IN'IERNAlIONAI JOURNAL OF LEPROSY^ volume 50, Number 2

Printed in the U.S.A.

Syphilis in Patients with Hansen's Disease'Katherine A. Murray'

The importance of serological testing forsyphilis has been well-documented 0), andHansen's disease (HD—leprosy) is one ofseveral conditions associated with chronicfalse positive test results for reagin ( L 1.2 . 2 ").However, a high prevalence of syphilis hasbeen suspected in leprosy patients (' 2 • 2"),but this has not yet been documented byany studies using clinicopathological crite-ria as well as serological tests. At the Na-tional Hansen's Disease Center in Carville,Louisiana, U.S.A., a study of all HD pa-tients seen between 1975-1979 was con-ducted in order to evaluate the frequencyof syphilis in this population.

Invasion of the human by Treponemapanic/um, the spirochete which causessyphilis, leads to the production of two typesof antibodies: a) nonspecific antibodies or"reagin – directed against the lipoidal anti-gens of T. pallidum, some of which crossreact with cardiolipin, and b) specific anti-treponemal antibodies measured in tests us-ing the treponeme itself as antigen ("'). TheVD Research Lab (VDRL) slide tests orrapid plasma reagin (RPR) card tests areused in screening populations for syphilishut, within any group, 18(,' to 55% of thepositive VDRL reactors will be false posi-tive ('". I ' 22 ). Therefore specific treponemaltests are needed to confirm the diagnosis ofsyphilis in a positive VDRL or RPR reac-tor.

These tests include a) T. pallidum im-mobilization (TPI), b) indirect immunollu-orescence with fluorescent treponemal an-

' Received for publication on 4 August 1981: ac-cepted for publication in revised form on 10 November1981.

' Presented in part at the 16th Annual Meeting ofthe P.H.S. Professional Association, 28 May 1981,Boston, Massachusetts, and at the 1st World Congresson Sexually-Transmitted Diseases, 19 November 1981,San Juan, Puerto Rico.

Use of trade names is for identification only anddoes not indicate endorsement by the U.S. PublicHealth Service.

' K. A. Murray, M.D., Staff Physician, NationalHansen's Disease Center, Carville, Louisiana 70721,U.S.A.

t ibod y absorption ( FTA - ABS), or c)microhemac,glutination for 7'. pallidum(MHA-TP) using sheep erythrocytes coatedwith T. pallidum antigen ('"). The VIA-ABSis more sensitive for diagnosing syphilis andis simpler to perform than the TPI, but bothtests have equal specificity (9. 21. 2S, 29x) Al-though the MHA -TP test is less expensiveand simpler to perform, it is said to be lessspecific for syphilis in populations with HDor autoimmune diseases where a large num-ber of false positive nontreponemal tests arefound (").

The Carville study was undertaken to as-certain the frequency of syphilis in the HDpopulation. Unlike previous studies of HDpatients in the Philippines ('=•'') these pa-tients had tuberculoid and borderline (di-morphous) as well as lepromatous Han-sen's disease. The RPR card test was usedrather than the VDRL slide test since theRPR has been shown to be more specificfor syphilis than the VDRL with HD sera(12. II. 29s) The FTA-ABS was used as atreponemal test because the FTA-ABS ap-pears to he more sensitive for detecting pri-mary syphilis (28, 21'

) and more specific thanhemagglutination tests in HD sera ('').

METHODS

From 1975 to 1979, serology testing wasdone on 630 Carville patients with the quan-titative RPR card test ( 2 '') (Macro-Vue,Brewer Diagnostic, Baltimore, Maryland,U.S.A.) and FTA-ABS (Clinical Sciences,Whippany, New Jersey, U.S.A.). RPR ti-ters were quantified by serial dilutions andFTA-ABS positivity was assessed visuallyas "borderline," +1, +2, +3, or +4. AllFTA -ABS tests were conducted and readby the same registered medical technolo-gist. Many patients had several serologysamples taken throughout the four-year pe-riod, comprising a total of 1002 specimensexamined. Annual results were tabulatedand the maximum titer and/or level of flu-orescence was used to categorize each pos-itive reactor.

