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 1

T. pallidum subsp pallidum “ “ subsp pertenue “ “ subsp endemicum Domain Bacteria Phylum Spirochaetaltes Class Spirochaetes Order Spirochaetales Family Spirochaetaceae Genus Treponema  Species T. pallidum T. pallidum subsp pallidum “ “ subsp pertenue “ “ subsp endemicum “ “ subsp carateum venereal treponematoses Yaws (Framboesia) Bejel Pinta non-venereal endemic treponematoses 99,8% genomic identity This spirocheta is invisible by light microscopy (a Dark-field microscopy has to be used) and can’t be cultured in medium culture but only can be mantained in rabbit tissue. The treponema pallidum specie includes 4 differnt pathogens antigenically and morphologically identical, with 99.8% of genomic identity Farnsworth and Rosen. Clinics in Dermatology (2006) 24, 181–190 2

In Europa da Americhe (teoria Colombiana) In Spagna e Portogallo da Africa Letteratura di riferimento: Syphilis – Its Early History and Treatment Until Penicillin and the debate on its origins. J of Military and Veterans’Health 2012, 20(4) 49-58 (stampata) 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

Letteratura di riferimento: Brief History of Syphilis. Tampa. J Med Life 2014; 15 (7) 4-10 (stampato)

Syphilis Sexual transmission Treponema pallidum subspec pallidum Transplacental transmission Direct non-sexual transmission Blood transfusion/organ transplantation 5

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 palmo- plantari) 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 60 - 30%  Risk of sexual transmission is concentrated in early syphilis, when moist mucocutaneous lesions of primary and secondary syphilis are present. Transmission is rare after first-second year from infection. Fetal infection is a result of haematogenous spread, dependent on spirochaetemia that is present in early stage, although transmission at delivery can result from direct contact with infectious genital lesions. The main factors that determine the probability of fetal transmission are stage of maternal infection and duaration of exposure in utero Vertical transmission 100 - 50 - 30 - 10% 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 stampato The increase in syphilis among MSM is a major public health concern, particularly because syphilis and the behaviors associated with acquiring it increase the likelihood of acquiring and transmitting human immunodeficiency virus (HIV) (6). There are reported rates of 50%–70% HIV coinfection among MSM infected with primary and secondary syphilis (7) and high HIV seroconversion rates following primary and secondary syphilis infection (8).  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) ♀ ♂ MSM Notiziario stampato ♂ hetero ♂

Diagnosi di sifilide DIAGNOSI SIEROLOGICA Test non treponemici: valutano l’attività della malattia e la risposta terapeutica dopo trattamento (VDRL, RPR) Test treponemici: basati sulla ricerca di anticorpi diretti contro antigeni specifici (TPHA, TPPA, FTA-ABS)

Tre differenti algoritmi per la sierodiagnosi di sifilide Tradizionale: sifilidi attive (BFP = falso positivo) RPR con titolo (non-treponemico quantitativo)

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%

Screening e diagnosi precoce 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 Marangoni. Clin Microbiol Infect 2008; 14 (11): 1065-8 Poland 0.16 2003 Rudnick. Euro Surveill 2005; 10:E050519.3 Czech Rep. 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) RR (IC 95%) P-value 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 22 (88) 45 (24.7) 15.3 (5.2-47) 0.0001 Maternal syphilis seroprevalence at delivery was 0.17%. 207 infants were born to 203 syphilis seropositive mothers. In 25 newborns it was possible to diagnose congenital syphilis (20/100 000 live births) Tridapalli et al. For the Italian Society of Neonatology. Arch Dis Child Fetal Neonatal Ed. 2012 May;97(3):F211-3. doi: 10.1136/adc.2010.183863. Epub 2010 Sep 24

Diagnosi di sifilide congenita ISOLAMENTO T.PALLIDUM DA LESIONE CERTAMENTE INFETTO SIEROLOGICO + IgM > 4VV TITOLO TPHA/RPR ˂ 4VV ALTA PROBABILITÀ DI INFEZIONE SEGNI/SINTOMI COMPATIBILI CLINICO BASSA PROBABILITÀ DI INFEZIONE ASINTOMATICO

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. I due articoli stampati

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 IC (95%) p Sesso (M) 5.2 1.8 – 14.8 0.001 Età (≥35 vs <35) 0.9 0.5 – 1.7 0.822 Nazionalità (Italia vs altro) 0.7 0.3 – 1.4 0.368 Trasmissione (sex vs altro) 2.8 1.2 – 6.7 0.020 Trasmissione (omo-bisex vs altre) 6.2 3.3 - 11.7 <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

