Bosshard, Philipp P.

Graf, Nicole

Knaute, Damaris Fröhlich

Kündig, Thomas

Lautenschlager, Stephan

Weber, Rainer

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1 F E B R U A R YCorrespondenceResponse of Treponemapallidum ParticleAgglutination Test Titers toTreatment of SyphilisTO THE EDITOR—We recently publishedon the serological response to treatmentof syphilis according to disease stageand human immunodeﬁciency virus(HIV) status [1]. In particular, we ana-lyzed the course of the Venereal Dis-ease Research Laboratory (VDRL) and aspeciﬁc immunoglobulin M captureenzyme-linked immunosorbent assaytest (Pathozyme-IgM) in 264 patients.Syphilis disease stage signiﬁcantly inﬂu-enced treatment response whereas HIVcoinfection had an impact only in pa-tients with primary syphilis.Because not much is known about theresponse of the widely used Treponemapallidum particle agglutination (TPPA)test titer to syphilis treatment, we alsoanalyzed the TPPA (Fujirebio, Tokyo,Japan) results. A total of 212 patientswith an initially positive TPPA test (titer≥1:80) were followed for at least 6months after treatment and had at least3 follow-up serologies.On average, a reduction of 3.3 dilu-tion steps in the TPPA titer was ob-served during a mean follow-upduration of 429 days (Table 1). However,only 117 (55%) patients showed a con-tinuous decrease of the TPPA titer, 30(14%) maintained a constant titer, 4(2%) had an increasing titer, and, mostinterestingly, 61 (29%) patients demon-strated a ≥2 dilution steps (≥4-fold)ﬂuctuating titer—that is, the titer somewhen during follow-up increased at least4-fold with subsequent decrease to thebaseline or a lower titer. In 17 of thesepatients the intermittent increase waseven ≥4 dilution steps. There was noassociation with HIV status (P = .117).None of the patients had clinical evi-dence for reinfection or by VDRL serol-ogy. We therefore conclude that a 4-foldor greater increase of the TPPA titerwithout other serological (eg, VDRL) orclinical evidence does not necessarily in-dicate syphilis reinfection.A second interesting observation wasthat 28 of 212 (13%) patients showed se-roreversion of the TPPA (Table 1). Se-roreversion was deﬁned as the lastfollow-up serum being nonreactive. In20 of these patients, >1 follow-up serum(up to 5) was nonreactive. The mediantime to seroreversion was only 227 days.Half (14 of 28) of the patients had rela-tively high initial titers of ≥1:1280. Se-roreversion was associated with HIVcoinfection (P = .004), especially in sec-ondary syphilis where 10 of 11 patientswere HIV positive. Although describedearlier [2–6], it is not widely knownamong clinical and laboratory staff thatTable 1. Characteristics and Treponema pallidum Particle Agglutination Test Results of212 Patients Who Were Followed for at Least 6 MonthsCharacteristicAll Patients(N = 212)TPPASeroreversion(n = 28)PValueaStage of syphilis .06bPrimary 74 16 (22)Secondary 105 11 (10)Tertiary 6 0Latent 27 1 (4)HIV serostatus .004bPositive 95 20 (21)Negative 117 8 (7)TPPA baseline titerMedian titer 1:10240 1:960 <.001cInterquartile range 1:1280–1:40960 1:160–1:3200TPPA follow-up titersMean decrease (dilution steps) 3.3 5.0 .001dPatients with ≥4-fold constant decrease 117 (55) NAPatients with ≥4-fold fluctuating titer 61 (29) NAPatients with constant titer (± 1 titer) 30 (14) NAPatients with ≥4-fold increasing titer 4 (2) NADuration of follow-up, d, mean (range) 429 (175–729) 491 (223–711) .274dDuration until seroreversion, d, mean (range) NA 227 (101–656)No. of