The cumulative serological results for

152

50, 2^

Murray: .S'yphilis in III)^ 153

TABLE I. Serological tests for syphilis on 630 Carville patients, /975-1979.

RPR^FTA-ABS^Number PercentPercent of posi-

tivesGroup

NegativePositivePositiveNegative

Total

NegativePositiveNegativePositive

501634917

630

79.610.07.72.7

100

48.838.013.2

100

each patient were tabulated together withthe patient's age, sex, ethnic group, Ridley-Jopling HD classification (2"). HD activity,and yes-no categorization as to the pres-ence of erythema nodosum leprosum (EN L)or reversal reactions. Each chart was alsoreviewed for previous history of trepone-matosis clinically and/or serologically (pos-itive TPI), previous history for nonlueticvenereal disease, and whether the trepo-nematosis was treated. Although darkfieldexaminations were unavailable, a painlessgenital chancre with regional lymphadenop-athy, Charcot joints of the knees, tabes dor-sails, paranoia and personality changesconsistent with neurosyphilis, condylomalata, optic atrophy without a history ofmethanol or toxin exposure, and either pos-itive serology or history of syphilis in aspouse without HD were among the criteriaconsistent with a past history of syphilis. Inone case syphilis was verified only on post-mortem examination.

The patient age distributions were com-pared using a single factor or one-way anal-ysis of variance to generate an F value orvariance ratio. The Bartlett's test for ho-mogeneity of variance was used to evaluateage differences among the three seroposi-tive groups. Chi-square analyses were usedto evaluate all other parameters. Signifi-cance was assessed at the 5% level of prob-ability (p = 0.05).

RESULTSMost patients were seronegative to both

tests, but 20%/r were positive to the RPRand/or FTA-ABS tests (Table I). Onehundred twelve (17.7% of the total) hadpositive RPR's; while 80 patients (12.7% ofthe total) had positive FTA-ABS tests. Mostof the positive patients, 63, (10% of the to-tal) were reactive in both the RPR and theETA-ABS; 49 (7.7%) were RPR reactive

only; and 17 (2.7%) were reactive only withthe FFA-ABS test. The three seropositivegroups were studied in more detail andcalled groups I, II and III, respectively.

Table 2 shows that each of the threegroups were equivalent with respect to age,sex, HD classification, and HD activity. HDpatients in all three groups were predomi-nantly at the lepromatous (LL) or border-line lepromatous (BL) end of the Ridley-Jopling classification spectrum. Although 37or 75% of the group II (RPR positive-F -FAnegative) patients had BL or LL HD, 7

TABLE 2. Characterization of the 129positive patients by serological

Group I(RPR+FTA+)

Group II Group III(RPR+^(RPR-ETA—)^FIA+)

No. of patients 63 49 17)t^of total) (49) (38) (13)

Mean age 59.7 53.5 61.7(median) (59) (54) (61)

No. of males 38 28 9of group) (60) (57) (53)

No. Hispanic patients 31 26 9(`,'^of group) (49) (53) (53)

HD classification[No. ( (,%i of group)]BE or LL 46 (73) 37 (76) 14 (82)Not leprosy 2 (3) 2 (3) 0 —

HD activity"[No. ((,'; of group))Active 25 (41) 22 (45) 6 (35)Quiescent 9 (15) 6 (15) 3 (18)Inactive 27 (44) 19 (40) 8 (47)

No. with ENV' 8 It) 2(`-; of group)^(13)^(21)^(12)

Active HD means the patient had bacteriologicallypositive disease with demonstrable acid-fast bacilli byskin scrapings and/or skin biopsy. Quiescent HD meansthe patient had no demonstrable acid-fast bacilli onskin scrapings and a skin biopsy was pending.

ENL means erythema nodosum leprosum, eitherclinically or on skin biopsy.

154^ International Journal of Leprosy^ 1982

TABLE 3. Venereal disease history andtreatment by serological group. Numbersare number of patients (% of the group).