Azithromycin-resistant T. pallidum is widespread in San Francisco Azithromycin-resistant T. pallidum is widespread in San Francisco. We recommend against using azithromycin for the management of syphilis in communities where macrolide-resistant T. pallidum is present and recommend active surveillance for resistance in sites where azithromycin is used. Klausner JD, Kohn RP, Kent CK. Azithromycin versus penicillin for early syphilis. N Engl J Med 2006; 354:203–5;

Neurosifilide e HIV: terapia There was no difference in the proportion of subjects in each group whose CSF measures improved. Significantly more ceftriaxone recipients had a decline in serum RPR titers (8 [80%] of 10 vs. 2 [13%] of 15; P = .003). Differences in the 2 groups limit comparisons between them. However, iv ceftriaxone may be an alternative to penicillin for treatment of HIV-infected patients with neurosyphilis and concomitant early syphilis. 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 10-90 giorni Esposizione Sifilide primaria Neurosifilide precoce Invasione del SNC 4-10 settimane 4-10 settimane 25-60% Asintomatica Sintomatica 5% Meningite acuta Neurite di nervi cranici Interessamento oculare Malattia meningo-vascolare Sifilide secondaria Ricaduta 24% Sifilide latente precoce Sifilide latente tardiva Il coinvolgimento del SNC può essere precoce Sifilide terziaria Sifilide terziaria Sifilide terziaria Sifilide terziaria Sifilide cardiovascolare 10% (20-30 anni dopo l’infezione) Sifilide cardiovascolare 10% (20-30 anni dopo l’infezione) Sifilide cardiovascolare 10% (20-30 anni dopo l’infezione) Sifilide cardiovascolare 10% (20-30 anni dopo l’infezione) Malattia delle gomme 15% (1-46 anni dopo l’infezione) Malattia delle gomme 15% (1-46 anni dopo l’infezione) Malattia delle gomme 15% (1-46 anni dopo l’infezione) Malattia delle gomme 15% (1-46 anni dopo l’infezione) Neurosifilide tardiva Neurosifilide tardiva Neurosifilide tardiva Neurosifilide tardiva Paralisi generale 2-5% (2-30 anni dopo) Paralisi generale 2-5% (2-30 anni dopo) Paralisi generale 2-5% (2-30 anni dopo) Paralisi generale 2-5% (2-30 anni dopo) Tabe dorsale 2-9% (3-50 anni dopo) Tabe dorsale 2-9% (3-50 anni dopo) Tabe dorsale 2-9% (3-50 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 di durata indeterminata 2 in fallimento terapeutico 122 rachicentesi 13 (76%) Asintomatici 17 (13.9%) Diagnosi di Neurosifilide 4 (24%) Con sintomi neurologici TUTTI in sifilide recente

Neurosifilide: epidemiologia Brescia, Gennaio 2005-Dicembre 2009 3. Analisi dei fattori associati alla diagnosi di neurosifilide ANALISI UNIVARIATA ANALISI MULTIVARIATA OR (IC 95%) P value Età N.A. 0.624 Genere maschile 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 3.33 (1.05-10.53) 0.040 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 Titolo sierico RPR >1:32 aumenta la probabilità di neurosifilide (p value: 0.09)

Neurosifilide in HIV: chi deve fare la rachicentesi? 1 SEGNI/SINTOMI DI INTERESSAMENTO NEUROLOGICO, OFTALMICO O UDITIVO Criteri di Marra et al., condivisi dalle linee guida europee del 2014 (IUSTI) NO SI Rachicentesi 2 FALLIMENTO TERAPEUTICO NO SI Rachicentesi 3 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 CDC, 2015 NO SI Rachicentesi 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) 5 cell/microlitro 20 cell/microlitro nei soggetti HIV O RPR/VDRL +

Neurosifilide: terapia

Neurosifilide: monitoraggio Normalization of serum RPR titer correctly predicts normalization of CSF and clinical measures after neurosyphilis treatment, and follow-up 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 Criteri di Marra et al., condivisi dalle linee guida europee del 2014 (IUSTI) NO 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 SI Rachicentesi Linee guida CDC, 2015 FALLIMENTO TERAPEUTICO NO SI Rachicentesi Sexually Transmitted Diseases Treatment Guidelines, 2015 Kimberly A. Workowski, Gail A. Bolan, MMWR Recomm Rep 2015;64