follow-up visits, mean (range) 4.6 (3–12) 4.8 (3–8) .139cData are presented as No. (%) unless otherwise specified.Abbreviations: HIV, human immunodeficiency virus; NA, not applicable; TPPA, Treponema pallidumparticle agglutination.a As compared with the subgroup without seroreversion.b Fisher exact test.c Exact Mann-Whitney test.d t test.CORRESPONDENCE • CID 2013:56 (1 February) • 463this may occur. It is generally believedthat the TPPA remains positive aftertreatment. The overall rate of 21% HIV-coinfected patients with TPPA serore-version, for unknown reasons, is higherthan the previously reported rates of5%–11.5% [2–5]. Additionally, we found7% HIV-negative patients with TPPAseroreversion. Only 2 previous studiesreported seroreversion among HIV-negative patients with rates of 3%–13%[2, 6]; other studies did not ﬁnd rever-sion among HIV-negative persons [3–5].In conclusion, a 4-fold or greater in-crease of the TPPA titer does not neces-sarily indicate reinfection or inadequatetherapy, and a negative TPPA titer doesnot exclude previous syphilis infection.NotePotential conﬂicts of interests. All authors:No reported conﬂicts.All authors have submitted the ICMJE Formfor Disclosure of Potential Conﬂicts of Interest.Conﬂicts that the editors consider relevant to thecontent of the manuscript have been disclosed.Philipp P. Bosshard,1 Nicole Graf,2Damaris Fröhlich Knaute,1 Thomas Kündig,1Stephan Lautenschlager,3,a and Rainer Weber4,a1Department of Dermatology, University HospitalZurich; 2Graf Biostatistics, Winterthur; 3OutpatientClinic of Dermatology and Venerology, City HospitalTriemli, and 4Division of Infectious Diseases andHospital Epidemiology, Department of Medicine,University Hospital Zurich, SwitzerlandReferences1. Fröhlich Knaute D, Graf N, Lautenschlager S,Weber R, Bosshard PP. Serological responseto treatment of syphilis according to diseasestage and HIV status [published onlineahead of print 5 September 2012]. Clin InfectDis 2012; 55:1615–22.2. Augenbraun M, Rolfs R, Johnson R, Joesoef R,Pope V. Treponemal speciﬁc tests for the sero-diagnosis of syphilis. Syphilis and HIV StudyGroup. Sex Transm Dis 1998; 25:549–52.3. Haas JS, Bolan G, Larsen SA, Clement MJ,Bacchetti P, Moss AR. Sensitivity of trepo-nemal tests for detecting prior treated syp-hilis during human immunodeﬁciency virusinfection. J Infect Dis 1990; 162:862–6.4. Janier M, Chastang C, Spindler E, et al. Aprospective study of the inﬂuence ofHIV status on the seroreversion of serologicaltests for syphilis. Dermatology 1999; 198:362–9.5. Johnson PD, Graves SR, Stewart L, Warren R,Dwyer B, Lucas CR. Speciﬁc syphilis serolog-ical tests may become negative in HIV infec-tion. AIDS 1991; 5:419–23.6. Romanowski B, Sutherland R, Fick GH,Mooney D, Love EJ. Serologic response totreatment of infectious syphilis. Ann InternMed 1991; 114:1005–9.aS. L. and R. W. contributed equally to this work.Correspondence: Philipp P. Bosshard, PhD, Department ofDermatology, University Hospital Zurich, Gloriastrasse 31,CH-8091 Zürich, Switzerland (philipp.bosshard@usz.ch).Clinical Infectious Diseases 2013;56(3):463–4© The Author 2012. Published by Oxford University Presson behalf of the Infectious Diseases Society of America. Allrights reserved. For Permissions, please e-mail: journals.permissions@oup.com.DOI: 10.1093/cid/cis850464 • CID 2013:56 (1 February) • CORRESPONDENCE

Response of Treponema pallidum Particle Agglutination Test Titers to Treatment of Syphilis

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