Group I(RPR+FTA+)

Group II(RPRFTA–)

Group III(RPR-FTA+)

History oftreponematoses

Yes" 40 (63) 2 (4) 2 (12)No 15 (24) 47 (96) 11^(65)Unknown x(13) 0 – 4 (23)

Treponemaldisease treated

Yes" 44 (70) 8 (16) 8 (47)No 15 (24) 35 (71) 4 (24)Unknown 4 (6) 6 (12) 5 (29)

History of nonlueticvenereal disease

Yes 16 (25) 4 (8) 3 (18)No 41 (65) 44 (90) 13 (76)Unknown 6 (10) 1^(2) I^(6)

" Statistically significant differences among the dif-ferent groups.

cases of borderline (dimorphous) HD and 3cases of tuberculoid HD had isolated RPRreactivity. Four of these ten non-leproma-tous cases were clinically inactive with noacid-fast organisms on skin scrapings or skinbiopsies.

More of the group II cases had reactionor EN I. than the patients in the other twogroups, but this was not statistically signif-icant (p = 0.35).

As shown in Table 3, group I patients, orthose with both RPR and FTA-ABS reac-tivity, gave a history of exposure to trepo-nemes as well as nonluetic venereal diseasemost frequently. Although most cases werestraightforward, one patient had yaws as achild; while another had syphilitic aortitisdocumented only on postmortem exami-nation, with "tree-barking" of the intimaand aneurysmal dilation of the ascendingaorta. Some of the RPR positive-FTA pos-itive patients were seen before TPI testswere phased out, and 23 out of 30 group Ipatients examined were positive with theTPI as well as the RPR and FTA-ABS tests.All 26 group I patients examined so far withthe MHA-TP test (V.D. Control Division,Atlanta, Georgia, U.S.A.) have been MHA-TP reactive as well. Sixty-three percent ofall group I patients had a history of syphilis

TABLE 4. Breakdown 4.veroiotnrai pos-itivity by serological group. Numbers arenumber of patients of the group).

Group I Group II Group III(RPR+^(RI'R+^(RPR– TotalFTA+) FIFA–)^FTA+)

FTA > +I 50 (79) 0 — 5 (29) 55FTA = NQ' 9 (14) (1 — I (6) 10FTA^+I 4 (6) (1 — 11 (65) 15RPR > 1:1 53 (84) 20 (41) — 73RPR^1:I 1 0 (16) 29 (59) 0 — 39

" NQ means FTA results were not quantified or atiter was not reported.

and 70% had been treated for syphilis as of1 January 1980.

Group II patients had the lowest frequen-cy of treponemal and nonluetic venerealdisease by history and clinical course.Ninety-six percent of them gave no historyof treponemal exposure but 16% were treat-ed anyway. A higher percentage (47%) ofthe group III patients received treatment forsyphilis when compared with those in groupII (16%).

All positive FTA-ABS tests were uni-formly immunofluorescent in a homoge-neous pattern. No abnormal or beadedforms were seen even among weakly reac-tive FTA-ABS specimens. As shown in Ta-ble 4, most (79%) of the group I specimenshad highly positive FTA-ABS tests. At least36 of these 63 sent had brightly fluorescentFTA-ABS tests, of grades +3 or +4 posi-tivity by visual assessment. Likewise, allbut two of the +3 to +4 tests were fromgroup I specimens and associated with pos-itive RPR tests. Most (65%) of the "bor-derline" or + 1 FTA-ABS cases were as-sociated with negative RPR tests.

Most of the high-titered RPR specimens,as with the strongly immunofluorescentETA-ABS tests, were associated with groupI sera. Conversely, 74% (29/39) of the low-titered RPR cases were associated withnegative FTA-ABS tests. Group II speci-mens with RPR titers of 1: 1 or less, includ-ing those weakly reactive, included all serafrom the ten dimorphous and tuberculoidcases of group II. All the high-titer groupII leprosy cases had lepromatous HD andRPR titers from 1:2 to 1:32 dilutions. Butone non-leprosy case was admitted to Car-

50, 2^ Murray: .S'yphilis in HD^

155

vine with RPR titers of 1:16 and a negativeFTA-ABS test. She was a 26-year-oldwoman presenting with lupus dermatitis whohad an inherited C2 or complement defi-ciency disease and systemic lupus erythe-matosus ('").

