Invasione
25-60%
del SNC
Asintomatica
Sintomatica 5%
Meningite acuta
Sifilide secondaria
Neurite di nervi cranici
Ricaduta
24%
Interessamento oculare
Sifilide latente
precoce
Malattia meningovascolare
Sifilide latente
tardiva
Sifilide terziaria
Sifilide
cardiovascolare
10%
(20-30 anni dopo
l’infezione)
Malattia delle gomme
15%
(1-46 anni dopo
l’infezione)
Neurosifilide tardiva
Paralisi generale
2-5%
(2-30 anni dopo)
Tabe dorsale
2-9%
(3-50 anni dopo)
Golden MR et al. Update on syphilis. Resurgence of an old problem, JAMA 2003
Brain:Psychiatric, meningovascular, motor,
seizures, masses, headache
Spine: Mass, meningomyelitis
Peripheral Nervous System
Neurosifilide: epidemiologia
Brescia, Gennaio 2005-Dicembre 2009
1.Prevalenza di neurosifilide nel campione in studio
329 pazienti
TPHA + e
HIV +
378 episodi
di sifilide
6 in sifilide recente
5 in sifilide latente tardiva o
122
rachicentesi
di durata indeterminata
13 (76%)
17 (13.9%)
Diagnosi di
Neurosifilide
Asintomatici
4 (24%)
Con sintomi
neurologici
2 in fallimento terapeutico
TUTTI in sifilide recente
Neurosifilide:
Neurosifilide:epidemiologia
epidemiologia
Brescia, Gennaio 2005-Dicembre 2009
Brescia, Gennaio 2005-Dicembre 2009
3.
Analisi dei fattori associati alla diagnosi di neurosifilide
ANALISI UNIVARIATA
OR (IC 95%)
P value
N.A.
0.624
1.17 (1.09-1.26)
0.594
Nazionalità italiana
4.62 (1.00-21.25)
0.051
Stadio sifilide recente
3.46 (1.10-10.87)
0.046
Presenza di segni/sintomi
neurologici
1.85 (0.53-6.42)
0.302
RPR positivo
1.20 (1.10-1.31)
0.073
RPR > 1:32
2.75 (0.97-7.84)
0.090
Linfociti T CD4 > 350 cell/mm3
1.30 (0.44-3.83)
0.788
TARV in corso
1.29 (0.46-3.59)
0.794
Età
Genere maschile

ANALISI MULTIVARIATA
OR (IC 95%)
P value
3.33 (1.0510.53)
0.040
Titolo sierico RPR >1:32 aumenta la probabilità di neurosifilide (p value: 0.09)
Neurosifilide in HIV: chi deve fare
la rachicentesi?
1
Criteri di Marra
et al., condivisi
dalle linee guida
europee del
2014 (IUSTI)
SEGNI/SINTOMI DI INTERESSAMENTO
NEUROLOGICO, OFTALMICO O UDITIVO
NO
2
FALLIMENTO
TERAPEUTICO
NO
3
Rachicentesi
SI
Rachicentesi
SI
CD4 <350 cellule/mm3 e/o titolo RPR >1:32
INDIPENDENTEMENTE DALLO STADIO
Follow-up sierologico
NO
SI
Rachicentesi
Marra CM et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features,
JID 2004
Neurosifilide in HIV: chi deve fare
la rachicentesi?
1
SEGNI/SINTOMI DI INTERESSAMENTO
NEUROLOGICO, OFTALMICO O UDITIVO
Linee guida
NO
SI
Rachicentesi
CDC, 2015
2
FALLIMENTO
TERAPEUTICO
NO
SI
Rachicentesi
Sexually Transmitted Diseases Treatment Guidelines, 2015 Kimberly A. Workowski, Gail A. Bolan, MMWR
Recomm Rep 2015;64
Neurosifilide in HIV: diagnosi
TPHA/FTA +
e
Incremento della conta
cellulare
(5–10/mm3)
O
RPR/VDRL +
5 cell/microlitro
20 cell/microlitro
nei soggetti HIV
Neurosifilide: terapia
Neurosifilide: monitoraggio
Normalization of serum RPR titer correctly predicts normalization of
CSF and clinical measures after neurosyphilis treatment, and followup lumbar puncture can be avoided
Normalization of Serum Rapid Plasma Reagin Titer Predicts normalization of Cerebrospinal Fluid and Clinical Abnormalities after
Treatment of Neurosyphilis M. Marra, Clare L. Maxwell, Lauren C. Tantalo Clin Infect Dis. 2008 October 1; 47(7): 893–899
Ringraziamenti
Dott.ssa Lina R. TOMASONI, AO Spedali Civili di Brescia
Dott.ssa Alessandra APOSTOLI, Università di Brescia
Neurosifilide in HIV: chi deve fare
la rachicentesi?
Nuovo caso di silide
in HIV
SEGNI/SINTOMI DI INTERESSAMENTO
NEUROLOGICO, OFTALMICO O UDITIVO
NO
Criteri di Marra
et al., condivisi
dalle linee guida
europee del
2014 (IUSTI)
SI
Rachicentesi
FALLIMENTO
TERAPEUTICO
NO
SI
Rachicentesi
CD4 <350 cellule/mm3 e/o titolo RPR >1:32
INDIPENDENTEMENTE DALLO STADIO
Follow-up sierologico
NO
SI
Rachicentesi
Marra CM et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features,
JID 2004
Neurosifilide in HIV: chi deve fare
la rachicentesi?
Nuovo caso di sifilide
in HIV
SEGNI/SINTOMI DI INTERESSAMENTO
NEUROLOGICO, OFTALMICO O UDITIVO
NO
Linee guida
CDC, 2015
SI
Rachicentesi
FALLIMENTO
TERAPEUTICO
NO
SI
Rachicentesi
Sexually Transmitted Diseases Treatment Guidelines, 2015 Kimberly A. Workowski, Gail A. Bolan, MMWR
Recomm Rep 2015;64