Reviewing each patient's history, clinicalfindings, and serological results revealedthat Group I patients represented those re-cently treated for syphilis, those treated fortertiary or late latent disease, or those withuntreated syphilis. Group ll patients werebiological false positive reactors to the RPRcard test. Group Ill patients were eithertreated syphilitics or possible false positiveFTA-ABS cases. Among these 17 group Illpatients, I had a positive and 3 had negativeTPI tests. One patient had a reactive FTA-ABS (+1) which was nonreactive on repeattesting one year later with a nonreactiveMHA-TP as well. Another group III casewho was repeatedly FTA-ABS reactive hada reactive MHA-TP test also: he had beentreated for syphilis decades ago.

DISCUSSIONTotal RPR positivity was nearly 18 ( in

this large population of HD patients, morethan the 3% to 10% seen in the general pop-ulation or in a large population of screenedrefugees but equivalent to that seenin drug addicts, lupus patients, or even HDpatients from the previous decade. It hasbeen reported that 15% of drug addicts, 16%of lupus patients, and 4r; to 19( of all HDpatients were reactive to the VDRL and/orthe RPR serology tests for syphilis and al-most half of these seropositive cases werefalse positive 12. 17. 19.29 , . In this study ofleprosy sera, just under one half or 44% ofall RPR positive cases were false positivewith a negative FTA-ABS test and neitherhistorical nor clinical evidence of trepone-mal infection.

Like most HD cases in the WesternHemisphere, the majority of the false pos-itive RPR reactors had lepromatous HD butthere were a few borderline (dimorphous)and tuberculoid cases as well, a fact not yetreported in the literature. False positivespecimens from borderline and tuberculoidcases, however, were always associatedwith low RPR titers.

Total FTA positivity in this study was12.7%, comparable to that seen in the gen-

eral population (1% to 17%) ( S•111,21•21 ) b uthigher than that seen in 250 lifelong celibatenuns (0.8%) Although a few HD casesmay represent a false positive immunollu-orescence, drug addicts (6%), lupus pa-tients (15%), and HD patients from the pre-vious decade (19%) appeared to have arange of' FTA positivity similar to that ofnormal populations (" . .'". 2 ").

The majority, or 56%, of the RPR posi-tive HI) cases were also reactive with theFTA-ABS test. These patients more fre-quently had a history of syphilis or trepo-nemal disease as well as nonluetic venerealdisease. They had high RPR titers and astrong degree of FTA-ABS immunolluores-cence. If the predictive value (PV) of a pos-itive test (") is defined as:

PV — true positivestrue positives +false positives

the predictive value for positivity of theideal test (with no false positives) would be100%. (This modified PV ratio is used be-cause the actual prevalence of syphilis isunknown among HD patients at this time,i.e., the number of sero-negative syphiliticswith HD is unknown). In our laboratory,the PV of the RPR test with high titers (1:2to 1:64 dilutions) was only 72.6% for as-sociated FTA-ABS reactivity and usuallyclinical and/or historical evidence of syph-ilis. But the highly-immunolluorescent FTA-ABS test was almost always associated withRPR reaginemia and seropositive syphiliticdisease. Thirty-six out of the 38 seroposi-tive specimens with grades +3 or +4 FTA-ABS fluorescence were associated with RPRpositivity, yielding a PV of 94.7: FTA-ABS reactivity of grades +2, +3, or +4fluorescence carried a PV of 90.9% for RPRpositivity. Thus RPR titers were less usefulthan highly positive FTA-ABS immunoflu-orescence ( +3, +4) for predicting seropos-itivity with the other serological test forsyphilis. Weak FTA-ABS immunolluores-cence was inconclusive.

Patients treated for syphilis with penicil-lin, erythromycin, or tetracycline ( 2 ) ex-perience a variable degree of seroconver-sion depending upon the time coursebetween exposure resulting in infection and

x 100%

1.56^ 11tl ernal ion a l .10111'11(1/ of 1,eprasy^ 1982

TA BIT 5. Serelo,l,, ical.sludie.■ with /II) patients.. Numbers are the percentage of the totalnumber of vera tested in each

StudyGarner, et al.,

1969 ( 13 )Garner and Back-house, 1972 (')

Scotti. el al.,1970 CI

Present study

No. of sera studied 270 (10(ri) 269 ( 100';) 206 (100r4) 630(100';)

RPR— FTA- 90'; 80';; 79';;RPR-^VDRL+ 1 Or 9'; 191

RPR+ FTA+ (Group I) 3 5 15 10RPR+ FTA— (Group 11) I 4 <I 8RPR— FIA+ (Group III) 4 <I 5 3

treatment. Strict microbial and serologicalcure is achieved only if treatment is givenwithin the first two years of infection ( 2 - 1 ).Those with tertiary or late latent syphilistreated many years after the initial infectionmay remain serofast with a positive RPRand FTA-ABS for life. But some patientstreated for secondary or late disease maybecome RPR negative in the next fewmonths while the ETA-ABS remains posi-tive for years. Thus 97% of untreated orpartially treated syphilitics are said to havea positive FTA-ABS 30 years after infec-tion ( 27), sometimes with a negative non-treponemal serology test. Using RPR neg-ative-FTA positive specimens, furtherstudies would be needed with another tre-ponemal test to differentiate treated syphil-is from a possible false positive FTA-ABSwith HD sera.

Previous reports on HD sera as well asthe present communication show that iso-lated FTA-ABS reactivity is uncommon(Table 5) ( It is unclear how manygroup III cases represented treated syphi-litics and how many may have been tran-siently false positive FTA-ABS tests. Gar-ner, et al. in 1973 conducted T. pallid/tinhemagglutination tests (TPHA, using tur-key rather than sheep red blood cells) on267 lepromatous HD patients from the Phil-ippines ("). They found only 14 cases ofsyphilis (5%) and all 14 were reactive withthe FTA-ABS, TPI, and TPHA tests. Nocases of isolated FTA-ABS reactivity wereseen but seven non-syphilitic HD cases hadisolated TPHA reactivity with nonreactiveFTA-ABS and nonreactive TPI tests. Therewas nothing to suggest a possible false pos-itive FTA-ABS, and the authors comment-ed only upon the poor specificity of theTPHA test. In our study with the FTA-ABS

test, we saw no abnormal or beaded formsof fluorescence among over 1000 specimensexamined, as is reportedly seen with somefalse positive FTA-ABS cases of systemiclupus erythematosus, rheumatoid arthritis,or other autoimmune diseases (IS. 2 ".").However, typical homogeneous fluores-cence with presumably no treponemal ex-posure has been reported in pregnancy (").

HD, especially when accompanied by re-versal reaction or ENL, shares several signsand symptoms with syphilis. The collapsednose (rhinopharyngitis mutilans), a multi-plicity of skin rashes, and peripheral neu-ropathy associated with extremity ulcera-tion may be seen in both diseases. Keratitis,uveitis, and orchitis occur in reactional HDas well as in syphilis ( 1 •'"'). Although onlysyphilis causes atrophy of the optic disc,both diseases may be associated with Char-cot joints of the lower extremities. Thereare similarities between the two diseases andextragenital syphilitic lesions could bemasked by active lepromatous leprosy par-ticularly if the patient also had ENL.

This study, reviewing four years of se-rological data from over 600 Carville pa-tients, found about 60 patients with bothHD and syphilis. These patients were truepositive serological reactors with clinicaland/or historical evidence of syphilis andseroreactivity to both the RPR and FTA-ABS tests. A few previously untreatedcases, initially thought to be false positivereactors to both tests, showed manifesta-tions of tertiary or late syphilis on furtherevaluation. It is clear that syphilis appearsmore commonly in HD patients than in thegeneral population, with rates higher thanthe 30 cases per 100,000 cited for the U.S.at large ("• 7 ), and that withholding antibiotictreatment from an untreated HD patient with

50, 2^ Murray: ,S)phili., in HD^ 157

both RPR and FTA-ABS reactivity, partic-ularly if the FTA-ABS is strongly immu-nolluorescent (+3, +4), is not justified. EachHD patient with a positive RPR and a pos-itive FTA-ABS test should be seriouslyevaluated for syphilis, and, if not yet treat-ed, the patient should be treated.

SUMMARYBetween 1975 and 1979, 630 patients with

leprosy or Hansen's disease (HD) were ex-amined clinically and screened for syphilisusing both the rapid plasma reagin (RPR)and fluorescent treponemal antibody ab-sorption (FTA-ABS) tests. Seropositivesyphilis was found more frequently than inthe general population; 10% were true pos-itive reactors with a reactive RPR, a reac-tive FTA-ABS, and historical, clinical, and/or postmortem evidence of syphilis. Only8% exhibited false positive tests for reaginwith a negative FTA-ABS and neither his-torical nor clinical evidence of treponemalinfection. Among those with FTA-ABS testreactivity, highly positive FTA-ABS im-munofluorescence (+3, +4) was highly pre-dictive for syphilis (94.7%). SeropositiveHD patients with both RPR and FTA-ABSreactivity should be seriously evaluated forsyphilis and, if not yet treated, they shouldbe treated.

RESUMENEntre 1975 y 1979, se estudiaron 630 pacientes con

lepra lepromatosa o enfermedad de Hansen (HD) tanto

desde el punto de vista clinic() como desde el puntode vista de una posible infeccitin sifilitica. Esta se es-

tableci6 usando Ia prueba rapida para reaginas plas-

maticas (RPR) y Ia prueba fluorescente de Ia absorciOndel anticuerpo anti-treponema (FFA-ABS). Se encon-tro que le seropositividad para sifilis fue mtis frecuenteen los enfermos de Hansen que en la poblaciOn gen-

eral; 10( de los casos fueron verdaderos reactores

positivos, con evidencias histOricas, clinicas, o post-mortem, de sifilis. Solo 8i de los casos dieron pruebas

positives fa lsas para reaginas (PRP), con una prueba

FTA-ABS negativa y sin evidencias histOricas o clini-

cas de infecciOn treponemal. Entre aquellos nositivospor Ia prueba FTA-ABS, una prueba francamente

positiva (3+, 4+) fue altamente predictiva de sifilis(94.7). Los pacientes con HI) que resulten positivos

por ambits pruebas deben examinarse cuidadosamentepara establecer Ia infecciOn sililitica y, en su caso,

deben recibir el tratamiento apropiado si atin no lo

reciben.

RESUME

Entre 1975 et 1979, 630 malades atteints de lepre

(maladie de Hansen) ont eta examines cliniquement,alin d'identifier ceux qui etaient atteints de syphilis,

par une methode utilisant, n la foil, la reaction rapide

de Ia reagine plasmatique (RPR), et des epreuves flu-orescentes d'absorption des anticorps treponemiques

(FTA-ABS). Les malades se sont reveles plus fre-quemment atteints de syphilis seropositive que lapopulation generale. Le taux de vrais positifs, c.it.d.

d'individus reagissant positivement pour le RPR, le

ETA-ABS, et presentant soit des antecedents de sy-

philis, soil des manifestations cliniques de la maladie,

soil des lesions raises en evidence it l'autopsie, atteig-

nail 10%. La proportion de malades presentant des

epreuves faussement positives pour Ia reagine, avecun FTA-ABS negatif, et aucune evidence anamnes-

tique ou clinique d'infection par treponemes atteignait

Parmi les individus reagissant positivement a IC-preuve des anticorps fluorescents (FIA-ABS), des re-sultats fortement positifs pour cette epreuve (3+, 4+)se sont reveles dotes dune valeur hautement predic-tive pour la syphilis (dans 94,7%). Les malades

seniens seropositifs reagissant it Ia fois it lepreuvela reagine (RPR) et aux anticorps fluorescents (FTA-

ABS), devraient etre serieusement etudies en vue demettre en evidence une syphilis eventuelle, et s'ils n'ontpas encore etc traites pour cette maladie, ils devraient

etre.

Acknowledgments. The author thanks Mr. Stephen

E. Keas who performed all RPR and FTA-ABS tests

in the hospital's clinical laboratory. The author ac-

knowledges the computer assistance of Mr. MelvynMorales and the consultative aid provided by the Lou-

isiana State University Department of ExperimentalStatistics (Baton Rouge). The author thanks Dr. Rob-

ert R. Jacobson, the Carville Editorial Committee, Dr.

Howard Jaffe and his associates of the Center for Dis-ease Control, Atlanta, Georgia, and Dr. A. Howard

Fieldsteel (SRI, California) for reviews and commen-

tary, and Ms. Sally Stoewer for secretarial preparation

of the manuscript.

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